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 Collaborative Review Group search strategy. Randomized and quasi-randomized controlled trials of intravenous midazolam use in neonates were identified by searching MEDLINE, EMBASE, the Cochrane Controlled Trials Register, reference lists of published studies, personal files, and abstracts published in Pediatric Research from 1990-1999.


METHODS
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
Two trials were eligible for inclusion in the review. Data on level of sedation from the two trials could not be combined because of differences in tools used to measure sedation levels. One study (Jacqz-Aigrain 1994) showed statistically a significant higher level of sedation in the midazolam group compared to the placebo group. The other study (Anand 1999) comparing midazolam to morphine and placebo found no statistically significant difference in sedation level among the three groups, but 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 both studies have not been validated in preterm infants, the effectiveness of midazolam as a sedative in this population could not be ascertained based on the findings of these two studies. In the study by Jacqz-Aigrain (1994), blood pressures were statistically significantly lower in the midazolam group than in the placebo group on days 1 and 2, although there was no statistically significant difference in the incidence of hypotension requiring albumin or vasoactive drugs between groups. The study by 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, the midazolam group had a statistically significantly longer duration of NICU stay compared to the placebo group (WMD 5.4 days, 95%CI 0.4, 10.5). (ABSTRACT TRUNCATED)
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Division of Neonatology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8. eugene.ng@sickkids.on.ca
Taddio
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Ohlsson
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D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage*; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D015931:Intensive Care, Neonatal; D008874:Midazolam / Q000008:administration & dosage*
D006993:Hypnotics and Sedatives; D008874:Midazolam