StaR Child Health: developing evidence-based guidance for the design, conduct, and reporting of pediatric trials.

Standards for Research in (StaR) Child Health was founded in 2009 to address the paucity and shortcomings of pediatric clinical trials. This initiative involves international experts who are dedicated to developing practical, evidence-based standards to enhance the reliability and relevance of pediatric clinical research. Through a systematic "knowledge to action" plan, StaR Child Health will make efforts to improve and expand the evidence base for child health across the world.

Mannose-binding lectin and infection risk in newborns: a systematic review.

The authors systematically reviewed the literature on mannose-binding lectin (MBL) and infections in newborns to determine whether infection risk is increased in MBL-deficient newborns. All original reports on MBL and infections in newborns were retrieved from Embase, Medline and CENTRAL from 1966 to December 2009. Information extracted from each article included study design, definitions of MBL deficiency and neonatal infection, follow-up period and risk factor analysis. The validity of each study was assessed. Eight prospective cohort studies, including 3166 (range 47-1832) premature or term neonates, were assessed. MBL levels were measured in five studies and MBL2 genotype in six studies. Definitions of MBL deficiency and infection varied. In three out of five phenotypic studies low MBL levels were statistically significantly associated with increased culture-confirmed sepsis rates, also after correction for gestational age or birth weight. In the first study, the median MBL level was decreased in newborns with confirmed sepsis (170 µg/l) compared with newborns without sepsis (1450 µg/l). In two other studies, culture-confirmed sepsis was associated with MBL levels ≤700 µg/l (OR 15.0, 95% CI 1.5 to 151.3) and ≤400 µg/l (OR 3.1), respectively. The remaining two studies investigated various non-culture-confirmed infections. Only one study included the timepoint of clinical suspicion of infection in multivariate analysis. Contradicting results were reported in six MBL2 genotypic studies. Newborns with low MBL levels appear to have culture-confirmed sepsis more frequently than MBL-sufficient newborns. However, the influence of confounding factors was analysed insufficiently. Variant MBL2 genotypes appear to have less influence.

[Serious concerns regarding research linking cot death with child day care]. / Ernstige bezwaren tegen het onderzoek naar het verband tussen wiegendood en kinderopvang.

A recent case-control study suggests that the risk of sudden infant death syndrome (SIDS) is strongly increased in children attending day care. There are several methodological concerns regarding this study. Problems with the selection of both cases and controls may have inflated the observed odds ratio. A similar overestimation of risk may have occurred because of confounding factors including age and socioeconomic status. The study is restricted to the very few SIDS cases that occur during day care hours, which reduces the statistical power and increases the likelihood of chance findings. Finally, if day care is a genuine risk factor for SIDS, prevalence rates of SIDS should be expected to be lower in countries with long maternity leave periods such as in Scandinavia, but this is not the case. Whether or not day care is a risk factor for SIDS can only be evaluated by further and better designed studies. At present, there is no scientific basis to discourage day care for young children.

Efficient ways exist to obtain the optimal sample size in clinical trials in rare diseases.

OBJECTIVE: Recruitment of pediatric patients in randomized clinical trials is hampered by the rarity of many conditions and by ethical constraints. The objective of this paper is to give an overview of design options to obtain a statistically valid result while including a minimum number of subjects. STUDY DESIGN AND SETTING: Overview and discussion of several approaches to conduct valid randomized clinical trials in rare diseases and vulnerable populations. RESULTS: Sequential designs have been developed as efficient ways to evaluate accumulating information from a clinical trial, thereby reducing the average size of trials. Different sequential procedures exist, including group sequential designs, boundaries designs, and adaptive designs. The sample size attained at the end of the trial is unknown at the start. The sample size for a given set of alpha, beta, and effect size may turn out to be larger than with a classical fixed sample size approach. Simulations have shown that on average, sample sizes are smaller. CONCLUSION: There are several possibilities to optimize the number of subjects in a clinical trial. The rarity of many disorders in children and the ethical requirements in this patient population should not obstruct the performance of well-designed research to support clinical decision making.

Granulocyte transfusions in neutropaenic children: a systematic review of the literature.

BACKGROUND: Granulocyte transfusions (GTX) have been used for decades in paediatric neutropaenic patients, but uncertainty remains regarding their effectiveness. We reviewed all the paediatric data available on GTX, to gain a insight in to the indications for use, favourable effects and side effects in patients and donors. METHODS: A comprehensive search was done in MEDLINE, EMBASE, LILACS and CENTRAL (1966 until 2006). All studies including children (1-18 years) who received GTX were included. RESULTS: A total of 66 observational studies were included:Seven using prophylactic and 59 therapeutic GTX. Of the therapeutic studies 55 reported a proven sepsis caused by Gram-negative bacteria (34%) or fungal disease (48%) as the indication for GTX. Concerning effectiveness 70% survival was reported, but no controlled studies were identified. Side effects were mentioned in 27 studies including mild respiratory symptoms, allergic reactions and infection related complications (CMV). Side effects in the donor were mainly flu-like illness. DISCUSSION: In this first review covering 30 years of experience on the use of GTX in children, we found no randomised evidence showing a positive benefit risk ratio. The available case reports and cohort studies alert us as to the potential benefits and harms of the use of GTX in neutropaenic children and provides the basis for a well designed trial in children.

Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis.

We investigated whether deficiency of mannose-binding lectin (MBL), a component of innate immunity, is associated with neonatal pneumonia and sepsis during the first 72 h, i.e. early onset, and during the first month after birth. In 88 neonatal intensive care patients (71 premature), MBL2 genotype and MBL plasma levels at birth were determined prospectively by Taqman analysis and enzyme-linked immunosorbent assay, respectively. Thirty-five neonates (40%) had low, i.e.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute, while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10 - 15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS), on the incidence of chronic lung disease, mortality and other complications associated with prematurity and assisted ventilation. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in April 2007. SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who were given IPPV. Randomisation and commencement of treatment needed to be as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. For all measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text. Meta-analysis was performed using a fixed effects model. Where heterogeneity was over 50%, the random effects RR is also given. MAIN RESULTS: Fifteen eligible studies of 3,585 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 - 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction was of borderline significance overall. Subgroups of trials showed a significant reduction in CLD with HFOV when high volume strategy for HFOV was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when randomisation occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group. In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 intraventricular haemorrhage and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group. AUTHORS' CONCLUSIONS: There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating HFOV and CV, and report important long-term neurodevelopmental outcomes.

[The practice guideline 'Volume suppletion in critically-ill neonates and children up to the age of 18 years' of the Dutch Paediatric Association]. / Richtlijn 'Volumesuppletie bij kritisch zieke pasgeborenen en kinderen tot 18 jaar' van de Nederlandse Vereniging voor Kindergeneeskunde.

Hypovolaemia is the most common cause of circulatory failure in children. Treatment consists of volume suppletion with a crystalloid or colloid solution; which agent is the best in children is not clear. This evidence-based practice guideline formulates recommendations as to which fluid should be used for volume suppletion in critically-ill neonates and children up to the age of 18 years with hypovolaemia. Before the guideline development first-choice fluid for volume resuscitation was in 50% a colloid and in 50% a crystalloid solution for both neonatologists and paediatric intensivists. The neonatologists used human albumin as a priority, and the paeditric intensivists predominantly used a synthetic colloid. The guideline was developed on the basis of a comprehensive search and analysis of the literature according to the principles of evidence-based guideline development. The recommendations were formulated by a committee based on evidence from the literature and, when evidence from the literature was insufficient, on consensus after discussion in the committee. Since colloids are much more expensive than crystalloids and can give an anaphylactic reaction, their added value over crystalloids must be proven. In sick neonates and children, insufficient clinical trials have been done to reach the conclusion that colloids are more effective than crystalloids in hypovolaemia. A number of meta-analyses in adults revealed excess mortality in the group treated with albumin, but one recent, large, randomised study showed no difference in mortality. No added value could be demonstrated for the administration of synthetic colloids. On the basis of data from the literature and considerations regarding the applicability of evidence in adults to children and neonates, the side effects of resuscitation fluids, pathophysiology and costs, the first-choice fluid for neonates and children with hypovolaemia is isotonic saline. Albumin should not be used for the treatment of hypovolaemia. The volume to be administered and the infusion rate depend on the severity of the hypovolaemia and should be determined on an individual basis.

High prevalence of mannose-binding lectin (MBL) deficiency in premature neonates.

Mannose-binding lectin (MBL) is a component of innate immunity and thus particularly important in neonates in whom adaptive immunity is not yet completely developed. Promoter polymorphisms and structural exon-1 mutations in the MBL2 gene cause reduced or deficient MBL plasma concentrations. The aim of our study was to determine the prevalence of MBL deficiency in neonates admitted to the neonatal intensive care unit (NICU). Eighty-five NICU patients (69 premature) were included in the study. We measured MBL concentrations in umbilical cord and neonatal blood within 24 h after birth by ELISA technique. MBL2 genotypes (n = 67) were determined by Taqman analysis. MBL concentrations were measured longitudinally during three weeks in 26 premature neonates. The association between pre- and intra-partum clinical data and MBL concentrations was investigated. At birth, 29 (42%) premature and six (38%) term neonates had MBL plasma concentrations < or = 0.7 microg/ml which was regarded as deficient. Twenty-one (38%) premature and four (36%) term neonates had variant MBL2 haplotypes, corresponding to exon-1 mutations and the LXPA haplotype. MBL concentrations increased over time in neonates with wild-type MBL2 haplotypes, but not in neonates with variant haplotypes. Low MBL plasma concentrations were related to lower gestational age and variant MBL2 haplotypes. Umbilical cord and neonatal MBL plasma concentrations appeared to be similar. In conclusion, almost half of our NICU patients, especially the premature ones, were MBL-deficient at birth. These infants may be at increased risk of neonatal infections. MBL concentration can reliably be measured in umbilical cord blood and it is positively correlated with gestational and postnatal age.

Systematic review of the optimal fluid for dilutional exchange transfusion in neonatal polycythaemia.

OBJECTIVES: Several studies have shown the efficacy of dilutional exchange transfusion (DET) in reducing haematocrit (Ht) and relieving clinical symptoms in neonatal polycythaemia. We conducted a systematic review to determine the efficacy of crystalloid versus colloid solutions used in DET in an effort to identify the best solution to replace red blood cells. METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched for relevant randomised controlled trials. Quality assessment and data analysis were performed using the methods and software of the Cochrane Collaboration. Relative risk (RR) and weighted mean difference (WMD) were calculated as measures of effect for categorical and continuous outcome data, respectively. Ninety five percent confidence intervals (95% CI) were calculated and a fixed effect model was used for meta-analysis. RESULTS: Six studies with a total of 235 newborns matched our inclusion criteria. When comparing crystalloid and colloid replacement solutions for DET, there was a clinically unimportant difference in Ht at 2-6 h and at 24 h in favour of colloidal solutions (WMD 2.29% (95% CI 1.28 to 3.31) and 1.74% (95% CI 0.80 to 2.68), respectively). This difference in post DET Ht was more evident when normal saline was compared to plasma but absent when normal saline was compared to 5% albumin. CONCLUSION: There is little difference in effectiveness between plasma, 5% albumin, and crystalloid solutions. Since normal saline is cheap, readily available, and does not carry the potential risk of transfusion associated infection, normal saline is the optimal dilutional fluid for exchange transfusion in polycythaemic neonates.

Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials.

The use of oral prophylactic antibiotics in oncology patients is still a matter of debate. A systematic review was performed to assess the evidence for the effectiveness of oral prophylactic antibiotics to decrease bacteraemia and infection-related mortality in oncology patients during neutropenic episodes. Medline, Embase and the Cochrane register of controlled trials were searched from 1966 until 2002. The main outcome was the number of patients with documented bacteraemia (Gram-negative or Gram-positive bacteraemia) and infection related mortality. Data-extraction and quality assessment were performed independently by two reviewers. A total of 22 trials met the inclusion criteria. Seventeen trials compared prophylaxis (quinolones or Trimethoprim/sulfamethoxazole (TMP/SMZ)) to no prophylaxis. The incidence of Gram-negative bacteraemia decreased significantly (pooled OR 0.39, 95% CI 0.24-0.62) without an increase in Gram-positive bacteraemia. Quinolone-based regimens showed a stronger reduction in Gram-negative bacteraemia while TMP/SMZ based regimens were more effective in Gram-positive bacteraemia. Infection related mortality due to bacterial causes decreased with the use of prophylactic antibiotics (pooled OR 0.49, 95% CI 0.27-0.88). No increase in fungaemia or fungal related mortality was seen with the use of oral prophylaxis. In conclusion, this study has shown that oral prophylactic antibiotics decreased Gram-negative bacteraemia and infection related mortality due to bacterial causes during neutropenic episodes in oncology patients.

[Systematic review of the effects of therapy in infants with the KISS-syndrome (kinetic imbalance due to suboccipital strain)]. / Systematisch literatuuronderzoek naar de effecten van behandeling bij zuigelingen met 'kopgewrichteninvloed bij storingen in de symmetrie' ('KISS-syndroom').

OBJECTIVE: To establish the effects of manual therapy, chiropractic, or osteopathic treatment of the KISS-syndrome (kinetic imbalance due to suboccipital strain) in infants with positional preference, plagiocephaly, and colic. DESIGN: Systematic review of the literature. METHOD: PubMed, Embase and the Cochrane Library were searched for articles on the effects of manual therapy, chiropractic and osteopathy on the KISS-syndrome. Experts in the field of manual medicine and osteopathy were asked to provide relevant articles. The bibliography in a textbook of manual therapy for children was hand-searched for additional references to the KISS-syndrome. RESULTS: No clinical trials were found that evaluated the effects of manual therapy or osteopathy on either the KISS-syndrome or its symptoms. Pooled analysis of two randomised clinical trials on the effects of chiropractic in infantile colic showed no statistically significant difference between active and control treatments. In addition, we found that 22% of infants showed short episodes of apnoea during manual therapy of the spine, and that one case has been described in which such apnoea resulted in death. CONCLUSION: Given the absence of evidence of beneficial effects of spinal manipulation in infants and in view of its potential risks, manual therapy, chiropractic and osteopathy should not be used in infants with the KISS-syndrome, except within the context of randomised double-blind controlled trials.

Neuromuscular paralysis for newborn infants receiving mechanical ventilation.

BACKGROUND: Ventilated newborn infants breathing in asynchrony with the ventilator are at risk for complications during mechanical ventilation, such as pneumothorax or intraventricular hemorrhage, and are exposed to more severe barotrauma, which consequently could impair their clinical outcome. Neuromuscular paralysis, which eliminates spontaneous breathing efforts of the infant, has potential advantages in this respect. However, a number of complications have been reported with muscle relaxation in infants, so that concerns exist regarding the safety of prolonged neuromuscular paralysis in newborn infants. OBJECTIVES: To determine whether routine neuromuscular paralysis of newborn infants receiving mechanical ventilation compared with no routine paralysis results in clinically important benefits or harms. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004), MEDLINE (from 1966 to April 2004) and EMBASE (from 1988 to April 2004) were searched. References of review articles were hand searched. Language restriction was not imposed. SELECTION CRITERIA: All trials using random or quasi-random patient allocation, in which the routine use of neuromuscular blocking agents during mechanical ventilation was compared to no paralysis or selective paralysis in newborn infants. Methodological quality was assessed blindly and independently by the two authors. DATA COLLECTION AND ANALYSIS: Data were abstracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with independent evaluation of trial quality, and abstraction and synthesis of data by both authors. Treatment effect was analysed using relative risk, risk difference and weighted mean difference. MAIN RESULTS: Ten possibly eligible trials were identified, of which six were included in the review. All the included trials studied preterm infants ventilated for respiratory distress syndrome, and used pancuronium as the neuromuscular blocking agent. In the analysis of the results of all trials, no significant difference was found in mortality, air leak or chronic lung disease, but there was a significant reduction in intraventricular hemorrhage and a trend towards less severe intraventricular hemorrhages. In the subgroup analysis of trials studying a selected population of ventilated infants with evidence of asynchronous respiratory efforts, a significant reduction in intraventricular hemorrhage (any grade and severe IVH) was found, and a trend towards less air leak. In the subgroup analysis of trials studying an unselected population of ventilated infants, no significant differences were found for any of the outcomes. AUTHORS' CONCLUSIONS: For ventilated preterm infants with evidence of asynchronous respiratory efforts, neuromuscular paralysis with pancuronium seems to have a favourable effect on intraventricular hemorrhage and possibly on air leak. Uncertainty remains, however, regarding the long term pulmonary and neurologic effects, and regarding the safety of prolonged use of pancuronium in ventilated newborn infants. There is no evidence from randomized trials on the effects of neuromuscular blocking agents other than pancuronium. The routine use of pancuronium or any other neuromuscular blocking agent in ventilated newborn infants cannot be recommended based on current evidence.

Pneumococcal vaccination for the elderly in The Netherlands? Assessment of the quality and content of available comparative studies.

BACKGROUND: A question that is currently topical in the Netherlands is whether it makes sense to introduce on a national scale vaccination against pneumococcal infections for elderly people who are at present receiving the influenza vaccination. We recently studied the scientific literature on the subject in an attempt to answer this question. METHODS: We searched for systematic reviews (SRs), randomised clinical trials (RCTs) and cohort studies in MEDLINE, EMBASE, the Cochrane Library, Current Controlled Trials and via Google (period 1966 to June 2002). The SRs and RCTs were assessed with a methodological checklist. RESULTS: We identified four SRs, two trials (of which one was pseudo-random) and one retrospective cohort study. The methodological quality of the SRs was reasonable and in this respect differed little among themselves. The SRs differed strongly with regard to subgroups, outcome measures, valency of vaccines, duration of follow-up and combination with influenza vaccination. The SRs showed that vaccination has more effect in low-risk groups, does not appear to be effective in high-risk patients and the elderly and is more effective in nonindustrialised countries. The outcomes based on the various outcome measures showed major differences. The three studies into the effectiveness of the pneumococcal vaccination in the elderly all showed major methodological shortcomings. For the majority of outcome measures the outcomes were negative. CONCLUSION: There is insufficient convincing evidence in favour of the introduction of the pneumococcal vaccination as a supplement to influenza vaccination for the elderly. It seems as if (international) opinion had already been fully formed before published studies and systematic reviews become available in the last few years. It is perhaps worth considering setting up a prospective trial in the elderly Dutch population.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease, without adverse effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in May 2003. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. Treatment effects were expressed using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. Ninety five percent confidence intervals were used for all measures of effect. MAIN RESULTS: Eleven eligible studies on 3,275 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28-30 days of age or at approximately term equivalent age. These results were consistent across studies. The effect of HFOV on CLD in survivors at term equivalent GA was inconsistent across studies and not significant overall. Pre-specified subgroup analyses according to use of a high volume strategy, or use of surfactant, did not identify subgroups in which there was evidence of effect on death, or in which the size of effect on CLD was substantially increased, or in which heterogeneity of treatment effect on CLD was removed. Short term neurological morbidity caused by HFOV was found in some studies, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 IVH and of periventricular leukomalacia. An adverse effect of HFOV on longer term neurodevelopment was found in one large trial but not in two other small trials which reported this outcome. REVIEWER'S CONCLUSIONS: There is no clear evidence from this systematic review that elective HFOV, as compared with CV, offers important advantages when used as the initial ventilation strategy to treat preterm babies with acute pulmonary dysfunction. There is no evidence of a reduction in death rate. There may be a small reduction in the rate of CLD with HFOV use but the evidence is weakened by the inconsistency of this effect across trials and is not significant overall. Adverse effects on short term neurological outcomes have been observed in some studies but these effects are not significant overall. Information about effects on long term outcome is not adequate overall. Any future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm), compare different strategies for generating HFOV and CV, and report important long term pulmonary and neurodevelopmental outcomes. Economic analysis should also be incorporated.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease, without adverse effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in October 2002. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. Treatment effects were expressed using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. 95% confidence intervals were used. MAIN RESULTS: Meta-analysis of the ten eligible studies comparing HFOV with CV revealed no evidence of effect on mortality at 28-30 days of age or at approximately term equivalent age. These results were consistent across studies. HFOV caused a significant reduction in CLD in survivors at term equivalent GA. However, the effect was not large in absolute terms [NNT 17 (10, 50)], and was inconsistent across studies. HFOV caused a significant reduction in the aggregated outcome, death or CLD at term equivalent GA. Again, however, the effect was not large [(NNT 20 (11, 100)] and was not consistent across studies. Pre-specified subgroup analyses according to use of a high volume strategy, or use of surfactant, did not identify subgroups in which there was evidence of effect on death, or in which the size of effect on CLD was substantially increased, or in which heterogeneity of treatment effect on CLD was removed. Short term neurological morbidity caused by HFOV was found in some studies, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 IVH and of periventricular leukomalacia. An adverse effect of HFOV on longer term neurodevelopment was found in one large trial but not in two other small trials which reported this outcome. REVIEWER'S CONCLUSIONS: There is strong evidence that HFOV had no significant effect on death as this result was consistent across trials. Although HFOV caused a modest reduction in CLD, this evidence is weaker, because of inconsistencies across trials in this effect. In general, subgroup analyses according to use of high volume strategy, or surfactant, did not remove this heterogeneity, which therefore remains largely unexplained. Any future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm), compare different strategies for generating HFOV and report important long term pulmonary and neurodevelopmental outcomes. Economic analysis should also be incorporated.

Audit of prenatal and postnatal diagnosis of isolated open spina bifida in three university hospitals in The Netherlands.

OBJECTIVE: To audit the current Dutch policy of prenatal detection of isolated open spina bifida based on offering detailed ultrasound examination only on indication. METHODS: A retrospective analysis of prenatally diagnosed isolated spina bifida cases and of newborns diagnosed with this condition was carried out in three university hospitals. The data were collected from databases and clinical records of the departments of prenatal diagnosis, obstetrics, neonatology, child neurology and neurosurgery of the three centers. RESULTS: Between January 1996 and December 1999, 88 cases of isolated open spina bifida were diagnosed prenatally by ultrasound investigation. Thirty-eight cases (43%) were diagnosed before the 24th week of gestation. Of these, 35 (92%) ended in termination of the pregnancy at the parents' request. Of the remaining 50 cases (57%) diagnosed after the 24th week of gestation, eight (16%) pregnancies were terminated beyond the legal limit for termination due to the severity of the condition. Of the 88 cases of isolated spina bifida, 25 infants (28%) were still alive at the age of 4 years. In the same audit period 112 newborn infants with isolated open spina bifida were admitted to the neonatology, child neurology, or neurosurgery ward of the three centers. Of these cases, 47 (42%) had been diagnosed prenatally and 65 (58%) were an unexpected finding at birth. In 24 infants (21%) surgical treatment was withheld because of the severity of the condition and predicted poor outcome, whereas the remaining 88 infants (79%) underwent surgical repair. CONCLUSION: The current practice in The Netherlands of offering ultrasound screening to high-risk patients only leads to the early detection of a minority of cases of spina bifida. Most cases are diagnosed either after the 24th week of gestation or they remain undiagnosed until after birth. When spina bifida is diagnosed before the 24th week of gestation the vast majority of parents opt for termination. In order to reduce the birth prevalence of spina bifida in The Netherlands the introduction of a policy of routine ultrasound screening should be considered.

[The practice of systematic reviews. XI. The Cochrane Library]. / De praktijk van systematische reviews. XI. De Cochrane Library.

Systematic reviews of the literature provide a summary of the current status of medical scientific research. They are important for the solution of medical questions by doctors active in clinical practice, may serve to support practice guidelines, and are used in health care to take policy decisions and to determine the research agenda. The Cochrane Library is the most important source of information on the efficacy of interventions in health care and comprises eight databases. The most relevant for doctors active in clinical practice are the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and the Cochrane Central Register of Controlled Trials. At present, the first two databases contain over 5000 systematic reviews of the literature. The third database listed above is the largest database in the world with references to (randomised) controlled studies.

Impaired cognition and schooling in adults with end stage renal disease since childhood.

AIMS: To determine cognitive and educational attainment in adults with end stage renal disease (ESRD) since childhood. METHODS: All Dutch patients with onset of ESRD at age 0-14 years between 1972 and 1992, who were born before 1979, were asked to perform the Wechsler Adult Intelligence Scale (WAIS) test. Educational attainment was assessed by a questionnaire. Determinants of cognitive performance were measured by reviewing medical charts in 37 hospitals. Data on cognition were compared to those of age matched controls who cooperated in the revision of the Dutch WAIS. National Dutch Statistics data were used to compare educational attainment. RESULTS: Data on intelligence and schooling were acquired in 126 of 187 patients (67%) and data on determinants of outcome in all patients. Clinical characteristics of participants and non-participants were comparable. Educational attainment of patients was low compared to the Dutch standard. Patient mean full scale IQ, performal IQ, and verbal IQ were 10.4, 9.2, and 9.7 points lower, respectively, compared to those of 36 controls. The lowest scores were observed in tasks which require concentration, memory, and general knowledge. Patients currently on dialysis and transplanted patients had similar IQ scores. Cumulative dialysis duration of more than four years was associated with a 3.4 times higher chance of having a full scale IQ of 1 SD below the mean. CONCLUSION: ESRD of childhood is associated with an impaired cognitive and educational attainment in adulthood. Long duration of dialysis may enhance intellectual impairment, which may not be reversible after renal transplantation.

[Systematic reviews in practice. IX. Determining their place in treatment recommendations in practice guidelines]. / De praktijk van systematische reviews. IX. Plaatsbepaling in behandelbeslissingen in richtlijnen.

In a systematic review (SR), the available evidence for a clinical problem is systematically and comprehensively collected from different studies, the likelihood of bias is assessed and the results are summarised in a reproducible manner. The results of an SR can be used in either individual patient care or the formulation of a practice guideline. Throughout the world, (national) organisations for guideline development use systems for classifying the validity of evidence according to the study design ('levels of evidence'), and this is also the case in the Netherlands. In formulating a treatment recommendation, consideration must be given to the various factors which determine the strength of the evidence: study design, consistency of the results (if more studies are available), quality of the individual studies, magnitude and precision of the reported effect and the clinical relevance of the outcome measures. If insufficient studies with the same outcome measure are available, problems can arise in an SR. In practice, problems can also arise with respect to estimating the cogency of an SR compared to another review or primary studies. For the same subject, there might be discordant reviews, differences between reviews and megatrials might exist or just one randomised clinical trial might be available. These problems can often be solved with the aid of a systematic analysis. This requires both methodological and clinical expertise.