Varsha Bhatt-Mehta

Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome.

To compare the efficacy of dopamine and dobutamine for the treatment of hypotension (mean arterial blood pressure, < or = 30 mm Hg) in preterm (< or = 34 weeks of gestation) infants with respiratory distress syndrome in the first 24 hours of life, we enrolled 63 hypotensive preterm infants in a randomized, blind trial. Inclusion criteria required an arterial catheter for measurement of mean arterial blood pressure, treatment with exogenous surfactant, and persistent hypotension after volume expansion with 20 ml/kg (packed erythrocytes if hematocrit < 0.40, 5% albumin if > or = 0.40). Intravenous study drug infusions were initiated at 5 micrograms/kg per minute and then increased in increments of 5 micrograms/kg per minute at 20-minute intervals until a mean arterial blood pressure > 30 mm Hg was attained and sustained for > or = 30 minutes (success) or a maximum rate of 20 micrograms/kg per minute was reached without resolution of hypotension (failure). The study groups at entry were comparable for birth weight, gestational age, postnatal age, gender, birth depression, hematocrit < 0.40, heart rate, oxygenation index, delivery route, maternal chorioamnionitis, and maternal magnesium or ritodrine therapy. No infants in the dopamine group had a treatment failure (0/31; 0%); (16%) of 32 infants failed to respond to dobutamine (p = 0.028). Success was attained at < or = 10 micrograms/kg per minute in 30 (97%) of 31 infants given dopamine and in 22 (69%) of 32 infants given dobutamine (p < 0.01). Among those treated successfully, the increase in mean arterial blood pressure was significantly higher in those given dopamine (mean, 11.3 vs 6.8 mm Hg; p = 0.003). We conclude that dopamine is more effective than dobutamine for the early treatment of hypotension in preterm infants with respiratory distress syndrome.

Continuous Quality Improvement: Reducing Unplanned Extubations in a Pediatric Intensive Care Unit

Objective. Unplanned extubation (UEX) is a potentially serious complication of mechanical ventilation. Limited information is available regarding factors that contribute to UEXs and subsequent reintubation of children. We monitored UEXs in our pediatric intensive care unit (PICU) for a 5-year period to assess the incidence and patient conditions associated with UEX and to evaluate whether targeted interventions were associated with a reduced rate of UEXs. Methods. Over a 5-year period, demographic and clinical information was collected prospectively on all patients who required an artificial airway while admitted to the PICU. Additional information was collected for patients who experienced an UEX. Educational sessions and care management protocols were developed, implemented, and modified according to issues identified via the monitoring program. Results. From a total of 2192 patients who required 13 630 airway days (AWD), 141 (6%) patients experienced 164 UEXs. The overall rate of UEX for the study period was 1.2 UEXs per 100 AWD, and this rate decreased from 1.5 in the first year to 0.8 in the last year. UEXs were more common in children who were younger than 5 years (1.6 vs 0.6 UEX per 100 AWD) compared with older children. The UEX children experienced significantly longer length of mechanical ventilation (6 vs 3 days) and longer length of PICU stay (8 vs 4 days) compared with non-UEX children. Forty-six percent of the UEXs occurred in patients who were weaning from mechanical ventilation, and 22% of those patients required reintubation. Conclusions. We conclude that UEX in pediatric patients is associated with longer length of mechanical ventilation and length of stay in the PICU. A continuous quality improvement monitoring and educational program that identified high-risk patients for UEX (younger patients) and patients who were at low risk for subsequent reintubation (weaning patients) contributed to a reduction of these potentially adverse events.

Maternal and transplacental pharmacokinetics of cefazolin

OBJECTIVE To evaluate the intrapartum pharmacokinetics of cefazolin, including delivery to amniotic fluid (AF) and fetal compartments, and to ascertain that adequate cefazolin concentrations are attained to exceed the mean concentration inhibiting 90% (MIC90) of group B streptococcus strains. METHODS Cefazolin (1 g) was administered intravenously at five separate time intervals (0.5, 1, 2, 4, and 6 hours) before elective cesarean at term to 26 women with intact membranes and with no significant infections or cardiovascular, liver, or renal disease. Samples of maternal blood, cord blood, and AF were obtained at the time of delivery. Exact collection times relative to cefazolin infusion were noted. Amniotic fluid contaminated with blood or meconium was excluded. Cefazolin concentration was measured by high‐pressure liquid chromatography. RESULTS All maternal and cord plasma cefazolin levels, except one, were above the MIC90 for Streptococcus agalactiae (group B streptococcus). For AF, all cefazolin levels, except two, were above the MIC90. CONCLUSIONS Cefazolin concentrations greater than or equal to the MIC90 for group B streptococcus were attained in nearly all maternal, fetal, and AF samples. This information, together with the knowledge that there is rare resistance of group B streptococcus to cefazolin, supports the use of cefazolin as a better alternative than clindamycin or erythromycin for group B streptococcus prophylaxis in patients with a nonanaphylactic penicillin allergy.

Gentamicin Pharmacokinetics in Term Neonates Receiving Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) may affect the pharmacokinetics of certain drugs. The objectives of this study were to determine (1) the pharmacokinetics of gentamicin in neonates on ECMO and compare them to reported values for a similar patient population not on ECMO, (2) if the pharmacokinetics of gentamicin differ between venous‐venous and venous‐arterial bypass, and (3) if the pharmacokinetics of gentamicin are affected by oxygenator surface area (0.6 m2 vs 0.8 m2 oxygenators). The medical records of 29 term neonates who received gentamicin while on ECMO were reviewed. Data collected included gentamicin dosage, peak and trough serum concentrations determined at steady state, duration of treatment, time on ECMO, daily weights, and pertinent laboratory values. An initial dosage of gentamicin 2.5 mg/kg every 18 hours is suggested for term neonates on ECMO. Dosage adjustments should be based on gentamicin serum concentrations, and modifications may also be required after ECMO.

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 &mgr;g/mL for 50% of the dose interval and >2 &mgr;g/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148). Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

Treatment of Apnea of Prematurity

In the last decade, knowledge regarding the neurodevelopment and functional aspects of the respiratory centers during postnatal maturation has increased substantially. However, an increase in such knowledge has not provided a basis for change in practice. The diagnosis of apnea of prematurity (AOP) is one of exclusion. All causes of secondary apnea must be ruled out before initiating treatment for AOP. Treatment will depend on the etiology as well as effectiveness and tolerability of the treatment by the patient. The primary goal of any treatment of AOP is to prevent the frequency of apnea lasting > 20 seconds, and/or those that are shorter, but associated with cyanosis and bradycardia.The clinical management of AOP is not much different today than it was two decades ago, with pharmacologic and nonpharmacologic treatment options remaining the mainstay of therapy. Methylxanthines are still the most widely used pharmacologic agents. Due to the wider therapeutic index of caffeine and ease of once daily administration, it should be the preferred agent. Doxapram, or nonpharmacologic treatment measures such as nasal continuous positive airway pressure, may be considered in infants who are unresponsive to methylxanthine treatment alone. Treatment should be continued until there is complete resolution of apnea, and for some time thereafter. The choice of method for weaning treatment remains one of individual physician preference. Discharge from hospital after apnea requires close monitoring and some infants will require home apnea monitors. The decision to provide a home apnea monitor should be individualized for each patient, depending on the effectiveness of treatment and clinical response.

Lack of Vancomycin-associated Nephrotoxicity in Newborn Infants: A Case-Control Study

Objective. The purpose of this study was to compare the incidence of nephrotoxicity, defined as doubling of baseline serum creatinine concentration, in newborn infants with peak vancomycin serum concentrations ≤40 μg/mL at steady state to infants with peak vancomycin serum concentrations >40 μg/mL. A secondary objective was to correlate concomitant disease states and potentially nephrotoxic drug therapy with rises in serum creatinine in vancomycin recipients. Methods. Newborn infants with culture-provenStaphylococcus aureus or coagulase-negative staphylococcal septicemia who received vancomycin therapy for >3 days between 1985 and 1995 were identified from an existing database and a review of medical record. All 69 patients included in the study had serial serum creatinine determinations, including a baseline value within 48 hours of starting treatment with vancomycin, and serum vancomycin concentrations determined after at least three doses, with peak and trough concentrations determined 1 hour after a 60-minute infusion and 15 to 30 minutes before a dose, respectively. Infants with congenital renal or cardiac anomalies were excluded. Demographic characteristics, vancomycin dosing regimen, serum vancomycin concentrations and sample times, concomitant drug therapy, and disease states were recorded. Patients were divided into group A (peak vancomycin concentration ≤40 μg/mL) and group B (peak vancomycin concentration >40 μg/mL). The change in serum creatinine concentration between the start and end of vancomycin therapy was determined. Nephrotoxicity was identified if serum creatinine doubled at any time from the start to the end of vancomycin therapy. Alternative definitions of nephrotoxicity (any rise in serum creatinine to >0.6 mg/dL or new abnormalities of urine sediment) were used in additional analyses. Results. A total of 69 evaluable patients (gestational age, 28.9 ± 3.0 weeks; birth weight, 1219 ± 516 g) were identified, 61 in group A and 8 in group B. Six patients in group A underwent doubling of serum creatinine concentration during vancomycin therapy, whereas none in group B did so. Serum creatinine doubled to >0.6 mg/dL in only 3 infants (all in group A). Any increase in serum creatinine to >0.6 mg/dL was seen in 10 infants, 9 of whom were in group A. No confounding variable, including previous or concomitant underlying disease states associated with renal dysfunction or treatment with other potentially nephrotoxic agents, were associated with a significant rise in serum creatinine. Conclusion. Vancomycin-associated nephrotoxicity is rare in neonates, even with serum peak concentrations >40 μg/mL.

Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns.

Objective:The purpose of this observation was to evaluate the safety and efficacy of hydrocortisone (HC) for the treatment of refractory hypotension in term and preterm infants. A secondary purpose was to determine the utility of serum cortisol concentrations in predicting the response to treatment.Study Design:This is a retrospective observational study of 117 infants treated with a standardized HC protocol for refractory hypotension. Refractory hypotension was defined as a mean arterial pressure (MAP) less than the gestational age (GA) despite a total inotrope dose of 20 μg per kg per min. Baseline serum cortisol concentrations were determined prior to treatment with stress dose HC.Result:Treatment with HC increased the MAP at 2, 6, 12 and 24 h after initiation, decreased the total inotrope dose at 6, 12 and 24 h, and was associated with resolution of oliguria. There was no correlation between the pretreatment baseline cortisol concentration and GA, birth weight or the response to treatment. The incidence of grades III to IV intraventricular hemorrhage, periventricular leukomalacia, bacterial or fungal sepsis and spontaneous intestinal perforation (SIP) after HC treatment was similar to institutional historic controls prior to institution of this standardized HC protocol.Conclusion:HC treatment was associated with a rapid resolution of cardiovascular compromise. The incidence of significant side effects was similar to that in previously published reports, including a comparable incidence of SIP. On the basis of our results, measuring baseline serum cortisol concentration to guide the management of refractory hypotension is unwarranted.

Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia

Objective: Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes. Setting: Level 3 neonatal ICU. Patients: Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia. Interventions: None. Design: A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not). Measurements and Main Results: Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital. Conclusions: Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

Management of Acute, Severe Asthma in Children:

OBJECTIVE: To briefly present the current options available for the treatment of acute, severe asthma in children, with a special focus on emergency department and inpatient treatment, and to describe newer therapies that may aid treatment in the future. DATA SOURCES AND STUDY SELECTION: A MEDLINE search (1966–May 2001) of the English-language literature pertaining to drug therapy of acute asthma was performed. Key word searches included acute asthma, albuterol, ipratropium, corticosteroids, magnesium, and theophylline. Additional articles from these sources and published national guidelines were identified. Relevant studies pertaining to current therapy of acute asthma in pediatric patients were selected; if there were minimal pediatric data, adult data were included. DATA SYNTHESIS: Asthma is a chronic, inflammatory disorder of the airways. Acute exacerbations can occur and are challenging to manage. Albuterol, ipratropium, and systemic corticosteroids have been shown to be effective in acute asthma exacerbations. Because some patients do not respond to maximal therapy, older therapies such as magnesium and theophylline are being reevaluated. Theophylline may have some therapeutic effect, but given its toxicity profile, it is unclear whether it offers any advantage over maximal β2-agonist therapy. There are only minimal published data evaluating the use of magnesium in pediatrics, and most are small trials or case reports. Newer therapies such as ventilation strategies with heliox and intravenous leukotriene modifiers currently being evaluated may or may not prove to be beneficial in the future. CONCLUSIONS: β2-agonists, ipratropium, and corticosteroids remain the most useful therapeutic agents for acute asthma exacerbations in pediatric patients. However, these agents are not ideal in all patients and, given the existing questions regarding safety and/or efficacy of available alternatives, more effective options are needed.