Dale R. Gerstmann

Reported Medication Use in the Neonatal Intensive Care Unit: Data From a Large National Data Set

OBJECTIVES. The objectives were (1) to identify the drugs reported most commonly during NICU care, (2) to examine how different methods of documenting drug use could influence prioritization of drugs for future research aimed at evaluating safety and efficacy, (3) to describe the demographic differences in the population samples for some specific medications, (4) to identify which reported medications are used for patient populations with >20% mortality rates, and (5) to examine how reports of drug use change over time. METHODS. A retrospective review of a large national data set was performed. RESULTS. The 10 medications reported most commonly for the NICU were ampicillin, gentamicin, ferrous sulfate, multivitamins, cefotaxime, caffeine citrate, furosemide, vancomycin, surfactant, and metoclopramide. Medications used for patient populations with >20% mortality rates included amphotericin, clonazepam, dobutamine, epinephrine, ethacrynic acid, insulin, lidocaine, metolazone, milrinone, inhaled nitric oxide, nitroglycerin, octreotide, pancuronium, phenytoin, sodium nitroprusside, sodium polystyrene sulfonate (Kayexalate), tris-hydroxymethylaminomethane acetate buffer, and tolazoline. Several of these drugs (eg, amphotericin B and bumetanide) were used primarily for extremely premature neonates, and this usage might explain the high mortality rates for the population of neonates treated with these medications. Other medications (clonazepam, milrinone, inhaled nitric oxide, and phenytoin) were used primarily for near-term and term infants. The explanation for the high mortality rates for these neonates is less clear and may be related primarily to the severity of illness for which the medications are used. Utilization rates for several different medications (eg, cisapride, metoclopramide, and dexamethasone) changed by >50% during the past 5 years. CONCLUSIONS. Data reported here are the first from a large national data set on the use of different medications for neonates admitted for intensive care and should be helpful in establishing priority agendas for future drug studies in this population.

The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants

Background: Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-β-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants. Methods: This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500–1000 g) were enrolled in the 0.75 mg/kg dosage group only. Results: The mean ± standard deviation gestational age in the >1000 g dosage group was 26.4 ± 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed. Conclusions: Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drugs elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

Empiric Use of Ampicillin and Cefotaxime, Compared With Ampicillin and Gentamicin, for Neonates at Risk for Sepsis Is Associated With an Increased Risk of Neonatal Death

BACKGROUND. We reported previously that the use of cephalosporin among premature neonates increased the risk of subsequent fungal sepsis. As a result, we recommended that ampicillin and gentamicin be used as empiric coverage for early-onset neonatal sepsis while culture results are awaited. OBJECTIVES. To describe antibiotic use during the first 3 days after birth for neonates admitted to the NICU and to evaluate the outcomes for neonates treated with 2 different antibiotic regimens. METHODS. We assembled a cohort of inborn neonates, from our deidentified administrative database, who had documented exposure to ampicillin during the first 3 days after birth. Infants treated concurrently with cefotaxime or gentamicin were evaluated, to identify the factors that were associated independently with death before discharge, with both univariate and multivariate analyses. RESULTS. There were 128914 neonates selected as the study cohort; 24111 were treated concurrently with ampicillin and cefotaxime and 104803 were treated concurrently with ampicillin and gentamicin. Logistic modeling showed that neonates treated with ampicillin/cefotaxime were more likely to die (adjusted odds ratio: 1.5; 95% confidence interval: 1.4–1.7) and were less likely to be discharged to home or foster care than were neonates treated with ampicillin/gentamicin. This observation was true across all estimated gestational ages. Other factors that were associated independently with death included immature gestational age, need for assisted ventilation on the day of admission to the NICU, indications of perinatal asphyxia or major congenital anomaly, and reported use of ampicillin/cefotaxime. CONCLUSIONS. For patients receiving ampicillin, the concurrent use of cefotaxime during the first 3 days after birth either is a surrogate for an unrecognized factor or is itself associated with an increased risk of death, compared with the concurrent use of gentamicin.

Ventilatory management of infant baboons with hyaline membrane disease: The use of high frequency ventilation

Abstract: We tested the hypothesis that high frequency oscillatory ventilation (HFOV) would result in decreased pulmonary barotrauma in infants with hyaline membrane disease by comparing HFOV at 10 Hz to conventional positive pressure ventilation with continual distending airway pressure (PPV/PEEP) in premature baboons with hyaline membrane disease. Nineteen baboon fetuses were randomized to one of two treatment groups, delivered at 140 ± 2 days, and, after stabilization and instrumentation of PPV/PEEP, placed in their respective ventilator group. Animals on conventional ventilation were managed by adjustment of tidal volume and frequency (to 1 Hz) to keep PaCO2 below 55 and by adjustment of the mean airway pressure. One of the “HFOV” group died of cardiovascular complications before going on HFOV and was eliminated from data analysis. The remaining HFOV baboons survived the 11-day experimental period without evidence of airleak. Six of the 11 prematures treated with PPV/PEEP developed pulmonary interstitial emphysema and/or pneumothorax and five of the animals died within 48 h. The intergroup differences in airleak were significant (p < 0.05). Mean airway pressure (measured at the proximal airway) was higher initially with HFOV but then was lowered more rapidly than in the PPV/PEEP animals. The arterial to alveolar oxygen ratio rose and the FIO2 could be lowered more rapidly with HFOV than with conventional ventilation. These differences reached significance by 20 h. After 60 h there were no significant differences between HFOV and the PPV/PEEP survivors. HFOV resulted in more uniform saccular expansion, higher arterial to alveolar oxygen ratio, less oxygen exposure, and decreased acute barotrauma when compared to PPV/PEEP. Although initially mean airway pressure was in the HFOV animals this was not associated with measurable baroinjury. These data support the efficacy of HFOV in the treatment of prematures with hyaline membrane disease.

Proximal, Tracheal, and Alveolar Pressures during High-Frequency Oscillatory Ventilation in a Normal Rabbit Model

ABSTRACT: To study the effect of different high-frequency oscillatory ventilation parameters on airway pressure we measured oscillatory pressure amplitude (| Paw |) and mean airway pressure (Paw)at three sites in open-chested normal rabbits: proximal, trachea, and alveolus. Five animals were studied to test a new pleural capsule design, which was then used in two groups of animals to measure right upper (n = 4)or middle (n = 5) lobe alveolar pressures. Animals were randomly sequenced through combinations of frequency (10, 15, and 20 Hz) and fractional inspiratory time (T) (0.3 and 0.5) while normoxic and encapnic. During capsule testing, we noted that alveolar pressures increased (p < 0.05) with increasing capsule mass. suggesting that compressive forces from the capsule may alter the capsule measurement. We thus used a lowmass (430 mg) transducer system in the rabbit high-frequency oscillatory ventilation experiments. Using multifactorial analysis of variance, we found significant main effects of Ti on Paw, and of measurement site on both |Paw| and Paw (p < 0.009). Frequency did not influence variations in either |Paw| Paw. For both Ti settings, alveolar upper lobe Paw was lower compared with that of the middle lobe (p < 0.0005). Lengthening Ti (03 to 0.5) increased tracheal Paw in each capsule group (p < 0.0005). At Ti = 0.5, tracheal Paw exceeded Paw measured proximally (p < 0.05). Our data support in vivo alveolar Paw inhomogeneity and demonstrate significant changes in pressures within the lung related to Ti during high-frequency oscillatory ventilation.

Lung protective strategies of ventilation in the neonate : what are they?

* Abbreviations: VILI = : ventilator-induced lung injury • ARDS = : acute respiratory distress syndrome • NIH = : National Institutes of Health • RDS = : respiratory distress syndrome • PEEP = : positive end–expiratory pressure • HFV = : high-frequency ventilation • EEP = : end–expiratory pressure • Fio2 = : fraction of inspired oxygen In the July 1999 issue of the Journal of the American Medical Association, Dr Leonard Hudson proclaims that “the concept of ventilator-induced lung injury (VILI) has come of age.”1 His comments were derived from a report by Ranieri et al2 which shows that a “lung-protective strategy” of respiratory support reduces cytokine levels in both the bronchoalveolar lavage fluid and serum of adult patients with acute respiratory distress syndrome (ARDS). Dr Hudsons enthusiasm is increased by the recent press release from the National Institutes of Health (NIH) ARDS Network Study, reporting positive results of a study evaluating a “lung-protective strategy” in >800 adults with ARDS. The NIH study was stopped early, when the safety monitoring committee noted “25% fewer deaths” among patients receiving small (6 mL/kg) rather than large (12 mL/kg) tidal volumes to support gas exchange. The importance of these observations is that they provide data in support of the hypothesis that VILI can cause biotrauma associated with a “mediator storm” (perhaps cytokines) that is responsible for distal organ dysfunction, subsequent multiorgan failure, and death.3 These adult data unequivocally prove that how we support gas exchange in patients with lung disease markedly affects outcome. Although it has been shown that pulmonary cytokine levels also appear to be elevated in some neonates on assisted ventilation, an exact relationship to neonatal lung injury has not yet been well defined.4–7 Proinflammatory mediators may be elevated because of fetal exposure to maternal inflammatory mediators, postnatal infection, or by release from preterm lungs attributable to ventilator-induced injury.5 The neonatal lung is still in stages of development and growth, therefore cytokine responses and effects may be immature and different from what is seen in adults. Indeed, data from Kwong et al8 ,9 suggests a possible relationship between cytokine signaling and …

High-frequency oscillatory ventilation Versus intermittent mandatory ventilation : early hemodynamic effects in the premature baboon with hyaline membrane disease

ABSTRACT: We studied the hemodynamic consequences during the first 24 h of life in premature baboons (140 d) with hyaline membrane disease that were treated with high-frequency oscillatory ventilation (HFOV) or conventional intermittent mandatory ventilation (IMV). Cardiac output and organ blood flow were measured at three time-points using the radiolabeled microsphere technique. Seven of seven HFOV and six of eight IMV animals survived the 24-h period. By design, initial mean airway pressure (Paw) was higher in the HFOV group (p < 0.01). HFOV Paw was progressively reduced during the study period because of improving oxygenation as measured by the arterial to alveolar oxygen ratio. In contrast, it was necessary to increase Paw in the IMV animals to maintain the arterial to alveolar oxygen ratio. By 23 h, the IMV group required higher Paw than the HFOV group (p < 0.05) and had a lower arterial to alveolar oxygen ratio (p < 0.05). We found no significant differences in left ventricular output, effective systemic flow, organ blood flow, or central venous pressure between the two groups at 3, 8, or 23 h. The HFOV strategy used in our study resulted in significant improvement in oxygenation during the initial 24 h of treatment without adverse effect on left ventricular output, cerebral blood flow, or central venous pressure. We conclude that when appropriate changes in Paw are made during HFOV in response to improvement in arterial oxgenation and changes in lung inflation as assessed by chest radiographs HFOV can be achieved without depressing cardiovascular dynamics more than during conventional therapy with IMV.

Pulmonary interstitial emphysema treated by high-frequency oscillatory ventilation

Twenty-seven low birth weight infants who developed pulmonary interstitial emphysema (PIE) and respiratory failure while on conventional ventilation were treated with high-frequency oscillatory ventilation (HFOV). The mean birth weight was 1.2 kg (range 0.55 to 2) with gestational age of 28 wk (range 25 to 34). Ten patients died, six of whom had documented sepsis with shock and were therefore excluded from analysis. All patients showed initial improvement on HFOV. Surviving patients showed continued improvement in oxygenation and ventilation at increasingly lower fraction of inspired oxygen and proximal airway pressure with resolution of PIE, while nonsurvivors progressively developed chronic respiratory insufficiency with continued PIE from which recovery was not possible. Overall survival in nonseptic patients was 80% (16 of 20). We found HFOV to be effective in the treatment of PIE and hypothesieze that interstitial airleak is decreased during HFOV because adequate ventilation is provided at lower peak distal airway pressures.

Extracorporeal membrane oxygenation and high-frequency oscillatory ventilation: potential therapeutic relationships

Eighteen neonates 33 to 42 wk gestational age with severe respiratory failure were referred for extracorporeal membrane oxygenation (ECMO). Sixteen ultimately met the ECMO criteria, of whom 15 were first offered high-frequency oscillatory ventilation (HFOV). Seven responded to HFOV alone and did not require ECMO treatment. Eight of the nine remaining patients were placed on ECMO support with HOFV. Infants who responded to HFOV alone tended to have pneumonia more than meconium aspiration, to be smaller and more immature, to have higher Apgar scores, and to have suffered severe hypoxia (alveolar-arterial oxygen pressure difference over 600 torr) for less time than the ECMO group. Although patient numbers are small, a trend is noted which favors HFOV treatment alone in terms of the duration of HFOV, the total duration of assisted ventilation, the rapidity with which extubation was accomplished, and the length of hospital stay.

A comparison of ventilation strategies for the use of high-frequency oscillatory ventilation in the treatment of hyaline membrane disease

To assess the efficacy of high frequency oscillatory ventilation (HFOV) in the management of infants with hyaline membrane disease (HMD), we compared two HFOV strategies with conventional positive pressure ventilation with positive end expiratory pressure (PPV) for 24 h in premature baboons (140 d gestation). Three out of 14 PPV, five out of five HFOV‐E (begun at birth; 15 Hz; I:E 1:2), and none of 10 HFOV‐L (begun after 3 h PPV; 10 Hz; I:E 1:2) were killed at 24 h for morphologic examination. Physiologic (Paw, Pa/AO2, IO2, B. P., pulse, blood gases) data on all animals in each group were assessed at each 3 h interval and over time. Intergroup differences in radiographs at 0 and 24 h and in morphology were quantitatively assessed by comparison with a panel of standards. All animals had radiographic HMD. Initial Paw was set higher with HFOV‐E (16.8) than PPV or HFOV‐L (14.1, 14.1). PPV baboons required increasing Paw to maintain constant Pa/AO2. Six out of 14 PPV animals developed airleak and three out of three had morphologic HMD. In contrast Pa/AO2 was higher in both HFOV groups at lower Paw by 24 h. None of 15 HFOV animals developed airleak. HFOV‐E lungs had dramatic differences in morphology with uniform saccular opening and decreased edema and hyaline membranes compared to PPV. HFOV‐L had less dramatic effects because of lower Paw and delayed application. Early use of HFOV at a high Paw favorably alters the course of HMD. Unless closely monitored, this strategy results in lung overinflation which may adversely affect venous return and cardiac output.