Blood pressure targets following return of circulation after pediatric cardiac arrest. PLS 4190-01 TF SR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: Alexis Topjian was an author on a number of the papers included in this systematic review.

CoSTR Citation

Nuthall G, Christoff A, Morrison LJ, Scholefield B on behalf of the Pediatric Life Support Task Force.

Blood pressure targets following return of circulation after cardiac arrest: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2024. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of blood pressure targets following return of circulation after cardiac arrest (Nuthall 2023 – PROSPERO CRD42023483865), by clinical content experts of the Pediatric Life Support Task Forces of ILCOR, with assistance from Jessie Cunningham, Information Specialist at The Hospital for Sick Children, Toronto, Canada. Evidence was sought and considered by members of the Pediatric Life Support Task Force group.

Systematic Review

Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available if published

Nuthall et al, Blood pressure targets following return of circulation after pediatric cardiac arrest: A Systematic Review (in preparation)

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Infants and children in any setting (in-hospital or out-of-hospital cardiac arrest) after return of spontaneous circulation (ROSC) or return of circulation (ROC)

Intervention: A specific blood pressure target

Comparators: No blood pressure target or a different blood pressure target

Outcomes: Survival or survival with favorable neurological outcome as per Pediatric Core Outcome Set for Cardiac Arrest (Topjian 2020, e1)

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) are excluded. All relevant publications in any language are included as long as there is an English abstract.

Timeframe: All years up to search date November 3^rd 2023.

Consensus on Science

Six studies were included from the systematic review (Topjian 2014, 1518; Topjian 2018, 143; Topjian 2019a, 88; Topjian 2019b, 24, Laverriere 2020, 143; Gardner 2023, 388). All six were non-randomized observational cohort studies, with five being secondary analyses. The review identified significant variation in BP target definitions (e.g. systolic, mean and diastolic BP; and >5th, >10th and >50th centile for age) and time frames for measurement (<20 minutes, 0 to 6 hours, within 24 hours, and within 0-72 hours). Two studies were excluded as the definition of hypotension could not be ascertained (Lin 2010, 410; Lin 2013, 439).

In our final analysis, we included four studies (Topjian 2014, 1518; Topjian 2018, 143; Topjian 2019a, 88; Laverriere 2020, 143) examining the BP targets of systolic BP >5th percentile for age compared with systolic BP ≤5th percentile within the first six hours post ROC. The pooled sample included 463/930 (49.8%) patients following in-hospital cardiac arrest (IHCA), and 467/930 (50.2%) after out-of-hospital cardiac arrest (OHCA). We also included one study (Gardiner 2023, p388) which enrolled 693 infants and children after IHCA (excluding patients requiring extra-corporeal life support). This study compared systolic BP >10th centile with systolic BP ≤10th centile within the first six hours post ROC. The systolic BP cut off at the 10th centile was generated from receiver operator characteristic curves and spline curves created from the study data.

For the critically important outcome of survival, we identified very-low-certainty evidence (downgraded for inconsistency and indirectness) from four observational studies (Topjian 2014, p1518; Topjian 2018, p143; Topjian 2019a, p88; Laverriere 2020, p143) enrolling 931 children after in-hospital or out-of-hospital cardiac arrests, in the first six hours post return of circulation (ROC), that showed benefit from exposure to a systolic BP >5th centile when compared with systolic BP ≤5th centile (pooled adjusted Relative Risk (aRR), 1.34; 95%CI, 1.07 to 1.52); P = 0.01); 143 more patients/1000 survived with the intervention [95% CI, 30 more patients/1000 to 219 more patients/1000 survived with the intervention]).

For the critically important outcome of survival with good neurological outcome, we identified very-low-certainty evidence (downgraded for inconsistency and indirectness) from two observational studies (Topjian 2014, 1518; Laverriere 2020, 143) enrolling 584 children after in-hospital or out-of-hospital cardiac arrests, in the first six hours post ROC, that showed benefit from exposure to a systolic BP >5th centile when compared with SBP ≤5th centile (pooled aRR, 1.30; 95%CI, 1.06 to 1.60); P = 0.01); 156 more patients/1000 survived with the intervention [95% CI, 31 more patients/1000 to 312 more patients/1000 survived with the intervention]).

For the critically important outcome of survival, we identified low-certainty evidence (downgraded for inconsistency and indirectness) from one study (Gardner 2023, 388), showing benefit from exposure to a systolic BP > 10th centile when compared with systolic BP ≤10th centile (aRR, 1.21; 95%CI, 1.00 to 1.33); P <0.01); 138 more patients/1000 survived with the intervention [95% CI, 66 more patients/1000 to 213 more patients/1000 survived with the intervention]).

For the critically important outcome of survival with good neurological outcome, we identified low-certainty evidence (downgraded for inconsistency and indirectness) from one study (Gardner 2023, 388), that showed benefit from exposure to a systolic BP >10th centile when compared with systolic BP ≤10th centile (aRR, 1.22; 95%CI, 1.10 to 1.35); P <0.01); 134 more patients/1000 survived with the intervention [95% CI, 61 more patients/1000 to 213 more patients/1000 survived with the intervention]).

Treatment Recommendations

We suggest in infants and children post return of circulation, following an in-hospital or out-of-hospital cardiac arrest, that a systolic blood pressure >10^th centile for age should be targeted (weak recommendation, very low certainty evidence).

Justification and Evidence to Decision Framework Highlights

The Pediatric Task Force considered that the measurement and treatment of blood pressure is a standard component of the post-resuscitation bundle of care after cardiac arrest. However, current post-cardiac arrest blood pressure treatment targets and thresholds for treatment have been suggested through expert consensus and evidence extrapolated from individual studies. The Pediatric Task Force therefore undertook an ILCOR led systematic review of the current evidence.

Measurement of blood pressure is a low-cost intervention and available in nearly all resource settings. However, the taskforce did not review the cost-effectiveness of intermittent, non-invasive blood pressure measurement with invasive arterial or continuous BP measurement.

There were no randomized controlled studies comparing two treatment approaches, or two BP targets following cardiac arrest. The available evidence consisted of observational data demonstrating the impact of exposure to two different blood pressure thresholds on clinically important outcomes. However, the blood pressure thresholds were chosen either a-priori by investigators as a clinically important threshold (eg ≤5^th centile), or the cut off value was derived statistically from the population data, as the most significant inflection point (≤10^th centile). The Pediatric Task Force focused on the impact of hypotension on clinical outcome and did not include studies assessing normotension or hypertension on outcomes. This will form part of future assessments.

The Pediatric Task Force considered the exposure overlap of the two thresholds <5th centile and <10th centile. It was not statistically possible to perform meta-regression to compare the two treatment targets. The consensus of the TF was that higher threshold cut off target (<10th centile) included the population included in the <5th centile group. In addition, acknowledging the low certainty of evidence, the target of >10th centile systolic BP was the more acceptable systolic BP goal and ensured avoidance of the 5th to 10th BP centiles that were associated with worse outcome in the larger study by Gardener (2023, 388).

The Pediatric Task Force felt, that although the effect size from the pooled studies is small, the value of the outcome is high and the potential impact on infants and children survivors globally is therefore large

Knowledge Gaps

• There are no interventional randomised controlled trials comparing benefits or harm of targeting specific blood pressure targets.
• Information on impact of pre-hospital blood pressure measurement or treatment for OHCA is missing.
• It is unclear if specific sub-groups of pediatric patients post return of circulation require different BP targets. Observational data demonstrates an association between exposure to lower BP targets and worse outcome; however, more data is required to demonstrate a causal relationship between treatment interventions to achieve higher BP targets and improved outcomes. In addition, the Pediatric Task Force was unable to assess the benefits or harm of exposure to hypertension in the period after cardiac arrest.
• We encourage consistent reporting of blood pressure monitoring definitions (eg site, repeated measurement, component of BP (systolic, diastolic, mean BP) and definitions of exposure to hypotension (e.g. single episode versus percentage of time).
• Majority of included data reports exposure to blood pressure thresholds within six hours; impact of blood pressure interventions outside this timeframe is important.
• It is unclear which strategy is optimal to achieve a BP above the threshold level (e.g. fluids, vasopressor support, mechanical support), and interventions themselves may be associated with harm.
• There is limited data if a BP target or another marker of end organ perfusion is the most appropriate target.
• Optimal blood pressure targets during extracorporeal life support (ECLS) post-cardiac arrest are unknown. Some patients on ECLS may have a lack of heart pulsatilty which also limits use of systolic BP targets in this patient group.
• There is limited data available on the optimal strategy to use when cerebral autoregulation is impaired.

ETD summary table: PLS 4190 01 Et D for Post ROSC Blood Pressure Targets

References

Gardner MM, Hehir DA, Reeder RW, Ahmed T, Bell MJ, Berg RA, Bishop R, Bochkoris M, Burns C, Carcillo JA, et al. Identification of post-cardiac arrest blood pressure thresholds associated with outcomes in children: an ICU-Resuscitation study. Crit Care. 2023;27:388. doi: 10.1186/s13054-023-04662-9

Laverriere EK, Polansky M, French B, Nadkarni VM, Berg RA, Topjian AA. Association of Duration of Hypotension With Survival After Pediatric Cardiac Arrest. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2020;21:143-149. doi: 10.1097/PCC.0000000000002119

Lin YR, Li CJ, Wu TK, Chang YJ, Lai SC, Liu TA, Hsiao MH, Chou CC, Chang CF. Post-resuscitative clinical features in the first hour after achieving sustained ROSC predict the duration of survival in children with non-traumatic out-of-hospital cardiac arrest. Resuscitation. 2010;81:410-417. doi: 10.1016/j.resuscitation.2010.01.006

Lin YR, Wu HP, Chen WL, Wu KH, Teng TH, Yang MC, Chou CC, Chang CF, Li CJ. Predictors of survival and neurologic outcomes in children with traumatic out-of-hospital cardiac arrest during the early postresuscitative period. J Trauma Acute Care Surg. 2013;75:439-447. doi: 10.1097/TA.0b013e31829e2543

Topjian AA, French B, Sutton RM, Conlon T, Nadkarni VM, Moler FW, Dean JM, Berg RA. Early postresuscitation hypotension is associated with increased mortality following pediatric cardiac arrest. Crit Care Med. 2014;42:1518-1523. doi: 10.1097/CCM.0000000000000216

Topjian AA, Sutton RM, Reeder RW, Telford R, Meert KL, Yates AR, Morgan RW, Berger JT, Newth CJ, Carcillo JA, et al. The association of immediate post cardiac arrest diastolic hypertension and survival following pediatric cardiac arrest. Resuscitation. 2019;141:88-95. doi: 10.1016/j.resuscitation.2019.05.033

Topjian AA, Telford R, Holubkov R, Nadkarni VM, Berg RA, Dean JM, Moler FW, Therapeutic Hypothermia After Pediatric Cardiac Arrest Trial I. Association of Early Postresuscitation Hypotension With Survival to Discharge After Targeted Temperature Management for Pediatric Out-of-Hospital Cardiac Arrest: Secondary Analysis of a Randomized Clinical Trial. JAMA Pediatr. 2018;172:143-153. doi: 10.1001/jamapediatrics.2017.4043

Topjian AA, Telford R, Holubkov R, Nadkarni VM, Berg RA, Dean JM, Moler FW, Therapeutic Hypothermia after Pediatric Cardiac Arrest Trial I. The association of early post-resuscitation hypotension with discharge survival following targeted temperature management for pediatric in-hospital cardiac arrest. Resuscitation. 2019;141:24-34. doi: 10.1016/j.resuscitation.2019.05.032