Neil N. Finer

Hypoxic-ischemic encephalopathy in term neonates: Perinatal factors and outcome

Ninety-five infants of 37 weeks gestation or greater with evidence of hypoxic-ischemic encephalopathy following perinatal asphyxia were prospectively identified in the neonatal period. The degree of encephalopathy was graded the staging system of Sarnat and Sarnat. Six infants died, 78 infants were sequentially followed in the Neonatal Follow-up Clinic, and in five additional infants, follow-up information was available. The mean duration of follow-up was 19.3 months. Fifty-eight (65%) of the 89 infants followed were normal or mildly handicapped, six (7%) died, and the remainder had significant handicap. There was no significant relationship between any of over 100 obstetrical antepartum or intrapartum variables and outcome. Infants with five-minute Apgar scores of 0 to 3, seizures within the first day of life, Stage II or III encephalopathy, or a suppressed electroencephalogram had a significantly greater incidence of severe handicap or death. In addition, although there were fewer females, they had a significantly greater incidence of handicap. There appeared to be an improved outcome in the last two years (1977-1978) compared to the first two years (1975-1976), suggesting that improved recognition and neonatal management may lead to a decrease in significant sequelae.

TERM INFANTS WITH HYPOXIC-ISCHEMIC ENCEPHALOPATHY: OUTCOME AT 3.5 YEARS

A total of 167 term neonates with a diagnosis of hypoxic‐ischemic encephalopathy (HIE) had detailed neurodevelopmental follow‐up at 3–5 years of age. All 66 children with mild HIE were free from handicap; all seven with severe HIE were severely handicapped; and of the 94 with moderate HIE at birth, 21‐3 per cent were handicapped. Mean IQ was significantly related to the category of HIE. Within the moderate HIE category, the neurological examination at discharge from the Neonatal Intensive Care Unit was more useful than the presence of neonatal convulsions in identifying children with subsequent developmental delay. Abnormalities on this examination related significantly to an increased number of handicapped children, decreased motor and language skills, and lower IQs. Although neonatal convulsions were associated with an increased number of handicapped children, they did not significantly affect most other developmental outcome measures. In term infants with documented HIE at birth, major neurodevelopmental dysfunction at 3–5 years depended more on prospectively established category of HIE than on other perinatal or social factors.

Nasotracheal intubation in the neonate: Physiologic responses and effects of atropine and pancuronium

Thirty infants with birth weights from 580 to 3450 gm (25 to 40 weeks gestation) were prospectively studied during nasotracheal intubation. The infants were randomized to receive atropine 0.01 mg/kg, atropine 0.01 mg/kg plus pancuronium 0.1 mg/kg, or no medication (controls) prior to intubation. There was a significant decrease in transcutaneous PO2 (27.3 torr, P less than 0.02), associated with significant increases in mean arterial blood pressure (57%, P less than 0.01) and intracranial pressure (mean increase 18.9 cm H2O, P less than 0.01) with intubation in all three groups of infants. Only in control infants and infants receiving atropine was there significant decrease in heart rate (52.2 and 36.2 bpm, respectively, P less than 0.01) during intubation. Control infants experienced a significantly greater decrease in heart rate and demonstrated the lowest mean heart rate, compared with the other two groups. Pancuronium plus atropine was associated with lesser increases in intracranial pressure and with the least changes in heart rate in response to intubation. There was no significant difference between the groups for changes in systemic blood pressure or transcutaneous PO2. Further studies are required to determine the clinical consequences, if any, of these responses, and the use of pretreatment in the neonate requiring intubation.

Physiologic effects of doxapram in idiopathic apnea of prematurity

Twelve premature infants with significant apnea of prematurity while receiving therapeutic doses of aminophylline were given an intravenous infusion of doxapram, 2 or 2.5 mg/kg/hr. The ventilatory effects of the medication were monitored by means of face mask spirometry and airway occlusion studies. Doxapram therapy was associated with significant increases in minute ventilation, tidal volume, mean inspiratory flow, and airway pressure 100 msec after occlusion. Respiratory frequency and the relative duration of inspiration and expiration were unchanged. Paco2 decreased significantly during the infusion. The apnea attack rate, monitored by continuous recording, was significantly reduced after the first 6 hours of therapy. Six hours after starting doxapram, mean arterial blood pressure was significantly elevated, and continued to increase during the 24 hours of therapy. Doxapram is effective in treatment of apnea of prematurity refractory to aminophylline, and appears to act by increasing respiratory center output.

Postextubation atelectasis: A retrospective review and a prospective controlled study

To determine the role of chest physiotherapy in the prevention of postextubation atelectasis in neonates intubated for greater than 24 hours, a retrospective survey compared the incidence of this complication in a newborn intensive care unit prior to and following the institution of a routine of chest physiotherapy. Eight of 23 infants extubated developed atelectasis in the pre-physio period, whereas only one collapse occurred in 20 infants treated with a routine of physiotherapy at extubation (P less than 0.025). Subsequently a prospective controlled trial compared the use of a routine of physiotherapy at extubation with no physiotherapy. Eight of 21 infants not receiving physiotherapy developed postextubation atelectasis and none of 21 infants receiving physiotherapy developed atelectasis (P less than 0.01). Seventy-six percent of the collapses involved the right upper lobe. A vigorous program of chest physiotherapy, including postural drainage emphasizing the positions of the right upper lobe and chest vibrations, will significantly reduce the incidence of postextubation atelectasis.

Obstructive, mixed, and central apnea in the neonate' Physiologic correlates

In an attempt to determine physiologic responses to neonatal apnea, we evaluated changes in heart rate and oxygen saturation as measured by pulse oximetry during 2082 episodes of apnea lasting 15 seconds or more in 47 infants less than 34 weeks of gestational age with idiopathic apnea of prematurity. Of these episodes, 832 (39.9%) were central, 1032 (49.6%) were mixed, and 218 (10.5%) were obstructive. Oxygen saturation decreased with increasing duration of apnea regardless of type or treatment, and the decrease in saturation was correlated with preapnea saturation. The baseline heart rate was similar for all apnea types. Infants receiving doxapram had a lower baseline heart rate (137.8 +/- 10.5 beats/min) than did infants receiving no therapy (142.8 +/- 16.6 beats/min) and infants receiving theophylline (149.7 +/- 15.0 beats/min) (p = < 0.001). A heart rate fall to less than 100 beats/min was seen more frequently with central apnea than with mixed or obstructive events, and in infants who were not receiving therapy. Falls in heart rate were significantly less in infants receiving doxapram (27.8% +/- 18.0%) than in infants receiving theophylline (44.5% +/- 19.0%) or no therapy (48.4% +/- 18.3%) (p = < 0.001). The most common heart rate pattern overall was a gradual decrease interrupted by accelerations, whereas an initial heart rate acceleration was the most common pattern in obstructive apnea. We conclude that heart rate response to neonatal apnea is a complex and is dependent on therapy and on type and duration of apnea.

A blinded, randomized, placebo-controlled trial to compare theophylline and doxapram for the treatment of apnea of prematurity

A blinded, randomized, placebo-controlled trial was conducted to evaluate the effectiveness of theophylline and doxapram therapy in 31 infants with significant apnea of prematurity. Of 10 infants, two had a short-term response to placebo, 8 of 10 infants to theophylline, and 7 of 11 infants to doxapram (placebo vs treatment with theophylline or doxapram: p = 0.01). The two infants who initially responded to placebo remained responsive for the duration of the study. Of the eight infants in whom treatment with placebo failed, five were randomly assigned to receive theophylline, for a total of 15 infants treated with theophylline, and two of the eight were randomly assigned to receive doxapram, for a total of 13 infants treated with doxapram; the remaining infant required tracheal intubation. Of the 15 infants randomly assigned to receive theophylline, seven responded for the duration of the study; of the eight infants who did not respond to treatment with theophylline, five responded to doxapram, one responded to a combination of theophylline and doxapram, and two remained resistant to treatment. Of the 13 infants randomly assigned to receive doxapram four responded for the duration of the study; of the nine who did not respond to doxapram, seven responded to theophylline, one responded to a combination of theophylline and doxapram, and one remained resistant to treatment. This study demonstrates that although therapy with theophylline or doxapram is associated with a significant short-term reduction in the incidence of apnea compared with that in placebo-treated infants, the long-term response to treatment is frequently incomplete and is not sustained more than 1 week.

The dose response of theophylline in the treatment of apnea of prematurity

In an effort to establish the minimum effective dose of theophylline in the treatment of idiopathic apnea of prematurity, a prospective trial of 22 infants with at least 0.33 episodes of apnea per hour were studied. Apnea was diagnosed exclusively by continuous recording of heart rate, respiratory impedance, end-tidal CO2, and either or both transcutaneous oxygen and pulse oximetry. Four discrete serum concentrations of theophylline (23 mumol/l or 4.2 mg/L, 47 mumol/L or 8.5 mg/L, 70 mumol/L or 12.7 mg/L, and 84 mumol/L or 15.3 mg/L) were attained by using repeated loading doses of 4 mg/kg and increasing the maintenance dose from 1 to 1.5 mg/kg to 2 to 2.5 mg/kg, given every 8 hours. Before treatment and 24 hours after each loading dose, airway occlusions and measures of tidal volume, minute ventilation, and respiratory timing were performed. The effectiveness of therapy was assessed by either a continuous computer data-acquisition system or paper recording for the duration of the study. Of the 22 infants, three responded at level 1, three at level 2, and 10 at level 3. One of the four infants loaded to the fourth level had a sustained response for a total cumulative response of 77%. The five remaining infants required additional treatment with doxapram or continuous positive airway pressure. There was a significant increase in inspiratory pressure 100 msec after airway occlusion, maximum inspiratory pressure during airway occlusion, tidal volume, ratio of tidal volume to inspiratory time (mean inspiratory flow), and minute ventilation from the pretreatment measurements to those at the maximum dose of theophylline. The apnea response did not correlate with these improvements in ventilation measures.

Caudal regression anomalad (sacral agenesis) in siblings

Hypoplasia of the caudal end of the spine and associated anomalies were observed in two male siblings who also had congenital heart disease. The disorder has overlapping features with the VATER association and the caudal regression anomalad, and probably has a genetic basis, although the mode of inheritance is not clear.

Plasma lactate as a predictor of early childhood neurodevelopmental outcome of neonates with severe hypoxaemia requiring extracorporeal membrane oxygenation.

Although plasma lactate concentration has been widely used as an indicator of tissue hypoxia, no clinical study has been conducted to relate these values to the neurological outcome of sick neonates. Seventeen consecutively cared for and surviving neonates with severe hypoxaemia requiring extracorporeal membrane oxygenation (ECMO) were evaluated at a mean age of 19.6 months. The serial plasma lactate concentrations were significantly correlated with the scores of the Bayley Scales of Infant Development. Admission and peak plasma lactate of < or = 15 mmol/l predicted favourable outcome (MDI and PDI > 70 and no disability): sensitivity 100%, specificity 88%, positive predictive value 90%, and negative predictive value 100%. Plasma lactate values could help predict neurodevelopmental outcome in these sick neonates.