Naloxone for preventing morbidity and mortality in newborn infants of greater than 34 weeks' gestation with suspected perinatal asphyxia.

BACKGROUND: Studies in animal models have suggested that naloxone, a specific opiate antagonist, may improve outcomes for newborn infants with perinatal asphyxia. OBJECTIVES: In newborn infants of greater than 34 weeks' gestation with suspected perinatal asphyxia: to assess the effects of naloxone versus placebo or no drug, and of single versus multiple doses of naloxone, on mortality, long term neurological problems, severity of hypoxic-ischaemic encephalopathy, and frequency of neonatal seizures. SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003), MEDLINE (1966 - August 2003), EMBASE (1980 - August 2003), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing naloxone versus placebo, or no drug, or another dose of naloxone, in newborn infants of greater than 34 weeks' gestation with suspected perinatal asphyxia. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two authors. The pre-specified outcomes for this review were: death before hospital discharge, severe neurodevelopmental disability, severity of hypoxic-ischaemic encephalopathy, and seizures in the neonatal period. MAIN RESULTS: We identified only one eligible randomised controlled trial. This study compared the use of naloxone with placebo in newborn infants with an Apgar score of six or less at one minute after birth. There were not any data on the pre-specified outcomes for this review. REVIEWER'S CONCLUSIONS: There are insufficient data available to evaluate the safety and effectiveness of the routine use of naloxone for newborn infants of greater than 34 weeks' gestation with suspected perinatal asphyxia. A further randomised controlled trial is needed to determine if naloxone benefits newborn infants with suspected perinatal asphyxia. Such a trial should assess clinically important outcomes such as mortality, and adverse short and long term neurological outcomes.

Prophylactic indomethacin for preterm infants: a systematic review and meta-analysis.

BACKGROUND: Rates of long term morbidity remain unacceptably high in infants surviving after preterm birth. Prophylactic indomethacin has been shown to effectively reduce the rate of intraventricular haemorrhage in this group but there is the potential for unwanted side effects because of reduced organ perfusion. OBJECTIVE: To examine the effect of prophylactic indomethacin on mortality and short and long term morbidity of preterm infants. DATA SOURCES: Medline (1966-2002), the Cochrane Controlled Trials Register and abstracts of the Society for Pediatric Research and the European Society for Pediatric Research were searched independently by both authors. REVIEW METHODS: Trials were included if they used a randomised design, enrolled preterm infants given intravenous indomethacin within 24 hours of birth, and reported any of the prespecified outcome measures. Each author extracted data and assessed trial quality independently, according to the methods of the Cochrane Collaboration. Data were combined in a meta-analysis where appropriate. RESULTS: Nineteen trials fulfilling the inclusion criteria were identified, of which four reported long term outcomes. Short term benefits of indomethacin were identified, including a reduction in the rate of severe intraventricular haemorrhage (relative risk (RR) 0.66 (95% confidence interval (CI) 0.53 to 0.82)) and the need for surgical ligation of a patent ductus arteriosus (RR 0.51 (95% CI 0.37 to 0.71)). No evidence of short term gastrointestinal or renal adverse effects was detected. There was no significant difference between indomethacin and control groups with respect to the important long term outcome of death or severe neurosensory impairment (RR 1.02 (95% CI 0.90 to 1.15)). CONCLUSIONS: Prophylactic indomethacin has a number of short term benefits for the preterm infant but there is no evidence to suggest that it results in an improvement in the rate of survival free of disability.

Naloxone for narcotic exposed newborn infants: systematic review.

BACKGROUND: Naloxone, a specific opiate antagonist, is available for the treatment of newborn infants with respiratory depression that may be due to transplacentally acquired opiates. AIMS: To determine if this treatment has any clinically important benefits, and whether there are any harmful effects. METHODS: Randomised controlled trials that compared naloxone with placebo or no drug for newborn infants with transplacental exposure to narcotics were systematically reviewed. The Cochrane Controlled Trials Register (CCTR; 2002, Issue 3), Medline (1966 to June 2002), and Embase (1988 to June 2002) were searched. Data were extracted, analysed, and synthesised using the standard methods of the Cochrane Neonatal Collaborative Review Group. RESULTS: Nine trials were found that fulfilled the specified inclusion criteria. Although there was evidence that naloxone increased alveolar ventilation, no data were found on the specified primary outcomes of this review: the need for assisted ventilation or admission to a neonatal unit. CONCLUSIONS: There is a need for a randomised controlled trial to determine if naloxone confers any clinically important benefits on newborn infants with respiratory depression that may be due to transplacentally acquired narcotic.

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.

BACKGROUND: Patent ductus arteriosus (PDA) and intraventricular haemorrhage (IVH) are both associated with increased mortality and morbidity in preterm infants. Indomethacin has been used successfully to treat symptomatic PDA and may also prevent or limit IVH in the neonatal period. There are however potential unwanted side effects of indomethacin, in particular a potential for reduced organ perfusion that might outweigh any clinical benefits. The prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA or IVH would be exposed to indomethacin, warrants particular scrutiny. OBJECTIVES: This review examines the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with PDA and IVH in preterm infants. SEARCH STRATEGY: An initial literature search was conducted in three computerised databases: MEDLINE; EMBASE; and the Oxford Database of Perinatal Trials in October 1994. The search was updated in February 1997 and October 2001. SELECTION CRITERIA: Strict selection criteria were applied to clinical trials: the population had to be newborn preterm infants (less than 37 completed weeks gestation); the intervention had to be prophylactic intravenous indomethacin; the trial had to be randomised and controlled; and at least one of several prespecified outcomes had to be reported in the results. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed using explicit criteria. Data on relevant outcome measures were extracted and, where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect. MAIN RESULTS: Nineteen eligible trials randomising 2872 infants were identified. There is no evidence of difference in mortality at latest follow-up between infants receiving prophylactic indomethacin and controls, pooled relative risk (RR) = 0.96 [95% CI 0.81 to 1.12]. There is no evidence to suggest prophylactic indomethacin is associated with any reduction in long-term neurosensory impairment, ie no significant difference in rates of cognitive delay, cerebral palsy, blindness or deafness. The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled RR = 0.44 [0.38 to 0.50] but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin reduces the need for surgical PDA ligation [RR = 0.51 (0.37,0.71)]. Prophylactic indomethacin significantly reduces the incidence of Grade 3 and 4 intraventricular haemorrhage, pooled RR = 0.66 [0.53 to 0.82]. There is no evidence of difference in rates of necrotising enterocolitis, excessive clinical bleeding or sepsis. Increased incidence of oliguria is seen with prophylactic indomethacin [RR = 1.90 (1.45,2.47] but this is not associated with major renal impairment. REVIEWER'S CONCLUSIONS: Prophylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus, the need for duct ligation and severe intraventricular haemorrhage. There is no evidence to suggest either benefit or harm in longer term outcomes including neurodevelopment. Depending on clinical circumstances and personal preferences, there may be a role for prophylactic indomethacin in some infants on some neonatal units.

Naloxone for narcotic-exposed newborn infants.

BACKGROUND: Naloxone, a specific opiate antagonist, is available for the management of newborn infants with respiratory depression that may be due to transplacentally-acquired opiates. However, it is unclear which groups of newborn infants may benefit from this therapy, and whether naloxone has any harmful effects. OBJECTIVES: In newborn infants who have been exposed trans-placentally to narcotics, does naloxone reduce the need for, or duration of, ventilatory support or neonatal unit admission. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002), MEDLINE (1966 - February 2002), EMBASE (1988 - February 2002), and previous reviews including cross references. SELECTION CRITERIA: Randomised controlled trials comparing the administration of naloxone versus placebo, or no drug, or another dose of naloxone, to newborn infants with suspected or confirmed trans-placental exposure to narcotics. DATA COLLECTION AND ANALYSIS: Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk, risk difference and weighted mean difference. MAIN RESULTS: We found nine trials that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal narcotic analgesia prior to delivery. The main outcomes reported were measures of respiratory function in the first six hours of life. Although we found some evidence that naloxone increases alveolar ventilation, we did not find any data on the pre-specified primary outcomes of this review: the need for assisted mechanical ventilation or admission to a neonatal unit. REVIEWER'S CONCLUSIONS: There is a need for a randomised controlled trial to determine if naloxone confers any clinically important benefits to newborn infants with respiratory depression that may be due to trans-placentally acquired narcotic.

Consent to autopsy for neonates.

OBJECTIVES: To determine parents' views on autopsy after treatment withdrawal. DESIGN: Face to face interviews with 59 sets of bereaved parents (108 individual parents) for whose 62 babies there had been discussion of treatment withdrawal. RESULTS: All except one couple were asked for permission for postmortem examination; 38% refused. The main reasons for declining were concerns about disfigurement, a wish to have the child left in peace, and a feeling that an autopsy was unnecessary because the parents had no unanswered questions. The diagnosis, the age of the child, and the approach of the consultant appeared to influence consent rates. Of those who agreed to autopsies, 92% were given the results by the neonatologist concerned. Whether or not they had agreed to the procedure, at 13 months no parent expressed regrets about their decision. CONCLUSIONS: Autopsy rates in the East of Scotland stand at 62%. Parents' perceptions are an important element in consent to postmortem examination.

Lingering death after treatment withdrawal in the neonatal intensive care unit.

OBJECTIVE: To explore parents' perceptions of treatment withdrawal and the dying process. DESIGN: Face to face interviews with 59 sets of parents of 62 babies in the East of Scotland three months and 13 months after death. RESULTS: 22% of the parents expressed reservations about the length of the dying process, which they reported in these instances had taken from three to 36 hours. Deaths that medical teams had predicted would be quick had, according to the parents' recollections, taken from 1.5 to 31 hours. When a baby died swiftly, this seemed to confirm the wisdom of the decision to stop. When babies lingered, doubts were raised. CONCLUSIONS: Parents need to be adequately prepared for what may happen after treatment withdrawal. The debate should be reopened about the best way to manage protracted deaths in line with parental need.

Intravenous indomethacin for preventing mortality and morbidity in very low birth weight infants.

BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: Indomethacin is used to treat symptomatic patent ductus arteriosus and may prevent or limit intraventricular haemorrhage in the neonatal period. This review examines the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with these conditions in infants weighing less than 1750 grams at birth. SEARCH STRATEGY: A literature search from January 1980 to October 1994 was made in three computerised data bases: Medline; Embase; and the Oxford Database of Perinatal Trials. The search was updated in February 1997. SELECTION CRITERIA: Strict selection criteria were applied to clinical trials: the population had to be newborn infants of birth weight < 1751 grams; the intervention had to be prophylactic intravenous indomethacin; the trial had to be randomised and controlled; and at least one of several prespecified outcomes had to be reported in the results. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed using explicit criteria. Data on relevant outcome measures were extracted on two separate occasions and, where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect. MAIN RESULTS: There is a trend towards reduced neonatal mortality in infants receiving prophylactic indomethacin, pooled relative risk (RR) = 0. 85 [95% CI 0.66 to 1.09]. The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled RR = 0.35 [0.26 to 0.47] but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin significantly reduces the incidence of Grade 3 and 4 intraventricular haemorrhage in treated infants, pooled RR = 0.60 [0.43 to 0.83]. There is no evidence to suggest prophylactic indomethacin is associated with any long term adverse effect although there is a trend in treated infants towards an increased incidence of necrotizing enterocolitis, and some evidence that treatment may transiently impair renal function. There is no evidence that haemostasis is disturbed. REVIEWER'S CONCLUSIONS: Prophylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus and severe intraventricular haemorrhage. There is no evidence at present of long-term harm. Further trials are needed to assess more precisely the effects, both beneficial and harmful, on short and long-term outcomes.

Predicting outcome in very low birthweight infants using an objective measure of illness severity and cranial ultrasound scanning.

AIM: To investigate the feasibility of developing an objective tool for predicting death and severe disability using routinely available data, including an objective measure of illness severity, in very low birthweight babies. METHOD: A cohort study of 297 premature babies surviving the first three days of life was made. Predictive variables considered included birthweight, gestation, 3 day cranial ultrasound appearances and 3 day CRIB (clinical risk index for babies) score. Models were developed using regression techniques and positive predictive values (PPV) and likelihood ratios (LR) were calculated. RESULTS: On univariate analysis, birthweight, gestation, 3 day CRIB score and 3 day cranial ultrasound appearances were each associated with death. On multivariate analysis, 3 day CRIB score and 3 day cranial ultrasound appearances remained independently associated. A 3 day CRIB score > 4 along with intraventricular haemorrhage (IVH) grade 3 or 4 was associated with a PPV of 64% and an LR of 9.8 (95% confidence limits 3.5, 27.9). Only 3 day CRIB score and 3 day cranial ultrasound appearances were associated with severe disability on univariate analysis. Both remained independently associated on multivariate analysis. A 3 day CRIB score > 4 along with an IVH grade of 3 or 4 was associated with a PPV of 60% and an LR of 24.2 (95% CI 4.4, 133.3). CONCLUSION: Incorporating objective measures of illness severity may improve current prediction of death and disability in premature infants.

Diagnostic tests for bacterial infection from birth to 90 days--a systematic review.

AIM: To determine the clinical value of common diagnostic tests for bacterial infection in early life. METHODS: A Medline search (1966-95) was undertaken to identify studies that reported the assessment of a diagnostic "test," predicting the presence or absence of bacterial infection in infants up to 90 days of age. The quality of each selected study was assessed using defined criteria. Data were extracted twice to minimise errors. RESULTS: Six hundred and seventy articles were identified. Two independent investigators agreed that 194 studies met the inclusion criteria (kappa = 0.85), 52 of which met primary quality criteria; 23 studies reported data on (a) haematological indices, (b) C reactive protein evaluation, and (c) surface swab assessment. For haematological indices, the likelihood ratios for individual tests ranged from 20.4 (95% confidence interval 7.3 to 56.8) for a white cell count < 7000/mm3 to 0.12 (0.04 to 0.37) for an immature:total (I:T) white cell ratio < 0.2. For C reactive protein evaluation, the likelihood ratios ranged from 12.56 (0.79 to 199.10) for a value of > 6 mg/l to 0.22 (0.08 to 0.65) for a negative value. For surface swab assessment, the likelihood ratios ranged from 33.6 (2.1 to 519.8) for a positive gastric aspirate culture to 0.08 (0.006 to 1.12) for microscopy of ear swab material that did not show any neutrophils. Likelihood ratios for combinations of these individual tests ranged from 10.17 (3.64 to 28.41) to 0.47 (0.22 to 1.00). CONCLUSIONS: The methodological quality of studies assessing the accuracy of diagnostic tests is generally poor. Even in rigorous studies, the reported accuracy of the tests varies enormously and they are of limited value in the diagnosis of infection in this population.

What do doctors record in the medical notes following discussion with the parents of sick premature infants?

UNLABELLED: In a retrospective review of medical notes we determined: (1) how often doctors record discussions with the parents of very low birth weight (VLBW) infants during the neonatal period; (2) what details of any discussion they actually record and; (3) if they are more likely to record discussion with the parents of sicker infants. A random sample (30%) of all VLBW infants admitted between 1989 and 1993 to a regional NICU was reviewed, n = 87. No discussion was documented in 47 cases, one of whom died, 24 had a single episode of discussion recorded and 16 had two or more episodes recorded. Specific discussion about prognosis was only recorded in the notes of 27 babies. Discussion was more likely to be documented in sicker infants as measured by CRIB (clinical risk index for babies) score, t = -3.9, P < 0.001. CONCLUSION: A record of discussion between medical staff and parents is found in the medical notes of less than half of all VLBW infants. These findings may have practical, ethical and legal implications.

Measurement properties of the Clinical Risk Index for Babies--reliabilty, validity beyond the first 12 hours, and responsiveness over 7 days.

OBJECTIVES: Clinical Risk Index for Babies (CRIB) is a simple instrument used to measure clinical risk and illness severity in very low birth-weight infants. We assessed its reliability, validity beyond the first 12 hrs after birth, and responsiveness to individual change in condition after 7 days. DESIGN: Cohort study. SETTING: Three tertiary and three nontertiary UK hospitals. PATIENTS: Three hundred ninety-eight infants whose birth weight was <1501 g or who were born before a 31-wk gestation period. INTERVENTIONS: Inter- and intrarater reliability of data extraction were assessed by Pearson and intraclass correlation. To validate CRIB, we tested the correlation between clinical risk and illness severity with the risk of: a) death; b) prolonged treatment with supplemental oxygen; and c) disability at 2 yrs. Logistic regression models were fitted to assess validity and responsiveness. MEASUREMENTS AND MAIN RESULTS: Reliability coefficients ranged from 0.76 (95% confidence interval, 0.71 to 0.81) to 0.97 (0.94 to 1.00). Throughout the first week, CRIB correlated with the risk of death (p < .001), prolonged treatment with oxygen (p < .001), and disability (p < .001 to p = .033). Improved condition, represented by a reduction in CRIB within the first week, was independently associated with lower risks of each adverse outcome, p < .05. CONCLUSIONS: During the first week, CRIB was reliable, valid, and responsive. These properties support the use of CRIB in the stratification of infants by risk and illness severity in cohort studies, and they also indicate that CRIB may have the potential to be used in other ways in the future.

CRIB (clinical risk index for babies) in relation to nosocomial bacteraemia in very low birthweight or preterm infants.

Positive blood cultures in very low birthweight or preterm infants usually reflect bacteraemia, septicaemia, or failure of asepsis during sampling and lead to increased costs and length of stay. Rates of nosocomial, or hospital acquired, bacteraemia may therefore be important indicators of neonatal unit performance, if comparisons are adjusted for differences in initial risk. In a preliminary study the risk of nosocomial bacteraemia was related to initial clinical risk and illness severity measured by the clinical risk index for babies (CRIB). Nosocomial bacteraemia was defined as clinically suspected infection with culture of bacteria in blood more than 48 hours after birth. One or more episodes of nosocomial bacteraemia were identified retrospectively in 36 of 143 (25%) infants in a regional neonatal unit between 1992 and 1994. Biologically plausible models were developed using regression analysis techniques. After correcting for period at risk, nosocomial bacteraemia was independently associated with gestation at birth and CRIB. Death was independently associated with CRIB, but not with nosocomial bacteraemia. CRIB may contribute, with other explanatory variables, to more comprehensive predictive models of death and nosocomial infection. These may facilitate future risk adjusted comparative studies between groups of neonatal units.

Prophylactic indomethacin: systematic review and meta-analysis.

AIMS: To examine the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with patent ductus arteriosus and intraventricular haemorrhage in infants weighing less than 1750 g at birth. METHODS: A literature search from 1980 onwards was made of three databases: Medline; Embase; and the Oxford Database of Perinatal Trials. Using strict criteria applied to randomised controlled trials only, two observers independently selected 14 studies for inclusion in the review. The methodological quality of each study was assessed independently by two observers using explicit criteria. Data on relevant outcome measures were extracted on two separate occasions. Where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect. RESULTS: There is a trend towards reduced neonatal mortality in infants receiving prophylactic indomethacin, pooled estimate of risk difference -0.025 (95% confidence interval (CI) -0.061, 0.010). The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled estimate of risk difference -0.217 (95% CI -0.275, -0.160), but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin significantly reduces the incidence of grades 3 and 4 intraventricular haemorrhage in treated infants, pooled estimate of risk difference -0.039 (95% CI -0.066, -0.011). However, there is no sound evidence assessing the long term effect of prophylaxis on neurodevelopmental outcome. Although there is a trend in treated infants towards an increased incidence of necrotising enterocolitis, pooled estimate of risk difference 0.015 (95% CI -0.002, 0.033), and some evidence that treatment may transiently impair renal function, there is no evidence that haemostasis is disturbed. CONCLUSION: Prophylactic treatment with indomethacin has several immediate benefits. However, more data are needed on the incidence of possible adverse effects and neurodevelopmental outcomes before routine use of this therapy can be recommended.