Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit.
BACKGROUND
The need for sedation for neonates undergoing uncomfortable procedures in the neonatal intensive care unit (NICU) has often been overlooked. Proper sedation may reduce stress and avoid complications during procedures such as mechanical ventilation. Midazolam is a short acting benzodiazepine that has been increasingly used in the NICU. However, the effectiveness of intravenous midazolam as a sedative in neonates has not been systematically evaluated.


OBJECTIVE
To determine whether intravenous midazolam infusion is an effective sedative, as evaluated by behavioural and/or physiologic measurements, for critically ill neonates undergoing intensive care, and to assess clinically significant short and long term adverse effects associated with its use.


METHODS
Literature search according to the Cochrane Neonatal Review Group search strategy. Randomized and quasi-randomized controlled trials of intravenous midazolam use in neonates were identified by searching the Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002), MEDLINE (1985-2002), EMBASE (1980-2002), reference lists of published studies, personal files, and abstracts published in Pediatric Research from 1990-2002.


METHODS
Randomized and quasi-randomized controlled trials of intravenous midazolam infusion in infants </= 28 days of age for sedation during mechanical ventilation or radiologic investigations were selected for review. Studies on midazolam use as an anesthetic or an anticonvulsant were excluded. Studies involving neonates and older infants and children were excluded if data for neonates could not be extracted.


METHODS
Data regarding the primary outcome of level of sedation (as evaluated by behavioural scales or physiologic parameters) were abstracted. Secondary outcomes including intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), death within 28 days of age, adverse effects associated with midazolam (hemodynamic and neurologic), days of ventilation, days of supplemental oxygen use, pneumothorax, length of NICU stay, and long term neurodevelopmental outcome were assessed. When appropriate, meta-analyses were performed using relative risk (RR), risk difference (RD), along with their 95% confidence intervals (95% CI) for categorical variables and weighted mean difference (WMD) for continuous variables.


RESULTS
Three trials were eligible for inclusion in the review. Data on level of sedation from the three trials could not be combined for meta-analysis because of differences in tools used to measure sedation levels. Two studies (Jacqz-Aigrain 1994, Arya 2001) showed a statistically significantly higher level of sedation in the midazolam group compared to the placebo group. The third study (Anand 1999) comparing midazolam to morphine and placebo found no statistically significant difference in sedation level among the three groups, but a statistically significantly higher level of sedation was found in the midazolam group compared with the placebo group during the treatment infusion. However, since the sedation scales used in all three studies have not been validated in preterm infants, the effectiveness of midazolam as a sedative in this population could not be ascertained. In the study by Jacqz-Aigrain et al (Jacqz-Aigrain 1994), blood pressure was statistically significantly lower in the midazolam group than in the placebo group on days one and two, although there was no statistically significant difference in the incidence of hypotension requiring albumin or vasoactive drugs between groups. The study by Anand et al (Anand 1999) showed a statistically significant higher incidence of adverse neurologic events (death, grade III-IV IVH, PVL) in the midazolam group compared with the other groups. In addition, meta-analysis of available data from two studies (Jacqz-Aigrain 1994, Anand 1999) showed a statistically significantly longer duration of NICU stay in the midazolam group compared to the placebo group (WMD 5.4 days, 95%CI 0.4, 10.5). Meta-analyses of other secondary outcomes showed no statistically significant differences between the midazolam and placebo groups.


CONCLUSIONS
There are insufficient data to promote the use of intravenous midazolam infusion as a sedative for neonates undergoing intensive care. This review raises concerns about the safety of midazolam in neonates. Further research on the effectiveness and safety of midazolam in neonates is needed.
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Department of Newborn and Developmental Paediatrics, Sunnybrook and Women's College Health Sciences Centre, 76 Grenville Street, Toronto, Ontario, Canada, M5S1B2. eugene.ng@swchsc.on.ca
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Ohlsson
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D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000009:adverse effects; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D007363:Intensive Care Units, Neonatal; D015931:Intensive Care, Neonatal; D008874:Midazolam / Q000008:administration & dosage* / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic
D006993:Hypnotics and Sedatives; D008874:Midazolam