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 microg 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.

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% (MIC(90)) 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 MIC(90) for Streptococcus agalactiae (group B streptococcus). For AF, all cefazolin levels, except two, were above the MIC(90). CONCLUSIONS: Cefazolin concentrations greater than or equal to the MIC(90) 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.

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 microg/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-proven Staphylococcus 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 microg/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 microg/mL.

Sedation in children: current concepts.

Sedation in children poses a great challenge, with the main concern one of safety. The importance of providing adequate sedation to children was realized only in the last decade and a half, and relevant data are severely lacking. Use of potent sedative agents is not without risk. Children are given sedative agents in a wide variety of settings by practitioners with different degrees of experience with the drugs and management of adverse effects. Controversial issues must be addressed in this area, and appropriate tools developed to measure sedation and individualize treatment based on the drugs' pharmacokinetic and pharmacodynamic properties.

Physical compatibility and chemical stability of atracurium besylate and midazolam hydrochloride during intravenous coinfusion.

The objective of this study was to evaluate the physical stability and chemical compatibility of midazolam hydrochloride and atracurium besylate for intravenous coadministration at concentrations normally encountered in clinical practice. Commercially available midazolam hydrochloride injection (Versed) and atracurium besylate injection (Tracrium, Glaxo Wellcome) were used to prepare four different drug combinations in 5% dextrose injection. The final concentration of midazolam (as the hydrochloride salt) and of atracurium (as the besylate salt) was 0.1 or 0.5 mg/mL and or 5 mg/mL, respectively. The chemical stability of midazolam and atracurium in combination was evaluated using a stability-indicating high-performance liquid chromatography assay, capable of simultaneous analysis of both compounds, developed in our laboratory Midazolam was detected using an ultraviolet detector and atracurium with a fluorescence detector. The analysis was done at room temperature under fluorescent lighting. All solutions were evaluated for physical stability by inspecting visually under normal fluorescent laboratory lighting for precipitate (against a black background) or gas formation and color change immediately following the admixture and then at one, two and three hours. The pH of these solutions was also measured at each time interval. Under the study conditions all test solutions retained greater than 90% of the initial concentration after three hours. There was no visible evidence of precipitation, color change, or gas formation in the test solution at any time following admixture; and the pH of the solutions was also unchanged during the three-hour study period. Midazolam hydrochloride and atracurium besylate are physicallly stable and chemically compatible for up to three hours at room temperature under normal fluorescent lighting at the concentrations used in this study and may be coinfused at a y-site without loss ofpotecncy.

Stability of ciprofloxacin in an extemporaneous oral liquid dosage form.

The stability of ciprofloxacin hydrochloride in an extemporaneously compounded oral liquid formulation was studied. A suspension was prepared by mixing four crushed, commercially available 750-mg tablets of ciprofloxacin hydrochloride with equal amounts of Ora Plus and simple syrup, NF to make a final volume of 60 mL. The final concentration of ciprofloxacin hydrochloride in the suspension was 50 mg/mL. Six identical suspensions were prepared, placed in amber, plastic prescription bottles and stored at room temperature (24 to 26 deg C) and under refrigeration (3 to 5 deg C). Immediately after preparation and at seven, 14, 28, and 56 days, samples were removed and assayed in duplicate by stability-indicating high-performance liquid chromatography. Color, odor and pH did not change appreciably over the study period. At least 99% of the inital ciprofloxacin hydrochloride concentration remained in all suspensions througout the study period. Ciprofloxacin hydrochloride 50 mg/mL compounded extemporaneously in equal amounts of Ora Plus and simple syrup, NF was stable at room temperature and under refrigeration for at least 56 days in amber, plastic prescription bottles.

Comparison of two methods of surfactant administration and the effect on dosing-associated hypoxemia.

OBJECTIVE: The purpose of our study was to test the hypothesis that surfactant dosing through a proximal sideport adapter on an endotracheal tube leads to more dosing-associated hypoxemia compared with a method of dosing that uses a double-lumen endotracheal tube. STUDY DESIGN: Using adequate sample size to compare significant changes in O2 saturation (power > 0.8, alpha < 0.05) we enrolled 36 infants with respiratory distress syndrome in this randomized trial. A 10% change in O2 saturation was considered clinically significant. Nineteen infants received 38 doses of surfactant through the sideport adapter. Seventeen infants received 31 doses of surfactant through the nonventilation lumen of a double-lumen endotracheal tube. Two main outcome measures were assessed: time-averaged O2 saturation values 30 minutes after dosing and the largest absolute fall in O2 saturation for each patient. RESULTS AND CONCLUSIONS: Time-averaged O2 saturation measures were higher in the proximal sideport group (p = 0.02), but the magnitude of difference was probably not clinically significant. No significant difference was detected between groups when we compared largest absolute drop in O2 saturation. Secondary analyses found no effect of birth weight or dose number (second vs third dose) on either outcome measure.

Prospective evaluation of two dosing equations for theophylline in premature infants.

STUDY OBJECTIVES: To evaluate prospectively the ability of two equations that we previously derived to predict maintenance theophylline dosages that provide a serum theophylline concentration (STC) of 8 micrograms/ml, the midtherapeutic range for treating apnea of prematurity; and to determine the number of further dosage adjustments and STC determinations required to achieve the target concentration in infants in whom it was not achieved initially. DESIGN: Prospective study. SETTING: A 37-bed neonatal intensive care unit. PATIENTS: Fifty-four infants 27-34 weeks' gestational age requiring intravenous hydrous aminophylline. INTERVENTIONS: Patients received a loading dose of 6 mg/kg intravenous aminophylline, followed by a maintenance dosage calculated using one of the two derived equations. The basis for equation selection was the gestational age of the patient. MEASUREMENTS AND MAIN RESULTS: Patients were stratified into two age groups: 27-30 weeks' gestational age (34 infants) and 31-34 weeks' gestational age (20 infants). The overall success rate for both equations in achieving the target concentration was 74%. When infants were stratified by gestational age, those dosed by Equation 1 had a 76% success rate and those dosed by Equation 2 had a 65% success rate. Overall, 14 of 54 infants received an average of 1.2 dosage adjustments. This represents more than a 50% reduction in the number of adjustments made before introduction of these equations. CONCLUSIONS: The ability of our previously derived equations to produce an STC within the midtherapeutic range for treating apnea of prematurity was demonstrated in the majority of patients studied (74%). Further, the number of subsequent dosage adjustments required to attain the target STC in infants who had failed to achieve this STC initially was significantly less than using older, more traditional regimens.

Current guidelines for the treatment of acute pain in children.

Premature and full-term neonates, infants and children are capable of experiencing pain just like adults, and deserve aggressive treatment. Assessment of pain is difficult in the preverbal group. However, physiological and behavioural responses to noxious stimuli are well developed even in the fetus, and modifying these responses through treatment can affect outcome. Treatment options include systemic opioid and nonopioid analgesics as well as local anaesthetics, all of which are effective when chosen on the basis of the type and intensity of the pain. Dosage modification is necessary based on age and organ function. Nonopioid analgesics are useful supplements to reduce opioid analgesic dose and should be used when indicated. Drug dependence and withdrawal can be avoided by using the opioids appropriately and following logical weaning schedules after long term use of these agents. Use of needles for administering analgesia is still an intimidating part of the process for young children. The development of drugs having fewer adverse effects and noninvasive administration techniques will be important research priorities in the future.

Accuracy and reliability of dosing equations to individualize theophylline treatment of apnea of prematurity.

Apnea of prematurity is associated with high morbidity and mortality. Treatment generally includes supplemental oxygen and theophylline or caffeine. The half-life of theophylline is prolonged in newborns because of their immature cytochrome P-450 system, and there is considerable variation in the drug's metabolism in infants. We compared the accuracy, precision, and reliability of two equations that use postnatal age (PNA) to determine a maintenance dosage of theophylline with a standard maintenance dosage (SMD) that produced a steady-state serum theophylline concentration (STC) of 8 micrograms/ml for apnea of prematurity in 46 infants less than 34 weeks' gestational age (GA) and less than 36 weeks' postconceptional age (PCA). The two equations were mg/kg/day = [(0.2 x PNA in wks) + 5], and mg/kg/day = [(0.3 x PNA in wks) + 8]. Their reliability to predict the SMD was determined by correlation analysis. The precision and accuracy with which they predicted SMD were determined and analyzed by chi 2. The SMD did not correlate with the maintenance dosages calculated by equations 1 and 2 (r = 0.296 and 0.296, p > 0.05 in both cases). Multiple linear regression of SMD versus GA, PNA, and PCA was not significant (r = 0.33, p = 0.32). After stratifying data based on GA and performing correlation analysis of SMD versus PNA, a weak but significant correlation (r = 0.42, p = 0.517) was found for infants with GA between 31 and 34 weeks. Poor correlation was found between SMD versus PNA for infants 27-30 weeks' GA. Two new equations of the best fit line were generated using the same data.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability of propofol with parenteral nutrient solutions during simulated Y-site injection.

The stability of propofol in three parenteral nutrient (PN) solutions was studied. Nine combinations of three PN solutions (with amino acid concentrations of 1.5, 2.5, and 5.0%) and three propofol concentrations (0.5, 2.0, and 3.0 mg/mL) were prepared in triplicate and stored at 22 degrees C under fluorescent light. Duplicate samples were visually inspected for color changes, precipitation, or gas formation, and the pH of the samples was determined. These samples were evaluated for propofol content by high-performance liquid chromatography at zero, one, three, and five hours. The stability of the vehicle for propofol injection (similar in composition to fat emulsion) was evaluated by visual inspection, pH determination, and particle-size measurements at zero, one, three, and five hours. The concentration of propofol in all of the propofol-PN combinations remained greater than 90% of the initial concentration except for the combination of propofol 0.5 mg/mL and the 1.5% amino acid PN solution, which contained only 72% of the initial propofol concentration five hours after the start of the study. Visual examination revealed no evidence of color change, precipitation, gas formation, creaming, or streaking in any of the propofol-PN solution combinations. No substantial changes in pH occurred. The particle size of the vehicle for propofol remained relatively constant throughout the study period. Propofol 2 and 3 mg/mL was stable for five hours during simulated Y-site injection with PN solutions containing 1.5, 2.5, and 5% amino acids. Propofol 0.5 mg/mL was stable during simulated Y-site injection with the same PN nutrition solutions for five hours, except for the solution containing 1.5% amino acid.

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.

Neonatal adrenergic blockade following single dose maternal labetalol administration.

A single 30 mg intravenous dose of labetalol given 20 minutes prior to cesarean delivery at 35 weeks of gestation for severe pregnancy-induced hypertension was associated with symptoms of beta-adrenergic blockade (hypoglycemia, bradycardia, hypotension) in preterm twins. The infants were subsequently found to have therapeutic labetalol concentrations (180 and 150 ng/mL) in umbilical cord blood. The pharmacology of transplacental labetalol is reviewed and potential mechanisms for neonatal beta-adrenergic blockade are discussed.

Fetal exposure to lisinopril: neonatal manifestations and management.

The use of angiotensin-converting enzyme (ACE) inhibitors in pregnancy has been associated with neonatal morbidity and mortality. The mechanism of renal dysfunction likely is related to fetal hypotension and prolonged decreased glomerular filtration. Six of 14 previously published cases of neonatal renal failure after maternal ACE inhibitor therapy resulted in death. Eight infants survived after peritoneal dialysis, some with residual renal impairment. Serum lisinopril levels and ACE activity in our patient indicate that during the anuric state the drug has an extremely prolonged half-life, and that it is removed by peritoneal dialysis. In view of this prolonged half-life and the drug's continued suppression of ACE activity and renal function, we recommend institution of early dialysis in infants with renal failure after maternal therapy with lisinopril.

Stability of midazolam hydrochloride in extemporaneously prepared flavored gelatin.

The stability of midazolam hydrochloride in flavored gelatin was evaluated after storage at 4 degrees C for 14 days and at -20 degrees C for 28 days. A flavored liquid gelatin mixture was prepared and mixed with midazolam hydrochloride injection in final concentrations of midazolam 1 and 2 mg/mL. Gelatin cups containing 5 and 15 mg of midazolam were prepared by measuring appropriate volumes of the gelatin stock solutions and were stored in a refrigerator at 4 degrees C or in a freezer at -20 degrees C. Immediately after preparation and at 7 and 14 days, three refrigerated and three frozen gelatin samples of each midazolam concentration were visually inspected, tested for pH, and assayed for midazolam concentration by high-performance liquid chromatography. The frozen gelatin samples were also evaluated at 21 and 28 days; three whole and three partial gelatin samples were assayed for midazolam content to determine the uniformity of drug distribution within each sample. All samples maintained greater than 96% of the initial midazolam concentration throughout the study. There was no appreciable change in color, odor, or pH. The midazolam content of the gelatin in the cups was uniform. An extemporaneously compounded preparation of midazolam hydrochloride in flavored gelatin was stable when stored for 14 days at 4 degrees C and for 28 days at -20 degrees C. Distribution of midazolam hydrochloride in the gelatin was uniform.

Stability of midazolam hydrochloride in parenteral nutrient solutions.

The compatibility and stability of midazolam hydrochloride in three parenteral nutrient (PN) solutions and the stability of 15 amino acids in the presence of midazolam hydrochloride were studied. Six combinations of three PN solutions with amino acid concentrations of 1.5%, 2.5%, and 5% and two midazolam concentrations (0.1 and 0.5 mg/mL) were prepared in triplicate and stored at room temperature under normal fluorescent lighting. Duplicate samples were visually inspected for color change, precipitation, or gas formation and tested for pH. The samples were evaluated for midazolam and amino acid content by high-performance liquid chromatography at zero, one, three, and five hours. Midazolam and amino acid concentrations did not change significantly during the study. There was no evidence of color change, precipitation, or gas formation with any midazolam-PN solution combination when the combinations were examined visually and under a microscope, and no substantial changes in pH occurred. Midazolam 0.1 and 0.5 mg/mL (as the hydrochloride salt) was stable in the three PN solutions studied; in addition, the amino acids present in the 1.5%, 2.5%, and 5% amino acid PN solutions were stable when combined with midazolam at concentrations of 0.1 and 0.5 mg/mL.

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.