Septicaemia in an Austrian neonatal intensive care unit: a 7-year analysis

The results of blood cultures and clinical data of 101 neonates with 110 episodes of septicaemia during a 7-y study period were reviewed. The overall incidence of culture-proven sepsis within the study period was 6.0 per 100 neonatal intensive care unit admissions and the mortality rate was 14%. Three groups of pathogens accounted for 70% of all isolates: coagulase-negative staphylococci (27%), aerobic Gram-negative rods (24%) and Enterococcus faecalis (19%). Group B streptococcus was the major pathogen of very early-onset septicaemia (within 24 h of birth), whereas late-onset infections were most commonly caused by coagulase-negative staphylococci. Birthweight <1500 g, gestational age <30 weeks of gestation and early onset of symptoms within the first week of life were associated with poor prognosis. In addition, the case fatality rate of episodes caused by Gram-negative organisms was significantly higher than that of Gram-positive bacteraemia.     

Overdoses of pethidine given to two preterm neonates

This paper reports two mechanically ventilated preterm babies who received overdoses of pethidine in the neonatal period. One of the neonates (gestational age 26 weeks, birthweight 1040 g) received repeated appropriate doses, which resulted in central nervous system irritability and convulsion due to accumulation of the drug and its metabolite, norpethidine. The other neonate (gestational age 27 weeks, birthweight 980 g) received a major (10-fold) overdose with little clinical effect. These two cases indicate notable individual variability in the responses of babies to pethidine. This is typical of other opioids, too. Therefore, the dosing of opioids to neonates should be titrated individually, and the patients should be observed carefully.     

Streptococcus group B and pregnancy: the therapeutic role of topical intravaginal clindamycin

OBJECTIVE: To evaluate the clinical and therapeutic efficacy of 2% clindamycin vaginal cream in pregnant women heavily colonized with group B streptococci (GBS). STUDY DESIGN: A prospective, clinical trial in which carriers of group B streptococci were randomized to receive topical intravaginal clindamycin or oral amoxicillin. PATIENTS: We randomized 105 pregnant women: 55 received 2% clindamycin vaginal cream (100 mg/day for 7 days) and 50 oral amoxicillin (2 g/day for 7 days). INTERVENTIONS: Patients were treated during pregnancy, none of them received intrapartum chemoprophylaxis. On the other hand, all the neonates, within 24 hours from delivery, were studied from the microbiological point of view, carrying out auricolar, nasal, oropharyngeal and umbilical cultures. RELIEFS: The eradication of the microorganism was evaluated by performing a vaginal culture after 6 weeks from the beginning of antibiotic therapy. RESULTS: The eradication rate of the microorganism was significantly higher in women treated with topical clindamycin compared with the group receiving oral amoxicillin (71% versus 36%; p < 0.05). The neonatal outcome was similar in the two groups in terms of gestational age at delivery and mean birthweight. None of the neonates was admitted to the neonatal intensive care unit and no cases of neonatal sepsis were recorded. CONCLUSIONS: From our experience we can conclude that, during pregnancy, a treatment with topical intravaginal clindamycin may be useful in the eradication of GBS.     

Three-dimensional electron microscopy of the photosystem II core complex

Risk factors for central venous catheter (CVC)-related bacteraemia among infants admitted to a neonatal intensive care unit (NICU) were analysed and the impact of surveillance and continuing education on the incidence of this complication investigated. Among patients admitted to a NICU, CVC-related bacteraemia increased from 1/15 (7%) in 1987 to 11/26 (42%) in 1988 (P = 0.01). Coagulase-negative staphylococci isolated from bacteraemia patients showed clonal diversity by plasmid and chromosomal fingerprinting. A review of CVC care procedures suggested breaches in aseptic techniques. Catheter-care technique was revised to ensure maximal aseptic precautions, including the use of sterile gloves, gown and drapes. The new policy was promoted by a continuing education programme and regular feed-back of CVC-related bacteraemia incidence to NICU staff. In the four-year follow-up period, the attack-rate of CVC-related bacteraemia decreased to 18/156 (12%) patients [relative risk (RR): 0.27, 95% confidence interval (CI); 0.15-0.51; P < 0.001 vs the previous period]. By using the Cox's model proportional hazards, very low birthweight and the period before use of strict aseptic CVC care were found to be predictors of increased risk of catheter-related bacteraemia after adjustment for duration of catheterization. These data provide further evidence that strict aseptic precautions during the maintenance and utilization of CVC can contribute to lower the risk of catheter infection in critically ill neonates. Regular feedback of surveillance data was associated with a progressive decrease in incidence of infection, suggesting that it improved staff compliance with aseptic precautions.     

Neonatal pediatrics in Denmark. Therapeutic routines in care of very low birth weight infants and very premature infants, 1990

A questionnaire on neonatal carried intensive care in Denmark was carried out in October 1990. The eighteen paediatric departments in the country with neonatal intensive care units all answered the questionnaire. The routines concerning transferral to a higher level of specialization, and the treatment procedures for children with a birthweight below 1500 grams and/or a gestational age under 32 weeks are described. Major regional variations were found in the degree of centralization of treatment, especially between the eastern and western part of Denmark. In an international perspective to neonatal intensive care Denmark seems to be modest with respect to initiation of treatment and the use of technology.     

Ampicillin-metronidazole treatment in idiopathic preterm labour: a randomised controlled multicentre trial

OBJECTIVE: To determine whether treatment with ampicillin and metronidazole in women with threatened idiopathic preterm labour will prolong the gestation and reduce maternal and neonatal infectious morbidity. DESIGN: Randomised controlled double-blind trial. SETTING: Six obstetric departments in the Copenhagen area. POPULATION: One hundred and twelve women with singleton pregnancies, with threatened idiopathic preterm labour and intact amniotic membranes at 26 to 34 weeks of gestation. METHODS: Random allocation to eight days intravenous and oral treatment with ampicillin and metronidazole, or placebo. MAIN OUTCOME MEASURES: Number of days from admission to delivery, gestational age at delivery, rates of preterm delivery, low birthweight, maternal infections and neonatal infections. RESULTS: Treatment with ampicillin and metronidazole was associated with a significant prolongation of pregnancy (admission to delivery 47.5 days versus 27 days, P < 0.05), higher gestational age at delivery (37 weeks versus 34 weeks, P < 0.05), decreased incidence of preterm birth (42% versus 65%, P < 0.05), and lower rate of admission to neonatal intensive care unit (40% versus 63%, P < 0.05), when compared with placebo treatment. Antibiotic treatment had no significant effects on infectious morbidity. CONCLUSIONS: Treatment with ampicillin and metronidazole in women with threatened idiopathic preterm labour significantly prolonged the gestation, but had no effects on maternal and neonatal infectious morbidity.     

Cost of care for a geographically determined population of low birthweight infants to age 8-9 years. I. Children without disability

AIM: To determine the extra cost of healthcare associated with low birthweight, in a cohort study of a geographically defined population in five health districts that comprise Merseyside. METHODS: The study comprised all children of birthweight < or = 1500 g and a 10% random sample of those weighing 1501-2000 g, without clinical disability, born in 1980 and 1981 to mothers resident in Merseyside, and their controls, matched by age, sex, and school class, followed up to age 8-9 years. RESULTS: The cost of care associated with the initial admission to the neonatal special/intensive care unit and subsequent use of hospital and family practitioner services was assessed. There were 641 survivors without disability and 227 non-survivors who weighed < or = 2000 g at birth. The mean cost of neonatal care per low birthweight child was 13 times greater than for a control child. For children weighing < or = 1000 g at birth, neonatal costs were 55 times greater than for the control children. Low birthweight children continue to use hospital and family practitioner services more intensively than controls to age 8-9 years. CONCLUSION: Low birthweight children used hospital and family practitioner services more intensively throughout the follow up period. Whether the increased use of health services persists into adolescence and adulthood is yet to be determined.     

Group B streptococcus: maternal carriage rate and early neonatal septicaemia

Between January 1984 and December 1994, 30 cases of early neonatal group B streptococcus (GBS) septicaemia were managed in the Neonatal Unit, University Hospital, Kuala Lumpur. Two neonates were outborn and 28 were inborn, giving an average annual incidence of neonatal GBS septicaemia of 0.4/1000 livebirths among inborn babies. In a separate survey over a three-month period, GBS genital carriage rate among 196 parturients was found to be 9.7%. Of the infants with GBS septicaemia, the mean gestational age was 37.5 +/- 3.8 weeks and the mean birthweight was 2540 +/- 716 g. Twelve (40%) were preterm infants and 14 (47%) were low birthweight infants. Male and female infants were almost equally affected. Prolonged rupture of membranes and maternal pyrexia accounted for only 5 (17%) and 3 (10%) of the cases respectively. Twenty-four (80%) neonates had onset of symptoms within 6 hours of life and respiratory symptoms were observed in 24 (80%) of the cases, while meningitis was uncommon. Six (20%) neonates died. Preterm and low birthweight infants had higher mortality than their term counterparts: 42% versus 6% and 36% versus 6% respectively. Of those who died, 4 (67%) required respiratory support right from birth and the mean time of onset of symptoms was 4 hours (range 0 to 21 hours) and the duration of survival was only 28.8 hours (range 12 to 38 hours). As the incidence of neonatal GBS septicaemia was low, mass screening and chemoprophylaxis for GBS were not recommended. All the GBS isolates were sensitive to penicillin and ampicillin, thus one of these antibiotics should be included in the antimicrobial therapy of septic neonates.     

Cardiac effects of short course dexamethasone in preterm infants

AIM: To examine the incidence and natural history of left ventricular hypertrophy (LVH) associated with the shorter 2-3 week course of dexamethasone, now more usual, for chronic lung disease. METHOD: Thirty one infants, gestational age 23-34 (median 26) weeks, birthweight 500-2054 (median 815)g, received dexamethasone, starting at 0.4-0.6 mg/kg/day, at a median of 11 days of age (range 2-34), weaning over a period of 2-3 weeks. Eighteen preterm neonates were studied as controls over a similar time period. Serial echocardiographic measurements of end diastolic interventricular septum (IVSd) and left ventricular posterior wall (LVPWd) thicknesses were taken before, and up to 48 days after, starting dexamethasone. Maximum Doppler blood flow velocities from the left ventricular outflow tract (LVOT) were measured. RESULTS: Left ventricular hypertrophy (LVH) occurred in 29 babies (94%). Median hypertrophy of the IVSd in those receiving dexamethasone was 67% and LVPWd 56% of baseline measurements, significantly greater than control infants (p < 0.001). LVH appeared by a median of three days, peaking by a median of 10 days. All resolved by a median of 27 days. LVOT obstruction was not seen. There was no significant correlation with birthweight, gestation, blood pressure, or glucose tolerance. CONCLUSIONS: LVH developed in almost all preterm neonates receiving a 2-3 week course of dexamethasone, but was of little clinical importance and always resolved. Echocardiography is probably not required routinely in infants receiving such short course dexamethasone for chronic lung disease.     

Elective cesarean section is preferred after the completion of a minimum of 38 weeks of pregnancy

OBJECTIVE: To determine the frequency of neonatal respiratory morbidity following elective caesarean delivery at term and to identify prognostic factors for this morbidity. DESIGN: Retrospective. SETTING: Academic Hospital Utrecht/Wilhelmina Children's Hospital Neonatal Intensive Care Unit, Utrecht, the Netherlands. METHOD: All elective caesarean deliveries in the Academic Hospital Utrecht from the period 1990-1995 were studied. Also, neonates were included who were admitted for intensive neonatal care because of respiratory insufficiency following elective caesarean delivery in the region surrounding Utrecht. An elective caesarean delivery was defined as a delivery performed after 37 weeks of gestation without any complicating factor that might influence the timing of delivery. Prognostic factors for neonatal morbidity after caesarean delivery were identified by multivariate logistic regression analysis. RESULTS: During 1990-1995, 272 elective caesarean deliveries after 37 weeks of gestation were performed that fulfilled the inclusion criteria; 5.1% of the neonates were admitted to the medium care unit because of respiratory problems. The relative risk of respiratory morbidity after delivery by caesarean section with a gestational age of 39-42 weeks compared with a gestational age of 37-38 weeks, was 0.14 (95% confidence interval: 0.03-0.64; p < 0.001). Male sex was a cofactor. Nine neonates of whom 8 (90%) had a gestational age of less than 39 weeks were admitted to the intensive care unit. CONCLUSION: Most of neonatal respiratory morbidity could have been avoided by postponement of the at-term elective caesarean section until a certain gestational age of at least 38 complete weeks. An elective caesarean section should not be performed before that period.     

Prediction of response to recombinant human erythropoietin (rHuEpo) in anemia of malignancy

BACKGROUND: Since only a portion of anemic patients outside the uremia setting benefit from erythropoietin treatment, a reliable means of predicting potential responders and nonresponders would be very useful. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 58 patients with refractory anemia associated with various malignant disorders who had been treated with subcutaneous rHuEpo. The starting rHuEpo dose was 375 U/kg/week for 4 weeks, and was increased to 750 U/kg/week for another 4 weeks if no response was observed. Response was defined as a Hb increase > or = 2 g/dL with no need for blood transfusion. We examined the value of various laboratory parameters (baseline levels, 2-week and 4-week changes) as predictors of response. Endogenous erythropoietin production was evaluated by its serum level and erythroid activity was assessed through reticulocyte count and circulating transferrin receptor. RESULTS: Forty-eight individuals were evaluable, 58% of whom responded to rHuEpo within 8 weeks. Multiple regression analysis showed that 53% of the variation in the 8-week Hb concentration was explained by variations in baseline serum erythropoietin and the 2-week change in serum transferrin receptor (p < 0.001). Based on these two parameters, response prediction in individual patients would have resulted in a sensitivity of 96%, a specificity of 79% and an overall accuracy of 88%. In addition, 58% of the variation in the 8-week Hb was explained by variations in the 4-week changes in Hb and reticulocyte count (p < 0.001). Utilizing these latter parameters and baseline serum erythropoietin, response prediction in individual patients would have resulted in a sensitivity of 92%, a specificity of 82% and an overall accuracy of 88%. CONCLUSIONS: This retrospective analysis suggests that response to rHuEpo can be reasonably predicted by pretreatment serum erythropoietin together with early changes in simple laboratory parameters.     

The premature infant below 1000 g

74 premature infants with a birth weight of 1000 g or less were hospitalized in the period 1963-1975. 20 babies survived the first 4 weeks of life and 2 died during the second month of life from progressive lung disease. 77% of all patients were mechanically ventilated and 9 ventilated patients survived. The main causes of death were cerebral hemorrhage, severe asphyxia and septicemia. Prognosis was impaired by hypothermia, IRDS, gestational age below 27 weeks and premature rupture of membranes with bacterial infection. At the age of 1 year 8 out of 12 survivors followed up showed normal mental and motoric development. 3 children had minor or obvious signs of cerebral paresis and one further child has partial retrolental fibroplasia. Due to modern intensive care the survival rate of these very small premature babies has now reached 40%. The prognosis is favourably influenced by optimal obstetric and neonatal care, while special precautions should be undertaken to avoid hypothermia. Our results with mechanical ventilation justify the administration of full intensive care to these very small premature babies.     

Transfusion and recombinant human erythropoietin requirements differ between dialysis modalities

BACKGROUND: Before the routine use of recombinant human erythropoietin (rHuEpo), patients dialysed by peritoneal dialysis (PD) received fewer blood transfusions than patients on haemodialysis (HD). We compared transfusion practices in these groups now that the use of rHuEpo has become standard, while controlling for variables known to influence anaemia of end-stage renal disease (ESRD). Maintenance rHuEpo doses were also compared. METHODS: Data were examined for 157 HD and 126 PD patients during a 2-year period. Potential confounders included age, gender, albumin, iron deficiency, parathyroid hormone (PTH), underlying renal disease, comorbid illness, renal transplant, dialysis adequacy and duration. An intent-to-treat analysis was used, with sensitivity analyses to account for change in treatment and transplant. RESULTS: Mean haemoglobin (Hb) was not different (10.47 g/dl for HD, 10.71 g/dl for PD; P = 0.45). Mean monthly transfusion rate was higher for HD (0.47 units per month vs 0.19; P < 0.01). More HD patients received at least one transfusion (52.9 vs 40.9%; P < 0.01). The maintenance rHuEpo dose was higher for HD (7370 U/week vs 5790 U/week; P = 0.01). The only factors associated with risk of being transfused were dialysis duration and mode of dialysis (less risk for PD, odds-ratio 0.57; 95% confidence interval 0.35-0.92). CONCLUSIONS: Despite the routine use of rHuEpo, HD patients received more blood and rHuEpo than PD patients to achieve the same Hb. No patient factors were identified to account for this difference. The use of fewer transfusions and less rHuEpo in PD represents an advantage over HD in terms of both cost and safety.     

Birthweight-specific trends in perinatal mortality by hospital category in South Australia, 1985-1990

OBJECTIVE: To investigate differences by birthweight in risk of perinatal death between level 3 hospitals (which provide care for high risk pregnancies and neonatal intensive care) and other hospitals in South Australia, using perinatal data for the 1985-1990 period. DESIGN: Analysis of birthweight-specific trends in risk of perinatal death by hospital category for singleton births, adjusting for risk factors. SUBJECTS: 114 725 singleton births of at least 400 g birthweight (or at least 20 weeks' gestation) born in hospitals in the 1985-1990 period and notified to the perinatal data collection. MAIN OUTCOME MEASURE: The relative odds of a perinatal death, as opposed to a live birth which survived the neonatal period. RESULTS: Births at level 3 hospitals had a higher crude risk of perinatal death than those at other hospitals, but this was due to the higher frequency of low birthweights at level 3 hospitals. For birthweights under 2000 g, and especially for the very low birth-weights, there was a higher risk at non-level-3 than level 3 hospitals. There was also the unexpected finding that births at level 3 hospitals in the 2500-2999 g range had a comparatively high risk of perinatal death. There was little difference in risk for births of higher birthweight. CONCLUSIONS: The greatly reduced risk of perinatal death in level 3 hospitals for babies with birthweights under 2000 g seems likely to be due to the specialist services in these hospitals. Further investigation is required to determine why babies in the 2500-2999 g range of birthweights had a comparatively high risk of perinatal death at these hospitals. This appears to be due, at least in part, to an excess contribution of deaths from congenital abnormalities. Also, it seems that the higher prevalence of complications in pregnancy in level 3 hospitals, and the transfers for induction of labour after intrauterine fetal death, would have made a contribution. These same factors may also have affected the risk in level 3 hospitals for higher birthweight births.     

Continuing evolution of regionalized perinatal care: community hospital neonatal convalescent care

We describe the convalescent care of 169 back-transported (to community hospitals) and 285 eligible but not back-transported very low birth weight (VLBW) infants. Eligible infants who were not back transported to a level I or II community hospital were transferred to a level II nursery within the Medical University of South Carolina (MUSC) for convalescent care. Study infants were admitted to the neonatal intensive care unit (NICU) at MUSC from July 1985 through June 1989. They were admitted after maternal transport to MUSC for imminent delivery (N = 159), out-born community delivery (N = 55), or in-born MUSC delivery (N = 240). The mean +/- SD birth weight and gestational age and the NICU admission diagnoses for the back-transported and non-back-transported neonates were similar. The mean +/- SD weight of neonates at the time they were back transported was significantly greater than the weight of neonates at the time of intrahospital transfer. In contrast, the discharge weight to home and total days hospitalized were significantly less in the back-transported infants. Five back-transported neonates (3%) and 12 non-back-transported neonates (4%) were readmitted to the NICU. The back-transported infants used more than 3,800 bed days at community hospitals that would otherwise have been spent in the regional center, thus facilitating increased parental and primary physician involvement in their care.     

Variation among neonatal intensive care units in narcotic administration

OBJECTIVES: To compare rates of narcotic administration for medically treated neonates in different neonatal intensive care units (NICUs) and to compare treated and untreated neonates to assess whether narcotics provided advantages or disadvantages for short-term outcomes, such as cardiovascular stability (ie, blood pressure and heart rate), hyperbilirubinemia, duration of respiratory support, growth, and the incidence of intraventricular hemorrhage. STUDY DESIGN: The medical charts of neonates weighing less than 1500 g, admitted to 6 NICUs (A-F), were abstracted. Neonates who had a chest tube or who had undergone surgery were excluded from the study, leaving the records of 1171 neonates. We modeled outcomes by linear or logistic regression, controlling for birth weight (<750, 750-999, and 1000-1499 g) and illness severity (low, 0-9; medium, 10-19; high, > or =20) using the Score for Neonatal Acute Physiology (SNAP), and adjusted for NICU. RESULTS: Narcotic use varied by birth weight (<750 g, 21%; 750-999 g, 13%; and 1000-1499 g, 8%), illness severity (low, 9%; medium, 19%; and high, 37%), day (1, 11%; 3, 6%; and 14, 2%), and NICU. We restricted analyses to the 1018 neonates who received mechanical ventilation on day 1. Logistic regression, adjusting for birth weight and SNAP, confirmed a 28.6-fold variation in narcotic administration (odds ratios, 4.1-28.6 vs NICU A). Several short-term outcomes also were associated with narcotic use, including more than 33 g of fluid retention on day 3 and a higher direct bilirubin level (6.8 micromol/L higher [0.4 mg/dL higher], P = .03). There were no differences in weight gain at 14 and 28 days or mechanical ventilatory support on days 14 and 28. Narcotic use was not associated with differences in worst blood pressure or heart rate or with increased length of hospital stay. CONCLUSIONS: Our study found a 28.6-fold variation among NICUs in narcotic administration in very low-birth-weight neonates. We were unable to detect any major advantages or disadvantages of narcotic use. We did not assess iatrogenic abstinence syndrome or long-term outcomes. These results indicate the need for randomized trials to rationalize these widely differing practices.     

Neonatal morbidity and mortality associated with triplet pregnancy

OBJECTIVE: To compare neonatal morbidity and mortality in a large cohort of triplet pregnancies with singleton and twin neonates managed at a single tertiary center over a short time. METHODS: Records from all triplet pregnancies managed and delivered from 1992 to 1996 were reviewed for neonatal outcome data. Pregnancies delivered before 20 weeks' gestation and neonates with lethal congenital anomalies were excluded. The comparison group comprised all singleton and twin neonates managed in the same neonatal intensive care unit (NICU) during the same period. RESULTS: During the 5-year period, 55 triplet pregnancies and their resulting 165 neonates were managed and delivered at this center. Their outcomes were compared with those of 959 singleton and 357 twin neonates born at similar gestational ages. The median gestational age at delivery for triplets was 32.1 weeks, and 149 of the 165 infants were admitted. Sixteen triplet neonates were not admitted to our neonatal intensive care unit, 12 because of previable gestational age, three because of stillbirth, and one because of a lethal congenital anomaly. The crude perinatal mortality rate in triplets was 121 per 1000 births, and there was no significant difference in outcome based on triplet birth order. There were no significant differences in survival rates between singleton, twin, and triplet neonates, with an overall neonatal survival of 95%, 95%, and 97%, respectively. The only significant differences in morbidity were an increased incidence of mild intraventricular hemorrhage (relative risk [RR] 6.20; 95% confidence interval [CI] 2.64, 14.61), mild retinopathy of prematurity (RR 20.05; 95% CI 3.59, 111.79), and severe retinopathy of prematurity (RR 46.69; 95% CI 6.25, 348.85) in triplets compared with singletons, and severe retinopathy of prematurity (RR 6.83; 95% CI 1.24, 37.56) in triplets compared with twins. CONCLUSION: When stratified by gestational age, triplet neonates delivered at 24-34 weeks' gestation have similar outcomes as singleton and twin neonates, with the only clinically significant difference being an increased incidence of retinopathy of prematurity in triplets.     

Population pharmacokinetic modeling in very premature infants receiving midazolam during mechanical ventilation: midazolam neonatal pharmacokinetics

BACKGROUND: Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. METHODS: Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. RESULTS: Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL CONCLUSIONS: Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.     

Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we conclude that the decision to use rHuEpo in an individual anemic patient with MM or NHL should be based on serum Epo levels, whereas the choice of the initial dosage should be based on residual marrow function.