Results of the search

We presented results of the search in the study flow diagram for the review update provided in Figure 1. We identified six RCTs on the use of intravenous midazolam in infants; we included three of these and excluded three.

Literature searches conducted in September 2009, March 2012 and June 2016 identified no additional trials.

Figure 1

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Study flow diagram: review update.

Included studies

For details, see Characteristics of included studies.

Jacqz‐Aigrain 1994 randomly assigned 46 preterm infants (25 at < 33 weeks' gestation and 21 at ≥ 33 weeks' gestation) ≤ 48 hours of age to receive midazolam infusion or manufactured placebo for five days while mechanically ventilated for respiratory distress syndrome. Twenty‐four infants received midazolam and 22 received placebo infusions. Researchers withdrew one infant in the midazolam group because of major neurological abnormalities at 24 hours of age; and two infants from the midazolam group and two from the placebo group within 72 hours owing to rapid clinical improvement. They noted contamination in one infant in the placebo group (midazolam was detectable in the serum at 24 hours). Baseline characteristics did not differ between groups. Severity of illness, as measured by mean airway pressure (MAP) while ventilated and fraction of inspired oxygen (FiO₂) from the time of enrolment to the end of the study, was not significantly different between groups. Investigators administered midazolam as an infusion at 60 microgram/kg/h for up to five days in infants at ≥ 33 weeks' gestation, and at 60 microgram/kg/h for one day followed by 30 microgram/kg/h for up to a total of five days in infants at < 33 weeks' gestation. They did not report the duration of the infusion. Weaning of sedatives was allowed after at least 48 hours of administration, but investigators did not specify a weaning protocol. The primary outcome was adequacy of sedation as measured by a behavioural score adapted from the clinical neurological and behavioural scoring system of Barrier (Barrier 1989) and by changes in physiological variables (heart rate and blood pressure). The sedation score consisted of five items that assessed facial expression, sucking, spontaneous motor activity, excitability/responsiveness to stimulation and excessive flexion, with scores ranging from 0 (sedation) to 5 (inadequate sedation). Care providers measured the sedation score four times per day during treatment (nurses twice, physicians twice). Secondary outcomes included days of ventilation support, days of supplemental oxygen, surfactant use, duration of NICU stay and common complications of preterm birth (e.g. pneumothorax, pulmonary interstitial emphysema, hypotension, chronic lung disease, necrotising enterocolitis, intracranial haemorrhage, persistent pulmonary hypertension of the newborn, death). Researchers reported outcomes for all 46 infants.

In a multi‐centre randomised pilot study (Anand 1999), investigators assigned 67 preterm infants of 24 to 32 weeks' gestation who were ≤ 72 hours of age and who were ventilated for less than eight hours to receive midazolam infusion, morphine infusion or dextrose placebo infusion for as long as sedation was considered necessary up to a maximum of 14 days. Twenty‐two infants received midazolam infusion, 24 received morphine infusion and 21 received dextrose placebo. The three groups did not differ significantly in baseline characteristics. Severity of illness at birth, as assessed by the Clinical Risk Index for Babies (CRIB) score (The International Neonatal Network), showed no significant differences among groups at birth (P = 0.24). However, severity of illness as measured by the Neonatal Medical Index (NMI) (Korner 1993) on the basis of response variables during the hospital stay showed significant differences in the distribution of risk categories among the three groups at discharge (P = 0.01). Researchers administered midazolam at 200 microgram/kg loading dose followed by an infusion of 20 microgram/kg/h, 40 microgram/kg/h or 60 microgram/kg/h for infants of gestational age 24 to 26 weeks, 27 to 20 weeks or 30 to 33 weeks, respectively. They administered morphine at 100 microgram/kg loading dose followed by an infusion of 10 microgram/kg/h, 20 microgram/kg/h or 30 microgram/kg/h for infants of gestational age 24 to 26 weeks, 27 to 29 weeks or 30 to 33 weeks, respectively. Duration of the infusion was not different among groups (5.1 days vs 3.4 days vs 5.0 days in the midazolam, morphine and placebo groups, respectively; P = 0.37). If necessary, they provided additional boluses of morphine and documented the frequency and amount given as measures of inadequate sedation. Investigators used a standardised protocol in weaning sedatives. The primary outcome was the incidence of adverse neurological events (defined as neonatal death, grade III or IV IVH or PVL). Researchers measured the adequacy of sedation by obtaining the COMFORT score, an eight‐item behavioural and physiological measurement of distress in the paediatric intensive care unit (Ambuel 1992). This score includes assessment of alertness, calmness/agitation, respiratory response, physical movement, mean arterial blood pressure, heart rate, muscle tone and facial tension, with scores ranging from 8 (sedated) to 40 (not adequately sedated). They measured adequacy of analgesia by obtaining the Premature Infant Pain Profile (PIPP) (Stevens 1996) in response to tracheal suctioning. The PIPP score includes assessment of gestational age, behavioural state, heart rate, oxygen saturation, brow bulge, eye squeeze and nasolabial furrow, with scores ranging from 0 (adequate analgesia) to 21 (inadequate analgesia). They obtained the two scores on all infants at baseline, after 24 hours of infusion and at 10 to 12 hours after discontinuation of the infusion. Other secondary outcomes included days of mechanical ventilation, continuous positive airway pressure, supplemental oxygen use, incidence of pneumothorax, duration of NICU and hospital stay, days to full enteral (full strength, full gavage, full oral) feeds, daily weight gain and neurodevelopmental outcomes at 36 weeks' corrected age as measured by Neurobehavioral Assessment of the Premature Infant (NAPI) examination cluster scores (Korner 1991). Researchers reported outcomes for all 67 infants.

Arya 2001 randomised 33 infants with birth weight < 2000 grams and requiring mechanical ventilation during the first week of life to receive midazolam or placebo infusion for sedation. Seventeen infants received midazolam and 16 received placebo. The two groups were similar in baseline characteristics. Severity of respiratory illness, as measured by peak inspiratory pressure (PIP), MAP, oxygenation index (OI) and the alveolar‐arterial oxygen gradient (AaDO₂), was similar between the two groups at the time of enrolment. Investigators administered midazolam intravenously at 200 microgram/kg loading dose followed by an infusion of 60 microgram/kg/h. Infants in both groups also received morphine infusion at 10 microgram/kg/h during the study period. The study concentrated on the first 48 hours of midazolam infusion and did not report on duration of benzodiazepine use nor on method of weaning. Three infants in each group did not complete the first 24 hours of the study, and four in each group did not complete 48 hours of the study. Reasons for withdrawal were death (13 infants) and extubation (one infant). Researchers included these infants in the analyses on an intention‐to‐treat basis. The primary outcome was adequacy of sedation as measured by a behavioural score adapted from the clinical neurological and behavioural scoring system of Barrier (Barrier 1989). This is the same scoring system used in Jacqz‐Aigrain 1994. Study authors assessed infants for adequacy of sedation before midazolam administration, then every six hours over the 48‐hour study period. Other measured outcomes included changes in physiological variables (heart rate and blood pressure), changes in oxygen requirement (FiO₂) and ventilation requirement (PIP, positive end‐expiratory pressure (PEEP), ventilator rate) and arterial blood gas as measured by mean daily values. Investigators documented complications related to mechanical ventilation (air leak, IVH) and potential adverse effects of midazolam (epileptiform movements, hypotension, tachycardia and oliguria) while reporting the duration of ventilation. They reported no long‐term outcomes but described outcomes for all 33 infants in the study.

Excluded studies

For details, see Characteristics of excluded studies. We excluded one trial that used a single bolus dose of intravenous midazolam (McCarver‐May 1996) and another trial that used intravenous midazolam for anaesthetic induction (Kawakami 1998). The third excluded trial (Parkinson 1997) used midazolam for sedation in individuals from one day to 15 years of age, and we could not extract data pertaining to neonates. The three trials included in this review (Anand 1999; Arya 2001; Jacqz‐Aigrain 1994) reported on the effectiveness of midazolam infusion and included a total of 146 infants.

Allocation

Risk of bias for random sequence generation was low in two studies (Anand 1999; Arya 2001) and unclear in one study (Jacqz‐Aigrain 1994). All three studies adequately concealed allocation (Anand 1999; Arya 2001; Jacqz‐Aigrain 1994).

Blinding

Risk of performance and detection was low in all three studies (Anand 1999; Arya 2001; Jacqz‐Aigrain 1994).

Incomplete outcome data

Investigators reported outcomes for all randomised infants.

Selective reporting

A protocol was not available for any of the three studies, so we could not judge whether deviations from the protocol occurred.

Other potential sources of bias

Included studies appeared free of other sources of bias. Anand 1999 received support from industry, and Arya 2001 and Jacqz‐Aigrain 1994 received midazolam and placebo from a pharmaceutical company.

Only Arya 2001 performed sample size calculation, and Anand 1999 stated that the study was a pilot trial. All three studies performed statistical analyses using an intention‐to‐treat approach.

Midazolam infusion versus placebo (comparison 1)

Anand 1999 evaluated outcomes by performing analysis of variance to detect statistically significant differences among midazolam, morphine and placebo groups. For this review, we performed comparisons between the midazolam group and the placebo group on relevant continuous outcome variables using information provided by the publication (sample size, mean, standard deviation (SD), standard error of the mean). For the current update of this review, we included an additional comparison of midazolam versus morphine infusion for the outcome of PIPP during drug infusion, as well as for poor neurological outcome by 28 days' postnatal age.

Secondary outcomes

Intraventricular haemorrhage (outcome 1.1)

Neither Jacqz‐Aigrain 1994 nor Anand 1999 found a statistically significant difference between midazolam and placebo groups in the incidence of IVH. Arya 2001 observed no intracranial haemorrhage during the 48‐hour study period in all enrolled neonates. Meta‐analysis of results of the three studies (n = 122) showed no statistically significant differences in the incidence of IVH of any grade (typical RR 1.68, 95% CI 0.87 to 3.24; typical RD 0.12, 95% CI ‐0.02 to 0.26; I² = 0% (none) for RR but 64% (moderate) for RD; Analysis 1.1).

Mortality (outcome 1.2)

Neither Jacqz‐Aigrain 1994 nor Anand 1999 found a statistically significant difference in mortality between midazolam and placebo groups. Arya 2001 did not report mortality as an outcome measure. However, six infants in the midazolam group and seven in the placebo group died before completing the 48‐hour study period. Meta‐analysis of results of the three studies showed no evidence of effect (typical RR 0.79, 95% CI 0.40 to 1.56; typical RD ‐0.05, 95% CI ‐0.18 to 0.09; I² = 0% (none for both RR and RD); Analysis 1.2).

Days on ventilation (outcome 1.3)

Combined results of Jacqz‐Aigrain 1994 and Anand 1999 showed no statistically significant difference in days of ventilation (WMD 3.6 days, 95% CI ‐0.2 to 7.4 days; I² = 0% (none); Analysis 1.3).

Arya 2001 presented data on days of ventilation as median values and ranges, so we could not combine these data with data from the other two studies. Median duration of ventilation (range) was 53 hours (7 to 216) in the midazolam group and 59 hours (13 to 194) in the placebo group.

Days on supplemental oxygen use (outcome 1.4)

Combined results of Jacqz‐Aigrain 1994 and Anand 1999 showed no statistically significant difference in days of supplemental oxygen use (WMD 0.6 days, 95% CI ‐5.3 to 6.6 days; I² = 0% (none); Analysis 1.4).

Pneumothorax (outcome 1.5)

All three studies (Anand 1999; Arya 2001; Jacqz‐Aigrain 1994) reported on pneumothorax (n = 122) and observed no significant effect of midazolam versus placebo for this outcome (typical RR 1.08, 95% CI 0.41 to 2.84; typical RD 0.01, 95% CI ‐0.10 to 0.12; I² = 0% (none for both); Analysis 1.5).

Length of NICU stay (outcome 1.6)

Jacqz‐Aigrain 1994 and Anand 1999 reported that length of NICU stay was not statistically significantly different between midazolam and placebo groups. Meta‐analysis of these data showed that the midazolam group had a statistically significantly longer length of stay in the NICU than the placebo group (WMD 5.4 days, 95% CI 0.4 to 10.5 days; I² = 0% (none); Analysis 1.6; Figure 4).

Figure 4

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Forest plot of comparison: 1 Midazolam versus placebo, outcome: 1.6 Length of NICU stay (days).

Arya 2001 did not report on length of NICU stay.

Average NAPI score at 36 weeks' postmenstrual age (outcome 1.7)

Anand 1999 reported average NAPI score at 36 weeks' postmenstrual age and found no significant difference between midazolam and placebo (dextrose) groups (MD ‐2.10, 95% CI ‐14.38 to 10.18; tests for heterogeneity not applicable; Analysis 1.7).

Poor neurological outcome up to 28 days' postnatal age (IVH grade III or IV, PVL or death at 28 days or sooner without discharge from the NICU) (outcome 1.8)

Anand 1999 reported on this outcome and described no statistically significant difference between midazolam and placebo (dextrose) groups (RR 1.34, 95% CI 0.50 to 3.56; RD 0.08, 95% CI ‐0.19 to 0.35; tests for heterogeneity not applicable; Analysis 1.8).

PIPP score during drug infusion (outcome 1.9)

Anand 1999 reported on this outcome and found a statistically significant difference between midazolam and placebo (dextrose) groups favouring the midazolam group (MD ‐3.80, 95% CI ‐5.93 to ‐1.67; tests for heterogeneity not applicable; Analysis 1.9; Figure 5).

Figure 5

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Forest plot of comparison: 1 Midazolam versus placebo, outcome: 1.9 PIPP score during drug infusion.

Occurrence of adverse effects associated with midazolam administration

Jacqz‐Aigrain 1994 observed no adverse neurological effects, but investigators excluded one infant in the midazolam group from the study within 24 hours owing to major neurological abnormalities. Researchers provided no details of this case and reported no statistically significant differences between groups in the incidence of hypotension requiring albumin or vasoactive drugs (8/24 vs 6/22).

Anand 1999 noted no adverse neurological effects associated with midazolam administration and did not report the incidence of hypotension.

Arya 2001 described no adverse neurological effects associated with midazolam administration. Researchers noted epileptiform movements of unknown cause in two infants in the placebo group and noted no significant hypotension in any infant during the study period.

Neurodevelopmental outcome

Jacqz‐Aigrain 1994 and Arya 2001 did not report long‐term neurodevelopmental outcomes.

Midazolam infusion versus morphine (comparison 2)

Poor neurological outcome by 28 days' postnatal age (IVH grade III or IV, PVL or death at 28 days or sooner without discharge from the NICU) (outcome 2.2)

Arya 2001 reported on this outcome in 46 infants. Investigators observed statistically significantly increased risk of poor neurological outcome by 28 days' postnatal age compared with infants treated with morphine (RR 7.64, 95% CI 1.02 to 57.21; RD 0.28, 95% CI 0.07 to 0.49; NNTH 4, 95% CI 2 to 14; test for heterogeneity not applicable; Analysis 2.2; Figure 6).

Figure 6

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Forest plot of comparison: 2 Midazolam versus morphine, outcome: 2.2 Poor neurological outcome up to 28 days' postnatal age.