Neonatal Life Support

Octubre - 2020

 

 

VI.- DRUG AND FLUID ADMINISTRATION


Although seldom needed, the short list of medications and fluids used for delivery room resuscitation of the newborn includes epinephrine and volume expanders.


1.- Epinephrine (Adrenaline) for Neonatal Resuscitation (NLS 593: SysRev)


When the heart is hypoxic and depleted of energy substrate to the point of cardiac arrest, providers must reestablish effective perfusion of the myocardium with
oxygenated blood.91 Epinephrine (adrenaline) causes vasoconstriction, which increases the amount of oxygenated blood entering the coronary arteries and improves myocardial blood flow. Perfusion of the myocardium with oxygenated blood facilitates the synthesis of ATP within myocardial mitochondria, thus enhancing cell viability, contractility, and ROSC.91


In 2010, the NLS CoSTR summarized the evidence comparing the endotracheal route with the intravenous (IV) route for delivery of epinephrine (adrenaline) and concluded that the IV route was preferable.12–14 The NLS Task Force has never conducted a SysRev to evaluate the evidence for epinephrine dose, dose interval, or other routes of delivery. In 2019, the NLS Task Force initiated a new SysRev to identify the evidence addressing these gaps.

 

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

  • Population: Among neonates (of any gestation) less than 28 days of age who have no detected cardiac output or who have asystole or heart rate less than 60/min despite ventilation and chest compressions

  • Intervention: Any nonstandard dose, interval, or route of epinephrine (adrenaline)

  • Comparator: Epinephrine (adrenaline) doses of 0.01 to 0.03 mg/kg via IV at intervals of every 3 to 5 minutes

  • • Outcome21:

    • Mortality before hospital discharge (critical)

    • Survival to neonatal unit admission (critical)

    • ROSC: incidence and time until (critical)

    • HIE stage moderate to severe (term infants only)90 (critical)

    • Intraventricular hemorrhage Grades 3 to 4 (preterm infants only) (critical)55

    • Necrotizing enterocolitis92 (important)

    • Retinopathy of prematurity56 (important)

    • Bronchopulmonary dysplasia54 (important)

    • Periventricular leukomalacia (critical)

    • Neurodevelopmental outcomes (critical)

  • Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Cohort studies may compare different interventions or include only 1 arm receiving 1 intervention. They were eligible for this review if they were considered representative of a defined population (eg, infants born at a hospital between specified dates). Otherwise, they were considered to be (ineligible) case series. All languages were eligible if there was an English abstract. Unpublished studies (eg, conference abstracts, trial protocols) were excluded.

  • Time frame: Literature search was from inception of the searched databases to March 6, 2019.

  • PROSPERO Registration: CRD42019132219


Consensus on Science


The SysRev identified 2 eligible studies including 97 newborn infants.92a A draft CoSTR document based on the SysRev was posted on the ilcor.org website for a 2-week public commenting period on February 18, 2020. Only 2 observational studies were found that addressed any of the comparisons prespecified in the PICOST.7,93 They included both preterm and term infants from the same neonatal unit, although the participants were from different epochs. The overall certainty of evidence was rated as very low for all outcomes, primarily for a very serious risk of bias and very serious imprecision. The individual studies were at a critical risk of bias due to confounding.


For the critical outcome of mortality before hospital discharge, we identified very low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from 1 observational study7 of 50 neonates treated with epinephrine (adrenaline). In this study, there was no benefit associated with initial endotracheal versus IV epinephrine (adrenaline) dose. This lack of benefit was observed despite the fact that larger initial doses of epinephrine (adrenaline) were given via the endotracheal route (0.03–0.05 mg endotracheal dose compared with 0.01 mg/kg per IV dose). See Table 3 for statistical data. In a post hoc analysis, we identified very low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from 2 observational studies7,93 of 97 neonates treated with epinephrine (adrenaline). These studies showed no significant association between route of administration of first dose and receipt of a second dose (RR, 1.94; 95% CI, 0.18–20.96; P=0.59; absolute risk difference, 654 more newborn infants; 95% CI, 570 fewer to 1000 more per 1000 newborn infants would receive additional epinephrine  (adrenaline) dose or doses after the first). This occurred despite infants receiving larger doses given via the endotracheal route in one of the studies.7

 

Table 3. Meta-Analysis of Outcomes After Initial Endotracheal Versus Intravenous Epinephrine

 

No studies specifically reported the critical outcome of survival to neonatal unit admission, but this was likely similar to the inverse of the reported outcome “failure to achieve ROSC.” We found only 1 eligible study comparing different doses of IV epinephrine (adrenaline). 7 This study of 30 neonates who received initial endotracheal epinephrine (adrenaline) allowed a post hoc comparison of 30 newborn infants who received 2 different doses (0.03 versus 0.05 mg/kg per dose) of  endotracheal epinephrine (adrenaline) in different epochs of the study. Although no statistically significant difference was found, there was such serious imprecision as to prevent any conclusion.


We did not find any eligible studies comparing different routes of administration other than the comparisons between IV versus endotracheal epinephrine (adrenaline). We did not find any eligible studies comparing different intervals of epinephrine (adrenaline) administration. We did not find any eligible studies that allowed comparison of any other prespecified important outcomes (HIE stage moderate-severe90 [term infants only]; intraventricular hemorrhage Grades 3–455 [preterm infants only]; other morbidities in early infancy [eg, necrotizing enterocolitis,92 retinopathy of prematurity,56 bronchopulmonary dysplasia,54  periventricular leukomalacia] or neurodevelopmental outcomes).


The NLS Task Force agreed that the key 2010 CoSTR recommendations about epinephrine (adrenaline) administration remain valid.12–14 The 2020 treatment recommendations include some minor editorial revisions in the indications for epinephrine (adrenaline) administration and more specific dose information and guidance about repeat doses than were contained in the 2010 treatment recommendations.

 

Treatment Recommendations


If the heart rate has not increased to 60/min or greater after optimizing ventilation and chest compressions, we suggest the administration of intravascular  epinephrine (adrenaline) (0.01–0.03 mg/kg) (weak recommendation,  very low-certainty evidence).
If intravascular access is not yet available, we suggest  administering endotracheal epinephrine (adrenaline) at a larger dose (0.05–0.1 mg/kg) than the dose used for IV administration (weak recommendation, very lowcertainty evidence). The administration of endotracheal epinephrine (adrenaline) should not delay attempts to establish vascular access (weak recommendation, very low-certainty evidence).


We suggest the administration of further doses of epinephrine (adrenaline) every 3 to 5 minutes, preferably intravascularly, if the heart rate remains less than 60/min  (weak recommendation, very low-certainty evidence). If the response to endotracheal epinephrine (adrenaline) is inadequate, we suggest that an   intravascular dose be given as soon as vascular access is obtained, regardless of the interval after any initial endotracheal dose (weak recommendation, very low- certainty evidence).


Justification and Evidence-to-Decision Framework Highlights
 

This topic was prioritized by the NLS Task Force because epinephrine (adrenaline) administration is considered to have a key role for newborns who have not responded to all previous steps in resuscitation. The last of NLS CoSTR addressing epinephrine (adrenaline) administration was conducted a decade ago,12–14 at a time when the ILCOR evidence evaluation did  not use the GRADE assessment tools. Finally, the NLS Task force was aware of new cohort studies published after 2010.


In making these recommendations, the NLS Task Force considered the fact that the very limited human infant evidence does not demonstrate greater effect of endotracheal versus IV epinephrine (adrenaline). Although the population identified for this SysRev was human neonates, the task force reviewed 1 animal study.
In a RCT of term lambs undergoing perinatal transition with asphyxia-induced cardiopulmonary arrest,94 peak plasma epinephrine (adrenaline) concentrations were higher and were achieved sooner after central venous epinephrine (adrenaline) (right atrium 470±250 ng/mL  or low umbilical venous cord 450±190 ng/mL at 1 minute) than after endotracheal epinephrine (adrenaline) (130±60 ng/mL at 5 minutes; P=0.03), despite lower administered central venous than endotracheal doses
(0.03 mg/kg central venous IV dose versus 0.1 mg/kg endotracheal dose).

 

In the same study, central venous compared with endotracheal epinephrine (adrenaline) administration resulted in a shorter median time (interquartile range) to achieve ROSC (2 [95% CI, 1.9–3] versus 4.5 [95% CI, 2.9–7.4] minutes; P=0.02), using a lower dose for central venous than for endotracheal administration. In addition, central venous compared with endotracheal epinephrine (adrenaline) administration resulted in higher rates of ROSC (86% [19/22] versus 54% [12/22]; P=0.02, respectively), using the same lower central venous compared with endotracheal doses.94


Subgroup Considerations


There was no evidence to suggest any variation in recommendations for subgroups of infants (eg, term versus preterm).
 

Implementation Considerations
 

This recommendation is similar to the 2010 treatment recommendation (ie, route and dose of epinephrine [adrenaline] NLS-008A, NLS-008B, NRP-009A, NRP- 009B) ,12–14 so the task force agreed that there are no new implications for implementation.


Monitoring and Implementation


We recommend that health services monitor the use of epinephrine (adrenaline) for newborn resuscitation, together with the outcomes of epinephrine (adrenaline)
treatment reported in this review. Wherever possible, this monitoring should include the characteristics of the infants, the resuscitation measures they have received before epinephrine (adrenaline), the dose(s), route(s) and treatment intervals, and any adverse effects of treatment. It is unlikely there will be clinical trials to provide high-certainty evidence on which to base future treatment recommendations about epinephrine (adrenaline) doses, administration time intervals, and delivery routes. However, collection and publication of clinical observational studies can increase the volume of good-quality data to validate or improve treatment recommendations.

 

Finally, the task force agreed that frequency of epinephrine (adrenaline) administration during resuscitation may reflect the quality of earlier steps in intrapartum management and resuscitation.


See Supplement Appendix A-3 for the evidence-todecision table associated with this SysRev.


Knowledge Gaps


The NLS Task Force identified the following specific gaps in knowledge :

  • Optimal (heart rate) thresholds for administration of epinephrine (adrenaline)

  • Optimal dose and interval of epinephrine (adrenaline)

  • Optimal epinephrine dose and intervals specific to gestational age

  • Optimal route and method of epinephrine (adrenaline) administration

  • Potential harms of epinephrine (adrenaline) (single or multiple doses)

  • Effect of vasoactive drugs other than epinephrine (adrenaline)

  • Human factors approach to achieve the timely administration of epinephrine (adrenaline)

  • Neurodevelopmental outcomes after epinephrine (adrenaline) use

Providers must make the decision to administer epinephrine (adrenaline) rapidly during newborn resuscitation. In addition, epinephrine (adrenaline) use is uncommon and unpredictable. As a result, it may be difficult to perform adequate and ethical randomized trials of human newborn infants with prior parental informed consent. Prospective, multicenter cluster-randomized trials could be a good option.  Newborn animal studies are also needed to address pharmacokinetics and pharmacodynamics to determine the optimal dose and route of epinephrine (adrenaline) to inform the optimal design of human infant studies.


2.- Intraosseous Versus Umbilical Vein for Emergency Access (NLS 616: SysRev)


In the rare circumstance where epinephrine (adrenaline) or volume is needed during neonatal resuscitation, vascular access is urgently required. There are
questions as to the best route of vascular access to use. The last SysRev about this topic for neonates was in 2010 (NLS-020A intraosseous [IO] versus
IV).12–14 In 2020, the NLS Task Force joined the Advanced Life Support Task Force and the Pediatric Life Support Task Force to complete a joint SysRev with
meta-analysis.95

 

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

  • Population: Newborn infants in any setting (inhospital or out-of-hospital) with cardiac arrest (includes severe bradycardia and inadequate perfusion requiring chest compressions)

  • Intervention: Placement of an IO cannula with drug administration through this IO site during cardiac arrest

  • Comparator: Placement of an IV cannula (umbilical vein in newborn infants) and drug administration through this IV during cardiac arrest

  • Outcome21:

    • Death during event, within 24 hours and before hospital discharge (critical)

    • Long-term neurodevelopmental outcomes (critical) 

    • ROSC: any signs of cardiac output with heart rate 60/min or greater, and time to ROSC (critical)

    • Brain injury (HIE Stage 2–3 Sarnat,90 [term only], intraventricular hemorrhage Grades 3–4,55 periventricular leukomalacia, preterm only) (critical)

    • Time to secure access (important)

    • Morbidity related to IO (osteomyelitis, fracture, epiphyseal plate injury, compartment syndrome) or to IV (extravasation, embolic phenomenon, phlebitis) (important)

  • Study design  :

    • Inclusion criteria: Randomized trials, non-RCTs, and observational studies (cohort studies and case-control studies) comparing IO with IV administration of drugs; randomized trials assessing the effect of specific drugs (eg, epinephrine [adrenaline]) in subgroups related to IO versus IV administration; studies assessing cost-effectiveness for a descriptive summary

    • Exclusion criteria: Ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, or unpublished studies

    • Search: All years and languages were included if there was an English abstract. MEDLINE (Ovid interface), Embase (Ovid interface), and Cochrane Central Register of Controlled Trials literature search was conducted from 1946 to September 12, 2019, as well as ongoing trials on International Clinical Trials Registry Platform.


A Priori Subgroups to Be Examined
 

Cardiac and noncardiac causes of circulatory collapse; gestational age (preterm less than 37 weeks and term 37 weeks or greater); delivery room or other site; inhospital or out-of-hospital; central or peripheral IV access; pediatric trained personnel versus non pediatric PROSPERO Registration: CRD42020150877


Consensus on Science
 

Although small clinical series and case reports suggest that medications and fluids can be successfully delivered  by the IO route during neonatal resuscitation, 96,97 case series also report complications with IO catheter insertion or use.96,98–102 To determine if IO or intravascular access is more effective for neonatal resuscitation, evidence from neonatal literature was sought and considered by the NLS Task Force as part of a joint effort with the Adult Life Support and Pediatric Life Support Task Forces. No studies meeting the a priori inclusion criteria were found for newborn infants, precluding meta-analysis in this population. A draft CoSTR was developed that reflected the lack of data and was posted on the ILCOR website; the draft was viewed more than 2600 times, and more than 50 comments were posted. The majority were supportive of the conclusions.


No evidence was identified for newborn infants comparing use of IO and IV cannulas for drug administration in any setting (in-hospital or out-of-hospital) for any prespecified outcome of the review. In 2010, the NLS Task Force said that temporary IO access to provide fluids and medications to resuscitate critically ill neonates may be indicated after unsuccessful attempts to establish IV vascular access or when caregivers are skilled at securing IO access.12–14 The 2020 SysRev identified reports of serious complications after use of IO access in neonates.96,98–102 As a result, the 2020 treatment recommendations are stronger in support of the umbilical venous route as the primary route for vascular access during delivery room resuscitation but continue to allow that in some circumstances the IO route is acceptable.


Treatment Recommendations


We suggest umbilical venous catheterization as the primary method of vascular access during newborn infant resuscitation in the delivery room. If umbilical venous access is not feasible, the intraosseous route is a reasonable alternative for vascular access during newborn resuscitation (weak recommendation, very low-certainty evidence).  Outside the delivery room setting, we suggest that either umbilical venous access or the IO route may be used to administer fluids and medications during newborn resuscitation (weak recommendation, very low-certainty evidence). The actual route used may depend on local availability of equipment, training, and experience.
 

Justification and Evidence-to-Decision Framework Highlights
 

In making this recommendation, we recognize the absence of data from human neonatal studies supporting any advantage of IO over umbilical venous access.
There are a number of case reports of serious adverse effects of IO access in neonates, including tibial fractures and extravasation of fluid and medications resulting in compartment syndrome and amputation.96,98–102 The rate of adverse effects attributable to emergency umbilical venous catheterization is unknown. However, public feedback emphasized umbilical access as the technique most commonly taught to and used by neonatal providers, recognizing that IO access may be helpful in out-of-hospital settings or later in the neonatal intensive care stay when the umbilical vein is no longer patent.


For further information, see the evidence-to-decision table in Supplement Appendix A-4.


Knowledge Gaps
 

The absence of clinical trials, cohort studies, and casecontrol studies leaves many gaps related to IO versus umbilical vein access during newborn resuscitation. We failed to identify even case series or case reports of IO use in neonatal resuscitation at delivery.


Specific research is required in preterm and term neonates :

  • Determination of time from start of CPR to achieving successful IO placement

  • Determination time from start of CPR to achieving successful IV placement in umbilical vein

  • Optimal IO device suitable for newborn infants

  • Optimal site (head of humerus, proximal tibia, other) for successful IO access and drug and fluid administration

  • Short- and long-term safety of IO placement during newborn resuscitation

  • Complications related to emergency umbilical venous catheterization

  • Pharmacokinetics and plasma availability of drugs administered through IO compared with IV routes

  • Optimal training for IO placement and IV umbilical vein placement during neonatal resuscitation

  • How to best secure and maintain any emergency vascular access devices

  • Optimal method to determine correct placement of any emergency vascular access device

  • Whether results of studies in animal and simulation models apply to clinical practice

  • IO access during neonatal resuscitation outside the delivery room


3.- Volume Infusion During Neonatal Resuscitation (NLS 598: EvUp)


In the absence of a history of blood loss, there is limited evidence of benefit from administration of volume during resuscitation of newborns who have not responded to chest compressions and epinephrine (adrenaline).  This topic was most recently reviewed by the NLS Task Force in 2010.12–14 In 2020, the NLS Task Force undertook an EvUp to see if additional literature warranted consideration of a request for a new SysRev.


The EvUp identified no human studies and a single animal RCT (see Supplement Appendix C-8); the results of this study supported the 2010 CoSTR for NLS treatment recommendations.12–14 The NLS Task Force agreed that there is no reason at this time to suggest a new SysRev or a change in the 2010 treatment recommendations.


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

  • Population: Term and preterm newborn infants who receive resuscitation immediately after birth and who have a heart rate less than 60/min after
    chest compressions and epinephrine (adrenaline) and/or suspected hypovolemia based on history and examination.

  • Intervention: Blood volume expansion with blood (red cells or whole blood), colloid (eg, albumin, plasma), crystalloid (eg, 0.9% sodium chloride) or
    other solution

  • Comparator: No blood volume expansion

  • Outcome21  :

    • Survival (to any stage) (critical)

    • Neurodevelopmental outcomes (with ageappropriate, validated tools) (critical)

    • Time to ROSC (or heart rate 60/min or greater) (important)

    • Subsequent use of vasopressor infusion(s) (important)

    • Blood pressure at specified time (important)

    • Pulmonary edema (important)

    • Serious neonatal morbidity (including intraventricular hemorrhage, necrotizing enterocolitis, persistent pulmonary hypertension of the newborn, HIE, pulmonary hemorrhage) (critical)

Treatment Recommendation
 

These treatment recommendations are unchanged from 2010.12–14
Early volume replacement with crystalloid or red cells is indicated for newborn infants with blood loss who are not responding to resuscitation. There is insufficient evidence to support the routine use of volume administration in the newborn infant with no blood loss who is refractory to ventilation, chest compressions, and epinephrine. Because blood loss may be occult, a trial of volume administration may be considered in newborn infants who do not respond to resuscitation.
 

Sodium Bicarbonate During Neonatal Resuscitation (NLS 606: EvUp)


In 2019, a request was made by members of the European Resuscitation Council for the NLS Task Force to consider an EvUp concerning the use of sodium bicarbonate during neonatal resuscitation. Since 2005, inconsistency has developed internationally as to whether sodium bicarbonate is even mentioned in council
guidelines. The 2010 CoSTR briefly mentioned that sodium bicarbonate may very rarely be useful after resu scitation. 12–14 In 2020, the NLS Task Force undertook

an EvUp to determine if additional evidence published after 2020 warranted consideration of a new SysRev.
The EvUp (see Supplement Appendix C-9) identified only evidence that supported the 2010 treatment recommendations. 12–14 Thus, the task force agreed that no SysRev or change in the 2010 treatment recommendation is warranted.

 

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

  • Population: Newborn infants who are receiving resuscitation in the hospital

  • Intervention: Sodium bicarbonate administration

  • Comparator: No sodium bicarbonate

  • Outcome21  :

    • Survival (to hospital discharge or as defined by authors) (critical)

    • ROSC (critical)

    • HIE stage moderate to severe90 (term infants only) (critical)

    • Intraventricular hemorrhage Grades 3 to 455 (preterm only) (critical)

    • Other morbidities in early infancy (eg, necrotizing enterocolitis,92 retinopathy of prematurity,56 bronchopulmonary dysplasia,54 periventricular leukomalacia) (important)

    • Neurodevelopmental outcomes (critical)


Treatment Recommendation


This treatment recommendation (below) is unchanged from 2010.12–14
Sodium bicarbonate is discouraged during brief CPR but may be useful during prolonged arrests after adequate ventilation is established and there is no response
to other therapies.