Guide to YKHC Medical Practices - User contributions [en]

Transcutaneous paCO2 Monitoring

2023-03-14T23:04:55Z

AndyS:

Transcutaneous CO2 (TC-CO2) monitors function by measuring the CO2 which diffuses out the skin. Modern TC-CO2 monitors are a highly accurate, non-invasive method for estimating paCO2.<ref name="Nassar2017">Nassar BS, Schmidt GA. [https://doi.org/10.1513/AnnalsATS.201701-034FR '''Estimating Arterial Partial Pressure of Carbon Dioxide in Ventilated Patients: How Valid Are Surrogate Measures?'''] Ann Am Thorac Soc. 2017 Jun;14(6):1005-1014. doi: 10.1513/AnnalsATS.201701-034FR. PMID: 28570147.</ref> 
 
[[File:Sentec.PNG|left]]
 
 

== Primary Purpose ==
YKDRH obtained TC-CO2 monitors for the purpose of monitoring paCO2 trends in patients receiving high-flow nasal cannula or non-invasive ventilation (i.e. CPAP/BiPAP). This was necessary because end-tidal CO2 monitoring is not compatible with these interventions.

== Important Points ==
# Applicable for all age groups (including extremely premature neonates).
# Initial reading requires approximately five minutes to establish.
# TC-CO2 is '''substantially more accurate''' than peripheral venous CO2 for estimating paCO2.<ref name="Nassar2017"/>
# Because CO2 takes several minutes to diffuse out of the skin, the displayed TC-CO2 reading at any given time reflects the paCO2 from 2-4 minutes prior.
# The tracing is a flat line (rather than the waveform created by exhaled air).
# TC-CO2 is used to follow paCO2 trends; it DOES NOT measure instantaneous levels. Therefore, TC-CO2 '''IS NOT''' an acceptable substitute for ET-CO2 in situations such as:
## Confirmation of ET-tube placement.
## CPR (neither for CPR adequacy nor ROSC identification).
## Respiratory monitoring during sedation.
## Any situation where monitoring for apnea or any rapid changes in paCO2.
# The accuracy of end-tidal CO2 as an estimate of paCO2 is largely dependent upon how closely a patient's lung function matches an ideal lung. For patients who are intubated for non-respiratory issues, their lung function should pretty closely approximate an ideal lung, and thus end-tidal CO2 should estimate paCO2 with reasonable accuracy. But for patients with lung processes which create V/Q mismatches, end-tidal CO2 is not a good estimate of paCO2. In such situations, TC-CO2 provides a MUCH MORE ACCURATE estimate paCO2.<ref name="Nassar2017"/> Thus, if paCO2 requires monitoring in patients with ARDS, bronchiolitis, pneumonia, etc., TC-CO2 should be considered regardless of the type of respiratory support the patient is receiving (i.e. none, high-flow, or intubated). In such a situation, an intubated patient might be monitored with end-tidal CO2 to watch for apnea and TC-CO2 to assess adequacy of ventilation over time.
 

== Device ==
YKDRH has acquired the '''Sentec''' Digital Monitoring System. 
The Sentec devices provides monitoring of:
# Instantaneous oximetry (with an adjustable duration trend line)
# Instantaneous heart rate (with an adjustable duration trend line)
# Delayed paCO2 (with an adjustable duration trend line)

== Resources ==
: [https://yk-health.org/wiki/File:Transcutaneous_CO2_monitor_SDMS_InstructionManual_EN.pdf Sentec Instruction Manual]
'''Instructional Videos:'''
: [https://www.youtube.com/watch?v=7d7XNtQNllA Neonatal Sensor Application for the Sentec Digital Transcutaneous Monitoring System]
: [https://www.youtube.com/watch?v=7HX7dgqieaM Sensor Application Adult Cheek for the Sentec Digital Transcutaneous Monitoring System]
 
'''PubMed Searches:'''
: [https://pubmed.ncbi.nlm.nih.gov/?term=(%22transcutaneous%20co2%22%5BTitle%5D%20OR%20%22transcutaneous%20carbon%20dioxide%22%5BTitle%5D)%20AND%20(infant%5BTitle%5D%20OR%20neonat*%5BTitle%5D%20OR%20child*%5BTitle%5D) ("transcutaneous co2"[Title<nowiki>]</nowiki> OR "transcutaneous carbon dioxide"[Title<nowiki>]</nowiki>) AND (infant[Title<nowiki>]</nowiki> OR neonat*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>)]
 

== REFERENCES ==
‎<references />

Transcutaneous paCO2 Monitoring

2023-03-14T21:52:27Z

AndyS:

Transcutaneous CO2 (TC-CO2) monitors function by measuring the CO2 which diffuses out the skin. Modern TC-CO2 monitors are a highly accurate, non-invasive method for estimating paCO2.<ref name="Nassar2017">Nassar BS, Schmidt GA. [https://doi.org/10.1513/AnnalsATS.201701-034FR '''Estimating Arterial Partial Pressure of Carbon Dioxide in Ventilated Patients: How Valid Are Surrogate Measures?'''] Ann Am Thorac Soc. 2017 Jun;14(6):1005-1014. doi: 10.1513/AnnalsATS.201701-034FR. PMID: 28570147.</ref> 
 
[[File:Sentec.PNG|left]]
 
 

== Primary Purpose ==
YKDRH obtained TC-CO2 monitors for the purpose of monitoring paCO2 trends in patients receiving high-flow nasal cannula or non-invasive ventilation (i.e. CPAP/BiPAP). This was necessary because end-tidal CO2 monitoring is not compatible with these interventions.

== Important Points ==
# Applicable for all age groups (including extremely premature neonates).
# Initial reading requires approximately five minutes to establish.
# TC-CO2 is '''substantially more accurate''' than peripheral venous CO2 for estimating paCO2.<ref name="Nassar2017"/>
# Because CO2 takes several minutes to diffuse out of the skin, the displayed TC-CO2 reading at any given time reflects the paCO2 from 2-4 minutes prior.
# The tracing is a flat line (rather than the waveform created by exhaled air).
# TC-CO2 is used to follow paCO2 trends; it DOES NOT measure instantaneous levels. Therefore, TC-CO2 '''IS NOT''' an acceptable substitute for ET-CO2 in situations such as:
## Confirmation of ET-tube placement.
## CPR (neither for CPR adequacy nor ROSC identification).
## Respiratory monitoring during sedation.
## Any situation where monitoring for apnea or any rapid changes in paCO2.

== Device ==
YKDRH has acquired the '''Sentec''' Digital Monitoring System. 
The Sentec devices provides monitoring of:
# Instantaneous oximetry (with an adjustable duration trend line)
# Instantaneous heart rate (with an adjustable duration trend line)
# Delayed paCO2 (with an adjustable duration trend line)

== Resources ==
: [https://yk-health.org/wiki/File:Transcutaneous_CO2_monitor_SDMS_InstructionManual_EN.pdf Sentec Instruction Manual]
'''Instructional Videos:'''
: [https://www.youtube.com/watch?v=7d7XNtQNllA Neonatal Sensor Application for the Sentec Digital Transcutaneous Monitoring System]
: [https://www.youtube.com/watch?v=7HX7dgqieaM Sensor Application Adult Cheek for the Sentec Digital Transcutaneous Monitoring System]
 
'''PubMed Searches:'''
: [https://pubmed.ncbi.nlm.nih.gov/?term=(%22transcutaneous%20co2%22%5BTitle%5D%20OR%20%22transcutaneous%20carbon%20dioxide%22%5BTitle%5D)%20AND%20(infant%5BTitle%5D%20OR%20neonat*%5BTitle%5D%20OR%20child*%5BTitle%5D) ("transcutaneous co2"[Title<nowiki>]</nowiki> OR "transcutaneous carbon dioxide"[Title<nowiki>]</nowiki>) AND (infant[Title<nowiki>]</nowiki> OR neonat*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>)]
 

== REFERENCES ==
‎<references />

File:Sentec.PNG

2023-03-14T21:42:12Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T18:38:09Z

AndyS:

Transcutaneous CO2 (TC-CO2) monitors function by measuring the CO2 which diffuses out the skin. Modern TC-CO2 monitors are a highly accurate, non-invasive method for estimating paCO2.<ref name="Nassar2017">Nassar BS, Schmidt GA. [https://doi.org/10.1513/AnnalsATS.201701-034FR '''Estimating Arterial Partial Pressure of Carbon Dioxide in Ventilated Patients: How Valid Are Surrogate Measures?'''] Ann Am Thorac Soc. 2017 Jun;14(6):1005-1014. doi: 10.1513/AnnalsATS.201701-034FR. PMID: 28570147.</ref> 
 

== Primary Purpose ==
YKDRH obtained TC-CO2 monitors for the purpose of monitoring paCO2 trends in patients receiving high-flow nasal cannula or non-invasive ventilation (i.e. CPAP/BiPAP). This was necessary because end-tidal CO2 monitoring is not compatible with these interventions.

== Important Points ==
# Applicable for all age groups (including extremely premature neonates).
# Initial reading requires approximately five minutes to establish.
# TC-CO2 is '''substantially more accurate''' than peripheral venous CO2 for estimating paCO2.<ref name="Nassar2017"/>
# Because CO2 takes several minutes to diffuse out of the skin, the displayed TC-CO2 reading at any given time reflects the paCO2 from 2-4 minutes prior.
# The tracing is a flat line (rather than the waveform created by exhaled air).
# TC-CO2 is used to follow paCO2 trends; it DOES NOT measure instantaneous levels. Therefore, TC-CO2 '''IS NOT''' an acceptable substitute for ET-CO2 in situations such as:
## Confirmation of ET-tube placement.
## CPR (neither for CPR adequacy nor ROSC identification).
## Respiratory monitoring during sedation.
## Any situation where monitoring for apnea or any rapid changes in paCO2.

== Device ==
YKDRH has acquired the '''Sentec''' Digital Monitoring System. 
The Sentec devices provides monitoring of:
# Instantaneous oximetry (with an adjustable duration trend line)
# Instantaneous heart rate (with an adjustable duration trend line)
# Delayed paCO2 (with an adjustable duration trend line)

== Resources ==
: [https://yk-health.org/wiki/File:Transcutaneous_CO2_monitor_SDMS_InstructionManual_EN.pdf Sentec Instruction Manual]
'''Instructional Videos:'''
: [https://www.youtube.com/watch?v=7d7XNtQNllA Neonatal Sensor Application for the Sentec Digital Transcutaneous Monitoring System]
: [https://www.youtube.com/watch?v=7HX7dgqieaM Sensor Application Adult Cheek for the Sentec Digital Transcutaneous Monitoring System]
 
'''PubMed Searches:'''
: [https://pubmed.ncbi.nlm.nih.gov/?term=(%22transcutaneous%20co2%22%5BTitle%5D%20OR%20%22transcutaneous%20carbon%20dioxide%22%5BTitle%5D)%20AND%20(infant%5BTitle%5D%20OR%20neonat*%5BTitle%5D%20OR%20child*%5BTitle%5D) ("transcutaneous co2"[Title<nowiki>]</nowiki> OR "transcutaneous carbon dioxide"[Title<nowiki>]</nowiki>) AND (infant[Title<nowiki>]</nowiki> OR neonat*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>)]
 

== REFERENCES ==
‎<references />

Transcutaneous paCO2 Monitoring

2023-03-13T18:36:11Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T18:31:48Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T18:29:57Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T17:15:02Z

AndyS:

File:Sentec TCCO2.png

2023-03-13T13:43:50Z

AndyS:

Trancutaneous paCO2 Monitoring

2023-03-13T13:28:30Z

AndyS: AndyS moved page Trancutaneous paCO2 Monitoring to Transcutaneous paCO2 Monitoring

#REDIRECT [[Transcutaneous paCO2 Monitoring]]

Transcutaneous paCO2 Monitoring

2023-03-13T13:28:30Z

AndyS: AndyS moved page Trancutaneous paCO2 Monitoring to Transcutaneous paCO2 Monitoring

Trancutaneous pCO2 Monitoring

2023-03-13T13:25:07Z

AndyS: AndyS moved page Trancutaneous pCO2 Monitoring to Trancutaneous paCO2 Monitoring

#REDIRECT [[Trancutaneous paCO2 Monitoring]]

Transcutaneous paCO2 Monitoring

2023-03-13T13:25:07Z

AndyS: AndyS moved page Trancutaneous pCO2 Monitoring to Trancutaneous paCO2 Monitoring

Transcutaneous paCO2 Monitoring

2023-03-13T13:24:22Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T13:22:59Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T13:20:21Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T12:48:49Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T12:42:24Z

AndyS:

File:Transcutaneous CO2 monitor SDMS InstructionManual EN.pdf

2023-03-13T12:29:52Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T12:29:16Z

AndyS:

Transcutaneous paCO2 Monitoring

2023-03-13T12:19:56Z

AndyS: Created page with "Transcutaneous CO2 (TC-CO2) monitors function by measuring the CO2 which diffuses out the skin. Modern TC-CO2 monitors are highly..."

Transcutaneous CO2 (TC-CO2) monitors function by measuring the CO2 which diffuses out the skin. Modern TC-CO2 monitors are highly accurate for measuring paCO2.<ref>Nassar BS, Schmidt GA. Estimating Arterial Partial Pressure of Carbon Dioxide in Ventilated Patients: How Valid Are Surrogate Measures? Ann Am Thorac Soc. 2017 Jun;14(6):1005-1014. doi: 10.1513/AnnalsATS.201701-034FR. PMID: 28570147.</ref> 

== Important Points ==
# Initial reading requires approximately five minutes to establish.
# TC-CO2 measures paCO2 trends; it DOES NOT measure instantaneous levels. Therefore, TC-CO2 is NOT an acceptable substitute for ET-CO2 in these situations:
## Confirmation of ET-tube placement.
## Respiratory monitoring during sedation.
## Any situation where apnea is a concern.

== REFERENCES ==
‎<references />

H Pylori Guideline Revision Supplement 2022

2022-03-22T13:39:22Z

AndyS:

This guideline revision page addresses only the methods and results of the 2022 guideline update. For a broader review of the topic of H. pylori in Alaska Natives and for prior and/or ANMC guidelines, see the [[Helicobacter_pylori_in_Alaska_Natives|'''Helicobacter pylori in Alaska Natives''']] page.
 
 

== Reason[s] for update ==
Routine review/update.
 
 

== Methods ==
* Review of latest ANMC H. pylori treatment guideline ([https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf Feb 19, 2020 ][https://web.archive.org/web/20201024034528/https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf , Archive]) 
* Updated literature search (PubMed, [https://pubmed.ncbi.nlm.nih.gov/?term=%28alaska%5BTitle%5D+OR+polar%5BTitle%5D+OR+arctic%5BTitle%5D%29+AND+helicobacter%5BTitle%2FAbstract%5D&sort=date (alaska[Title<nowiki>]</nowiki> OR polar[Title<nowiki>]</nowiki> OR arctic[Title<nowiki>]</nowiki>) AND helicobacter[Title/Abstract<nowiki>]</nowiki>]). This is a broader search than previously in that it looks for "helicobacter" in the abstract as well as the title.
* Attendance at the 2019 Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium
:: >Hosted by the CDC in Anchorage, Alaska
:: >Experts were longstanding, world-renown researchers
:: >Results were published in ''Gastroenterology'' in April 2020<ref name="Nolen2020">Nolen LD, Vindigni SM, Parsonnet J; Symposium leaders. Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium. Gastroenterology. 2020 Apr;158(5):1197-1201. doi: 10.1053/j.gastro.2019.11.299. PMID: 31836529; PMCID: [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7103478/ PMC7103478]. DOI:[https://doi.org/10.1053/j.gastro.2019.11.299 10.1053/j.gastro.2019.11.299]</ref>
* Pediatric H. pylori literature review:
:: >PUBMED, [https://pubmed.ncbi.nlm.nih.gov/?term=pylori%5BTitle%5D+AND+%28pediatric*%5BTitle%5D+OR+child*%5BTitle%5D%29+AND+%28review%5BTitle%5D+OR+overview%5BTitle%5D+OR+guideline*%5BTitle%5D%29 pylori[Title<nowiki>]</nowiki> AND (pediatric*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>) AND (review[Title<nowiki>]</nowiki> OR overview[Title<nowiki>]</nowiki> OR guideline*[Title<nowiki>]</nowiki>)]
 

==Results==
# ANMC H. Pylori Treatment Guideline has no significant changes pertinent to the YKHC guideline. Of note, ANMC has started a study of offering EGD for gastric cancer screening for patients with a first-degree relative (parent, sibling, or child) with gastric cancer; they are treating to eradicate H. pylori in this group regardless of findings; but this treatment is limited to the study patients and thus is not applicable to our practice in Bethel.
# PubMed search returned 49 articles, 12 of which were published since the last literature review. Only one of these articles addresses treatment in our setting, which is the CDC conference summary,<ref name="Nolen2020"/> which continues to explicitly advocate the current algorithm/guideline (which was originally published by an international, circumpolar expert group in 2016<ref name=mcmahon2016>McMahon BJ, Bruce MG, Koch A, et al. The diagnosis and treatment of Helicobacter pylori infection in Arctic regions with a high prevalence of infection: Expert Commentary. Epidemiology and Infection. 2016;144(2):225-233. PMID:[https://pubmed.ncbi.nlm.nih.gov/26094936/ 26094936]. PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4697284/ PMC4697284]. doi:[https://doi.org/10.1017/s0950268815001181 10.1017/S0950268815001181].</ref>)
# Pediatric PubMed search returned 50 results, the most pertinent being the ''Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016)''<ref name=NASPGHAN>Jones NL, Koletzko S, Goodman K, Bontems P, Cadranel S, Casswall T, Czinn S, Gold BD, Guarner J, Elitsur Y, Homan M, Kalach N, Kori M, Madrazo A, Megraud F, Papadopoulou A, Rowland M; ESPGHAN, NASPGHAN. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. doi: 10.1097/MPG.0000000000001594. PMID: 28541262.</ref>
 

== Discussion ==
* The YKHC H. pylori guideline continues to be consistent with the ANMC H. pylori guideline.
* For adults, the YKHC guideline is very different than the standard of care in the remainder of the U.S. which endorsed the "test-and-treat" strategy. The prevalence of H. pylori in the Alaska Native population is far too high for such a strategy.
* For pediatrics, the YKHC guideline (which treats pediatrics identical to adults) is consistent with national guidelines (i.e. NASPGHAN<ref name="Nolen2020"/>)
* The only minor issue with the YKHC guideline is that it does not address recent recommendations regarding new, commercially available, rapid H. pylori culture and sensitivities to guide initial antimicrobial choice.
 

==Guideline Changes==
# Under treatment indications, "Intestinal Metaplasia" is changed to "Gastric Intestinal Metaplasia" (to prevent any confusion with Barrett's esophagus).
# Addition of box specifying test-of-cure details:
:::* ≥4wks after COMPLETION of treatment.
:::* Either urea breath test (UBT), stool antigen test, or endoscopic biopsy (if indicated for other reasons; using either pathology or CLO-test).
:::* Regardless of test, no antibiotics or bismuth for FOUR weeks prior.
:::* Regardless of test, no PPI for TWO weeks prior.
 

==Topics for Exploration==
Commercial (i.e. non-CDC) rapid H. pylori culture/sensitivities which can be used to guide antimicrobial therapy for primary treatment.
 
 
 

Author: Andrew W. Swartz, MD
 
 

==References==
----

H Pylori Guideline Revision Supplement 2022

2022-03-22T13:36:39Z

AndyS:

This guideline revision page addresses only the methods and results of the 2022 guideline update. For a broader review of the topic of H. pylori in Alaska Natives and for prior and/or ANMC guidelines, see the [[Helicobacter_pylori_in_Alaska_Natives|'''Helicobacter pylori in Alaska Natives''']] page.
 
 

== Reason[s] for update ==
Routine review/update.
 
 

== Methods ==
* Review of latest ANMC H. pylori treatment guideline ([https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf Feb 19, 2020 ][https://web.archive.org/web/20201024034528/https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf , Archive]) 
* Updated literature search (PubMed, [https://pubmed.ncbi.nlm.nih.gov/?term=%28alaska%5BTitle%5D+OR+polar%5BTitle%5D+OR+arctic%5BTitle%5D%29+AND+helicobacter%5BTitle%2FAbstract%5D&sort=date (alaska[Title<nowiki>]</nowiki> OR polar[Title<nowiki>]</nowiki> OR arctic[Title<nowiki>]</nowiki>) AND helicobacter[Title/Abstract<nowiki>]</nowiki>]). This is a broader search than previously in that it looks for "helicobacter" in the abstract as well as the title.
* Attendance at the 2019 Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium
:: >Hosted by the CDC in Anchorage, Alaska
:: >Experts were longstanding, world-renown researchers
:: >Results were published in ''Gastroenterology'' in April 2020<ref name="Nolen2020">Nolen LD, Vindigni SM, Parsonnet J; Symposium leaders. Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium. Gastroenterology. 2020 Apr;158(5):1197-1201. doi: 10.1053/j.gastro.2019.11.299. PMID: 31836529; PMCID: [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7103478/ PMC7103478]. DOI:[https://doi.org/10.1053/j.gastro.2019.11.299 10.1053/j.gastro.2019.11.299]</ref>
* Pediatric H. pylori literature review:
:: >PUBMED, [https://pubmed.ncbi.nlm.nih.gov/?term=pylori%5BTitle%5D+AND+%28pediatric*%5BTitle%5D+OR+child*%5BTitle%5D%29+AND+%28review%5BTitle%5D+OR+overview%5BTitle%5D+OR+guideline*%5BTitle%5D%29 pylori[Title<nowiki>]</nowiki> AND (pediatric*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>) AND (review[Title<nowiki>]</nowiki> OR overview[Title<nowiki>]</nowiki> OR guideline*[Title<nowiki>]</nowiki>)]
 

==Results==
# ANMC H. Pylori Treatment Guideline has no significant changes pertinent to the YKHC guideline. Of note, ANMC has started a study of offering EGD for gastric cancer screening for patients with a first-degree relative (parent, sibling, or child) with gastric cancer; they are treating to eradicate H. pylori in this group regardless of findings; but this treatment is limited to the study patients and thus is not applicable to our practice in Bethel.
# PubMed search returned 49 articles, 12 of which were published since the last literature review. Only one of these articles addresses treatment in our setting, which is the CDC conference summary,<ref name="Nolen2020"/> which continues to explicitly advocate the current algorithm/guideline (which was originally published by an international, circumpolar expert group in 2016<ref name=mcmahon2016>McMahon BJ, Bruce MG, Koch A, et al. The diagnosis and treatment of Helicobacter pylori infection in Arctic regions with a high prevalence of infection: Expert Commentary. Epidemiology and Infection. 2016;144(2):225-233. PMID:[https://pubmed.ncbi.nlm.nih.gov/26094936/ 26094936]. PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4697284/ PMC4697284]. doi:[https://doi.org/10.1017/s0950268815001181 10.1017/S0950268815001181].</ref>)
# Pediatric PubMed search returned 50 results, the most pertinent being the ''Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016)''<ref name=NASPGHAN>Jones NL, Koletzko S, Goodman K, Bontems P, Cadranel S, Casswall T, Czinn S, Gold BD, Guarner J, Elitsur Y, Homan M, Kalach N, Kori M, Madrazo A, Megraud F, Papadopoulou A, Rowland M; ESPGHAN, NASPGHAN. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. doi: 10.1097/MPG.0000000000001594. PMID: 28541262.</ref>
 

== Discussion ==
* The YKHC H. pylori guideline continues to be consistent with the ANMC H. pylori guideline.
* For adults, the YKHC guideline is very different than the standard of care in the remainder of the U.S. which endorsed the "test-and-treat" strategy. The prevalence of H. pylori in the Alaska Native population is far too high for such a strategy.
* For pediatrics, the local guideline (which treats pediatrics identical to adults) is consistent with national guidelines (i.e. NASPGHAN<ref name="Nolen2020"/>)
* The only minor issue with the YKHC guideline is that it does not address recent recommendations to utilize newly developed, commercially available, rapid H. pylori culture and sensitivities to guide initial H. pylori antimicrobial choice.
 

==Guideline Changes==
# Under treatment indications, "Intestinal Metaplasia" is changed to "Gastric Intestinal Metaplasia" (to prevent any confusion with Barrett's esophagus).
# Addition of box specifying test-of-cure details:
:::* ≥4wks after COMPLETION of treatment.
:::* Either urea breath test (UBT), stool antigen test, or endoscopic biopsy (if indicated for other reasons; using either pathology or CLO-test).
:::* Regardless of test, no antibiotics or bismuth for FOUR weeks prior.
:::* Regardless of test, no PPI for TWO weeks prior.
 

==Topics for Exploration==
Commercial (i.e. non-CDC) rapid H. pylori culture/sensitivities which can be used to guide antimicrobial therapy for primary treatment.
 
 
 

Author: Andrew W. Swartz, MD
 
 

==References==
----

H Pylori Guideline Revision Supplement 2022

2022-03-22T13:34:24Z

AndyS:

This guideline revision page addresses only the methods and results of the 2022 guideline update. For a broader review of the topic of H. pylori in Alaska Natives and for prior and/or ANMC guidelines, see the [[Helicobacter_pylori_in_Alaska_Natives|'''Helicobacter pylori in Alaska Natives''']] page.
 
 

== Reason[s] for update ==
Routine review/update.
 
 

== Methods ==
* Review of latest ANMC H. pylori treatment guideline ([https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf Feb 19, 2020 ][https://web.archive.org/web/20201024034528/https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf , Archive]) 
* Updated literature search (PubMed, [https://pubmed.ncbi.nlm.nih.gov/?term=%28alaska%5BTitle%5D+OR+polar%5BTitle%5D+OR+arctic%5BTitle%5D%29+AND+helicobacter%5BTitle%2FAbstract%5D&sort=date (alaska[Title<nowiki>]</nowiki> OR polar[Title<nowiki>]</nowiki> OR arctic[Title<nowiki>]</nowiki>) AND helicobacter[Title/Abstract<nowiki>]</nowiki>]). This is a broader search than previously in that it looks for "helicobacter" in the abstract as well as the title.
* Attendance at the 2019 Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium
:: >Hosted by the CDC in Anchorage, Alaska
:: >Experts were longstanding, world-renown researchers
:: >Results were published in ''Gastroenterology'' in April 2020<ref name="Nolen2020">Nolen LD, Vindigni SM, Parsonnet J; Symposium leaders. Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium. Gastroenterology. 2020 Apr;158(5):1197-1201. doi: 10.1053/j.gastro.2019.11.299. PMID: 31836529; PMCID: [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7103478/ PMC7103478]. DOI:[https://doi.org/10.1053/j.gastro.2019.11.299 10.1053/j.gastro.2019.11.299]</ref>
* Pediatric H. pylori literature review:
:: >PUBMED, [https://pubmed.ncbi.nlm.nih.gov/?term=pylori%5BTitle%5D+AND+%28pediatric*%5BTitle%5D+OR+child*%5BTitle%5D%29+AND+%28review%5BTitle%5D+OR+overview%5BTitle%5D+OR+guideline*%5BTitle%5D%29 pylori[Title<nowiki>]</nowiki> AND (pediatric*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>) AND (review[Title<nowiki>]</nowiki> OR overview[Title<nowiki>]</nowiki> OR guideline*[Title<nowiki>]</nowiki>)]
 

==Results==
# ANMC H. Pylori Treatment Guideline has no significant changes pertinent to the YKHC guideline. Of note, ANMC has started a study of offering EGD for gastric cancer screening for patients with a first-degree relative (parent, sibling, or child) with gastric cancer; they are treating to eradicate H. pylori in this group regardless of findings; but this treatment is limited to the study patients and thus is not applicable to our practice in Bethel.
# PubMed search returned 49 articles, 12 of which were published since the last literature review. Only one of these articles addresses treatment in our setting, which is the CDC conference summary,<ref name="Nolen2020"/> which continues to explicitly advocate the current algorithm/guideline (which was originally published by an international, circumpolar expert group in 2016<ref name=mcmahon2016>McMahon BJ, Bruce MG, Koch A, et al. The diagnosis and treatment of Helicobacter pylori infection in Arctic regions with a high prevalence of infection: Expert Commentary. Epidemiology and Infection. 2016;144(2):225-233. PMID:[https://pubmed.ncbi.nlm.nih.gov/26094936/ 26094936]. PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4697284/ PMC4697284]. doi:[https://doi.org/10.1017/s0950268815001181 10.1017/S0950268815001181].</ref>)
# Pediatric PubMed search returned 50 results, the most pertinent being the ''Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016)''<ref name=NASPGHAN>Jones NL, Koletzko S, Goodman K, Bontems P, Cadranel S, Casswall T, Czinn S, Gold BD, Guarner J, Elitsur Y, Homan M, Kalach N, Kori M, Madrazo A, Megraud F, Papadopoulou A, Rowland M; ESPGHAN, NASPGHAN. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. doi: 10.1097/MPG.0000000000001594. PMID: 28541262.</ref>
 

== Discussion ==
* The YKHC H. pylori guideline continues to be consistent with the ANMC H. pylori guideline.
* For adults, the local guideline is very different than the standard of care in the remainder of the U.S. which endorsed the "test-and-treat" strategy. The prevalence of H. pylori in the Alaska Native population far to high for such a strategy.
* For pediatrics, the local guideline (which treats pediatrics identical to adults) is consistent with national guidelines (i.e. NASPGHAN<ref name="Nolen2020"/>)
* The only minor issue with the local guideline is that it does address recent recommendations to utilize newly developed, commercially available, rapid H. pylori culture and sensitivities to guide initial H. pylori antimicrobial choice.
 

==Guideline Changes==
# Under treatment indications, "Intestinal Metaplasia" is changed to "Gastric Intestinal Metaplasia" (to prevent any confusion with Barrett's esophagus).
# Addition of box specifying test-of-cure details:
:::* ≥4wks after COMPLETION of treatment.
:::* Either urea breath test (UBT), stool antigen test, or endoscopic biopsy (if indicated for other reasons; using either pathology or CLO-test).
:::* Regardless of test, no antibiotics or bismuth for FOUR weeks prior.
:::* Regardless of test, no PPI for TWO weeks prior.
 

==Topics for Exploration==
Commercial (i.e. non-CDC) rapid H. pylori culture/sensitivities which can be used to guide antimicrobial therapy for primary treatment.
 
 
 

Author: Andrew W. Swartz, MD
 
 

==References==
----

H Pylori Guideline Revision Supplement 2022

2022-03-22T13:08:22Z

AndyS:

This guideline revision page addresses only the methods and results of the 2022 guideline update. For a broader review of the topic of H. pylori in Alaska Natives and for prior and/or ANMC guidelines, see the [[Helicobacter_pylori_in_Alaska_Natives|'''Helicobacter pylori in Alaska Natives''']] page.
 
 

== Reason[s] for update ==
Routine 2-year review/update.
 
 

== Methods ==
* Review of latest ANMC H. pylori treatment guideline ([https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf Feb 19, 2020 ][https://web.archive.org/web/20201024034528/https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf , Archive]) 
* Updated literature search (PubMed, [https://pubmed.ncbi.nlm.nih.gov/?term=%28alaska%5BTitle%5D+OR+polar%5BTitle%5D+OR+arctic%5BTitle%5D%29+AND+helicobacter%5BTitle%2FAbstract%5D&sort=date (alaska[Title<nowiki>]</nowiki> OR polar[Title<nowiki>]</nowiki> OR arctic[Title<nowiki>]</nowiki>) AND helicobacter[Title/Abstract<nowiki>]</nowiki>]). This is a broader search than previously in that it looks for "helicobacter" in the abstract as well as the title.
* Attendance at the 2019 Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium
:: >Hosted by the CDC in Anchorage, Alaska
:: >Experts were longstanding, world-renown researchers
:: >Results were published in ''Gastroenterology'' in April 2020<ref name="Nolen2020">Nolen LD, Vindigni SM, Parsonnet J; Symposium leaders. Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium. Gastroenterology. 2020 Apr;158(5):1197-1201. doi: 10.1053/j.gastro.2019.11.299. PMID: 31836529; PMCID: [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7103478/ PMC7103478]. DOI:[https://doi.org/10.1053/j.gastro.2019.11.299 10.1053/j.gastro.2019.11.299]</ref>
* Pediatric H. pylori literature review:
:: >PUBMED, [https://pubmed.ncbi.nlm.nih.gov/?term=pylori%5BTitle%5D+AND+%28pediatric*%5BTitle%5D+OR+child*%5BTitle%5D%29+AND+%28review%5BTitle%5D+OR+overview%5BTitle%5D+OR+guideline*%5BTitle%5D%29 pylori[Title<nowiki>]</nowiki> AND (pediatric*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>) AND (review[Title<nowiki>]</nowiki> OR overview[Title<nowiki>]</nowiki> OR guideline*[Title<nowiki>]</nowiki>)]
 

==Results==
# ANMC H. Pylori Treatment Guideline has no significant changes pertinent to the YKHC guideline. Of note, ANMC has started a study of offering EGD for gastric cancer screening for patients with a first-degree relative (parent, sibling, or child) with gastric cancer; they are treating to eradicate H. pylori in this group regardless of findings; but this treatment is limited to the study patients and thus is not applicable to our practice in Bethel.
# PubMed search returned 49 articles, 12 of which were published since the last literature review. Only one of these articles addresses treatment in our setting, which is the CDC conference summary,<ref name="Nolen2020"> which continues to explicitly advocate the current algorithm/guideline (which was originally published by an international, circumpolar expert group in 2016<ref name=mcmahon2016>McMahon BJ, Bruce MG, Koch A, et al. The diagnosis and treatment of Helicobacter pylori infection in Arctic regions with a high prevalence of infection: Expert Commentary. Epidemiology and Infection. 2016;144(2):225-233. PMID:[https://pubmed.ncbi.nlm.nih.gov/26094936/ 26094936]. PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4697284/ PMC4697284]. doi:[https://doi.org/10.1017/s0950268815001181 10.1017/S0950268815001181].</ref>)
# Pediatric PubMed search returned 50 results, the most pertinent being the ''Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016)''<ref name=NASPGHAN>Jones NL, Koletzko S, Goodman K, Bontems P, Cadranel S, Casswall T, Czinn S, Gold BD, Guarner J, Elitsur Y, Homan M, Kalach N, Kori M, Madrazo A, Megraud F, Papadopoulou A, Rowland M; ESPGHAN, NASPGHAN. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. doi: 10.1097/MPG.0000000000001594. PMID: 28541262.</ref>
 

== Discussion ==
* The YKHC H. pylori guideline continues to be consistent with the ANMC H. pylori guideline.
* For adults, the local guideline is very different than the standard of care in the remainder of the U.S. which endorsed the "test-and-treat" strategy. The prevalence of H. pylori in the Alaska Native population far to high for such a strategy.
* For pediatrics, the local guideline (which treats pediatrics identical to adults) is consistent with national guidelines (i.e. NASPGHAN<ref name="Nolen2020"/>)
* The only minor issue with the local guideline is that it does address recent recommendations to utilize newly developed, commercially available, rapid H. pylori culture and sensitivities to guide initial H. pylori antimicrobial choice.
 

==Guideline Changes==
# Under treatment indications, "Intestinal Metaplasia" is changed to "Gastric Intestinal Metaplasia" (to prevent any confusion with Barrett's esophagus).
# Addition of box specifying test-of-cure details:
:::* ≥4wks after COMPLETION of treatment.
:::* Either urea breath test (UBT), stool antigen test, or endoscopic biopsy (if indicated for other reasons; using either pathology or CLO-test).
:::* Regardless of test, no antibiotics or bismuth for FOUR weeks prior.
:::* Regardless of test, no PPI for TWO weeks prior.
 

==Topics for Exploration==
Commercial (i.e. non-CDC) rapid H. pylori culture/sensitivities which can be used to guide antimicrobial therapy for primary treatment.
 
 
 

Author: Andrew W. Swartz, MD
 
 

==References==
----

H Pylori Guideline Revision Supplement 2022

2022-03-22T12:43:44Z

AndyS:

This guideline revision page addresses only the methods and results of the 2022 guideline update. For a broader review of the topic of H. pylori in Alaska Natives and for prior and/or ANMC guidelines, see the [[Helicobacter_pylori_in_Alaska_Natives|'''Helicobacter pylori in Alaska Natives''']] page.
 
 

== Reason[s] for update ==
Routine 2-year review/update.
 
 

== Methods ==
* Review of latest ANMC H. pylori treatment guideline ([https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf Feb 19, 2020 ][https://web.archive.org/web/20201024034528/https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf , Archive]) 
* Updated literature search (PubMed, [https://pubmed.ncbi.nlm.nih.gov/?term=%28alaska%5BTitle%5D+OR+polar%5BTitle%5D+OR+arctic%5BTitle%5D%29+AND+helicobacter%5BTitle%2FAbstract%5D&sort=date (alaska[Title<nowiki>]</nowiki> OR polar[Title<nowiki>]</nowiki> OR arctic[Title<nowiki>]</nowiki>) AND helicobacter[Title/Abstract<nowiki>]</nowiki>]). This is a broader search than previously in that it looks for "helicobacter" in the abstract as well as the title.
* Attendance at the 2019 Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium
:: >Hosted by the CDC in Anchorage, Alaska
:: >Experts were longstanding, world-renown researchers
:: >Results were published in ''Gastroenterology'' in April 2020<ref name="Nolen2020">Nolen LD, Vindigni SM, Parsonnet J; Symposium leaders. Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium. Gastroenterology. 2020 Apr;158(5):1197-1201. doi: 10.1053/j.gastro.2019.11.299. PMID: 31836529; PMCID: [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7103478/ PMC7103478]. DOI:[https://doi.org/10.1053/j.gastro.2019.11.299 10.1053/j.gastro.2019.11.299]</ref>
* Pediatric H. pylori literature review:
:: >PUBMED, [https://pubmed.ncbi.nlm.nih.gov/?term=pylori%5BTitle%5D+AND+%28pediatric*%5BTitle%5D+OR+child*%5BTitle%5D%29+AND+%28review%5BTitle%5D+OR+overview%5BTitle%5D+OR+guideline*%5BTitle%5D%29 pylori[Title<nowiki>]</nowiki> AND (pediatric*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>) AND (review[Title<nowiki>]</nowiki> OR overview[Title<nowiki>]</nowiki> OR guideline*[Title<nowiki>]</nowiki>)]
 

==Results==
# ANMC H. Pylori Treatment Guideline has no significant changes pertinent to the YKHC guideline. Of note, ANMC has started a study of offering EGD for gastric cancer screening for patients with a first-degree relative (parent, sibling, or child) with gastric cancer; they are treating to eradicate H. pylori in this group regardless of findings; but this treatment is limited to the study patients and thus is not applicable to our practice in Bethel.
# PubMed search returned 49 articles, 12 of which were published since the last literature review. Only one of these articles addresses treatment in our setting, which is the CDC conference summary,<ref name="Nolen2020"/> which continues to explicitly advocate the current algorithm/guideline (which was originally published by an international, circumpolar expert group in 2016<ref name=mcmahon2016>McMahon BJ, Bruce MG, Koch A, et al. The diagnosis and treatment of Helicobacter pylori infection in Arctic regions with a high prevalence of infection: Expert Commentary. Epidemiology and Infection. 2016;144(2):225-233. PMID:[https://pubmed.ncbi.nlm.nih.gov/26094936/ 26094936]. PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4697284/ PMC4697284]. doi:[https://doi.org/10.1017/s0950268815001181 10.1017/S0950268815001181].</ref>)
# Pediatric PubMed search returned 50 results, the most pertinent being the ''Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016)''<ref>Jones NL, Koletzko S, Goodman K, Bontems P, Cadranel S, Casswall T, Czinn S, Gold BD, Guarner J, Elitsur Y, Homan M, Kalach N, Kori M, Madrazo A, Megraud F, Papadopoulou A, Rowland M; ESPGHAN, NASPGHAN. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. doi: 10.1097/MPG.0000000000001594. PMID: 28541262.</ref>
 

==Guideline Changes==
# Under treatment indications, "Intestinal Metaplasia" is changed to "Gastric Intestinal Metaplasia" (to prevent any confusion with Barrett's esophagus).
# Addition of box specifying test-of-cure details:
:::* ≥4wks after COMPLETION of treatment.
:::* Either urea breath test (UBT), stool antigen test, or endoscopic biopsy (if indicated for other reasons; using either pathology or CLO-test).
:::* Regardless of test, no antibiotics or bismuth for FOUR weeks prior.
:::* Regardless of test, no PPI for TWO weeks prior.
 

==Topics for Exploration==
Commercial (i.e. non-CDC) rapid H. pylori culture/sensitivities which can be used to guide antimicrobial therapy for primary treatment.
 
 
 

Author: Andrew W. Swartz, MD
 
 

==References==
----

H Pylori Guideline Revision Supplement 2022

2022-03-22T12:35:57Z

AndyS:

This guideline revision page addresses only the methods and results of the 2022 guideline update. For a broader review of the topic of H. pylori in Alaska Natives and for prior and/or ANMC guidelines, see the [[Helicobacter_pylori_in_Alaska_Natives|'''Helicobacter pylori in Alaska Natives''']] page.
 
 

== Reason[s] for update ==
Routine 2-year review/update.
 
 

== Methods ==
* Review of latest ANMC H. pylori treatment guideline ([https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf Feb 19, 2020 ][https://web.archive.org/web/20201024034528/https://anmc.org/files/CG_HelicobacterPyloriGuideline.pdf , Archive]) 
* Updated literature search (PubMed, [https://pubmed.ncbi.nlm.nih.gov/?term=%28alaska%5BTitle%5D+OR+polar%5BTitle%5D+OR+arctic%5BTitle%5D%29+AND+helicobacter%5BTitle%2FAbstract%5D&sort=date (alaska[Title<nowiki>]</nowiki> OR polar[Title<nowiki>]</nowiki> OR arctic[Title<nowiki>]</nowiki>) AND helicobacter[Title/Abstract<nowiki>]</nowiki>]). This is a broader search than previously in that it looks for "helicobacter" in the abstract as well as the title.
* Attendance at the 2019 Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium
:: >Hosted by the CDC in Anchorage, Alaska
:: >Experts were longstanding, world-renown researchers
:: >Results were published in ''Gastroenterology'' in April 2020<ref name="Nolen2020">Nolen LD, Vindigni SM, Parsonnet J; Symposium leaders. Combating Gastric Cancer in Alaska Native People: An Expert and Community Symposium. Gastroenterology. 2020 Apr;158(5):1197-1201. doi: 10.1053/j.gastro.2019.11.299. PMID: 31836529; PMCID: [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7103478/ PMC7103478]. DOI:[https://doi.org/10.1053/j.gastro.2019.11.299 10.1053/j.gastro.2019.11.299]</ref>
* Pediatric H. pylori literature review:
:: >PUBMED, [https://pubmed.ncbi.nlm.nih.gov/?term=pylori%5BTitle%5D+AND+%28pediatric*%5BTitle%5D+OR+child*%5BTitle%5D%29+AND+%28review%5BTitle%5D+OR+overview%5BTitle%5D+OR+guideline*%5BTitle%5D%29 pylori[Title<nowiki>]</nowiki> AND (pediatric*[Title<nowiki>]</nowiki> OR child*[Title<nowiki>]</nowiki>) AND (review[Title<nowiki>]</nowiki> OR overview[Title<nowiki>]</nowiki> OR guideline*[Title<nowiki>]</nowiki>)]
:: >Review of the ''Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016)''<ref>Jones NL, Koletzko S, Goodman K, Bontems P, Cadranel S, Casswall T, Czinn S, Gold BD, Guarner J, Elitsur Y, Homan M, Kalach N, Kori M, Madrazo A, Megraud F, Papadopoulou A, Rowland M; ESPGHAN, NASPGHAN. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. doi: 10.1097/MPG.0000000000001594. PMID: 28541262.</ref>
 

==Results==
# ANMC H. Pylori Treatment Guideline has no significant changes pertinent to the YKHC guideline. Of note, ANMC has started a study of offering EGD for gastric cancer screening for patients with a first-degree relative (parent, sibling, or child) with gastric cancer; they are treating to eradicate H. pylori in this group regardless of findings; but this treatment is limited to the study patients and thus is not applicable to our practice in Bethel.
# PubMed search returned 49 articles, 12 of which were published since the last literature review. Only one of these articles addresses treatment in our setting, which is the CDC conference summary,<ref name="Nolen2020"/> which continues to explicitly advocate the current algorithm/guideline (which was originally published by an international, circumpolar expert group in 2016<ref name=mcmahon2016>McMahon BJ, Bruce MG, Koch A, et al. The diagnosis and treatment of Helicobacter pylori infection in Arctic regions with a high prevalence of infection: Expert Commentary. Epidemiology and Infection. 2016;144(2):225-233. PMID:[https://pubmed.ncbi.nlm.nih.gov/26094936/ 26094936]. PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4697284/ PMC4697284]. doi:[https://doi.org/10.1017/s0950268815001181 10.1017/S0950268815001181].</ref>)
 

==Guideline Changes==
# Under treatment indications, "Intestinal Metaplasia" is changed to "Gastric Intestinal Metaplasia" (to prevent any confusion with Barrett's esophagus).
# Addition of box specifying test-of-cure details:
:::* ≥4wks after COMPLETION of treatment.
:::* Either urea breath test (UBT), stool antigen test, or endoscopic biopsy (if indicated for other reasons; using either pathology or CLO-test).
:::* Regardless of test, no antibiotics or bismuth for FOUR weeks prior.
:::* Regardless of test, no PPI for TWO weeks prior.
 
 

Author: Andrew W. Swartz, MD
 

==References==
----

Cardiac Biomarkers in Pediatrics

2022-02-12T08:36:41Z

AndyS: /* hs-cTnT */

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
The [https://en.wikipedia.org/wiki/Troponin troponin Wikipedia article] provides an excellent, succinct review of the biochemistry of troponin. In summary, the troponin complex is a molecule bound to myosin within muscle cells and involved in muscle contraction. Troponin-I and troponin-T are specific to cardiac muscle. 

Troponin "leaks" from cardiomyocytes when cell membrane permeability is increased; this condition is termed myocardial "injury," and it can be caused by both ischemic and non-ischemic processes. Ischemic processes include acute coronary syndrome and chronic coronary ischemia (such as ischemic cardiomyopathy), while non-ischemic processes include a multitude of diverse conditions (such as inflammation, apoptosis, cytotoxicity, infiltrative diseases, hypoxemia, shock, ventricular strain, trauma, etc).<ref name=Ammann2004>Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ. 2004 May 1;328(7447):1028-9. doi:[https://doi.org/10.1136/bmj.328.7447.1028 10.1136/bmj.328.7447.1028]. PMID:[https://pubmed.ncbi.nlm.nih.gov/15117768/ 15117768]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc403831/ PMC403831]. (available on Sci-Hub)</ref> Clinical decisions regarding elevated troponin must incorporate an understanding non-ischemic myocardial injury. Indeed, while ischemic causes of myocardial injury predominate in older adults, non-ischemic causes vastly predominate in all pediatric age groups.<ref name=Wang2021/>
 

=== Normal Range[s] in Pediatric Age Groups ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH). Search methods are documented in the ''Methods'' section (below).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

:;Guo et al (2021)<ref>Guo Q, Yang D, Zhou Y, Zhang S, Zhu T, Wang A, Lei M, Yang X. Establishment of the reference interval for high-sensitivity cardiac troponin T in healthy children of Chongqing Nan'an district. Scand J Clin Lab Invest. 2021 Nov;81(7):579-584. doi:[https://doi.org/10.1080/00365513.2021.1979245 10.1080/00365513.2021.1979245]. Epub 2021 Sep 28. PMID:[https://pubmed.ncbi.nlm.nih.gov/34581638/ 34581638]. (obtained through the Alaska Medical Library)</ref>
::From January 2017 to February 2020, 4,617 questionnaires distributed to children from Chongqing Southeast Hospital (China), pediatricians physically examined respondents to confirm no health issues, 3,463 children included in the study, ages 0-14y, analyzed by sex. Results are presented in Table-4.
:::*The combination of large sample size and pediatrician physical exams to confirm no underlying health problems makes this undoubtedly the most robust data available at the time of this writing (January 2022).
{| class="wikitable" style="margin: auto;"
|+ Table-4.
|-
! Age !! n !! 99th percentile
|-
| 1d(UCB) || style="text-align:center;" | 34 || style="text-align:center;" | 60.8
|-
| 1d(VB) || style="text-align:center;" | 253 || style="text-align:center;" | 78.8
|-
| 2–28d || style="text-align:center;" | 236 || style="text-align:center;" | 96.6
|-
| 29d–<3m || style="text-align:center;" | 178 || style="text-align:center;" | 58.6
|-
| 3–<6m || style="text-align:center;" | 177 || style="text-align:center;" | 34.2
|-
| 6m–<1y || style="text-align:center;" | 377 || style="text-align:center;" | 16.2
|-
| 1–<3y || style="text-align:center;" | 899 || style="text-align:center;" | 11.4
|-
| 3–<6y (M) || style="text-align:center;" | 361 || style="text-align:center;" | 8
|-
| 3–<6y (F) || style="text-align:center;" | 327 || style="text-align:center;" | 7.8
|-
| 6–14y (M) || style="text-align:center;" | 373 || style="text-align:center;" | 7.8
|-
| 6–14y (F) || style="text-align:center;" | 248 || style="text-align:center;" | 7.3
|}
 
:::*Figure-1 is an adaptation of Guo et al's figure illustrating the distribution of hs-cTnT versus age:
[[File:Guo et al Fig-2.PNG|frameless|center|526px]]
=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

File:Guo et al Fig-2.PNG

2022-02-12T08:29:16Z

AndyS:

Cardiac Biomarkers in Pediatrics

2022-01-22T02:00:30Z

AndyS: /* Biochemistry */

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
The [https://en.wikipedia.org/wiki/Troponin troponin Wikipedia article] provides an excellent, succinct review of the biochemistry of troponin. In summary, the troponin complex is a molecule bound to myosin within muscle cells and involved in muscle contraction. Troponin-I and troponin-T are specific to cardiac muscle. 

Troponin "leaks" from cardiomyocytes when cell membrane permeability is increased; this condition is termed myocardial "injury," and it can be caused by both ischemic and non-ischemic processes. Ischemic processes include acute coronary syndrome and chronic coronary ischemia (such as ischemic cardiomyopathy), while non-ischemic processes include a multitude of diverse conditions (such as inflammation, apoptosis, cytotoxicity, infiltrative diseases, hypoxemia, shock, ventricular strain, trauma, etc).<ref name=Ammann2004>Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ. 2004 May 1;328(7447):1028-9. doi:[https://doi.org/10.1136/bmj.328.7447.1028 10.1136/bmj.328.7447.1028]. PMID:[https://pubmed.ncbi.nlm.nih.gov/15117768/ 15117768]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc403831/ PMC403831]. (available on Sci-Hub)</ref> Clinical decisions regarding elevated troponin must incorporate an understanding non-ischemic myocardial injury. Indeed, while ischemic causes of myocardial injury predominate in older adults, non-ischemic causes vastly predominate in all pediatric age groups.<ref name=Wang2021/>
 

=== Normal Range[s] in Pediatric Age Groups ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH). Search methods are documented in the ''Methods'' section (below).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

:;Guo et al (2021)<ref>Guo Q, Yang D, Zhou Y, Zhang S, Zhu T, Wang A, Lei M, Yang X. Establishment of the reference interval for high-sensitivity cardiac troponin T in healthy children of Chongqing Nan'an district. Scand J Clin Lab Invest. 2021 Nov;81(7):579-584. doi:[https://doi.org/10.1080/00365513.2021.1979245 10.1080/00365513.2021.1979245]. Epub 2021 Sep 28. PMID:[https://pubmed.ncbi.nlm.nih.gov/34581638/ 34581638]. (obtained through the Alaska Medical Library)</ref>
::From January 2017 to February 2020, 4,617 questionnaires distributed to children from Chongqing Southeast Hospital (China), pediatricians physically examined respondents to confirm no health issues, 3,463 children included in the study, ages 0-14y, analyzed by sex. Results are presented in Table-4.
:::*The combination of large sample size and pediatrician physical exams to confirm no underlying health problems makes this undoubtedly the most robust data available at the time of this writing (January 2022).
{| class="wikitable" style="margin: auto;"
|+ Table-4.
|-
! Age !! n !! 99th percentile
|-
| 1d(UCB) || style="text-align:center;" | 34 || style="text-align:center;" | 60.8
|-
| 1d(VB) || style="text-align:center;" | 253 || style="text-align:center;" | 78.8
|-
| 2–28d || style="text-align:center;" | 236 || style="text-align:center;" | 96.6
|-
| 29d–<3m || style="text-align:center;" | 178 || style="text-align:center;" | 58.6
|-
| 3–<6m || style="text-align:center;" | 177 || style="text-align:center;" | 34.2
|-
| 6m–<1y || style="text-align:center;" | 377 || style="text-align:center;" | 16.2
|-
| 1–<3y || style="text-align:center;" | 899 || style="text-align:center;" | 11.4
|-
| 3–<6y (M) || style="text-align:center;" | 361 || style="text-align:center;" | 8
|-
| 3–<6y (F) || style="text-align:center;" | 327 || style="text-align:center;" | 7.8
|-
| 6–14y (M) || style="text-align:center;" | 373 || style="text-align:center;" | 7.8
|-
| 6–14y (F) || style="text-align:center;" | 248 || style="text-align:center;" | 7.3
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-22T01:41:40Z

AndyS:

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
The [https://en.wikipedia.org/wiki/Troponin troponin Wikipedia article] provides an excellent, succinct review of the biochemistry of troponin. In summary, the troponin complex is a molecule bound to myosin within muscle cells and involved in muscle contraction. Troponin-I and troponin-T are specific to cardiac muscle. 

Troponin I and T "leak" from cardiomyocytes when cell membrane permeability is increased; this condition is referred to as myocardial "injury," and can be caused by both ischemic and non-ischemic processes. Ischemic processes include acute coronary syndrome and chronic coronary ischemia (such as ischemic cardiomyopathy), while a multitude of non-ischemic processes can yield myocardial cell "injury" (including inflammation, apoptosis, cytotoxicity, infiltrative diseases, hypoxemia, shock, ventricular strain, trauma, etc).<ref name=Ammann2004>Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ. 2004 May 1;328(7447):1028-9. doi:[https://doi.org/10.1136/bmj.328.7447.1028 10.1136/bmj.328.7447.1028]. PMID:[https://pubmed.ncbi.nlm.nih.gov/15117768/ 15117768]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc403831/ PMC403831]. (available on Sci-Hub)</ref> Clinical decisions regarding elevated troponin must incorporate an understanding non-ischemic myocardial injury. Indeed, while ischemic causes of myocardial injury predominate in older adults, non-ischemic causes vastly predominate in the pediatric age groups.<ref name=Wang2021/>
 

=== Normal Range[s] in Pediatric Age Groups ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH). Search methods are documented in the ''Methods'' section (below).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

:;Guo et al (2021)<ref>Guo Q, Yang D, Zhou Y, Zhang S, Zhu T, Wang A, Lei M, Yang X. Establishment of the reference interval for high-sensitivity cardiac troponin T in healthy children of Chongqing Nan'an district. Scand J Clin Lab Invest. 2021 Nov;81(7):579-584. doi:[https://doi.org/10.1080/00365513.2021.1979245 10.1080/00365513.2021.1979245]. Epub 2021 Sep 28. PMID:[https://pubmed.ncbi.nlm.nih.gov/34581638/ 34581638]. (obtained through the Alaska Medical Library)</ref>
::From January 2017 to February 2020, 4,617 questionnaires distributed to children from Chongqing Southeast Hospital (China), pediatricians physically examined respondents to confirm no health issues, 3,463 children included in the study, ages 0-14y, analyzed by sex. Results are presented in Table-4.
:::*The combination of large sample size and pediatrician physical exams to confirm no underlying health problems makes this undoubtedly the most robust data available at the time of this writing (January 2022).
{| class="wikitable" style="margin: auto;"
|+ Table-4.
|-
! Age !! n !! 99th percentile
|-
| 1d(UCB) || style="text-align:center;" | 34 || style="text-align:center;" | 60.8
|-
| 1d(VB) || style="text-align:center;" | 253 || style="text-align:center;" | 78.8
|-
| 2–28d || style="text-align:center;" | 236 || style="text-align:center;" | 96.6
|-
| 29d–<3m || style="text-align:center;" | 178 || style="text-align:center;" | 58.6
|-
| 3–<6m || style="text-align:center;" | 177 || style="text-align:center;" | 34.2
|-
| 6m–<1y || style="text-align:center;" | 377 || style="text-align:center;" | 16.2
|-
| 1–<3y || style="text-align:center;" | 899 || style="text-align:center;" | 11.4
|-
| 3–<6y (M) || style="text-align:center;" | 361 || style="text-align:center;" | 8
|-
| 3–<6y (F) || style="text-align:center;" | 327 || style="text-align:center;" | 7.8
|-
| 6–14y (M) || style="text-align:center;" | 373 || style="text-align:center;" | 7.8
|-
| 6–14y (F) || style="text-align:center;" | 248 || style="text-align:center;" | 7.3
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-22T01:35:08Z

AndyS: /* Biochemistry */

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
The [https://en.wikipedia.org/wiki/Troponin troponin Wikipedia article] provides an excellent, succinct review of the biochemistry of troponin. In summary, the troponin complex is a molecule bound to myosin within muscle cells and involved in muscle contraction. Troponin-I and troponin-T are specific to cardiac muscle. 

Troponin I and T "leak" from cardiomyocytes when cell membrane permeability is increased; this condition is referred to as myocardial "injury," and can be caused by both ischemic and non-ischemic processes. Ischemic processes include acute coronary syndrome and chronic coronary ischemia (such as ischemic cardiomyopathy), while a multitude of non-ischemic processes can yield myocardial cell "injury" (including inflammation, apoptosis, cytotoxicity, infiltrative diseases, hypoxemia, shock, ventricular strain, trauma, etc).<ref name=Ammann2004>Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ. 2004 May 1;328(7447):1028-9. doi:[https://doi.org/10.1136/bmj.328.7447.1028 10.1136/bmj.328.7447.1028]. PMID:[https://pubmed.ncbi.nlm.nih.gov/15117768/ 15117768]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc403831/ PMC403831]. (available on Sci-Hub)</ref> Clinical decisions regarding elevated troponin must incorporate an understanding non-ischemic myocardial injury.
 

=== Normal Range[s] ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH). Search methods are documented in the ''Methods'' section (below).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

:;Guo et al (2021)<ref>Guo Q, Yang D, Zhou Y, Zhang S, Zhu T, Wang A, Lei M, Yang X. Establishment of the reference interval for high-sensitivity cardiac troponin T in healthy children of Chongqing Nan'an district. Scand J Clin Lab Invest. 2021 Nov;81(7):579-584. doi:[https://doi.org/10.1080/00365513.2021.1979245 10.1080/00365513.2021.1979245]. Epub 2021 Sep 28. PMID:[https://pubmed.ncbi.nlm.nih.gov/34581638/ 34581638]. (obtained through the Alaska Medical Library)</ref>
::From January 2017 to February 2020, 4,617 questionnaires distributed to children from Chongqing Southeast Hospital (China), pediatricians physically examined respondents to confirm no health issues, 3,463 children included in the study, ages 0-14y, analyzed by sex. Results are presented in Table-4.
:::*The combination of large sample size and pediatrician physical exams to confirm no underlying health problems makes this undoubtedly the most robust data available at the time of this writing (January 2022).
{| class="wikitable" style="margin: auto;"
|+ Table-4.
|-
! Age !! n !! 99th percentile
|-
| 1d(UCB) || style="text-align:center;" | 34 || style="text-align:center;" | 60.8
|-
| 1d(VB) || style="text-align:center;" | 253 || style="text-align:center;" | 78.8
|-
| 2–28d || style="text-align:center;" | 236 || style="text-align:center;" | 96.6
|-
| 29d–<3m || style="text-align:center;" | 178 || style="text-align:center;" | 58.6
|-
| 3–<6m || style="text-align:center;" | 177 || style="text-align:center;" | 34.2
|-
| 6m–<1y || style="text-align:center;" | 377 || style="text-align:center;" | 16.2
|-
| 1–<3y || style="text-align:center;" | 899 || style="text-align:center;" | 11.4
|-
| 3–<6y (M) || style="text-align:center;" | 361 || style="text-align:center;" | 8
|-
| 3–<6y (F) || style="text-align:center;" | 327 || style="text-align:center;" | 7.8
|-
| 6–14y (M) || style="text-align:center;" | 373 || style="text-align:center;" | 7.8
|-
| 6–14y (F) || style="text-align:center;" | 248 || style="text-align:center;" | 7.3
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-21T21:04:06Z

AndyS:

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
The [https://en.wikipedia.org/wiki/Troponin troponin Wikipedia article] provides an excellent, succinct review of the biochemistry of troponin. In summary, the troponin complex is a molecule bound to myosin within muscle cells and involved in muscle contraction. Troponin-I and troponin-T are specific to cardiac muscle. Troponin I and T are released from cardiomyocytes due to multiple types of myocardial cell "injury" (including ischemia, necrosis, apoptosis, cytotoxicity, inflammation, etc). Clinical decision making must incorporate the understanding that troponin I and T can undergo non-ischemic release (such as during non-ischemic heart failure, non-ischemic inflammation, and other conditions which injure the cardiomyocites without associated ischemia.<ref name=Ammann2004>Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ. 2004 May 1;328(7447):1028-9. doi:[https://doi.org/10.1136/bmj.328.7447.1028 10.1136/bmj.328.7447.1028]. PMID:[https://pubmed.ncbi.nlm.nih.gov/15117768/ 15117768]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc403831/ PMC403831]. (available on Sci-Hub)</ref>
 
=== Normal Range[s] ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH). Search methods are documented in the ''Methods'' section (below).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

:;Guo et al (2021)<ref>Guo Q, Yang D, Zhou Y, Zhang S, Zhu T, Wang A, Lei M, Yang X. Establishment of the reference interval for high-sensitivity cardiac troponin T in healthy children of Chongqing Nan'an district. Scand J Clin Lab Invest. 2021 Nov;81(7):579-584. doi:[https://doi.org/10.1080/00365513.2021.1979245 10.1080/00365513.2021.1979245]. Epub 2021 Sep 28. PMID:[https://pubmed.ncbi.nlm.nih.gov/34581638/ 34581638]. (obtained through the Alaska Medical Library)</ref>
::From January 2017 to February 2020, 4,617 questionnaires distributed to children from Chongqing Southeast Hospital (China), pediatricians physically examined respondents to confirm no health issues, 3,463 children included in the study, ages 0-14y, analyzed by sex. Results are presented in Table-4.
:::*The combination of large sample size and pediatrician physical exams to confirm no underlying health problems makes this undoubtedly the most robust data available at the time of this writing (January 2022).
{| class="wikitable" style="margin: auto;"
|+ Table-4.
|-
! Age !! n !! 99th percentile
|-
| 1d(UCB) || style="text-align:center;" | 34 || style="text-align:center;" | 60.8
|-
| 1d(VB) || style="text-align:center;" | 253 || style="text-align:center;" | 78.8
|-
| 2–28d || style="text-align:center;" | 236 || style="text-align:center;" | 96.6
|-
| 29d–<3m || style="text-align:center;" | 178 || style="text-align:center;" | 58.6
|-
| 3–<6m || style="text-align:center;" | 177 || style="text-align:center;" | 34.2
|-
| 6m–<1y || style="text-align:center;" | 377 || style="text-align:center;" | 16.2
|-
| 1–<3y || style="text-align:center;" | 899 || style="text-align:center;" | 11.4
|-
| 3–<6y (M) || style="text-align:center;" | 361 || style="text-align:center;" | 8
|-
| 3–<6y (F) || style="text-align:center;" | 327 || style="text-align:center;" | 7.8
|-
| 6–14y (M) || style="text-align:center;" | 373 || style="text-align:center;" | 7.8
|-
| 6–14y (F) || style="text-align:center;" | 248 || style="text-align:center;" | 7.3
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-21T15:45:42Z

AndyS:

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
The [https://en.wikipedia.org/wiki/Troponin troponin Wikipedia article] provides an excellent, succinct review of the biochemistry of troponin. In summary, the troponin complex is a molecule bound to myosin within muscle cells and involved in muscle contraction. Troponin-I and troponin-T are specific to cardiac muscle. Troponin I and T are released from cardiomyocytes due to multiple types of myocardial cell "injury" (including ischemia, necrosis, apoptosis, cytotoxicity, inflammation, etc). Clinical decision making must incorporate the understanding that troponin I and T can undergo non-ischemic release (such as during non-ischemic heart failure, non-ischemic inflammation, and other conditions which injure the cardiomyocites without associated ischemia.<ref name=Ammann2004>Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ. 2004 May 1;328(7447):1028-9. doi:[https://doi.org/10.1136/bmj.328.7447.1028 10.1136/bmj.328.7447.1028]. PMID:[https://pubmed.ncbi.nlm.nih.gov/15117768/ 15117768]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc403831/ PMC403831]. (available on Sci-Hub)</ref>
 
=== Normal Range[s] ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH). Search methods are documented in the ''Methods'' section (below).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-21T15:35:50Z

AndyS:

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
The [https://en.wikipedia.org/wiki/Troponin troponin Wikipedia article] provides an excellent, succinct review of the biochemistry of troponin. In summary, the troponin complex is a molecule bound to myosin within muscle cells and involved in muscle contraction. Troponin-I and troponin-T are specific to cardiac muscle. Troponin I and T are released from cardiomyocytes due to multiple types of myocardial cell "injury" (including ischemia, necrosis, apoptosis, cytotoxicity, inflammation, etc). Clinical decision making must incorporate the understanding that troponin I and T can undergo non-ischemic release (such as during non-ischemic heart failure, non-ischemic inflammation, and other conditions which injure the cardiomyocites without associated ischemia.<ref name=Ammann2004>Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ. 2004 May 1;328(7447):1028-9. doi:[https://doi.org/10.1136/bmj.328.7447.1028 10.1136/bmj.328.7447.1028]. PMID:[https://pubmed.ncbi.nlm.nih.gov/15117768/ 15117768]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc403831/ PMC403831]. ([https://web.archive.org/web/20220121152936/https://jcp.bmj.com/content/jclinpath/57/10/1025.full.pdf Archived])</ref>
 
=== Normal Range[s] ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH). Search methods are documented in the ''Methods'' section (below).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-21T15:12:09Z

AndyS:

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
Released due to multiple types of myocardial injury (ischemia, necrosis, apoptosis, cytotoxicity, inflammation). Certain levels, ''in the proper context'', constitute the definition of myocardial infarction. However, troponin can undergo ''non-ischemic'' release during heart failure, inflammation, and other conditions (such as infiltrative diseases).'''[REF]'''
 
=== Normal Range[s] ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborns in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several notable findings:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-21T15:02:07Z

AndyS:

'''Bottom Line Up Front (BLUF):''' 

#Compared to healthy adults, the serum troponin and BNP levels in healthy neonates and infants less than 1 year have normal ranges with 99th percentiles nearly two orders of magnitude greater.
#HIGH-SENSITIVITY TROPONIN-T (hs-cTnT)
##As a biomarker, troponin occupies a relatively unique position in medicine. Unlike most biomarker cut-offs, which are based upon a desired sensitivity/specificity for diagnosis of a condition, troponin cut-offs are an arbitrarily chosen percentile of the values observed in a healthy population. A troponin value above the 99th percentile in healthy persons is the DEFINITION of "myocardial injury" (regardless of the clinical situation of the individual patient). Therefore, the troponin cut-off does not have a sensitivity/specificity for "myocardial injury," it simply IS myocardial injury. This is a relatively unique role for a serum biomarker, outranking even the concept of "gold standard".
## As of January 2022, studies have only recently begun to quantify the distributions and normal ranges of troponin levels in healthy infants and children. At less than one year of age, the 99th percentile is markedly higher than in adults. At around one year the 99th percentiles are similar, and after one year the 99th percentiles are lower than in adults. Though sex-adjusting the 99th percentiles is not problematic, age-adjusting is: a hs-cTnT of 70 would be ''POSITIVE'' at 60 days old but ''NEGATIVE'' at 61 days old.<ref name=Jehlicka2021>Jehlicka P, Rajdl D, Sladkova E, Sykorova A, Sykora J. Dynamic changes of high-sensitivity troponin T concentration during infancy: Clinical implications. Physiol Res. 2021 Mar 17;70(1):27-32. doi:[https://doi.org/10.33549/physiolres.934453 10.33549/physiolres.934453]. Epub 2021 Jan 14. PMID:[https://pubmed.ncbi.nlm.nih.gov/33453718/ 33453718]. [http://web.archive.org/web/20220120164022/https://www.biomed.cas.cz/physiolres/pdf/2021/70_27.pdf Archived]</ref> In such a setting, decision making is less clear and the definition of "myocardial injury" starts seeming rather arbitrary (if not meaningless).
## ''Myocardial injury is NOT synonymous with ischemia''. Numerous non-ischemic causes of myocardial injury exist, such as infiltrative diseases, trauma, inflammation, etc. In fact, non-ischemic etiologies are greatly predominant in all pediatric age groups.<ref name=Wang2021>Wang AP, Homme JL, Qureshi MY, Sandoval Y, Jaffe AS. High-Sensitivity Troponin T Testing for Pediatric Patients in the Emergency Department. Pediatr Cardiol. 2021 Nov 17. doi:[https://doi.org/10.1007/s00246-021-02726-7 10.1007/s00246-021-02726-7]. Epub ahead of print. PMID:[https://pubmed.ncbi.nlm.nih.gov/34787696/ 34787696]. (available on Sci-Hub)</ref>
#N-TERMINAL pro-BNP (N-Pro-BNP): Diagnostic cut-offs have been published for several disease conditions in some pediatric age groups, but few have been validated.
#Indeed, considering the markedly higher normal ranges, and as argued by Assandro et al in 2013,<ref name=Assandro2013>Assandro P, Vidoni M, Starc M, Barbi E. Troponin T should not be considered as a screening test for pediatric myocarditis. Pediatr Emerg Care. 2013 Aug;29(8):955. doi:[https://doi.org/10.1097/pec.0b013e31829eca1d 10.1097/PEC.0b013e31829eca1d]. PMID:[https://pubmed.ncbi.nlm.nih.gov/23925259/ 23925259]. (available on Sci-Hub)</ref> these cardiac biomarkers ''may'' lack the ability to distinguish disease from non-disease in some (or all) pediatric age groups.
#No one should order a cardiac biomarker in a pediatric patient ''with the intent to rule-in or rule-out disease'' without:
#* Evidence that the marker can distinguish disease from non-disease (as represented by the [https://en.wikipedia.org/wiki/Receiver_operating_characteristic AUROC]) in the age group in question.
#* Knowledge of the diagnostic cut-off for the disease in question, as well as the sensitivity and specificity associated with that cut-off.
#False-positive interpretation of cardiac biomarkers can lead to unnecessary invasive testing, which is itself a harm, but which also carries a non-negligible risk of additional harm (i.e. procedural complications).
#If a consultant recommends ordering a troponin or BNP in one of these age groups, the consulting provider should inquire about the diagnostic cut-off,† the sensitivity, and the specificity; if the consultant cannot provide this information, further research and/or additional consultants should be strongly considered prior to ordering these tests. There is very little clinical utility to a test result which no one knows how to interpret, and there is a risk of harm from a test result which is likely to be misinterpreted.
#This page is not applicable to the following topics:
#* Following cardiac biomarker trends for an already-diagnosed condition.
#* Use cardiac biomarkers in preterm infants.
 
 
__TOC__
 
 

== hs-cTnT ==
=== Biochemistry ===
Released due to multiple types of myocardial injury (ischemia, necrosis, apoptosis, cytotoxicity, inflammation). Certain levels, ''in the proper context'', constitute the definition of myocardial infarction. However, troponin can undergo ''non-ischemic'' release during heart failure, inflammation, and other conditions (such as infiltrative diseases).'''[REF]'''
 
=== Normal Range[s] ===
Only studies reporting values for the Roche hs-cTnT Gen 5 STAT assay are presented here (because other assays and/or troponin types have different cut-offs and are thus not pertinent to clinical decision making at YKDRH).
 
 

:;Jehlicka et al (2018)<ref>Jehlicka P, Huml M, Rajdl D, Mockova A, Matas M, Dort J, Masopustova A. How to interpret elevated plasmatic level of high-sensitive troponin T in newborns and infants? Physiol Res. 2018 May 4;67(2):191-195. doi:10.33549/physiolres.933704. Epub 2018 Jan 5. PMID:29303610.</ref>
::Prospective, single-cohort study of cord blood of 241 healthy, term newborn in the Czech Republic. The authors report means and quartile values similar to other studies of hs-cTnT, but they report 97.5th percentiles rather than 99th percentiles. These results help understand the distribution newborn hs-cTnT levels, but without the 99th percentiles use of this data is limited and thus not presented here. However, the authors report several findings worthy of presenting:
:::*''"The difference between hscTnT concentrations in boys and girls tended to be statistically significant (38.7 ng/l [33.0 to 52.8 ng/l] and 36.7 ng/l [29.2 to 47.1 ng/l], respectively, p=0.052)."''
:::*''"The concentration of hscTnT was found to be significantly lower in newborns delivered via Cesarean section when compared with vaginal delivery (35.0 ng/l [28.5 to 43.4 ng/l] and 38.9 ng/l [32.6 to 48.4 ng/l], respectively, p=0.0084)."''
:::*''"The hscTnT level correlated inversely with the base status (BE: rho=-0.14, p=0.03) and with the pH level of the umbilical cord blood (rho=-0.14, p=0.03)."''
:::*''"Elevated plasma concentrations of hscTnT decreased to adult range within six months."''
 
:;Bohn et al (2019)<ref name=Bohn2019>Bohn MK, Higgins V, Kavsak P, Hoffman B, Adeli K. High-Sensitivity Generation 5 Cardiac Troponin T Sex- and Age-Specific 99th Percentiles in the CALIPER Cohort of Healthy Children and Adolescents. Clin Chem. 2019 Apr;65(4):589-591. doi:[https://doi.org/10.1373/clinchem.2018.299156 10.1373/clinchem.2018.299156]. Epub 2019 Feb 8. PMID:[https://pubmed.ncbi.nlm.nih.gov/30737206/ 30737206]. [http://web.archive.org/web/20220121142237/https://watermark.silverchair.com/clinchem0589.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAtgwggLUBgkqhkiG9w0BBwagggLFMIICwQIBADCCAroGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMl4zG0GFTLFsAxQlSAgEQgIICi9rtEHt0uQdmISjuSqNplYMUPPB2BYgbGVmyTaXZCCBLN7trLTiIoyta3WQgX29Or77tWs5ehXEXxDOcDbihDW-7vNziCRnzM_fs6hEbx7xOaWWy0YnGxX8gtsBgYTZMmHu2BD9gkV4ZJTO6Y26yR2pxB320Uq5aCNyvmrTl_gJx6XeVAUrAKQJ-qRgbPcxu8jC-BtUK3cxHW183n6k9-Sq0o1bjy1kJCUVZhGoLJasd6KuY9EhabfNvVrhnc5E3boLF-lNoof8pChLa-b9MHHg01m334zOpSyAdXSa8yUpEr3fyBoPk_A_EoshIfwEpu4nGGwhe8M8hwiOulBtlUp-oQt8neYVyqCobZcr2De8SHQoaeGSUXAK_Fv4XXACdl_C3NcyPJglzTvV67-Vfszd-4owWEuHDVUcv9UvtE21xJzuHGteyEbM67f1yjQ2uP0MJLNWtPNuEj-yj3S4PC8F4SeWUWV0y2bosDKsbU5KlYE5c65giuFvZQOLTtarmeXohElWPZHEe5GN2ekDEkvuUpQ57T8szWd7-LH1CG-jPrYSLEgf-8QI0MmV9zRm7rXYcpsVAvR0LHCm6DJU8ko-Ktjn9iAgp4Nq25ez3ZhrmlR-cZ78iTB3qi48imUEXDlitUEeo4nz1SoFMo0QokNrNc1D0sihRyoUcd4C_mkjU16tfLesK8Xr9gGgrdX2iYHGQVI7bsErMVjUVn-LdSctjFPWDCH67Yh3SRMFBQLsdGnzm9Uru5PXC_4mJg7WUirlQ_HQuY17dg3ImamMekHiRVxvkToTRtB9mbCMHiYsfc87iQm-QxYMcNYHj3YiD4EOVeBIUkEjx-al-r3jDMe_Qn3xF6nM4hPHEog Archived]</ref>
::Unclear if retrospective or prospective; samples from "apparently" healthy infants (<1y) obtained from local maternity wards and outpatient clinics in Toronto, Canada; samples from >1 obtained from the "CALIPER biobank." Table-1 shows the reported 99th percentiles. Additionally, the authors report several notable observations:
:::*''"hs-cTnT concentrations were markedly increased from 0 to <6 months and subsequently decreased and narrowed at 1 year."''
:::*''"Although hs-cTnT concentrations from 0 to <1 year were normally distributed, hs-cTnT concentrations for both sexes of age 1 to <19 years were highly skewed."''
:::*The authors comment about their 1y to 19y age group having 99th percentile cut-offs of 11 (F) and 14 (M) and this differing from the manufacturer package insert. They astutely note that the major cause for this difference is likely their use of a different reference population, and they highlight that neither reference population had imaging done (i.e. structural and coronary cardiac evaluations) to show that they were truly healthy with regard to establishing a distribution in "healthy" individuals.
{| class="wikitable" style="margin: auto;"
|+ Table-1.
|-
! Age !! n !! 99th percentile
|-
| 0 – <6m || style="text-align:center;" | 55 || style="text-align:center;" | 93
|-
| 6m – <1y || style="text-align:center;" | 44 || style="text-align:center;" | 21
|-
| 1 – <19y F || style="text-align:center;" | 249 || style="text-align:center;" | 11
|-
| 1 – <19y M || style="text-align:center;" | 249 || style="text-align:center;" | 14
|}
 
:;Karlen et al (2019)<ref name=Karlen2019>Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac Troponin T in Healthy Full-Term Infants. Pediatr Cardiol. 2019 Dec;40(8):1645-1654. doi:[https://doi.org/10.1007/s00246-019-02199-9 10.1007/s00246-019-02199-9]. Epub 2019 Sep 5. PMID:[https://pubmed.ncbi.nlm.nih.gov/31489446/ 31489446]; PMCID:[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6848050/ PMC6848050].</ref>
::Prospective, inpatient, single-cohort study of 158 [expected] healthy, term newborns, in Stockholm, Sweden. Summary results are shown in Table-2. The authors reported subgroup results for planned cesarean section versus vaginal delivery in their Table-3 (within the article). Regarding sex differences, the authors report "''When analyzing hs-cTnT in all infants (irrespective of mode of delivery), male infants had significantly higher values in cord blood than female infants (39[30–51] ng/L vs 28[24–39] ng/L, p = 0.001). However, in samples taken at 2–5 days of age the significant difference disappeared (96[62–157] ng/L vs 85[47–158] ng/L, p = 0.40)''."
{| class="wikitable" style="margin: auto;"
|+ Table-2.
|-
! Age !! n !! 99th percentile
|-
| Cord || style="text-align:center;" | 105 || style="text-align:center;" | 88
|-
| 2-5d || style="text-align:center;" | 73 || style="text-align:center;" | 664
|}
 

:;Lam et al (2020)<ref name=Lam2020>Lam E, Higgins V, Zhang L, Chan MK, Bohn MK, Trajcevski K, Liu P, Adeli K, Nathan PC. Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort. J Appl Lab Med. 2021 Mar 1;6(2):344-353. doi:[https://doi.org/10.1093/jalm/jfaa090 10.1093/jalm/jfaa090]. PMID:[https://pubmed.ncbi.nlm.nih.gov/32995884/ 32995884]. (available on Sci-Hub)</ref>
::Multi-center, outpatient study of 484 healthy outpatient pediatric patients in Toronto, Canada, aged 0 to 19 years. Both hs-cTnT and N-Pro-BNP were studied. Table-3 shows the study's reported age ranges and associated 99th percentile cut-offs for hs-cTnT. Within the article, Fig-1 shows the distribution of troponin versus age with different colors representing male and female values. The authors report finding no difference by sex, but the analysis was probably limited by sample size.
{| class="wikitable" style="margin: auto;"
|+ Table-3.
|-
! Age !! n !! 99th percentile
|-
| 0–<6 m || style="text-align:center;" | 64 || style="text-align:center;" | 87
|-
| 6 m–<1y || style="text-align:center;" | 45 || style="text-align:center;" | 39
|-
| 1–<19 years || style="text-align:center;" | 131 || style="text-align:center;" | 11
|}
 

=== Diagnostic Cutoff[s] ===
99th percentile for a healthy population. Since this is a definition (as discussed above), the term "diagnostic cut-off" does not clearly apply to this cut-off.
 
=== Validated Clinical Use[s] ===
 
 

== N-Pro-BNP ==
=== Biochemistry ===
Released solely due to myocardial stretch/strain of the left ventricle, which is usually synonymous with heart failure.'''[REF]'''
 
=== Normal Range[s] ===
 
=== Diagnostic Cutoff[s] ===
 
=== Validated Clinical Use[s] ===
 
 

== METHODS ==
Literature searches were performed for the specific test types available at YKDRH:
# high-sensitivity Troponin T
# N-Terminal pro-BNP
Broader searches, such as for troponin in general are prone to return results for conventional low sensitivity troponin or for troponin-I; data from these are not applicable to interpretation of high-sensitivity troponin-T. Similarly, data regarding B-type natriuretic peptide (BNP) cannot be applied to the test which we have, which is N-Terminal Pro-BNP.
 

;Troponin-T PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29&size=200 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infan*[Title] OR child*[Title] or adolescen*[Title]) AND ("high-sensitiv*"[Title] AND "troponin T"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infan*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22high-sensitiv*%22%5BTitle%5D+AND+%22troponin+T%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
;BNP PubMed Search
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29&sort=date&size=100 Search]
 
:: ''with diagnostic outcomes:''
:(pediatric*[Title] OR neonat*[Title] OR newborn*[Title] OR infant*[Title] OR child*[Title] or adolescen*[Title]) AND ("N-Terminal pro-B-Type Natriuretic Peptide"[Title]) AND ("receiver operating characteristic"[Title/Abstract] OR "ROC curve"[Title/Abstract] OR AUROC[Title/Abstract] OR specificity[Title/Abstract] OR cut-off[Title/Abstract] OR cutoff[Title/Abstract] OR "Diagnostic accuracy"[Title/Abstract]) [https://pubmed.ncbi.nlm.nih.gov/?term=%28pediatric*%5BTitle%5D+OR+neonat*%5BTitle%5D+OR+newborn*%5BTitle%5D+OR+infant*%5BTitle%5D+OR+child*%5BTitle%5D+or+adolescen*%5BTitle%5D%29+AND+%28%22N-Terminal+pro-B-Type+Natriuretic+Peptide%22%5BTitle%5D%29+AND+%28%22receiver+operating+characteristic%22%5BTitle%2FAbstract%5D+OR+%22ROC+curve%22%5BTitle%2FAbstract%5D+OR+AUROC%5BTitle%2FAbstract%5D+OR+specificity%5BTitle%2FAbstract%5D+OR+cut-off%5BTitle%2FAbstract%5D+OR+cutoff%5BTitle%2FAbstract%5D+OR+%22Diagnostic+accuracy%22%5BTitle%2FAbstract%5D%29&size=200 Search]
 
 

== NOTES ==
'''†''' A percentile cutoff in a healthy population is NOT the same as a diagnostic cutoff; a percentile is an observation detached from clinical implication, whereas diagnostic cut-off has an associated sensitivity and specificity for diagnosing a particular disease/condition.
 

 
 

== REFERENCES ==
<references />
 
 

;Keywords:
:Cardiac Biomarker Troponin BNP Pediatric Neonate Newborn Infant Toddler Child Adolescent

;Author[s]:
:Andrew W. Swartz, MD

;Reviewer[s]:
:Leslie Herrmann, MD

Cardiac Biomarkers in Pediatrics

2022-01-21T05:50:49Z

AndyS:

Cardiac Biomarkers in Pediatrics

2022-01-21T05:00:05Z

AndyS:

Cardiac Biomarkers in Pediatrics

2022-01-21T04:59:10Z

AndyS: /* METHODS */

Cardiac Biomarkers in Pediatrics

2022-01-21T04:48:33Z

AndyS: /* METHODS */

Cardiac Biomarkers in Pediatrics

2022-01-21T03:59:53Z

AndyS: /* METHODS */

Cardiac Biomarkers in Pediatrics

2022-01-21T03:53:56Z

AndyS:

Cardiac Biomarkers in Pediatrics

2022-01-21T02:33:58Z

AndyS:

Cardiac Biomarkers in Pediatrics

2022-01-21T02:12:16Z

AndyS:

Cardiac Biomarkers in Pediatrics

2022-01-21T01:26:39Z

AndyS:

High-sensitivity Troponin-T

2022-01-20T22:15:25Z

AndyS: /* Definitions */

''see [[Acute Coronary Syndrome|Acute Coronary Syndrome Wiki Supplement Page]] for other information associated with Acute Coronary Syndrome''

On November 12, 2019, the Yukon-Kuskokwim Delta Regional Hospital (YKDHR) switched cardiac troponin assay to the Roche Diagnostics [https://diagnostics.roche.com/us/en/products/params/elecsys-troponin-t-high-sensitive-tnt-hs.html ''Elecsys® Troponin T Gen 5 STAT'']. This is a high-sensitivity fifth-generation cardiac troponin assay. Details are available in the [http://yk-health.org/images/b/b9/Elecsys_Troponin_T_Gen_5_STAT%2C_-07398000160_2_en_cc4d61e9-73c6-e811-2d93-00215a9b3428.pdf manufacturer's package insert].

Cardiac troponin assays measure the concentration of either troponin-T or troponin-I. Both high-sensitivity and traditional troponin assays measure the exact same molecule, but high-sensitivity assays measure ''much'' more precisely and at ''much'' lower concentrations. The high-sensitivity and traditional assays can be distinguished by the units in which they are reported: high-sensitivity assays are reported in ng/'''L''' whereas the traditional assays are reported in ng/'''mL'''.
:::Conversion between the results can be done by moving the decimal point three places: a traditional concentration of 0.4 ng/mL is equivalent to a high-sensitivity concentration of 400 ng/L, and a high-sensitivity concentration of 14 ng/L is equivalent to a traditional concentration of 0.014 ng/mL. This latter conversion illustrates that the high-sensitivity assays accurately measure concentrations which are two orders of magnitude lower than the assay we were previously using.

Though high-sensitivity troponin assays have been used in Europe and Canada since approximately 2009, the first U.S. FDA approval occurred in 2017.

''NOTE: The information below is not a guideline, but rather excerpts and links intended to augment and/or help develop clinical judgement.''
 
 
 
__TOC__
 
 
== Definition ==
To qualify as ''high-sensitivity'' (or ''highly-sensitive''), a cardiac troponin assay must be able to detect a level of cardiac troponin in >50% of normal individuals.<ref name="ACC_whitepaper_2018">High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami. Accessed December 3, 2019.</ref> This means that the majority of patients ''without'' cardiac ischemia ''will have'' a detectable level of cardiac troponin. This has substantial implications for how clinicians conceptualize and interpret cardiac troponin levels.
 
 

== Statistical/Epidemiological Properties ==
=== Diagnostic Performance ===
:High-sensitivity troponin assays have a much higher sensitivity for ACS than conventional assays, which yields a much higher '''negative predictive value''' ('''NPV'''). This allows clinicians to more quickly and accurately identify those chest pain patients who do not have ACS and who are at very low risk of 30-day MACE (major adverse cardiac events).

:Yet the increased sensitivity comes at the cost of decreased specificity, yielding a lower '''positive predictive value''' ('''PPV'''). The clinical consequence of this is summed up well by Dr. Rebecca Vigen of UTSWMS (University of Texas Southwestern Medical Center) grand rounds transcript:
::::''As the MI probability goes down, the additional positive test results with the hs-cTnT assay vs. the standard assay increases (false positives). Therefore, the proportion of positive tests with the high-sensitivity assay who do not have myocardial infarction will increase''.<ref>Vigen R. Providing High Value Care to Patients with Acute Chest Pain. Grand Rounds Presentation presented at the: Grand Rounds; June 14, 2019; University of Texas Southwestern Medical Center. https://cme.utsouthwestern.edu/sites/default/files/em1906g_061419_protocol_vigen.pdf. Accessed December 5, 2019.</ref>
 
:The following data reported by de Lemos et al. (2011)<ref>de Lemos JA, Morrow DA, deFilippi CR. Highly sensitive troponin assays and the cardiology community: a love/hate relationship? Clin Chem. 2011;57(6):826-829. doi:[https://doi.org/10.1373/clinchem.2011.163758 10.1373/clinchem.2011.163758]</ref> illustrates the effect:
 
{| class="wikitable" style="width: 85%;margin: auto;"
|+ style="caption-side:bottom;text-align:left;" |Additional cTnT values above the MI-detection threshold with a highly sensitive (hs) cTnT assay,
compared with a standard cTnT assay, across differing MI probabilities in the target population.
|-
! scope="col"| MI probability
! scope="col"| Positive tests with standard assay, /1000 patients
! scope="col"| Positive tests with hs assay, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay meeting MI definition, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay not meeting MI definition, /1000 patients
|-
| style="text-align:center;"| 17%
| style="text-align:center;" | 199
| style="text-align:center;" | 328
| style="text-align:center;" | 21
| style="text-align:center;" | 108
|-
| style="text-align:center;"| 10%
| style="text-align:center;" | 146
| style="text-align:center;" | 275
| style="text-align:center;" | 12
| style="text-align:center;" | 117
|-
| style="text-align:center;"| 5%
| style="text-align:center;" | 108
| style="text-align:center;" | 237
| style="text-align:center;" | 8
| style="text-align:center;" | 121
|-
| style="text-align:center;"| 3%
| style="text-align:center;" | 93
| style="text-align:center;" | 222
| style="text-align:center;" | 3
| style="text-align:center;" | 126
|}
 
:de Lemos derived these outcomes from calculations using the limit of detection for the conventional troponin assay and with the 99th percentile for the high-sensitivity troponin assay. However, clinicians must recognize that these calculations to not include the delta troponin (discussed below), but rather single values.
 
=== Population Distribution ===
:The manufacturer recommended rule-out cutoffs (99% ULN) are based upon the following distribution:
 
 
[[File:Hs-Tnt 4G histogram Giannitsis 2009.jpg|thumb|700px|center|Troponin-T distribution in healthy individuals.<ref>Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56(2):254-261. doi:[https://doi.org/10.1373/clinchem.2009.132654 10.1373/clinchem.2009.132654]</ref>]]
 
 

== Delta (Δ) versus Level ==
With traditional troponin assays, a troponin level was not detectable in most patients who lack cardiac ischemia. Emergency departments typically performed serial measurements to see if the troponin ''level'' became detectable over time. Therefore the ''level'' of the troponin was the focus while quantifying the magnitude of the ''delta (Δ)'' (i.e. the change of the level over time) was a secondary consideration.

Due to the high-sensitivity assays' ability to detect a troponin level in most patients who lack cardiac ischemia, many experts recommend a reversal in diagnostic thinking with regard to ACS/AMI: for most patients the delta (Δ) should be the focus while the level is a secondary consideration.<ref>Helman, A. McRae, A. Lang, E. Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift. Emergency Medicine Cases. July, 2019. https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin. Accessed December 2, 2019.</ref>

However, there are initial levels below which a delta is not required:
::::* If >= 3 hours since onset of symptoms and a normal EKG, then an initial troponin level < 6 ng/L can rule-out ACS.
 
 

== Troponin Delta ==
=== Terminology ===
:For verbal communiction, delta's are most easily understood with the phrase Δ1h ("delta-1-h"). Starting the phrase with "delta" signals the listener that which is coming (i.e. a duration and magnitude).<ref>Personal opinion of Andrew W. Swartz, MD</ref>
 

=== Relative versus Absolute Delta (Δ) ===
:With traditional troponin assays, a delta of 20% was often used to rule-in ACS.

:However, common situations arise with high-sensitivity troponin assays where relative deltas can lead to both over- and underdiagnosis. For example, if the initial troponin level is 5 ng/L, then a delta of 1 ng/L is a 20% rise, despite the change being within the expected margin of error of the assay. Alternately, the 20% relative change can miss ACS in patients with chronically elevated troponin levels.

:Therefore many experts recommend using an absolute delta to rule-out or rule-in ACS.

=== Delta Cutoffs ===
:The YKDHR Laboratory recommends that a Δ1h < 3 ng/L be used to rule-out ACS.

:However, the ACC's (American College of Cardiology) whitepaper specifically recommends against this Δ1h cutoff due to being too similar to the Roche assay's margin of error; they explicitly suggest a cutoff of Δ2h < 4 ng/L.<ref name="ACC_whitepaper_2018"/>
 

== Troponin Level ==
=== Level Cutoffs ===
Hs-cTnT is considered "positive" when above the gender-specific 99th percentile URL (upper reference range). Per eMail from Scott Cox (YKDHR Director of Diagnostic Services) on 11/10/2019, the following cutoff are recommended for our assay:
{| class="wikitable" style="margin: auto;"
|+Positive Values
|-
| Women || >= '''14''' ng/L
|-
| Men || >= '''22''' ng/L
|}
 
 
Per the ACC white paper (see below): 
* A single Hs-cTnT >= '''100''' ng/L is diagnostic of AMI (in the appropriate clinical context). 
* When chest pain has been present for >= 3 hours, a single Hs-cTnT < '''6''' ng/L has been reported to rule out AMI with essentially 100% negative predictive value.

 
== Diagnostic Algorithms ==
=== ACC ===
The following diagnostic algorithm has been proposed for high-sensitivity cardiac troponin-T by the ACC (American College of Cardiology), though they caution that "''The safety of this approach is currently unclear''":<ref name="ACC_whitepaper_2018"/>
 
[[File:ACC Whitepaper Figure-1 2018-07-16.PNG]]
 
 
 
=== UTSW/Parkland ===
The algorithm used by ''University of Texas Southwestern Medical Center'' is shown for illustrative purposes in an ACEP Webinar (see below, page 16):
 
[[File:UTSW-Parkland hs-cTnT pathway.PNG|1000px]]
 
 
Note that this algorithm does not include risk stratification, such as with the HEART score. Yet the same Webinar contains other algorithms which separate out Hs-cTnT and call the risk stratification a HEAR score (or "modified-HEART" score) and guide diagnosis/management based upon different combinations of Hs-cTnT and HEAR values. Yet other algorithms in the same Webinar recommend skipping risk stratification in those who have low- or high-risk EKG/Hs-cTnT results and only risk stratifying those with intermediate-risk EKG/Hs-cTnT results.
 
 
=== Australian ACRE Project ===

This diagnostic algorithm guides the user to one of four etiologies for HS-cTnT elevation:
# Type-1 MI
# Type-2 MI
# Acute myocardial injury
# Chronic myocardial injury

However, users will note that the following two terms are used without definition:
# ''Evidence for acute myocardial ischemia''
# ''Evidence of acute coronary atherothrombosis''

Per recommendation of the author, this algorithm has been edited to contain the cutoffs specific to our lab/assay:
 

[[File:ACRE Algorithm modified-cutoffs.svg.png|900px]]

The original PDF is available [https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf here] ([https://web.archive.org/web/20200221184332/https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf archived])

== Helpful Links ==
'''ACC (American College of Cardiology)'''
:[https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami ''High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI'' (July 16, 2018)]
:[https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/08/24/00/09/fourth-universal-definition-of-mi-esc-2018 ''SUMMARY: Fourth Universal Definition of Myocardial Infarction'' (Aug 25, 2018)]
 
'''ACEP'''
:[https://www.acep.org/globalassets/sites/acep/media/equal-documents/webinar_chestpainw3_hsctn2.pdf ''Webinar: Incorporating High-Sensitivity Troponin into Your ED'']
:[https://www.acep.org/patient-care/clinical-policies/nonst-elevation-acute-coronary-syndromes/ ''Critical Issues in the Evaluation and Management of Emergency Department Patients with Suspected Non–ST-Elevation Acute Coronary Syndromes'' (Jun 2018)]
 

'''MD Calc'''
:[https://www.mdcalc.com/heart-score-major-cardiac-events HEART Score for Major Cardiac Events]
 

''' ACEP''Now''''' Articles
:03-19-2019: [https://www.acepnow.com/article/high-sensitivity-cardiac-troponin-tests-for-acute-myocardial-infarction-may-be-flawed/ ''High Sensitivity Cardiac Troponin Tests for Acute Myocardial Infarction May be Flawed'']
:09-18-2019: [https://www.acepnow.com/article/chest-pain-patients-high-sensitivity-troponin-tests-new-frontier/2/ ''Chest-Pain Patients and High-Sensitivity Troponin Tests: the New Frontier'']
 

'''PodCasts'''
: 02-20-2020: EMCrit #266: [https://emcrit.org/emcrit/high-sensitivity-troponins/ ''High Sensitivity Troponins with Louise Cullen''] (Duration: 26:04) [https://web.archive.org/web/20200222031331/https://emcrit.org/emcrit/high-sensitivity-troponins/ Archived]

: 01-18-2020: SGEM #280: [http://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ ''THIS OLD HEART OF MINE AND TROPONIN TESTING''] (Duration: 30:10) [https://web.archive.org/web/20200222031814/https://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ Archived]

: 07-30-2019: Emergency Medicine Cases (Ep 128) [https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ ''Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift''] (Duration: 1:34:36) [https://web.archive.org/web/20191213102014/https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ Archived]

== High-sensitivity troponin Myths versus Reality ==
Myths:
:* ''more patients will undergo catheterization''
:* ''ED stays will be longer''
:* ''there will be fewer ED discharges''
:* ''there will be more stress tests''
 

'''FACT''': the APACE trial showed that adoption of a high-sensitivity troponin assay was associated with no change in the number of catheterizations, decreased "normal cath" results, shorter ED stays, more ED discharges, and fewer stress tests.<ref>Twerenbold R, Jaeger C, Rubini Gimenez M, et al. Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction. Eur Heart J. 2016;37(44):3324-3332. doi:[https://doi.org/10.1093/eurheartj/ehw232 10.1093/eurheartj/ehw232]</ref>
 

'''FACT''': Across numerous trials, increasing troponin sensitivity has shown a dose-response relationship with increased ED discharges.
 
 
== Controversies ==
=== Recommended 99% URL Cutoffs ===
==== Mariathas el al (Mar 2019) ====
::In March 2019 Mariathas el al. reported in the BMJ<ref>Mariathas M, Allan R, Ramamoorthy S, et al. True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study. BMJ. 2019;364:l729. doi:[https://doi.org/10.1136/bmj.l729 10.1136/bmj.l729]</ref> that they found a very different distribution and 99% ULR when they analyzed 20,000 consecutive blood samples collected in all settings (outpatient, ED, inpatient, etc.) drawn for any reason in a large UK hospital. Overall, over five percent of patients had a troponin-I result greater than the manufacturer recommended 99% cutoff of 40 ng/L, and far too many older patients and inpatients exceed this recommended cutoff:
 
<gallery mode="slideshow">
File:Hs-TnI histogram Mariathas 2019.jpg|Overall distribution. (Note that the vertical axis is logarithmic, which substantially [over]emphasizes the appearance of the frequency of the higher troponin levels.)
File:Hs-TnI Variation-with-setting Mariathas 2019.jpg|Abnormals versus setting
File:Hs-TnI Variation-with-age Mariathas 2019.jpg|Abnormals versus age
</gallery>

:The implications of such a degree of variation are substantial, and may indicate that individual institutions need to calculate their own age-adjusted 99% cutoffs in order to obtain the intended outcomes. Additionally, clinicians likely need to integrate patient age and clinical context into their interpretation of hs-Tn levels. Though hs-Tn's have been shown to improve outcomes when evaluating acute chest pain in emergency departments, there is no data to indicate that diagnosing ''myocardial injury'' in 15% of medical ward patients, 20% of older persons, and 40% of ICU patients will lead to patient-important improvements.

:However... readers are strongly encouraged to read all seven of the [https://www.bmj.com/content/364/bmj.l729/rapid-responses responses]. In particular, Paul Collinson makes a strong argument that the authors are mis-interpreting their data because they are including a substantial number of UNhealthy individuals (i.e with CHF, CKI, etc.), whereas the appropriate cutoffs are [by definition] derived from healthy individuals. All of the responses are thoughtful, and both the article and the responses provide interesting thoughts about troponin levels and binary versus [https://en.wikipedia.org/wiki/Bayesian_inference Bayesian] interpretation of results.
 
 
=== The significance of ''Myocardial Injury'' ===
==== Acute ====
::There is no standard-of-care workup for this finding in the absence of myocardial ischemia. Can it be attributed to a tachyarrythmia, sepsis, etc? Or should a PE be ruled-out? Does it mandate an echocardiogram?

==== Chronic ====
::This is certainly not amenable to ED intervention. Again, it is not clear what the standard-of-care disposition of this finding will be.
 
 

== Definitions ==
*'''Myocardial injury'''
::Elevated cardiac troponin values (cTn) with at least one value above the 99th percentile upper reference limit (URL).<ref name="FUDoMI">Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Journal of the American College of Cardiology. 2018;72(18):2231-2264. doi:[https://doi.org/10.1016/j.jacc.2018.08.1038 DOI: 10.1016/j.jacc.2018.08.1038]</ref> ''NOTE: "myocardial injury" is NOT synonymous with ischemia, as injury can be due to non-ischemic conditions such as infiltrative diseases, trauma, inflammation, heart failure, etc.''
*'''Acute myocardial injury'''
::Myocardial injury with a diagnostic rise and/or fall of cTn values.<ref name="FUDoMI"/>
*'''Acute myocardial infarction''' (types 1, 2 and 3 MI)
::Acute myocardial injury '''and''' at least one of the following:<ref name="FUDoMI"/>
::::- Symptoms consistent with acute coronary occlusion;
::::- New ischemic ECG changes;
::::- Development of pathological Q waves;
::::- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology;
::::::- Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs).
 
 
 

== References ==

High-sensitivity Troponin-T

2022-01-20T22:07:37Z

AndyS: /* Troponin Delta */

''see [[Acute Coronary Syndrome|Acute Coronary Syndrome Wiki Supplement Page]] for other information associated with Acute Coronary Syndrome''

On November 12, 2019, the Yukon-Kuskokwim Delta Regional Hospital (YKDHR) switched cardiac troponin assay to the Roche Diagnostics [https://diagnostics.roche.com/us/en/products/params/elecsys-troponin-t-high-sensitive-tnt-hs.html ''Elecsys® Troponin T Gen 5 STAT'']. This is a high-sensitivity fifth-generation cardiac troponin assay. Details are available in the [http://yk-health.org/images/b/b9/Elecsys_Troponin_T_Gen_5_STAT%2C_-07398000160_2_en_cc4d61e9-73c6-e811-2d93-00215a9b3428.pdf manufacturer's package insert].

Cardiac troponin assays measure the concentration of either troponin-T or troponin-I. Both high-sensitivity and traditional troponin assays measure the exact same molecule, but high-sensitivity assays measure ''much'' more precisely and at ''much'' lower concentrations. The high-sensitivity and traditional assays can be distinguished by the units in which they are reported: high-sensitivity assays are reported in ng/'''L''' whereas the traditional assays are reported in ng/'''mL'''.
:::Conversion between the results can be done by moving the decimal point three places: a traditional concentration of 0.4 ng/mL is equivalent to a high-sensitivity concentration of 400 ng/L, and a high-sensitivity concentration of 14 ng/L is equivalent to a traditional concentration of 0.014 ng/mL. This latter conversion illustrates that the high-sensitivity assays accurately measure concentrations which are two orders of magnitude lower than the assay we were previously using.

Though high-sensitivity troponin assays have been used in Europe and Canada since approximately 2009, the first U.S. FDA approval occurred in 2017.

''NOTE: The information below is not a guideline, but rather excerpts and links intended to augment and/or help develop clinical judgement.''
 
 
 
__TOC__
 
 
== Definition ==
To qualify as ''high-sensitivity'' (or ''highly-sensitive''), a cardiac troponin assay must be able to detect a level of cardiac troponin in >50% of normal individuals.<ref name="ACC_whitepaper_2018">High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami. Accessed December 3, 2019.</ref> This means that the majority of patients ''without'' cardiac ischemia ''will have'' a detectable level of cardiac troponin. This has substantial implications for how clinicians conceptualize and interpret cardiac troponin levels.
 
 

== Statistical/Epidemiological Properties ==
=== Diagnostic Performance ===
:High-sensitivity troponin assays have a much higher sensitivity for ACS than conventional assays, which yields a much higher '''negative predictive value''' ('''NPV'''). This allows clinicians to more quickly and accurately identify those chest pain patients who do not have ACS and who are at very low risk of 30-day MACE (major adverse cardiac events).

:Yet the increased sensitivity comes at the cost of decreased specificity, yielding a lower '''positive predictive value''' ('''PPV'''). The clinical consequence of this is summed up well by Dr. Rebecca Vigen of UTSWMS (University of Texas Southwestern Medical Center) grand rounds transcript:
::::''As the MI probability goes down, the additional positive test results with the hs-cTnT assay vs. the standard assay increases (false positives). Therefore, the proportion of positive tests with the high-sensitivity assay who do not have myocardial infarction will increase''.<ref>Vigen R. Providing High Value Care to Patients with Acute Chest Pain. Grand Rounds Presentation presented at the: Grand Rounds; June 14, 2019; University of Texas Southwestern Medical Center. https://cme.utsouthwestern.edu/sites/default/files/em1906g_061419_protocol_vigen.pdf. Accessed December 5, 2019.</ref>
 
:The following data reported by de Lemos et al. (2011)<ref>de Lemos JA, Morrow DA, deFilippi CR. Highly sensitive troponin assays and the cardiology community: a love/hate relationship? Clin Chem. 2011;57(6):826-829. doi:[https://doi.org/10.1373/clinchem.2011.163758 10.1373/clinchem.2011.163758]</ref> illustrates the effect:
 
{| class="wikitable" style="width: 85%;margin: auto;"
|+ style="caption-side:bottom;text-align:left;" |Additional cTnT values above the MI-detection threshold with a highly sensitive (hs) cTnT assay,
compared with a standard cTnT assay, across differing MI probabilities in the target population.
|-
! scope="col"| MI probability
! scope="col"| Positive tests with standard assay, /1000 patients
! scope="col"| Positive tests with hs assay, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay meeting MI definition, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay not meeting MI definition, /1000 patients
|-
| style="text-align:center;"| 17%
| style="text-align:center;" | 199
| style="text-align:center;" | 328
| style="text-align:center;" | 21
| style="text-align:center;" | 108
|-
| style="text-align:center;"| 10%
| style="text-align:center;" | 146
| style="text-align:center;" | 275
| style="text-align:center;" | 12
| style="text-align:center;" | 117
|-
| style="text-align:center;"| 5%
| style="text-align:center;" | 108
| style="text-align:center;" | 237
| style="text-align:center;" | 8
| style="text-align:center;" | 121
|-
| style="text-align:center;"| 3%
| style="text-align:center;" | 93
| style="text-align:center;" | 222
| style="text-align:center;" | 3
| style="text-align:center;" | 126
|}
 
:de Lemos derived these outcomes from calculations using the limit of detection for the conventional troponin assay and with the 99th percentile for the high-sensitivity troponin assay. However, clinicians must recognize that these calculations to not include the delta troponin (discussed below), but rather single values.
 
=== Population Distribution ===
:The manufacturer recommended rule-out cutoffs (99% ULN) are based upon the following distribution:
 
 
[[File:Hs-Tnt 4G histogram Giannitsis 2009.jpg|thumb|700px|center|Troponin-T distribution in healthy individuals.<ref>Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56(2):254-261. doi:[https://doi.org/10.1373/clinchem.2009.132654 10.1373/clinchem.2009.132654]</ref>]]
 
 

== Delta (Δ) versus Level ==
With traditional troponin assays, a troponin level was not detectable in most patients who lack cardiac ischemia. Emergency departments typically performed serial measurements to see if the troponin ''level'' became detectable over time. Therefore the ''level'' of the troponin was the focus while quantifying the magnitude of the ''delta (Δ)'' (i.e. the change of the level over time) was a secondary consideration.

Due to the high-sensitivity assays' ability to detect a troponin level in most patients who lack cardiac ischemia, many experts recommend a reversal in diagnostic thinking with regard to ACS/AMI: for most patients the delta (Δ) should be the focus while the level is a secondary consideration.<ref>Helman, A. McRae, A. Lang, E. Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift. Emergency Medicine Cases. July, 2019. https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin. Accessed December 2, 2019.</ref>

However, there are initial levels below which a delta is not required:
::::* If >= 3 hours since onset of symptoms and a normal EKG, then an initial troponin level < 6 ng/L can rule-out ACS.
 
 

== Troponin Delta ==
=== Terminology ===
:For verbal communiction, delta's are most easily understood with the phrase Δ1h ("delta-1-h"). Starting the phrase with "delta" signals the listener that which is coming (i.e. a duration and magnitude).<ref>Personal opinion of Andrew W. Swartz, MD</ref>
 

=== Relative versus Absolute Delta (Δ) ===
:With traditional troponin assays, a delta of 20% was often used to rule-in ACS.

:However, common situations arise with high-sensitivity troponin assays where relative deltas can lead to both over- and underdiagnosis. For example, if the initial troponin level is 5 ng/L, then a delta of 1 ng/L is a 20% rise, despite the change being within the expected margin of error of the assay. Alternately, the 20% relative change can miss ACS in patients with chronically elevated troponin levels.

:Therefore many experts recommend using an absolute delta to rule-out or rule-in ACS.

=== Delta Cutoffs ===
:The YKDHR Laboratory recommends that a Δ1h < 3 ng/L be used to rule-out ACS.

:However, the ACC's (American College of Cardiology) whitepaper specifically recommends against this Δ1h cutoff due to being too similar to the Roche assay's margin of error; they explicitly suggest a cutoff of Δ2h < 4 ng/L.<ref name="ACC_whitepaper_2018"/>
 

== Troponin Level ==
=== Level Cutoffs ===
Hs-cTnT is considered "positive" when above the gender-specific 99th percentile URL (upper reference range). Per eMail from Scott Cox (YKDHR Director of Diagnostic Services) on 11/10/2019, the following cutoff are recommended for our assay:
{| class="wikitable" style="margin: auto;"
|+Positive Values
|-
| Women || >= '''14''' ng/L
|-
| Men || >= '''22''' ng/L
|}
 
 
Per the ACC white paper (see below): 
* A single Hs-cTnT >= '''100''' ng/L is diagnostic of AMI (in the appropriate clinical context). 
* When chest pain has been present for >= 3 hours, a single Hs-cTnT < '''6''' ng/L has been reported to rule out AMI with essentially 100% negative predictive value.

 
== Diagnostic Algorithms ==
=== ACC ===
The following diagnostic algorithm has been proposed for high-sensitivity cardiac troponin-T by the ACC (American College of Cardiology), though they caution that "''The safety of this approach is currently unclear''":<ref name="ACC_whitepaper_2018"/>
 
[[File:ACC Whitepaper Figure-1 2018-07-16.PNG]]
 
 
 
=== UTSW/Parkland ===
The algorithm used by ''University of Texas Southwestern Medical Center'' is shown for illustrative purposes in an ACEP Webinar (see below, page 16):
 
[[File:UTSW-Parkland hs-cTnT pathway.PNG|1000px]]
 
 
Note that this algorithm does not include risk stratification, such as with the HEART score. Yet the same Webinar contains other algorithms which separate out Hs-cTnT and call the risk stratification a HEAR score (or "modified-HEART" score) and guide diagnosis/management based upon different combinations of Hs-cTnT and HEAR values. Yet other algorithms in the same Webinar recommend skipping risk stratification in those who have low- or high-risk EKG/Hs-cTnT results and only risk stratifying those with intermediate-risk EKG/Hs-cTnT results.
 
 
=== Australian ACRE Project ===

This diagnostic algorithm guides the user to one of four etiologies for HS-cTnT elevation:
# Type-1 MI
# Type-2 MI
# Acute myocardial injury
# Chronic myocardial injury

However, users will note that the following two terms are used without definition:
# ''Evidence for acute myocardial ischemia''
# ''Evidence of acute coronary atherothrombosis''

Per recommendation of the author, this algorithm has been edited to contain the cutoffs specific to our lab/assay:
 

[[File:ACRE Algorithm modified-cutoffs.svg.png|900px]]

The original PDF is available [https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf here] ([https://web.archive.org/web/20200221184332/https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf archived])

== Helpful Links ==
'''ACC (American College of Cardiology)'''
:[https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami ''High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI'' (July 16, 2018)]
:[https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/08/24/00/09/fourth-universal-definition-of-mi-esc-2018 ''SUMMARY: Fourth Universal Definition of Myocardial Infarction'' (Aug 25, 2018)]
 
'''ACEP'''
:[https://www.acep.org/globalassets/sites/acep/media/equal-documents/webinar_chestpainw3_hsctn2.pdf ''Webinar: Incorporating High-Sensitivity Troponin into Your ED'']
:[https://www.acep.org/patient-care/clinical-policies/nonst-elevation-acute-coronary-syndromes/ ''Critical Issues in the Evaluation and Management of Emergency Department Patients with Suspected Non–ST-Elevation Acute Coronary Syndromes'' (Jun 2018)]
 

'''MD Calc'''
:[https://www.mdcalc.com/heart-score-major-cardiac-events HEART Score for Major Cardiac Events]
 

''' ACEP''Now''''' Articles
:03-19-2019: [https://www.acepnow.com/article/high-sensitivity-cardiac-troponin-tests-for-acute-myocardial-infarction-may-be-flawed/ ''High Sensitivity Cardiac Troponin Tests for Acute Myocardial Infarction May be Flawed'']
:09-18-2019: [https://www.acepnow.com/article/chest-pain-patients-high-sensitivity-troponin-tests-new-frontier/2/ ''Chest-Pain Patients and High-Sensitivity Troponin Tests: the New Frontier'']
 

'''PodCasts'''
: 02-20-2020: EMCrit #266: [https://emcrit.org/emcrit/high-sensitivity-troponins/ ''High Sensitivity Troponins with Louise Cullen''] (Duration: 26:04) [https://web.archive.org/web/20200222031331/https://emcrit.org/emcrit/high-sensitivity-troponins/ Archived]

: 01-18-2020: SGEM #280: [http://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ ''THIS OLD HEART OF MINE AND TROPONIN TESTING''] (Duration: 30:10) [https://web.archive.org/web/20200222031814/https://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ Archived]

: 07-30-2019: Emergency Medicine Cases (Ep 128) [https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ ''Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift''] (Duration: 1:34:36) [https://web.archive.org/web/20191213102014/https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ Archived]

== High-sensitivity troponin Myths versus Reality ==
Myths:
:* ''more patients will undergo catheterization''
:* ''ED stays will be longer''
:* ''there will be fewer ED discharges''
:* ''there will be more stress tests''
 

'''FACT''': the APACE trial showed that adoption of a high-sensitivity troponin assay was associated with no change in the number of catheterizations, decreased "normal cath" results, shorter ED stays, more ED discharges, and fewer stress tests.<ref>Twerenbold R, Jaeger C, Rubini Gimenez M, et al. Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction. Eur Heart J. 2016;37(44):3324-3332. doi:[https://doi.org/10.1093/eurheartj/ehw232 10.1093/eurheartj/ehw232]</ref>
 

'''FACT''': Across numerous trials, increasing troponin sensitivity has shown a dose-response relationship with increased ED discharges.
 
 
== Controversies ==
=== Recommended 99% URL Cutoffs ===
==== Mariathas el al (Mar 2019) ====
::In March 2019 Mariathas el al. reported in the BMJ<ref>Mariathas M, Allan R, Ramamoorthy S, et al. True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study. BMJ. 2019;364:l729. doi:[https://doi.org/10.1136/bmj.l729 10.1136/bmj.l729]</ref> that they found a very different distribution and 99% ULR when they analyzed 20,000 consecutive blood samples collected in all settings (outpatient, ED, inpatient, etc.) drawn for any reason in a large UK hospital. Overall, over five percent of patients had a troponin-I result greater than the manufacturer recommended 99% cutoff of 40 ng/L, and far too many older patients and inpatients exceed this recommended cutoff:
 
<gallery mode="slideshow">
File:Hs-TnI histogram Mariathas 2019.jpg|Overall distribution. (Note that the vertical axis is logarithmic, which substantially [over]emphasizes the appearance of the frequency of the higher troponin levels.)
File:Hs-TnI Variation-with-setting Mariathas 2019.jpg|Abnormals versus setting
File:Hs-TnI Variation-with-age Mariathas 2019.jpg|Abnormals versus age
</gallery>

:The implications of such a degree of variation are substantial, and may indicate that individual institutions need to calculate their own age-adjusted 99% cutoffs in order to obtain the intended outcomes. Additionally, clinicians likely need to integrate patient age and clinical context into their interpretation of hs-Tn levels. Though hs-Tn's have been shown to improve outcomes when evaluating acute chest pain in emergency departments, there is no data to indicate that diagnosing ''myocardial injury'' in 15% of medical ward patients, 20% of older persons, and 40% of ICU patients will lead to patient-important improvements.

:However... readers are strongly encouraged to read all seven of the [https://www.bmj.com/content/364/bmj.l729/rapid-responses responses]. In particular, Paul Collinson makes a strong argument that the authors are mis-interpreting their data because they are including a substantial number of UNhealthy individuals (i.e with CHF, CKI, etc.), whereas the appropriate cutoffs are [by definition] derived from healthy individuals. All of the responses are thoughtful, and both the article and the responses provide interesting thoughts about troponin levels and binary versus [https://en.wikipedia.org/wiki/Bayesian_inference Bayesian] interpretation of results.
 
 
=== The significance of ''Myocardial Injury'' ===
==== Acute ====
::There is no standard-of-care workup for this finding in the absence of myocardial ischemia. Can it be attributed to a tachyarrythmia, sepsis, etc? Or should a PE be ruled-out? Does it mandate an echocardiogram?

==== Chronic ====
::This is certainly not amenable to ED intervention. Again, it is not clear what the standard-of-care disposition of this finding will be.
 
 

== Definitions ==
*'''Myocardial injury'''
::Elevated cardiac troponin values (cTn) with at least one value above the 99th percentile upper reference limit (URL).<ref name="FUDoMI">Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Journal of the American College of Cardiology. 2018;72(18):2231-2264. doi:[https://doi.org/10.1016/j.jacc.2018.08.1038 DOI: 10.1016/j.jacc.2018.08.1038]</ref>
*'''Acute myocardial injury'''
::Myocardial injury with a rise and/or fall of cTn values.<ref name="FUDoMI"/>
*'''Acute myocardial infarction''' (types 1, 2 and 3 MI)
::Acute myocardial injury '''and''' at least one of the following:<ref name="FUDoMI"/>
::::::- Symptoms consistent with acute coronary occlusion;
::::::- New ischaemic ECG changes;
::::::- Development of pathological Q waves;
::::::- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology;
::::::- Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs).
 
 
 

== References ==

High-sensitivity Troponin-T

2022-01-20T22:07:06Z

AndyS: /* Delta (Δ) versus Level */

''see [[Acute Coronary Syndrome|Acute Coronary Syndrome Wiki Supplement Page]] for other information associated with Acute Coronary Syndrome''

On November 12, 2019, the Yukon-Kuskokwim Delta Regional Hospital (YKDHR) switched cardiac troponin assay to the Roche Diagnostics [https://diagnostics.roche.com/us/en/products/params/elecsys-troponin-t-high-sensitive-tnt-hs.html ''Elecsys® Troponin T Gen 5 STAT'']. This is a high-sensitivity fifth-generation cardiac troponin assay. Details are available in the [http://yk-health.org/images/b/b9/Elecsys_Troponin_T_Gen_5_STAT%2C_-07398000160_2_en_cc4d61e9-73c6-e811-2d93-00215a9b3428.pdf manufacturer's package insert].

Cardiac troponin assays measure the concentration of either troponin-T or troponin-I. Both high-sensitivity and traditional troponin assays measure the exact same molecule, but high-sensitivity assays measure ''much'' more precisely and at ''much'' lower concentrations. The high-sensitivity and traditional assays can be distinguished by the units in which they are reported: high-sensitivity assays are reported in ng/'''L''' whereas the traditional assays are reported in ng/'''mL'''.
:::Conversion between the results can be done by moving the decimal point three places: a traditional concentration of 0.4 ng/mL is equivalent to a high-sensitivity concentration of 400 ng/L, and a high-sensitivity concentration of 14 ng/L is equivalent to a traditional concentration of 0.014 ng/mL. This latter conversion illustrates that the high-sensitivity assays accurately measure concentrations which are two orders of magnitude lower than the assay we were previously using.

Though high-sensitivity troponin assays have been used in Europe and Canada since approximately 2009, the first U.S. FDA approval occurred in 2017.

''NOTE: The information below is not a guideline, but rather excerpts and links intended to augment and/or help develop clinical judgement.''
 
 
 
__TOC__
 
 
== Definition ==
To qualify as ''high-sensitivity'' (or ''highly-sensitive''), a cardiac troponin assay must be able to detect a level of cardiac troponin in >50% of normal individuals.<ref name="ACC_whitepaper_2018">High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami. Accessed December 3, 2019.</ref> This means that the majority of patients ''without'' cardiac ischemia ''will have'' a detectable level of cardiac troponin. This has substantial implications for how clinicians conceptualize and interpret cardiac troponin levels.
 
 

== Statistical/Epidemiological Properties ==
=== Diagnostic Performance ===
:High-sensitivity troponin assays have a much higher sensitivity for ACS than conventional assays, which yields a much higher '''negative predictive value''' ('''NPV'''). This allows clinicians to more quickly and accurately identify those chest pain patients who do not have ACS and who are at very low risk of 30-day MACE (major adverse cardiac events).

:Yet the increased sensitivity comes at the cost of decreased specificity, yielding a lower '''positive predictive value''' ('''PPV'''). The clinical consequence of this is summed up well by Dr. Rebecca Vigen of UTSWMS (University of Texas Southwestern Medical Center) grand rounds transcript:
::::''As the MI probability goes down, the additional positive test results with the hs-cTnT assay vs. the standard assay increases (false positives). Therefore, the proportion of positive tests with the high-sensitivity assay who do not have myocardial infarction will increase''.<ref>Vigen R. Providing High Value Care to Patients with Acute Chest Pain. Grand Rounds Presentation presented at the: Grand Rounds; June 14, 2019; University of Texas Southwestern Medical Center. https://cme.utsouthwestern.edu/sites/default/files/em1906g_061419_protocol_vigen.pdf. Accessed December 5, 2019.</ref>
 
:The following data reported by de Lemos et al. (2011)<ref>de Lemos JA, Morrow DA, deFilippi CR. Highly sensitive troponin assays and the cardiology community: a love/hate relationship? Clin Chem. 2011;57(6):826-829. doi:[https://doi.org/10.1373/clinchem.2011.163758 10.1373/clinchem.2011.163758]</ref> illustrates the effect:
 
{| class="wikitable" style="width: 85%;margin: auto;"
|+ style="caption-side:bottom;text-align:left;" |Additional cTnT values above the MI-detection threshold with a highly sensitive (hs) cTnT assay,
compared with a standard cTnT assay, across differing MI probabilities in the target population.
|-
! scope="col"| MI probability
! scope="col"| Positive tests with standard assay, /1000 patients
! scope="col"| Positive tests with hs assay, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay meeting MI definition, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay not meeting MI definition, /1000 patients
|-
| style="text-align:center;"| 17%
| style="text-align:center;" | 199
| style="text-align:center;" | 328
| style="text-align:center;" | 21
| style="text-align:center;" | 108
|-
| style="text-align:center;"| 10%
| style="text-align:center;" | 146
| style="text-align:center;" | 275
| style="text-align:center;" | 12
| style="text-align:center;" | 117
|-
| style="text-align:center;"| 5%
| style="text-align:center;" | 108
| style="text-align:center;" | 237
| style="text-align:center;" | 8
| style="text-align:center;" | 121
|-
| style="text-align:center;"| 3%
| style="text-align:center;" | 93
| style="text-align:center;" | 222
| style="text-align:center;" | 3
| style="text-align:center;" | 126
|}
 
:de Lemos derived these outcomes from calculations using the limit of detection for the conventional troponin assay and with the 99th percentile for the high-sensitivity troponin assay. However, clinicians must recognize that these calculations to not include the delta troponin (discussed below), but rather single values.
 
=== Population Distribution ===
:The manufacturer recommended rule-out cutoffs (99% ULN) are based upon the following distribution:
 
 
[[File:Hs-Tnt 4G histogram Giannitsis 2009.jpg|thumb|700px|center|Troponin-T distribution in healthy individuals.<ref>Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56(2):254-261. doi:[https://doi.org/10.1373/clinchem.2009.132654 10.1373/clinchem.2009.132654]</ref>]]
 
 

== Delta (Δ) versus Level ==
With traditional troponin assays, a troponin level was not detectable in most patients who lack cardiac ischemia. Emergency departments typically performed serial measurements to see if the troponin ''level'' became detectable over time. Therefore the ''level'' of the troponin was the focus while quantifying the magnitude of the ''delta (Δ)'' (i.e. the change of the level over time) was a secondary consideration.

Due to the high-sensitivity assays' ability to detect a troponin level in most patients who lack cardiac ischemia, many experts recommend a reversal in diagnostic thinking with regard to ACS/AMI: for most patients the delta (Δ) should be the focus while the level is a secondary consideration.<ref>Helman, A. McRae, A. Lang, E. Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift. Emergency Medicine Cases. July, 2019. https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin. Accessed December 2, 2019.</ref>

However, there are initial levels below which a delta is not required:
::::* If >= 3 hours since onset of symptoms and a normal EKG, then an initial troponin level < 6 ng/L can rule-out ACS.
 
 

== Troponin Delta ==

== Troponin Level ==
=== Level Cutoffs ===
Hs-cTnT is considered "positive" when above the gender-specific 99th percentile URL (upper reference range). Per eMail from Scott Cox (YKDHR Director of Diagnostic Services) on 11/10/2019, the following cutoff are recommended for our assay:
{| class="wikitable" style="margin: auto;"
|+Positive Values
|-
| Women || >= '''14''' ng/L
|-
| Men || >= '''22''' ng/L
|}
 
 
Per the ACC white paper (see below): 
* A single Hs-cTnT >= '''100''' ng/L is diagnostic of AMI (in the appropriate clinical context). 
* When chest pain has been present for >= 3 hours, a single Hs-cTnT < '''6''' ng/L has been reported to rule out AMI with essentially 100% negative predictive value.

 
== Diagnostic Algorithms ==
=== ACC ===
The following diagnostic algorithm has been proposed for high-sensitivity cardiac troponin-T by the ACC (American College of Cardiology), though they caution that "''The safety of this approach is currently unclear''":<ref name="ACC_whitepaper_2018"/>
 
[[File:ACC Whitepaper Figure-1 2018-07-16.PNG]]
 
 
 
=== UTSW/Parkland ===
The algorithm used by ''University of Texas Southwestern Medical Center'' is shown for illustrative purposes in an ACEP Webinar (see below, page 16):
 
[[File:UTSW-Parkland hs-cTnT pathway.PNG|1000px]]
 
 
Note that this algorithm does not include risk stratification, such as with the HEART score. Yet the same Webinar contains other algorithms which separate out Hs-cTnT and call the risk stratification a HEAR score (or "modified-HEART" score) and guide diagnosis/management based upon different combinations of Hs-cTnT and HEAR values. Yet other algorithms in the same Webinar recommend skipping risk stratification in those who have low- or high-risk EKG/Hs-cTnT results and only risk stratifying those with intermediate-risk EKG/Hs-cTnT results.
 
 
=== Australian ACRE Project ===

This diagnostic algorithm guides the user to one of four etiologies for HS-cTnT elevation:
# Type-1 MI
# Type-2 MI
# Acute myocardial injury
# Chronic myocardial injury

However, users will note that the following two terms are used without definition:
# ''Evidence for acute myocardial ischemia''
# ''Evidence of acute coronary atherothrombosis''

Per recommendation of the author, this algorithm has been edited to contain the cutoffs specific to our lab/assay:
 

[[File:ACRE Algorithm modified-cutoffs.svg.png|900px]]

The original PDF is available [https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf here] ([https://web.archive.org/web/20200221184332/https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf archived])

== Helpful Links ==
'''ACC (American College of Cardiology)'''
:[https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami ''High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI'' (July 16, 2018)]
:[https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/08/24/00/09/fourth-universal-definition-of-mi-esc-2018 ''SUMMARY: Fourth Universal Definition of Myocardial Infarction'' (Aug 25, 2018)]
 
'''ACEP'''
:[https://www.acep.org/globalassets/sites/acep/media/equal-documents/webinar_chestpainw3_hsctn2.pdf ''Webinar: Incorporating High-Sensitivity Troponin into Your ED'']
:[https://www.acep.org/patient-care/clinical-policies/nonst-elevation-acute-coronary-syndromes/ ''Critical Issues in the Evaluation and Management of Emergency Department Patients with Suspected Non–ST-Elevation Acute Coronary Syndromes'' (Jun 2018)]
 

'''MD Calc'''
:[https://www.mdcalc.com/heart-score-major-cardiac-events HEART Score for Major Cardiac Events]
 

''' ACEP''Now''''' Articles
:03-19-2019: [https://www.acepnow.com/article/high-sensitivity-cardiac-troponin-tests-for-acute-myocardial-infarction-may-be-flawed/ ''High Sensitivity Cardiac Troponin Tests for Acute Myocardial Infarction May be Flawed'']
:09-18-2019: [https://www.acepnow.com/article/chest-pain-patients-high-sensitivity-troponin-tests-new-frontier/2/ ''Chest-Pain Patients and High-Sensitivity Troponin Tests: the New Frontier'']
 

'''PodCasts'''
: 02-20-2020: EMCrit #266: [https://emcrit.org/emcrit/high-sensitivity-troponins/ ''High Sensitivity Troponins with Louise Cullen''] (Duration: 26:04) [https://web.archive.org/web/20200222031331/https://emcrit.org/emcrit/high-sensitivity-troponins/ Archived]

: 01-18-2020: SGEM #280: [http://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ ''THIS OLD HEART OF MINE AND TROPONIN TESTING''] (Duration: 30:10) [https://web.archive.org/web/20200222031814/https://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ Archived]

: 07-30-2019: Emergency Medicine Cases (Ep 128) [https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ ''Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift''] (Duration: 1:34:36) [https://web.archive.org/web/20191213102014/https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ Archived]

== High-sensitivity troponin Myths versus Reality ==
Myths:
:* ''more patients will undergo catheterization''
:* ''ED stays will be longer''
:* ''there will be fewer ED discharges''
:* ''there will be more stress tests''
 

'''FACT''': the APACE trial showed that adoption of a high-sensitivity troponin assay was associated with no change in the number of catheterizations, decreased "normal cath" results, shorter ED stays, more ED discharges, and fewer stress tests.<ref>Twerenbold R, Jaeger C, Rubini Gimenez M, et al. Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction. Eur Heart J. 2016;37(44):3324-3332. doi:[https://doi.org/10.1093/eurheartj/ehw232 10.1093/eurheartj/ehw232]</ref>
 

'''FACT''': Across numerous trials, increasing troponin sensitivity has shown a dose-response relationship with increased ED discharges.
 
 
== Controversies ==
=== Recommended 99% URL Cutoffs ===
==== Mariathas el al (Mar 2019) ====
::In March 2019 Mariathas el al. reported in the BMJ<ref>Mariathas M, Allan R, Ramamoorthy S, et al. True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study. BMJ. 2019;364:l729. doi:[https://doi.org/10.1136/bmj.l729 10.1136/bmj.l729]</ref> that they found a very different distribution and 99% ULR when they analyzed 20,000 consecutive blood samples collected in all settings (outpatient, ED, inpatient, etc.) drawn for any reason in a large UK hospital. Overall, over five percent of patients had a troponin-I result greater than the manufacturer recommended 99% cutoff of 40 ng/L, and far too many older patients and inpatients exceed this recommended cutoff:
 
<gallery mode="slideshow">
File:Hs-TnI histogram Mariathas 2019.jpg|Overall distribution. (Note that the vertical axis is logarithmic, which substantially [over]emphasizes the appearance of the frequency of the higher troponin levels.)
File:Hs-TnI Variation-with-setting Mariathas 2019.jpg|Abnormals versus setting
File:Hs-TnI Variation-with-age Mariathas 2019.jpg|Abnormals versus age
</gallery>

:The implications of such a degree of variation are substantial, and may indicate that individual institutions need to calculate their own age-adjusted 99% cutoffs in order to obtain the intended outcomes. Additionally, clinicians likely need to integrate patient age and clinical context into their interpretation of hs-Tn levels. Though hs-Tn's have been shown to improve outcomes when evaluating acute chest pain in emergency departments, there is no data to indicate that diagnosing ''myocardial injury'' in 15% of medical ward patients, 20% of older persons, and 40% of ICU patients will lead to patient-important improvements.

:However... readers are strongly encouraged to read all seven of the [https://www.bmj.com/content/364/bmj.l729/rapid-responses responses]. In particular, Paul Collinson makes a strong argument that the authors are mis-interpreting their data because they are including a substantial number of UNhealthy individuals (i.e with CHF, CKI, etc.), whereas the appropriate cutoffs are [by definition] derived from healthy individuals. All of the responses are thoughtful, and both the article and the responses provide interesting thoughts about troponin levels and binary versus [https://en.wikipedia.org/wiki/Bayesian_inference Bayesian] interpretation of results.
 
 
=== The significance of ''Myocardial Injury'' ===
==== Acute ====
::There is no standard-of-care workup for this finding in the absence of myocardial ischemia. Can it be attributed to a tachyarrythmia, sepsis, etc? Or should a PE be ruled-out? Does it mandate an echocardiogram?

==== Chronic ====
::This is certainly not amenable to ED intervention. Again, it is not clear what the standard-of-care disposition of this finding will be.
 
 

== Definitions ==
*'''Myocardial injury'''
::Elevated cardiac troponin values (cTn) with at least one value above the 99th percentile upper reference limit (URL).<ref name="FUDoMI">Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Journal of the American College of Cardiology. 2018;72(18):2231-2264. doi:[https://doi.org/10.1016/j.jacc.2018.08.1038 DOI: 10.1016/j.jacc.2018.08.1038]</ref>
*'''Acute myocardial injury'''
::Myocardial injury with a rise and/or fall of cTn values.<ref name="FUDoMI"/>
*'''Acute myocardial infarction''' (types 1, 2 and 3 MI)
::Acute myocardial injury '''and''' at least one of the following:<ref name="FUDoMI"/>
::::::- Symptoms consistent with acute coronary occlusion;
::::::- New ischaemic ECG changes;
::::::- Development of pathological Q waves;
::::::- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology;
::::::- Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs).
 
 
 

== References ==

High-sensitivity Troponin-T

2022-01-20T22:05:51Z

AndyS: /* Statistical/Epidemiological Properties */

''see [[Acute Coronary Syndrome|Acute Coronary Syndrome Wiki Supplement Page]] for other information associated with Acute Coronary Syndrome''

On November 12, 2019, the Yukon-Kuskokwim Delta Regional Hospital (YKDHR) switched cardiac troponin assay to the Roche Diagnostics [https://diagnostics.roche.com/us/en/products/params/elecsys-troponin-t-high-sensitive-tnt-hs.html ''Elecsys® Troponin T Gen 5 STAT'']. This is a high-sensitivity fifth-generation cardiac troponin assay. Details are available in the [http://yk-health.org/images/b/b9/Elecsys_Troponin_T_Gen_5_STAT%2C_-07398000160_2_en_cc4d61e9-73c6-e811-2d93-00215a9b3428.pdf manufacturer's package insert].

Cardiac troponin assays measure the concentration of either troponin-T or troponin-I. Both high-sensitivity and traditional troponin assays measure the exact same molecule, but high-sensitivity assays measure ''much'' more precisely and at ''much'' lower concentrations. The high-sensitivity and traditional assays can be distinguished by the units in which they are reported: high-sensitivity assays are reported in ng/'''L''' whereas the traditional assays are reported in ng/'''mL'''.
:::Conversion between the results can be done by moving the decimal point three places: a traditional concentration of 0.4 ng/mL is equivalent to a high-sensitivity concentration of 400 ng/L, and a high-sensitivity concentration of 14 ng/L is equivalent to a traditional concentration of 0.014 ng/mL. This latter conversion illustrates that the high-sensitivity assays accurately measure concentrations which are two orders of magnitude lower than the assay we were previously using.

Though high-sensitivity troponin assays have been used in Europe and Canada since approximately 2009, the first U.S. FDA approval occurred in 2017.

''NOTE: The information below is not a guideline, but rather excerpts and links intended to augment and/or help develop clinical judgement.''
 
 
 
__TOC__
 
 
== Definition ==
To qualify as ''high-sensitivity'' (or ''highly-sensitive''), a cardiac troponin assay must be able to detect a level of cardiac troponin in >50% of normal individuals.<ref name="ACC_whitepaper_2018">High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami. Accessed December 3, 2019.</ref> This means that the majority of patients ''without'' cardiac ischemia ''will have'' a detectable level of cardiac troponin. This has substantial implications for how clinicians conceptualize and interpret cardiac troponin levels.
 
 

== Statistical/Epidemiological Properties ==
=== Diagnostic Performance ===
:High-sensitivity troponin assays have a much higher sensitivity for ACS than conventional assays, which yields a much higher '''negative predictive value''' ('''NPV'''). This allows clinicians to more quickly and accurately identify those chest pain patients who do not have ACS and who are at very low risk of 30-day MACE (major adverse cardiac events).

:Yet the increased sensitivity comes at the cost of decreased specificity, yielding a lower '''positive predictive value''' ('''PPV'''). The clinical consequence of this is summed up well by Dr. Rebecca Vigen of UTSWMS (University of Texas Southwestern Medical Center) grand rounds transcript:
::::''As the MI probability goes down, the additional positive test results with the hs-cTnT assay vs. the standard assay increases (false positives). Therefore, the proportion of positive tests with the high-sensitivity assay who do not have myocardial infarction will increase''.<ref>Vigen R. Providing High Value Care to Patients with Acute Chest Pain. Grand Rounds Presentation presented at the: Grand Rounds; June 14, 2019; University of Texas Southwestern Medical Center. https://cme.utsouthwestern.edu/sites/default/files/em1906g_061419_protocol_vigen.pdf. Accessed December 5, 2019.</ref>
 
:The following data reported by de Lemos et al. (2011)<ref>de Lemos JA, Morrow DA, deFilippi CR. Highly sensitive troponin assays and the cardiology community: a love/hate relationship? Clin Chem. 2011;57(6):826-829. doi:[https://doi.org/10.1373/clinchem.2011.163758 10.1373/clinchem.2011.163758]</ref> illustrates the effect:
 
{| class="wikitable" style="width: 85%;margin: auto;"
|+ style="caption-side:bottom;text-align:left;" |Additional cTnT values above the MI-detection threshold with a highly sensitive (hs) cTnT assay,
compared with a standard cTnT assay, across differing MI probabilities in the target population.
|-
! scope="col"| MI probability
! scope="col"| Positive tests with standard assay, /1000 patients
! scope="col"| Positive tests with hs assay, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay meeting MI definition, /1000 patients
! scope="col"| Additional positive tests with hs assay vs standard assay not meeting MI definition, /1000 patients
|-
| style="text-align:center;"| 17%
| style="text-align:center;" | 199
| style="text-align:center;" | 328
| style="text-align:center;" | 21
| style="text-align:center;" | 108
|-
| style="text-align:center;"| 10%
| style="text-align:center;" | 146
| style="text-align:center;" | 275
| style="text-align:center;" | 12
| style="text-align:center;" | 117
|-
| style="text-align:center;"| 5%
| style="text-align:center;" | 108
| style="text-align:center;" | 237
| style="text-align:center;" | 8
| style="text-align:center;" | 121
|-
| style="text-align:center;"| 3%
| style="text-align:center;" | 93
| style="text-align:center;" | 222
| style="text-align:center;" | 3
| style="text-align:center;" | 126
|}
 
:de Lemos derived these outcomes from calculations using the limit of detection for the conventional troponin assay and with the 99th percentile for the high-sensitivity troponin assay. However, clinicians must recognize that these calculations to not include the delta troponin (discussed below), but rather single values.
 
=== Population Distribution ===
:The manufacturer recommended rule-out cutoffs (99% ULN) are based upon the following distribution:
 
 
[[File:Hs-Tnt 4G histogram Giannitsis 2009.jpg|thumb|700px|center|Troponin-T distribution in healthy individuals.<ref>Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56(2):254-261. doi:[https://doi.org/10.1373/clinchem.2009.132654 10.1373/clinchem.2009.132654]</ref>]]
 
 

== Delta (Δ) versus Level ==

== Troponin Delta ==

== Troponin Level ==
=== Level Cutoffs ===
Hs-cTnT is considered "positive" when above the gender-specific 99th percentile URL (upper reference range). Per eMail from Scott Cox (YKDHR Director of Diagnostic Services) on 11/10/2019, the following cutoff are recommended for our assay:
{| class="wikitable" style="margin: auto;"
|+Positive Values
|-
| Women || >= '''14''' ng/L
|-
| Men || >= '''22''' ng/L
|}
 
 
Per the ACC white paper (see below): 
* A single Hs-cTnT >= '''100''' ng/L is diagnostic of AMI (in the appropriate clinical context). 
* When chest pain has been present for >= 3 hours, a single Hs-cTnT < '''6''' ng/L has been reported to rule out AMI with essentially 100% negative predictive value.

 
== Diagnostic Algorithms ==
=== ACC ===
The following diagnostic algorithm has been proposed for high-sensitivity cardiac troponin-T by the ACC (American College of Cardiology), though they caution that "''The safety of this approach is currently unclear''":<ref name="ACC_whitepaper_2018"/>
 
[[File:ACC Whitepaper Figure-1 2018-07-16.PNG]]
 
 
 
=== UTSW/Parkland ===
The algorithm used by ''University of Texas Southwestern Medical Center'' is shown for illustrative purposes in an ACEP Webinar (see below, page 16):
 
[[File:UTSW-Parkland hs-cTnT pathway.PNG|1000px]]
 
 
Note that this algorithm does not include risk stratification, such as with the HEART score. Yet the same Webinar contains other algorithms which separate out Hs-cTnT and call the risk stratification a HEAR score (or "modified-HEART" score) and guide diagnosis/management based upon different combinations of Hs-cTnT and HEAR values. Yet other algorithms in the same Webinar recommend skipping risk stratification in those who have low- or high-risk EKG/Hs-cTnT results and only risk stratifying those with intermediate-risk EKG/Hs-cTnT results.
 
 
=== Australian ACRE Project ===

This diagnostic algorithm guides the user to one of four etiologies for HS-cTnT elevation:
# Type-1 MI
# Type-2 MI
# Acute myocardial injury
# Chronic myocardial injury

However, users will note that the following two terms are used without definition:
# ''Evidence for acute myocardial ischemia''
# ''Evidence of acute coronary atherothrombosis''

Per recommendation of the author, this algorithm has been edited to contain the cutoffs specific to our lab/assay:
 

[[File:ACRE Algorithm modified-cutoffs.svg.png|900px]]

The original PDF is available [https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf here] ([https://web.archive.org/web/20200221184332/https://clinicalexcellence.qld.gov.au/sites/default/files/2019-02/Poster%20-%20Clinical%20interpretation%20of%20hs-cTn_V3.1.pdf archived])

== Helpful Links ==
'''ACC (American College of Cardiology)'''
:[https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami ''High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI'' (July 16, 2018)]
:[https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/08/24/00/09/fourth-universal-definition-of-mi-esc-2018 ''SUMMARY: Fourth Universal Definition of Myocardial Infarction'' (Aug 25, 2018)]
 
'''ACEP'''
:[https://www.acep.org/globalassets/sites/acep/media/equal-documents/webinar_chestpainw3_hsctn2.pdf ''Webinar: Incorporating High-Sensitivity Troponin into Your ED'']
:[https://www.acep.org/patient-care/clinical-policies/nonst-elevation-acute-coronary-syndromes/ ''Critical Issues in the Evaluation and Management of Emergency Department Patients with Suspected Non–ST-Elevation Acute Coronary Syndromes'' (Jun 2018)]
 

'''MD Calc'''
:[https://www.mdcalc.com/heart-score-major-cardiac-events HEART Score for Major Cardiac Events]
 

''' ACEP''Now''''' Articles
:03-19-2019: [https://www.acepnow.com/article/high-sensitivity-cardiac-troponin-tests-for-acute-myocardial-infarction-may-be-flawed/ ''High Sensitivity Cardiac Troponin Tests for Acute Myocardial Infarction May be Flawed'']
:09-18-2019: [https://www.acepnow.com/article/chest-pain-patients-high-sensitivity-troponin-tests-new-frontier/2/ ''Chest-Pain Patients and High-Sensitivity Troponin Tests: the New Frontier'']
 

'''PodCasts'''
: 02-20-2020: EMCrit #266: [https://emcrit.org/emcrit/high-sensitivity-troponins/ ''High Sensitivity Troponins with Louise Cullen''] (Duration: 26:04) [https://web.archive.org/web/20200222031331/https://emcrit.org/emcrit/high-sensitivity-troponins/ Archived]

: 01-18-2020: SGEM #280: [http://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ ''THIS OLD HEART OF MINE AND TROPONIN TESTING''] (Duration: 30:10) [https://web.archive.org/web/20200222031814/https://thesgem.com/2020/01/sgem280-this-old-heart-of-mine-and-troponin-testing/ Archived]

: 07-30-2019: Emergency Medicine Cases (Ep 128) [https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ ''Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift''] (Duration: 1:34:36) [https://web.archive.org/web/20191213102014/https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin/ Archived]

== High-sensitivity troponin Myths versus Reality ==
Myths:
:* ''more patients will undergo catheterization''
:* ''ED stays will be longer''
:* ''there will be fewer ED discharges''
:* ''there will be more stress tests''
 

'''FACT''': the APACE trial showed that adoption of a high-sensitivity troponin assay was associated with no change in the number of catheterizations, decreased "normal cath" results, shorter ED stays, more ED discharges, and fewer stress tests.<ref>Twerenbold R, Jaeger C, Rubini Gimenez M, et al. Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction. Eur Heart J. 2016;37(44):3324-3332. doi:[https://doi.org/10.1093/eurheartj/ehw232 10.1093/eurheartj/ehw232]</ref>
 

'''FACT''': Across numerous trials, increasing troponin sensitivity has shown a dose-response relationship with increased ED discharges.
 
 
== Controversies ==
=== Recommended 99% URL Cutoffs ===
==== Mariathas el al (Mar 2019) ====
::In March 2019 Mariathas el al. reported in the BMJ<ref>Mariathas M, Allan R, Ramamoorthy S, et al. True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study. BMJ. 2019;364:l729. doi:[https://doi.org/10.1136/bmj.l729 10.1136/bmj.l729]</ref> that they found a very different distribution and 99% ULR when they analyzed 20,000 consecutive blood samples collected in all settings (outpatient, ED, inpatient, etc.) drawn for any reason in a large UK hospital. Overall, over five percent of patients had a troponin-I result greater than the manufacturer recommended 99% cutoff of 40 ng/L, and far too many older patients and inpatients exceed this recommended cutoff:
 
<gallery mode="slideshow">
File:Hs-TnI histogram Mariathas 2019.jpg|Overall distribution. (Note that the vertical axis is logarithmic, which substantially [over]emphasizes the appearance of the frequency of the higher troponin levels.)
File:Hs-TnI Variation-with-setting Mariathas 2019.jpg|Abnormals versus setting
File:Hs-TnI Variation-with-age Mariathas 2019.jpg|Abnormals versus age
</gallery>

:The implications of such a degree of variation are substantial, and may indicate that individual institutions need to calculate their own age-adjusted 99% cutoffs in order to obtain the intended outcomes. Additionally, clinicians likely need to integrate patient age and clinical context into their interpretation of hs-Tn levels. Though hs-Tn's have been shown to improve outcomes when evaluating acute chest pain in emergency departments, there is no data to indicate that diagnosing ''myocardial injury'' in 15% of medical ward patients, 20% of older persons, and 40% of ICU patients will lead to patient-important improvements.

:However... readers are strongly encouraged to read all seven of the [https://www.bmj.com/content/364/bmj.l729/rapid-responses responses]. In particular, Paul Collinson makes a strong argument that the authors are mis-interpreting their data because they are including a substantial number of UNhealthy individuals (i.e with CHF, CKI, etc.), whereas the appropriate cutoffs are [by definition] derived from healthy individuals. All of the responses are thoughtful, and both the article and the responses provide interesting thoughts about troponin levels and binary versus [https://en.wikipedia.org/wiki/Bayesian_inference Bayesian] interpretation of results.
 
 
=== The significance of ''Myocardial Injury'' ===
==== Acute ====
::There is no standard-of-care workup for this finding in the absence of myocardial ischemia. Can it be attributed to a tachyarrythmia, sepsis, etc? Or should a PE be ruled-out? Does it mandate an echocardiogram?

==== Chronic ====
::This is certainly not amenable to ED intervention. Again, it is not clear what the standard-of-care disposition of this finding will be.
 
 

== Definitions ==
*'''Myocardial injury'''
::Elevated cardiac troponin values (cTn) with at least one value above the 99th percentile upper reference limit (URL).<ref name="FUDoMI">Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Journal of the American College of Cardiology. 2018;72(18):2231-2264. doi:[https://doi.org/10.1016/j.jacc.2018.08.1038 DOI: 10.1016/j.jacc.2018.08.1038]</ref>
*'''Acute myocardial injury'''
::Myocardial injury with a rise and/or fall of cTn values.<ref name="FUDoMI"/>
*'''Acute myocardial infarction''' (types 1, 2 and 3 MI)
::Acute myocardial injury '''and''' at least one of the following:<ref name="FUDoMI"/>
::::::- Symptoms consistent with acute coronary occlusion;
::::::- New ischaemic ECG changes;
::::::- Development of pathological Q waves;
::::::- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology;
::::::- Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs).
 
 
 

== References ==