Max Perlman

A simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn

Assessment of the glomerular filtration rate (GFR) in the newborn is often imprecise because of difficulties in urine collection and because the plasma creatinine level, the traditional marker of renal function, is influenced by many factors in this age group. Gentamicin is given to most preterm infants for suspected or proved sepsis. This drug is eliminated almost entirely by the kidney and its rate of elimination parallels the GFR. We calculated gentamicin pharmacokinetic parameters (t½, volume of distribution, and clearance) from three consecutive concentration‐time points (trough, peak, and next trough levels) in 38 newborn infants. Creatinine clearance was measured by the conventional method. Both t½ (r = 0.74; P < 0.001) and gentamicin clearance (r = 0.77; P < 0.001) correlated well with measured creatinine clearance. There was no correlation between these variables and urine output. Gentamicin elimination t½ and clearance are useful indices of GFR in the newborn infant and can be easily calculated during routine therapeutic drug monitoring.

High-frequency oscillation in the rescue of infants with persistent pulmonary hypertension

High-frequency oscillatory ventilation (HFOV) was used to treat 41 infants with persistent pulmonary hypertension of the newborn (PPHN). Of the 37 patients who showed early improvement on HFOV, three died. The remaining 34 patients demonstrated, within one hour of the switchover to HFOV, a rise in mean arterial/alveolar oxygen tension ratio (PaO2/PaO2) from 0.093 +/- 0.041 (SD) to 0.132 +/- 0.051 (p less than .001), and a fall in mean PaCO2 from 42 +/- 10 to 34 +/- torr 9 (p less than .01). Mean airway pressure (Paw) fell significantly (p less than .01) within 12 h. The mean duration of conventional mechanical ventilation before starting HFOV was longer in 13 patients who developed bronchopulmonary dysplasia (BPD) than in 21 non-BPD patients (44.7 +/- 32.3 vs. 19.1 +/- 15.6 h, p less than .002), as was the duration of exposure to Paw greater than 15 cm H2O during that treatment mode (31.8 +/- 21.3 vs. 9.5 +/- 6.0 h, p less than .001). HFOV is often effective in the treatment of patients with PPHN, and early initiation of this type of mechanical ventilation may be associated with a reduced incidence of BPD.

Possible indomethacin-aminoglycoside interaction in preterm infants

THE COMBINED USE OF AMINOGLYCOSIDES, which are eliminated almost entirely by the kidney, ~ and indomethacin, which tends to impair renal function, z may promote aminoglycoside accumulation and resulting toxicity 3-5 in preterm infants. We recently reported the interaction between indometh~tcin and digoxin in this age group resulting in significan t elevation of digoxin serum concentrations to potentially toxic levels. 6 In the present study, we prospectively assessed the effect of indomethacin on aminoglycoside serum Concentrations when both were given in clinically recommended doses.

Aminoglycoside‐related nephrotoxicity in the premature newborn

The nephrotoxicity of gentamicin and amikacin was compared during presumed sepsis in 107 premature neonates. To examine the possibility that nephrotoxicity was directly associated with the clinical conditions of “sepsis,” a control group of 26 chloramphenicol‐treated newborns was also studied. Two markers of proximal renal tubular injury, N‐ acetyl‐ β‐glucosaminidase (NAG) and β2‐microglobulin, were measured in 6‐hr aliquots of urine. Because urine creatinine excretion increased with postconception age, markers were expressed in terms of excretion rate rather than per milligram of creatinine. The NAG excretion rate was significantly higher in gentamicin‐treated patients (138 ± 10 U/min, mean ± SE) than in amikacin‐treated patients (85 ± 7 U/min) but did not differ between patients treated with amikacin and those treated with chloramphenicol (81 ±11 U/min). Excretion of β2‐microglobulin did not differ among the three patient groups. We conclude that amikacin may be less nephrotoxic than gentamicin in the premature newborn.

Hypoxic-Ischemic Encephalopathy: Challenges in Outcome and Prediction

The outcomes of hypoxic-ischemic encephalopathy vary between death and intact survival. The spectrum of long-term morbidity in survivors ranges from mild motor and cognitive deficits to cerebral palsy and severe cognitive deficits. Our literature review reinforces the notion that the spectrum of hypoxic-ischemic encephalopathy outcomes represents a continuum, which has important implications for the prediction of outcome and the indications for intervention. We summarize predictive criteria at 3 time points: the first 6 hours of life, 6-72 hours of life, and at hospital discharge. In this era of neuroprotection, predictive models that aid therapeutic decision making, including the withdrawal of support, need to be revised.

Time to Adopt Cooling for Neonatal Hypoxic-Ischemic Encephalopathy: Response to a Previous Commentary

O THE BASIS of opinions of problematic evidence, Kirpalani et al1 stated that the “standard of care” criteria for adopting hypothermia for neonatal hypoxicischemic encephalopathy (HIE) had not been met. They argued for a “conservative approach.” Clinicians who are “impressed” by their evidence are not mandated to offer cooling and can ethically continue to randomly assign patients “into ongoing, or new trials.” Yet, the authors considered the evidence to be “certainly” sufficiently strong for cautious use of this treatment by clinicians who are “impressed with the results.” These apparently conflicting statements are reinforced by previous confusing statements by co-author Barks2: “Many of us, including this author and the lead author [Dr Shankaran] of the Network trial,[3] who caution against uncontrolled adoption of cooling, have lost equipoise, and we are now cooling babies who meet the eligibility criteria of our original trials,” and the semantically elusive, “In a small number of experienced centers, it is a novel therapy that has become ‘standard care’ (without randomization), but it is not yet the ‘standard of care’ (emphasis in the original). Evolution in this field has outdated this conservative approach. One cooling trial (Infant Cooling Evaluation [ICE])4 was stopped prematurely, the research protocol of another has been altered,5 a third trial (Trial of Whole Body Hypothermia for Perinatal Asphyxia [TOBY])6 was stopped at the end of the funding period before achieving its revised sample size, and 3 independent systematic reviews4,7,8 have confirmed the efficacy and safety of cooling. Today’s question is whether it is acceptable for individual hospitals or physicians to withhold from parents information about and access to cooling. We question the lingering concerns about the methodology of the trials raised by Kirpalani et al.1 The importance of the answer is illustrated by predictive calculations: Of the 15 to 18 infants born daily in the United States with moderate-to-severe asphyxia, 10 to 12 of them die or develop moderate-to-severe disability; providing hypothermia to all would likely prevent 3 infants from either death or moderate-to-severe disability without causing any clinically significant adverse effects.8 This is an enormous effect size. We address the issues raised by Kirpalani et al1 in the order in which they were presented originally.

Symptomatic Hypoglycemia in Otherwise Healthy, Breastfed Term Newborns

Transient symptomatic neonatal hypoglycemia, a diagnosis that is made in the neonatal nursery, is not usually associated with apparently normal infants who have been discharged from hospital. We describe 3 such cases that presented at home on day 3 of life with seizures or life-threatening apneas. We postulate that early discharge of apparently normal infants with marginal nutritional or metabolic adaptation, may expose some infants to postdischarge (but still neonatal) hypoglycemia and its attendant risks.

The impact of early obstetric discharge on newborn health care.

The impetus for shorter hospital stay of mother and newborn infant after delivery is based on economic constraints and parental preference. Earlier published studies did not demonstrate any increase in morbidity rate with shorter stay, but these studies were limited by methodologic flaws and biases that limited the validity and generalizability of the conclusions. More recent studies showed that readmission rates increased with shorter stay and that the severity of illness of readmitted infants may have increased. In addition, the interpretation of current newborn screening tests may not be applicable when performed prior to early discharge. In light of recent changes in neonatal hospital length of stay, a careful review and update of current guidelines and practices for newborn care are required.

Prognostic value of EEG in neonatal bacterial meningitis

The contribution of electroencephalogram (EEG) findings early in the course of neonatal bacterial meningitis to the prediction of severe adverse outcome was assessed in a retrospective cohort study. Infants had known outcomes to 1 year of age and an EEG performed during the first week of illness. EEGs were subclassified as follows: overall EEG description, background activity, presence of positive rolandic sharp waves, presence of seizure activity, and presence of focal abnormal activity. EEG patterns predictive of severe adverse outcome were identified by univariate and multivariate analyses. Of 101 infants admitted with bacterial meningitis, 37 had an EEG performed. Of the 37 infants, 21 had adverse outcomes; nine infants died, and 12 infants had moderate or severe disability. EEG background activity and overall EEG description were identified as predictors of adverse outcome; multivariate analysis indicated that the latter was a stronger predictor (sensitivity 88%, specificity 90%). Infants with normal or mildly abnormal EEGs had good outcomes whereas those with moderate to markedly abnormal EEGs died or survived with adverse outcome. The accuracy of predictions increased when EEGs were repeated. In a high-risk population of infants with bacterial meningitis, moderate-to-markedly abnormal EEG reliably predicts adverse outcome.

Recovery of metabolic acidosis in term infants with postasphyxial hypoxic-ischemic encephalopathy*

Aims: To describe the base deficit (BD) values and the rate of postnatal recovery of the BD of infants with hypoxic ischemic encephalopathy due to intrapartum asphyxia; and to explore the relationships between the rate of recovery of BD, severe adverse outcome and different time patterns (acute total vs prolonged partial) of asphyxia. Methods: Clinical and laboratory data were collected from the neonatal period (n= 244) and outcome data to a minimal age of 1 y (n= 218). Rates of recovery of BD were described in four 60 min blocks of time. The values of rate of recovery were compared between the outcome groups, ignoring correlation structure within subjects and with adjustment by the generalized estimating equations method. Results: The BD normalized within 4 h of birth in all but 9 of 244 infants. The rates of recovery of BD in infants with good and severe adverse outcome respectively were 0.11 [95% confidence interval (95% CI) 0.07, 0.14] and 0.09 (95% CI 0.07, 0.12) mmol l‐1 min‐1 over the first 4 h after birth. The rates of recovery were similar with or without buffer therapy, and after acute near‐total and prolonged partial asphyxia.