Neonatal Life Support

Octubre - 2020




1.-  Impact of Duration of Intensive Resuscitation (NLS 896: SysRev)

It can be difficult for clinicians to decide how long resuscitative efforts should continue in a newborn infant with no heart rate and/or absent respirations with a very low heart rate after sustained resuscitative efforts.12–14 This critical decision involves knowing when to redirect the care of the newborn infant from resuscitation to the provision of comfort and contact with the parents. If such a decision is made too early, some infants with potential to survive with good neurodevelopmental outcome may die. If the decision is made too late, there is likely to be a diminishing potential for survival, especially without severe neurological injury.

In recent years, long-term outcomes for survivors requiring prolonged resuscitation have improved somewhat. In 2015, the CoSTR focused on the following question: “In infants with a gestational age of 36 weeks or greater and an Apgar score of 0 for 10 minutes or longer, despite ongoing resuscitation, what is the rate of survival to NICU admission and death or neurocognitive impairment at 18 to 22 months?” In 2019, the NLS Task Force revised the question slightly to better  reflect the questions clinicians and families ask in such a crisis situation.

The current PICOST attempts to reduce the emphasis on the Apgar score at 10 minutes and puts more focus on the incremental time of resuscitation exposure from
birth as related to outcome.

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

  • Population: Newborn infants presenting with at least 10 minutes of asystole, bradycardia (heart rate less than 60/min), or pulseless electric activity after birth for which CPR is indicated

  • Intervention: Ongoing CPR for incremental time intervals beyond 10 minutes after birth

  • Comparator: CPR discontinued at 10 minutes after birth

  • Outcome21 :

    • Survival (to any age) (critical)

    • Neurodevelopmental outcomes (critical)

    • Composite of survival to any age without moderate or severe neurodisability (critical)

  • Study design: Cross-sectional or cohort studies were eligible for inclusion. Ancillary analyses of RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies, case series) were eligible for inclusion. All years and languages were included if there was an English abstract. Conference abstracts and trial protocols were excluded.

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

A Priori Subgroups to Be Examined

Hypothermia postresuscitative care among newborn infants 36 weeks’ or greater gestational age; 36 weeks’ or greater gestational age versus less than 36 weeks’;
birthweight 2500 g or greater; infants enrolled in population-level cohort studies
PROSPERO Registration: CRD42020157370

Consensus on Science

The SysRev102a identified 15 studies that included 470 infants (see
Figure 2). 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 studies103–117 reporting outcomes of 470 newborns to last known followup (range: 4 months–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%.


Figure 2. Modified flow diagram of number of studies and infants included for each specified outcome for infants experiencing resuscitation that
exceeded 10 minutes.   Moderate to severe NDI was defined by each study.


Among all 470 newborns reported in the literature, including studies that required survival  to NICU admission or enrollment in a cooling protocol for inclusion, 187 (39.8%) survived to last follow-up. The decision was made not to calculate confidence intervals as a result of heterogeneity across 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.103,104,106–112,114–117 Neurodevelopmental outcomes were assessed in 80 survivors. Thirty infants among 80 survivors (37.5%) did not have moderate or severe NDI (range: 0% to 100%).  There was important heterogeneity across studies (and in some cases within studies) about the timing and tools used to assess neurodevelopmental outcomes that precluded calculation of confidence intervals.

For the composite critical outcome of survival without NDI, we identified very low-certainty evidence (downgraded for risk of bias and inconsistency) from 13 studies of 277 infants103,104,106–112,114–117 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 across studies (and in some cases, within studies) about the timing and tools used to assess neurodevelopmental outcomes that precluded calculation of confidence intervals. Note: Neurodevelopmental outcomes in postdischarge follow-up were reported in 13 studies using structured exams.  103,104,106–112,114–117 In 11 studies, these assessments used validated developmental assessment tools.106–112,114–117


These tools included developmental assessment tools such as the Bayley Scales of Infant and Toddler Development (any version) or a Japanese version of the Bayley Scales (Kyoto Scale of Psychological Development); motor assessment tools such as Gross Motor Function Classification System or Peabody Developmental Motor Scales; and cognitive evaluation tools such as Stanford-Binet Test, Griffiths Scales of Child Development (any version), or Wechsler Preschool and Primary Scale of Intelligence (any version).


Two studies103,104 reported only a formal neurological evaluation of the survivors. Auditory and visual assessment varied among studies. Of note, children assessed only by screening tools (such as Denver Developmental Screening Test) in any study were analyzed as lost to followup. Time of follow-up for the 80 survivors assessed for NDI was 12 months or greater in 83% (66/80) of the infants (range: 12 months–8 years) and less than 12 months in 6% (5/80) of the infants. Time of assessment was not reported in 1 study114 with 11% (9/80) survivors.  Moderate and severe NDI were defined by each study.

Subgroup Considerations

Prespecified subgroup analyses for the specified critical outcomes of survival to last follow-up, survival without  NDI, and the composite of survival without  moderate to severe NDI are depicted in Table 4. 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.


Table 4. Subgroup Analyses for Specified Outcomes for Infants Who Had Resuscitation That Exceeded 10 Minutes.

Treatment Recommendations

Failure to achieve return of spontaneous circulation in newborn infants despite 10 to 20 minutes of intensive resuscitation is associated with a high risk of mortality and a high risk of moderate-to-severe neurodevelopmental impairment among survivors. However, there is no evidence that any specific duration of resuscitation consistently predicts mortality or moderate-to-severe neurodevelopmental impairment. If, despite provision of all the recommended steps of resuscitation and excluding reversible causes, a newborn infant requires ongoing cardiopulmonary resuscitation (CPR) after birth, we suggest discussion of discontinuing resuscitative efforts with the clinical team and family. A reasonable time frame to consider this change in goals of care is around 20 minutes after birth. (Weak recommendation, very low-certainty 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 ROSC and long-term survival may still be achievable, and continuing resuscitation for too long, when ROSC may occur but survival is associated with a high risk of severe neurological injury. The appreciable number of survivors without moderate or severe NDI after 10 minutes or greater of resuscitation suggests that early cessation of resuscitation may preclude survival of some infants who may have a good   outcome.

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 ROSC 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 were assessed after discharge, 20% of all infants survived without moderate-to-severe NDI, and 37% of the survivors did not have moderate or severe NDI.107,109–112,116,117  The evidence supporting this recommendation is of very low certainty.


However, we value the possibility of survival and intact survival after ongoing resuscitation. In a large multisite cohort of 659 newborn infants who survived to discharge after more than 1 minute of chest compressions in the delivery room, 25% of survivors received 10 minutes or more of resuscitation.118 This study did not specifically report on infants with 10-minute Apgar scores of 0 or 1. While these data indicate that survival to discharge is possible after a lengthy duration of CPR, neurodevelopmental outcomes among survivors in this study were not reported.

Extremely limited data are available about outcomes of newborn infants who received 20 or more minutes of CPR after birth. Five studies included in this systematic review110–112,116,117 reported results for 39 newborn infants in whom first detectable heart rate or heart rate 100/min or greater occurred at or beyond 20 minutes after birth. Of these, 38% (15/39) survived until last follow up and 40% (6/15) of survivors did not have moderate or severe neuroimpairment.
The task force agreed that in addition to considering duration of resuscitation, it was important to consider whether all recommended resuscitation interventions
were provided. Studies suggest that the time taken to accomplish steps of a resuscitation up to the point of administration of 1 or more doses of epinephrine varies
widely across studies but may take as long as 20 minutes.7,93,111,119 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
might mean in some cases that the full repertoire of recommended resuscitation interventions were not provided before cessation of resuscitation.


Another issue considered by the task force was the potential impact on 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 (see Figure 2). For those infants who ultimately die in early infancy, achieving even this shortterm 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 cease. 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 of the value of extending life, the quality of life, and the acceptance of comfort care as an option, may influence the decision.120–122 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, the family’s stated preferences and values, and the availability of postresuscitative resources, such as neonatal intensive care, and neuroprotective strategies, such as therapeutic hypothermia. Finally, in lowresource settings, where emphasis is given to face-mask ventilation with 21% oxygen for nonbreathing neonates, 123 advanced resuscitation procedures and prolonging resuscitation may not be an option. Therefore, caution must be taken in the global adoption of this treatment recommendation as 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. High-quality resuscitation should be available for infants in need, and training of skills and team performance are 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 postresuscitation care is another aspect that may be considered in the decision-making process.


Monitoring and Implementation

It is important to monitor both short- and long-term outcomes for infants who had a prolonged interval between birth and ROSC. 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.

Prolonged CPR after birth is relatively rare, so an international registry of events, with detailed description of procedures and their timing in the delivery room, postresuscitation care, and neurological outcomes assessed in follow-up, would provide essential evidence to inform the discussion  f how long is too long. Such a registry would also provide valuable information about variability in practice regarding duration of resuscitation in different settings.

For more information, refer to the evidence-to-decision table in Supplement Appendix A-5.

Knowledge Gaps

Many studies reported only outcomes of infants who survived resuscitation and met a specific study eligibility criterion, such as NICU admission or initiation of therapeutic hypothermia. Therefore, estimates of mortality after prolonged resuscitation are likely to underestimate the true rate of death after prolonged resuscitation because this would need to also include infants for whom resuscitation had failed. Studies that account for the full population of newborn infants who receive CPR after birth by using consistent definitions of stillbirths and resuscitation failures are needed to identify the incidence of death and NDI after prolonged resuscitation of term and preterm infants. In addition, the extent and timing of resuscitation interventions 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 responses to resuscitation beyond 10 minutes. More granular information about the interval from birth to detectable heart rate that uses objective measures such as ECG and time to ROSC is needed to inform more precise recommendations about the duration of intensive resuscitation after birth.

Additionally, as the ECG is used more frequently in the delivery room environment, additional information about the presenting rhythm (bradycardia, asystole, pulseless electric activity) preceding chest compressions will be helpful to identify outcomes after 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 the following  :

  • A priori definitions of stillbirths and completeness of resuscitation attempts

  • Complete description of cointerventions (resuscitation procedures), timing of procedures at birth, and interventions in postresuscitative care

  • Description of methods to assess the heart rate during resuscitation by using objective measures, such as ECG, and report of timing for detection of heart rate and heart rate 60/min or greater and 100/min or greater

  • Complete follow-up of survivors with accurate and consistent methods of assessment of neurodevelopment, comparable across studies and population