10-Minute Apgar Score following HIE

Outcome of Term Infants Using Apgar Scores at 10 Minutes Following Hypoxic-Ischemic Encephalopathy. 

OBJECTIVE: The objective of this study was to determine whether Apgar scores at 10 minutes are associated with death or disability in early childhood after perinatal hypoxic-ischemic encephalopathy.    
      
METHODS: This was a secondary analysis of infants who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hypothermia trial. Infants who were born at 36 weeks’ gestation and had clinical and/or biochemical abnormalities at birth and encephalopathy at <6 hours were studied. Logistic regression and classification and regression-tree analysis were used to determine associations between Apgar scores at 10 minutes and neurodevelopmental outcome, adjusting for covariates. Death or disability (moderate or severe) at 18 to 22 months of age was the measured outcome.

RESULTS: Twenty of 208 infants were excluded (missing data). More than 90% of the infants had Apgar scores of 0 to 2 at 1 minute, and Apgar scores at 5 and 10 minutes shifted to progressively higher values; at 10 minutes, 27% of infants had Apgar scores of 0 to 2. After adjustment, each point decrease in Apgar score at 10 minutes was associated with a 45% increase in the odds of death or disability. Death or disability occurred in 76%, 82%, and 80% of infants with 10-minute Apgar scores of 0, 1, and 2, respectively. Classification and regression-tree analysis indicated that Apgar scores at 10 minutes were discriminators of outcome.  

CONCLUSIONS: Apgar scores at 10 minutes provide useful prognostic data before other evaluations are available for infants with hypoxic-ischemic encephalopathy. Death or moderate/severe disability is common but not uniform with Apgar scores of <3; caution is needed before adopting a specific time interval to guide duration of resuscitation.(Laptook AR, Shankaran S, Ambalavanan N, et al.  PEDIATRICS (Dec 2009); 124:1619-1626.)   

Anti-Reflux Medications in Preemies

Cross-Over Trial of Treatment for Bradycardia Attributed to Gastroesophageal Reflux in Preterm Infants.  

Objective.  To determine whether anti-reflux medications reduce bradycardia episodes attributed to clinically suspected gastroesophageal reflux (GER).

Study design.  We conducted a masked trial comparing metoclopramide, 0.2 mg/kg/dose q 6 hours, and ranitidine, 2 mg/kg/dose q 8 hours, with saline placebo. Each infant served as his own control. Preterm infants having >3 bradycardia episodes per 2 days were eligible if the clinician intended to begin anti-reflux medications for bradycardia attributed to GER.

Results.  The mean (SD) birth weight was 1238 (394) g and gestational age was 29 (3) weeks. Eighteen infants were enrolled at 35 (22) days of age. There were 4.6 (3.1) and 3.6 (2.7) bradycardia episodes per day in the drug and placebo periods, respectively. The mean difference (drug minus placebo) was 0.94 (95% CI, 0.04 to 1.95) (P = .04 by t test). There was a decrease in bradycardia episodes over time (P < .001 by nonparametric repeated-measures analysis of variance).

Conclusions.  Anti-reflux medications did not reduce, and may have increased, bradycardia episodes in preterm infants with GER. Because there was an improvement of bradycardia episodes over time, unrelated to treatment, unmasked therapeutic trials of medications are likely to lead to misleading conclusions. ( Wheatley E, and Kennedy KA.  J Pediatr (October 2009); 155: 516-521.e1)

Comments:  

We have now reviewed at least 8 articles demonstrating the lack of benefit from GE reflux meds in preventing apnea and bradycardia in preterm infants. To make matters worse, the present study actually showed a statistically-significant INCREASE in bradycardia episodes when these drugs were used.  Enough is enough!  Let’s stop using anti-reflux medications to treat bradycardic episodes in preemies.- -Andy Kairalla, Baptist Children's Hospital

The treatment choice in this study is unconventional as metoclopramide is an anti-emetic rather than a prokinetic agent. In other studies use of thickeners and alginates may have caused any reflux to be more prolonged even if episodes less frequent. There is a need for good DBRCTs using each treatment alone to answer the question on when or if to treat suspected GER in preemies. The subjects also should be grouped by type of bradycardia - with or without evidence of central, obstructive or mixed apnoea as well as any evidence of slow tolerance of feeds.
-Una MacFadyen, Stirling Royal Infirmary

Energy Expenditure for Breastfeeding and Bottle-Feeding Preterm Infants

OBJECTIVE: We hypothesized that resting energy expenditure (REE) would be higher after breastfeeding than after bottle-feeding.
METHODS: Nineteen preterm infants (gestational age: 32 weeks) in stable condition who were nourished entirely with their mothers' breast milk were assigned randomly to feeding either by bottle or at the breast. Each infant served as his or her own control subject. REE was measured for 20 minutes after feeding. Breastmilk quantity was evaluated with prefeeding and postfeeding weighing. REE values for bottle-feeding and breastfeeding were compared with paired t tests.
RESULTS: Contrary to our null hypothesis, the group's mean REE values after bottle-feeding and breastfeeding were very similar (284.7 ± 26.8 kJ/kg per day [68.3 ± 6.4 kcal/kg per day] vs 282.6 ± 28.5 kJ/kg per day [67.5 ±6.8 kcal/kg per day]; not significant). The duration of feeding was significantly longer for breastfeeding than for bottle-feeding (20.1 ± 7.9 vs 7.8 ± 2.9 minutes; P < .0001).
CONCLUSION: There was no significant difference in REE when infants were breastfed versus bottle-fed. Longer feeding times at the breast did not increase REE. We speculate that it is safe to recommend feeding at the breast for infants born at >32 weeks when they can tolerate oral feeding. (Irit Berger, Valentin Weintraub, et al. PEDIATRICS Vol. 124 No. 6 December 2009, pp. e1149-e1152)

Platelet transfusions in neonates are associated with increased mortality, even when they're given to treat severe thrombocytopenia, investigators report.

Based on this finding, Dr. Robert D. Christensen and associates at Intermountain Healthcare in Salt Lake City recommend that for neonates with a very low risk for intravascular hemorrhage, platelet transfusions should not be given solely to keep platelet counts above an arbitrary level.

Instead, they advise in the December issue of Pediatrics, platelet transfusions should be reserved for infants with bruising, oozing, or bleeding.

"Past studies have examined neonates with low platelet counts, but this study uniquely focuses on neonates with severe thrombocytopenia," Dr. Christensen told Reuters Health.

Out of 11,281 admissions to Intermountain Healthcare level III NICUs from 2003 to 2007, 273 infants (12.4%) had at least one platelet count no higher than 50,000/microliter.

Forty-two of these patients had two or more platelet counts of no more than 50,000/microliter, and 235 (86%) received a median of 5 platelet transfusions.

"No deaths occurred among those who received no platelet transfusions, whereas the mortality rate increased in a step-wise manner according to the number of platelet transfusions received," the authors report.

On the other hand, there was no association between platelet counts and mortality.

There was also no significant correlation between platelet counts and pulmonary, gastrointestinal, or intraventricular bleeding.

Dr. Christensen said he suspects that many platelet transfusions in the NICU provide little benefit while possessing all the risks of blood transfusions.

"We must more precisely define the risks and benefits of platelet transfusion practices," he continued. "We must reevaluate the paradigm of administering platelet transfusions prophylactically, to non-bleeding neonates, just because their platelet count has fallen below an arbitrary level."

Sildenafil use in Neonatology:

The Use of Sildenafil in Persistent Pulmonary Hypertension of the Newborn We evaluated the effectiveness of sildenafil in the treatment of neonatal pulmonary hypertension. We performed a double-blind randomized clinical trial in 51 full-term infants with persistent pulmonary hypertension confirmed by Doppler echocardiography. Patients were divided in two groups: 20 infants in group A received placebo when the oxygenation index was >20, and 31 infants in group B received 3 mg/kg of oral sildenafil every 6 hours. Arterial blood gases were taken at 1, 4, 7, 13, 19, and 25 hours after treatment was started. Main outcome measures were oxygenation changes, time on mechanical ventilation, and mortality. Both groups were comparable in general variables as well as in illness severity. We observed better oxygenation parameters after 7 hours of sildenafil treatment, but no significant changes were found in the placebo group. Mortality was higher in the placebo group (40%) than in those infants who received sildenafil (6%;p = 0.004), although no difference was found in time on mechanical ventilation between groups. Our results confirm that sildenafil may be a useful adjuvant therapy for term infants with pulmonary hypertension in centers lacking inhaled nitric oxide and extracorporeal membrane oxygenation. (Arturo Vargas-Origel, Guadalupe Gómez-Rodríguez, et al. In Amer J Perinatol :DOI: 10.1055/s-0029-1239496)

Intravenous Sildenafil in the Treatment of PPHN

Objective: To evaluate the safety of intravenous (IV) sildenafil, an inhibitor of cyclic guanosine monophosphate–specific phosphodiesterase, in treating near-term and term newborns with persistent pulmonary hypertension of the newborn (PPHN).

Study design: This was an open-label, dose-escalation trial in newborns with PPHN and an oxygenation index (OI) > 15. Sildenafil was delivered by continuous IV infusion for at least 48 hours and up to 7 days.

Results: Five centers enrolled a total of 36 neonates with PPHN at a mean of 34 ± 17 hours of age; 29 of these neonates were already receiving inhaled nitric oxide (iNO). A significant improvement in OI (28.7 to 19.3; P = .0002) was observed after 4 hours of sildenafil infusion in the higher dose cohorts. Thirty-five neonates survived; 1 neonate required extracorporeal membrane oxygenation (ECMO) support. In 4 neonates, sildenafil was stopped due to adverse events. Seven neonates were enrolled before developing the need for iNO. In these neonates, OI improved significantly by 4 hours after initiation of sildenafil infusion (24.6 to 14.7; P = .009); 6 neonates completed treatment without the need for iNO or ECMO.

Conclusions: IV sildenafil was well tolerated, and acute and sustained improvements in oxygenation were noted in those neonates who received the higher infusion doses. (Robin H. Steinhorn,  John P. Kinsella, et al. In Jr of Pediatr, Published online 16 October 2009. Available from: http://www.jpeds.com/article/PIIS0022347609005605/abstract?rss=yes)

Sildenafil for Chronic Lung Disease

 Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease. 

 Objective.  To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy.

Study design.  We conducted a retrospective review of 25 patients <2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening with serial echocardiograms.

Results.  Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow-up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis.

Conclusion.  These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD.  (Mourani PM, Sontag MK, Ivy DD, and Abman SH.  J Pediatr (March 2009); 154: 379-384.) 

Comments.  Sildenafil treats pulmonary hypertension by selective inhibition of the PDE-5 enzyme thus increasing intracellular levels of cGMP.  The effectiveness of this medication to treat pulmonary hypertension in the immediate neonatal period had been demonstrated in at least 1 small randomized, controlled trial.   We now see another potential use for sildenafil – the treatment of PH in older infants with chronic lung disease.   Sildenafil treatment offers several advantages over treatment with inhaled nitric oxide in this setting:

1)       Much lower cost

2)       Oral route of delivery

3)       Possibility for home treatment

4)       Apparently well tolerated, even for very long courses of treatment (up to 600 days in this series). 

As the authors point out, this retrospective series does not prove either the long-term efficacy or safety of Sildenafil for use in this setting.  A large multicenter randomized, controlled trial is needed for that.  In the meantime, caution is urged. 

Late Preterm C/section Outcomes: Elective deliveries before 39 weeks should be discouraged
Incidence of Early Neonatal Mortality and Morbidity after Late-Preterm and Term Cesarean Delivery. 

OBJECTIVE. To determine the age-stratified risk of intrapartum and neonatal mortality as well as morbidities of clinical relevance after elective cesarean delivery (ECD).

METHODS. This work was a cohort study including 56 549 prospectively recorded late-preterm and term deliveries. We analyzed the effect of cesarean delivery (CD) before the onset of labor on the following multiple neonatal outcomes before hospital discharge, compared with planned vaginal delivery (PVD) and emergency CD: mortality, birth depression, special care admission, and respiratory morbidity. We adjusted for confounders by multivariate analysis and stratified the risk according to gestational age (GA).

RESULTS. Mortality and morbidities had a strong GA-related trend with the lowest incidences consistently found between 38 and 40 weeks of gestation independent of delivery mode. Compared with infants delivered via PVD, infants delivered via ECD had significantly higher rates of mortality (adjusted risk ratio [aRR]: 2.1), risk of special care admission (aRR: 1.4), and respiratory morbidity (aRR: 1.8) but not of depression at birth (aRR: 1.1). Compared with emergency CD, newborns delivered via ECD had less depression at birth (aRR: 0.6) and admission to special care (aRR: 0.8), but mortality (aRR: 0.8) and respiratory morbidity (aRR: 1.0) rates were similar.

CONCLUSIONS. Gestational age–specific risk estimates are lowest between 38 and 40 weeks and should be included in the informed-consent process. The information should also be used to allow for appropriate preparation with respect to adequate staff and equipment. ECD is consistently associated with increased intrapartum and neonatal mortality, risk of admission, and respiratory morbidity compared with PVD and has no advantage over emergency CD in terms of mortality. Neonatal morbidities are lower after ECD than emergency CD only with term births. Our data provide evidence that ECD should not be performed before term. (De Luca R, Boulvain M, Irion O, et al.  Pediatrics (Jun 2009); 123: e1064 – e1071.)  

Comments. Adverse neonatal outcomes decrease with increasing GA independent of delivery mode, with the lowest risk between 38 and 40 weeks' gestation. This study adds further insights into the “great imposters” i.e. the late preterm (34-36 weeks) and early term (37-38 weeks) infants.  Elective deliveries before 39 weeks should be discouraged. DB

Do neonatal seizures cause brain injury?

In pediatrics, seizures are most frequent in infants and the most frequent association (cause) is hypoxic-ischemia associated with birth. The question asked by Glass et al is whether these seizures injure the brain beyond that caused by the hypoxic-ischemia. They assessed the amount of brain injury detected by MRI and then correlated neurologic outcomes for asphyxiated term infants with seizures. Their conclusion is that seizures probably increase the injury and compromise neurodevelopmental outcomes. Although this conclusion is consistent with animal models, the “probably” as a qualifier results from the complexity of the clinical material and the use of medications to treat seizures, as discussed in an editorial by Silverstein. The medications used to treat seizures in newborns can impair brain development in animal models. Further, the identification of clinical seizures is quite imprecise, and the description of the seizure activity by continuous EEG monitoring is complex. The use of hypothermia to treat asphyxiated infants with or without seizures will further complicate outcome analyses. However, this report is an important contribution that should stimulate further research into the recognition and appropriate treatment of neonatal seizures; the pay-off may be better outcomes. (Jr of Pediatrics, September 2009)

Hypothermia for HIE – TOBY Trial Results

Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy.

Background Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain.

Methods We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5°C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes.

Results Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P=0.03 for each) and the Gross Motor Function Classification System (P=0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associated with cooling.

Conclusions Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors. (Azzopardi DV, Strohm B, Edwards AD, et al. for the TOBY Study Group.    N Engl J Med (Oct 1, 2009); 361:1349-1358.) 

Comments.  We now have the long-awaited TOBY trial results.  This is the third large RCT that showed benefit from moderate hypothermia for neonatal encephalopathy.  The previous trials were the NICHD (see 6-040) and Cool Cap (see 6-039) studies.  The TOBY trial found that cooled infants had increased survival without neurologic abnormality, reduced risk of cerebral palsy, and improved scores on the Bailey MDI and PDI developmental indices.   While there were minor differences between study protocols and results, the basic results of all 3 trials were very similar.  Hypothermia works, and should be offered to all term and near-term babies with moderate or severe neonatal encephalopathy.  This therapy should no longer be considered investigational.(Andy Kairalla, In NeoNotes Journal Club)

Fan Cooling for Encephalopathy

Induced Hypothermia for Infants With Hypoxic- Ischemic Encephalopathy Using a Servo-Controlled Fan
 
 OBJECTIVE. Several trials suggest that hypothermia is beneficial in selected infants with hypoxic-ischemic encephalopathy. However, the cooling methods used required repeated interventions and were either expensive or reported significant temperature variation. The objective of this pilot study was to describe the use, efficacy, and physiologic impact of an inexpensive servo-controlled cooling fan blowing room-temperature air.

 

 PATIENTS AND METHODS. A servo-controlled fan was manufactured and used to cool 10 infants with hypoxic-ischemic encephalopathy to a rectal temperature of 33°C to 34°C. The infants were sedated with phenobarbital, but clonidine was administered to some infants if shivering or discomfort occurred. A servo-controlled radiant warmer was used simultaneously with the fan to prevent overcooling. The settings used on the fan and radiant warmer differed slightly between some infants as the technique evolved.
RESULTS. A rectal temperature of 34°C was achieved in a median time of 58 minutes. Overcooling did not occur, and the mean temperature during cooling was 33.6°C ± 0.2°C. Inspired oxygen requirements increased in 6 infants, and 5 infants required inotropic support during cooling, but this was progressively reduced after 1 to 2 days. Dehydration did not occur. Five infants shivered when faster fan speeds were used, but 4 of the 5 infants had hypomagnesemia. Shivering was controlled with clonidine in 4 infants, but 1 infant required morphine.
CONCLUSIONS. Servo-controlled fan cooling with room-temperature air, combined with servo-controlled radiant warming, was an effective, simple, and safe method of inducing and maintaining rectal temperatures of 33°C to 34°C in sedated infants with hypoxic-ischemic encephalopathy. After induction of hypothermia, a low fan speed facilitated accurate temperature control, and warmer-controlled rewarming at 0.2°C increments every 30 minutes resulted in more appropriate rewarming than when 0.5°C increments every hour were used, (Horn A, Neon C,  Thompson C, et al. In  Pediatrics (June 2009); 123: e1090-e1098)
Comments.  This is a unique idea for inducing hypothermia treatment to treat neonatal encephalopathy.  It appears to work well, and should avoid the skin changes seen with the cool cap or cooling blanket methods for hypothermia.  Although the efficacy of this method of hypothermia has not been tested, I don’t suspect that the mode of inducing hypothermia will affect outcomes.