Impact of duration of intensive resuscitation (NLS #895): Systematic Review

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 were recused from the discussion as they declared a conflict of interest: None

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: Elizabeth E. Foglia and Myra H. Wyckoff authored studies cited in this CoSTR that were not included in the systematic review.

CoSTR Citation

Foglia EE, Weiner G, de Almeida MF, Liley HG, Aziz K, Fabres J, Fawke J, Hosono S, Isayama T, Kapadia VS, Kim HS, Liley HG, McKinlay CJD, Mildenhall L, Perlman JM, Roehr CC, Schmoelzer GM, Szyld E, Trevisanuto D, Velaphi S, Rabi Y, Wyllie JP, Wyckoff MH and Guinsburg R. Impact of duration of intensive neonatal resuscitation at birth. [Internet] Brussels, Belgium. International Liaison Committee on Resuscitation (ILCOR) Neonatal Life Support Task Force, February 19, 2020. 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 available literature regarding the impact of duration of intensive neonatal resuscitation at birth (PROSPERO registration CRD42020157370 https://www.crd.york.ac.uk/pro... by Neonatal Life Support Task Force with involvement of clinical content experts. Evidence for neonatal literature was sought and considered by the Newborn Life Support Task Force with the help of an Information Specialist from Apex Information. These data were taken into account when formulating the Treatment Recommendations.

Systematic Review

Webmaster to insert the Systematic Review citation and link to PubMed using this format when it is available.

To be submitted in March 2020

PICOST

Population: Newborn infants presenting with at least 10 minutes of asystole, bradycardia (heart rate <60 beats per minute), or pulseless electrical activity after birth for which cardiopulmonary resuscitation is indicated.

Intervention: Ongoing cardiopulmonary resuscitation for incremental time intervals beyond 10 minutes after birth.

Comparator: Cardiopulmonary resuscitation discontinued at 10 minutes after birth

Outcomes:

• Survival to any age

• Long term neurodevelopmental outcomes
• Composite of survival to any age without moderate or severe neurodisability

Study Designs: Cross sectional or cohort studies were eligible for inclusion. Ancillary analyses of randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies, case series) were eligible for inclusion. All languages were eligible if there was an English abstract. Unpublished studies (e.g., conference abstracts, trial protocols) were excluded.

A priori subgroups to be examined:

Hypothermia post-resuscitative care among newborn infants ≥ 36 weeks gestational age; Gestational age ≥36 weeks vs <36 weeks; Birthweight ≥2500 vs <2500 grams; Infants enrolled in population-level cohort studies.

Timeframe: All years were included from inception of the searched databases to October 17, 2019.

PROSPERO Registration CRD42020157370.

RISK OF BIAS:

Bias was assessed per outcome by modified ROBINS-I tool since our literature review only yielded case series and small cohort studies.

Consensus on Science

Attached: Figure: Modified flow diagram of number of studies and infants included for each specified outcome for infants who had resuscitation continued beyond 10 minutes. Moderate to severe neuroimpairment was defined by each study.

NLS-896-Impact-of-Duration-of-Resus-Co STR-2.19.20_Fi GURE

For the critical outcome of survival until last follow up, we identified very low certainty evidence (downgraded for risk of bias and inconsistency) from 15 studies {Ayrapetian 2017 545; Casalaz 1998 112; Haddad 2000 1210; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77} reporting outcomes of 470 newborns to last known follow up (which ranged from 4 months to 8 years of age). The number of enrolled newborns ranged from 3 to 177 per study. Across studies, reported survival rates to last follow up ranged from 1.7% to 100%. Among all 470 newborns reported in the literature, including studies that required survival to NICU admission or enrolment in a cooling protocol for inclusion, 187 (39.8%) survived to last follow up. The decision was made not to calculate confidence intervals due to the heterogeneity of included studies.

For the critical outcome of neurodevelopmental outcomes among survivors, we identified very low certainty evidence (downgraded for risk of bias and inconsistency) from 13 studies including 277 infants {Ayrapetian 2017 545; Casalaz 1998 112; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15}. Neurodevelopmental outcomes were assessed in 80 survivors. Thirty (37.5%) did not have moderate or severe neurodevelopmental impairment (range 0-100%). There was important heterogeneity between studies (and in some cases- within studies) regarding the timing and tools used to assess neurodevelopmental outcomes. The decision was made not to calculate confidence intervals due to the heterogeneity of included studies.

For the composite critical outcome of survival without neurodevelopmental impairment, we identified very low certainty evidence (downgraded for risk of bias and inconsistency) from 13 studies of 277 infants {Ayrapetian 2017 545; Casalaz 1998 112; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15} reporting neurodevelopmental outcomes. Among all 277 infants reported in these studies, 69% died before last follow up, 18% survived with moderate to severe impairment, and 11% survived without moderate to severe impairment (2% lost to follow up). There was important heterogeneity between studies (and in some cases, within studies) regarding the timing and tools used to assess neurodevelopmental outcomes. The decision was made not to calculate confidence intervals due to the heterogeneity of included studies.

Note: Neurodevelopmental outcomes in post-discharge follow up were reported in 13 studies using structured exams. {Ayrapetian 2017 545; Casalaz 1998 112; Harrington 2007 463.e1; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15}. In 11 studies, these assessments using validated developmental assessment tools {Ayrapetian 2017 545; Jain 1991 778; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Socol 1994 991; Sproat 2017 F262; Zhang 2019 Jun15}. These tools included developmental assessment tools such as the Bayley Scales of Infant and Toddler Development (BSID, any version) or a Japanese version of BSID (Kyoto Scale of Psychologic Development – KSPD); motor assessment tools such as Gross Motor Function Classification System (GMFCS) or Peabody Developmental Motor Scales; and cognitive evaluation tool such as Stanford-Binet Test, Griffiths Scales of Child Development (any version) or Wechsler Preschool and Primary Scale of Intelligence (any version). Two studies {Casalaz 1998 112; Harrington 2007 463.e1} reported only a formal neurologic evaluation of the survivors. Auditory and visual assessment varied among studies. Of note, children assessed by screening tools only in any studies (such as Denver Developmental Screening Test) were analyzed as lost to follow-up. Time of follow-up for the 80 survivors assessed for neurodevelopmental impairment was ≥12 months in 66/80 (83%) infants (range: 12 months - 8 years) and <12 months in 5/80 (6%) infants. Time of assessment was not reported in 1 study {Patel 2004 136} with 9/80 (11%) survivors. Moderate and severe neurodevelopmental impairment were considered according to each study definition.

SUBGROUP CONSIDERATIONS

Table: Subgroup analyses for specified outcomes for infants who had resuscitation continued beyond 10 minutes

* 8 studies with 105 infants reported post-discharge outcomes

**11 studies with 166 infants reported post-discharge outcomes

***5 studies with 42 infants reported post-discharge outcomes

Population-level studies: {Casalaz 1998 112; Harrington 2007 463.e1; Jain 1991 778; Sproat 2017 F262; Zhang 2019 Jun15}

Studies with any infants treated with therapeutic hypothermia: {Ayrapetian 2017 545; Kasdorf 2015 F102; Natajaran 2013 F473; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77}

Studies with any infants born at gestational age ≥36 weeks: {Ayrapetian 2017 545; Casalaz 1998 112; Harrington 2007 463.e1; Kasdorf 2015 F102; Natajaran 2013 F473; Patel 2004 136; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77}

Studies with any infants born at gestational age < 36 weeks {Casalaz 1998 112; Harrington 2007 463.e1; Shah 2015 492; Sproat 2017 F262; Zhang 2019 Jun15; Zhong 2019 77}.

Insufficient details about birthweight precluded the planned subgroup analysis based on birthweight.

Given the small sample sizes and heterogeneity of study characteristics, there is no strong evidence on which to base recommendations for specific subgroups of infants.

Treatment Recommendations

Failure to achieve return of spontaneous circulation in newborn infants after 10-20 minutes of intensive resuscitation is associated with a high risk of mortality and a high risk of moderate to severe neuroimpairment among survivors. However, there is no evidence that any specific duration of resuscitation consistently predicts mortality or moderate to severe neurodevelopmental impairment. If a newborn infant requires ongoing cardiopulmonary resuscitation (CPR) after birth despite completing all the recommended steps of resuscitation and excluding reversible causes, we suggest initiating discussion of discontinuing resuscitative efforts with the clinical team and family. A reasonable timeframe for this change in goals of care is around 20 minutes after birth. (Weak recommendation, very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

In making this recommendation, we recognize the need to balance the risk of ceasing resuscitation too early, when return of spontaneous circulation and long-term survival may still be achievable, and continuing resuscitation for too long, when return of spontaneous circulation may occur but survival is associated with a high risk of severe neurologic injury. The appreciable number of survivors who do not have moderate or severe neurodevelopmental impairment after ≥10 minutes of resuscitation suggests that early cessation of resuscitation may preclude survival of some infants who may have had a good prognosis.

While an Apgar score of 0 or 1 at 10 minutes is a strong predictor of mortality and morbidity, recent case reports and series have reported favorable outcomes among newborn infants with Apgar scores of 0 or 1 at 10 minutes after birth who achieved return of spontaneous circulation and received therapeutic hypothermia. In this subgroup of newborns with severe depression at birth, both survival and survival without moderate to severe impairment have been reported. Among 105 such infants reported in the literature with Apgar scores 0 or 1 who were successfully resuscitated, were treated with therapeutic hypothermia, and assessed after discharge, 20% survived without moderate to severe impairment and 37% of survivors did not have moderate or severe neurodisability {Ayrapetian 2017 545; Kasdorf 2015 F102; Natajaran 2013 F473; Sarkar 2010 F423; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15}.

The evidence supporting this recommendation is of very low certainty. However, we value the possibility of survival and intact survival following ongoing resuscitation. In a large multisite cohort of 659 newborn infants who survived to discharge following >1 minute chest compressions in the delivery room, 25% of survivors received 10 minutes or more of CPR {Foglia 2020 pii: S0300-9572(20)30031-9}. This study did not specifically report on infants with 10-minute Apgar scores of zero or one. While these data indicate that survival to discharge is possible following a prolonged duration of CPR, neurodevelopmental outcomes among survivors in this study were not reported.

Extremely limited data are available regarding outcomes of infants who received 20 or more minutes of CPR after birth. Six studies included in this systematic review {Ayrapetian 2017 545; Shah 2015 492; Shibasaki 2020 64; Sproat 2017 F262; Zhang 2019 Jun15} reported results for 39 patients in which first detectable heart rate or heart rate ≥100 beats per minute occurred at or beyond 20 minutes after birth. Of these patients, 15/39 (38%) survived until last follow up and 6/15 (40%) survivors did not have moderate or severe neuroimpairment.

The Task Force considered that as well as duration of resuscitation, it was important to consider whether all recommended resuscitation interventions had been provided. Studies suggest that the time taken to accomplish steps of a resuscitation up to the point of administration of one or more doses of epinephrine varies widely across studies but may take as long as 20 minutes {Barber 2006 1028; McKinsey 2016 F244; Halling 2017 232; Sprout 2017 F262}. The variation in the interval from birth to completion of these steps may depend on the characteristics and time to attendance of the resuscitation team. Thus, using a single time interval after birth to discontinue intensive resuscitation for all newborns implies might mean that in some cases, the full repertoire of recommended resuscitation interventions had not yet been provided before cessation of resuscitation.

Another issue considered by the Task Force is the potential impact for infants and their families. Among the included studies, most deaths occurred either in the delivery room/birth suite or during the initial hospitalization. In this systematic review, rates of survival to discharge were similar to rates of survival to last follow up (Figure). For those infants who ultimately die in early infancy, achieving even this short-term survival may provide the family the time and opportunity to participate in decision making and care of their infant. Moreover, intact survival is possible among surviving infants. In this systematic review, 38% of surviving infants did not have moderate or severe impairment.

Given these considerations, we do not recommend a specific duration of resuscitation after which point resuscitative efforts should be ceased. Instead, we suggest that providers consider changing the goals of care if a newborn infant has not responded to all recommended steps of resuscitation that are appropriate to the given setting. We acknowledge that cultural and religious differences, including different perceptions on the value of extending life, the quality of life, and the acceptance of comfort care as an option, may influence the decision {Cuttini 2000 212; Fanaroff 2014 701; Schijvers 2018 1710}.

Ultimately, the decision to initiate and continue resuscitative efforts should be individualized and informed by factors such as gestational age, the presence of congenital anomalies, the timing of perinatal insult (if known), the perceived adequacy of resuscitative interventions performed, the family’s stated preferences and values, and the availability of post-resuscitative resources such as neonatal intensive care and neuroprotective strategies, such as therapeutic hypothermia. Finally, in low resource settings, where emphasis is given to face mask ventilation with 21% oxygen for non-breathing neonates {Kamath-Rayne 2018 538}, advanced resuscitation procedures and prolonging resuscitation may not be an option. Therefore, caution must be taken to globally adopt this treatment recommendation, and local/regional discussion and customization are necessary.

IMPLEMENTATION CONSIDERATIONS

Acceptability of the intervention should be thoroughly discussed in the different settings according to cultural, ethical and moral standards that prevail in each country or region. Optimal resuscitation should be available for infants in need, and training of skills and team performance is critical to achieve it. Communication with families should be optimized, and whenever possible, parents’ wishes and values must be considered even in urgent and stressful situations. Availability of neonatal intensive care and neuroprotective strategies for post-resuscitation care is another aspect that may be considered in the decision process

MONITORING AND IMPLEMENTATION

Monitoring and evaluation of prognosis of infants that receive prolonged resuscitation at birth is extremely important. In addition, although health equity was not objectively reported for prolonged neonatal resuscitation, it is possible that prolonged resuscitation may be offered to a higher proportion of infants in higher-resource settings; outcomes may also be better in settings with full availability of intensive care and neuroprotective strategies. Since prolonged CPR after birth is relatively rare, an international registry of events, with detailed description of procedures and their timing in the delivery room, post-resuscitation care and neurologic outcomes assessed in follow-up would provide essential evidence to inform the discussion of “how long is too long.” Such a registry would also provide valuable information on variations in practice regarding duration of resuscitation in different settings.

Knowledge Gaps

Many studies only reported outcomes of infants who survived resuscitation and met a specific study eligibility criterion, such as neonatal intensive care unit admission or initiation of therapeutic hypothermia. Therefore, estimates of mortality following prolonged resuscitation likely underestimate the actual incidence of death when failed resuscitations are considered. Studies accounting for the full population of newborn infants who receive CPR after birth, using consistent definitions of stillbirths and resuscitation failures, are needed to identify the incidence of mortality and neurodevelopmental impairment after prolonged resuscitation of term and preterm infants.

In addition, the extent and timing of resuscitation procedures were not reported in most studies; therefore, prognosis of newborn infants after prolonged resuscitation at birth is inferred from the available data. Further, most available studies characterized the infant’s response to resuscitation using the Apgar score at 10 minutes, which is prone to subjective assessment and does not provide information about ongoing assessments or response to resuscitation beyond 10 minutes. More granular information about the interval from birth to detectable heart rate using objective measures such as electrocardiogram (ECG) and time to return of spontaneous circulation is needed to inform more precise recommendations regarding the duration of intensive resuscitation after birth. Additionally, as ECG has become more frequently used in the delivery room environment, additional information about the presenting rhythm (bradycardia, asystole, pulseless electrical activity) preceding chest compressions will be helpful to identify outcomes following these varied presentations.

Therefore, studies that report outcomes on the full population of infants who present without signs of life and receive intensive resuscitation are needed with:

• - A priori definitions of stillbirths and complete resuscitation attempts
• - Complete description of co-interventions (resuscitation procedures), timing of procedures at birth, and interventions in post-resuscitative care
• - Description of methods to assess the heart rate during resuscitation using objective measures, such as ECG, and report of timing for detection of heart rate and heart rate >60 and >100 beats per minute
• - Complete follow up of survivors with accurate and consistent methods of assessment of neurodevelopment, comparable across studies and population

Attachments

Evidence-to-Decision Table: NLS-896-Impact-of-Duration-of-Resus

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