Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit

Ng E, Taddio A, Ohlsson A

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 21/08/2006
Date of last substantive update: 17/09/2002
Date of last minor update: 10/08/2006
Date next stage expected 01/09/2004
Protocol first published:
Review first published: Issue 2, 2000

Contact reviewer

Eugene Ng
Staff Neonatologist
Department of Newborn and Developmental Paediatrics
Sunnybrook and Women's College Health Sciences Centre
76 Grenville Street
Toronto
Ontario CANADA
M5S1B2
Telephone 1: 416-323-6400 extension: 3368
Facsimile: 416-323-6274
E-mail: eugene.ng@swchsc.on.ca

Contribution of reviewers

E Ng:
Development and writing of protocol
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data independent of co-reviewer
Entering data into Revman
Writing of result section
Writing of discussion section

A Taddio:
Development of protocol
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data independent of co-reviewer
Verifying data entered into Revman

A Ohlsson:
Development of protocol
Verifying data entered into Revman
Revision of the final review

Internal sources of support

Sunnybrook and Women's College Health Sciences Centre, Toronto, CANADA
The Hospital for Sick Children, Toronto, CANADA
Mount Sinai Hospital, Toronto, CANADA

External sources of support

None

What's new

This review updates the existing review: "Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit" originally published in The Cochrane Library, Issue 2, 2000 (Ng 2000).

A new search was done in September 2002, and one additional randomized controlled trial was identified for inclusion. No change in the conclusion was made as a result of this update.

An updated search done in August 2006 found no additional studies. No change in the conclusion has been made as a result of this update.

Dates

Date review re-formatted: / /
Date new studies sought but none found: 01/08/2006
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 17/09/2002
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

There is no evidence to show the benefit of midazolam as a sedative for newborn babies in neonatal intensive care.

Newborn babies undergoing uncomfortable procedures in intensive care units may need sedation to reduce stress and avoid complications. It is difficult to measure their pain so sedatives or pain killers are sometimes overlooked for newborn babies. Midazolam is a short acting sedative increasingly used in Neonatal intensive care. The review of trials found no evidence to support the use of midazolam as a sedative for neonates undergoing intensive care. Babies receiving midazolam stayed in hospital longer and had more adverse effects. More research is needed to address the safety and effect of midazolam.

Abstract

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.

Objectives

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.

Search strategy

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 Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2006), MEDLINE (1985 - 2006), EMBASE (1980 - 2006), reference lists of published studies, personal files, and abstracts published in Pediatric Research from 1990-2006.

Selection criteria

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.

Data collection & analysis

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.

Main 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.

Reviewers' 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.

Background

Term and preterm infants are capable of perceiving pain and stress (Anand 1987). In the neonatal intensive care unit (NICU), supportive and investigative management of sick infants frequently requires painful and/or uncomfortable procedures. However, since pain and stress are subjective phenomena and are difficult to evaluate in pre-verbal infants, the use of appropriate analgesia and of sedatives is often overlooked by care providers. It has been suggested that responses to pain may compromise clinical conditions (Anand 1992), and that adequate sedation during mechanical ventilation may decrease stress (Quinn 1993) and facilitate effective ventilation so that complications such as pneumothoraces and intraventricular hemorrhages may be prevented (Greenough 1983, Perlman 1985).

Benzodiazepines, administered as intravenous infusions or as intravenous boluses, are used to provide sedation, but not analgesia, in many clinical settings. This class of sedatives acts on specific receptors in the central nervous system. These receptors, which are present in the fetus from seven weeks gestation (Hebebrand 1988), potentiate the neuronal inhibitory pathways mediated by gamma-aminobutyric acid (GABA) (Jacqz-Aigrain 1996).

Midazolam is a short acting benzodiazepine that has increasingly been used in the NICU. The pharmacokinetics of midazolam in neonates have been studied. It is preferred over other benzodiazepines because of its water solubility and rapid clearance (Jacqz-Aigrain 1992). Although its elimination half-life is significantly shorter than that of other benzodiazepines such as diazepam, its elimination is delayed in preterm neonates compared with older infants and children (Lee 1999). Functional immaturity of the hepatic and renal systems in preterm neonates probably accounts for the slower elimination of midazolam.

The effectiveness of intravenous midazolam as a sedative in neonates has not been systematically reviewed. Moreover, its safety at the currently recommended dosage in critically ill neonates is not well established.

Objectives

The primary objective of this review was to assess the effectiveness of intravenous midazolam infusion for sedation, as evaluated by behavioural and/or physiologic measurements of sedation levels, in critically ill neonates in the NICU.

Secondary objectives included:

1. Incidence of intraventricular hemorrhage/periventricular leukomalacia
2. Mortality
3. Occurrence of adverse effects associated with the use of midazolam (hypotension, neurologic abnormalities)
4. Days of ventilation
5. Days of supplemental oxygen use
6. Incidence of pneumothorax
7. Length of NICU stay
8. Long term neurodevelopmental outcome

Criteria for considering studies for this review

Types of studies

Randomized controlled trials or quasi-randomized trials in which the use of intravenous midazolam infusion was compared to placebo or other sedatives in neonates undergoing intensive care.

Types of participants

Infants </= 28 days of age admitted to the NICU and who required sedation for medical interventions.

Types of interventions

Continuous intravenous infusion of midazolam in the dose range of 20 - 60 mcg/kg/hr administered for at least 24 hours for sedation during mechanical ventilation and radiologic investigative procedures.
Studies using a combination of midazolam and an analgesic for neonates undergoing painful procedures were excluded. Studies that investigated the use of intravenous bolus doses of midazolam were excluded, unless the bolus was followed by an infusion. Studies on the use of midazolam as an anesthetic induction agent or as an anticonvulsant were also excluded.

Types of outcome measures

Primary outcome was level of sedation, evaluated by:

Behavioural measures: facial actions, excitability, muscle tone, physical movements and respiratory behaviour which may be evaluated by age-appropriate scoring systems; and

Physiologic parameters: changes in heart rate, respiratory rate, blood pressure, oxygen saturation, and plasma cortisol or catecholamine levels, measured at baseline and at regular intervals during midazolam administration.

Secondary outcomes were:

1. Intraventricular hemorrhage [defined by classification of Papile et al (Papile 1978)]
2. Periventricular leukomalacia (defined as periventricular cysts on brain imaging, but excluding subependymal or choroid plexus cysts)
3. Mortality (death within 28 days of life)
4. Adverse effects associated with use of midazolam: hypotension (significant drop from baseline compared with controls), neurologic abnormalities (epileptiform activities, movement disorders, myoclonus, hypertonia, hypotonia)
5. Days of mechanical ventilation
6. Days of supplemental oxygen use
7. Pneumothorax
8. Days of NICU stay
9. Neurodevelopmental outcome, as evaluated by a validated developmental assessment tool

Search strategy for identification of studies

See: Collaborative Review Group Search Strategy

Randomized and quasi-randomized controlled trials of intravenous midazolam in infants were identified from the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2006), MEDLINE (from 1985 to August 2006) and EMBASE (1980 - 2006) using the MeSH headings: midazolam; infant, newborn. In addition, bibliographies of articles, personal files, and abstracts published in Pediatric Research from 1990-2006 were manually searched. Language restrictions were not imposed. Attempts were made to contact investigators of studies meeting the inclusion criteria to gather additional data for analysis. No attempt was made to identify unpublished studies. Studies involving neonates and older infants and children were excluded if data for neonates could not be extracted.

Methods of the review

Standard methodology for performing systematic reviews according to the Cochrane Neonatal Review Group was used.

Studies included in the review were randomized or quasi-randomized controlled trials involving neonates (</= 28 days of age), with a treatment group and a placebo group. Studies reporting outcome measures including physiological, behavioural, and hormonal changes, as well as adverse neurological outcomes were accepted for review.

The decision to include or exclude a specific study was made independently by two reviewers (EN, AT). In case of discrepancies a decision was made by consensus of the three authors (EN, AT, AO).

Quality of the trials included was evaluated using the following criteria:

1) Blinding of randomization
2) Blinding of intervention
3) Complete follow up
4) Blinding of outcome measurement

A data collection form was created and the following data were abstracted from the included studies: demographics of the participants, age at enrollment into study, inclusion and exclusion criteria, sample size, treatment and control groups regimens, and outcomes. Data were abstracted by two reviewer authors independently (EN, AT) and differences resolved by consensus.

Statistical analysis: Treatment effects were described using relative risk (RR) and risk difference (RD) for categorical outcomes, and weighted mean difference (WMD) for outcomes measured on a continuous scale. 95% confidence intervals were used. When there were at least two randomized controlled trials that evaluated the effectiveness of intravenous midazolam infusions using the same outcome measures, the results were pooled to obtain an overall estimate of effect size using Revman 4.1. A fixed effect model was assumed for meta-analysis. Heterogeneity was examined using the I² statistic.

Description of studies

For details see: Table, Characteristics of Included Studies, and table, characteristics of excluded studies.

Six randomized, controlled trials on the use of intravenous midazolam in infants were identified. One trial using a single bolus dose of intravenous midazolam was excluded (McCarver-May 1996). Another trial using intravenous midazolam for anesthetic induction was excluded (Kawakami 1998). In the third excluded trial (Parkinson 1997), midazolam was used for sedation in patients from one day to 15 years of age, and data for the neonates could not be extracted. The three trials included in this review (Jacqz-Aigrain 1994, Anand 1999, Arya 2001) reported on the effectiveness of midazolam infusion and included a total of 146 infants.

In the study by Jacqz-Aigrain et al (Jacqz-Aigrain 1994), 46 preterm infants (25 were < 33 weeks, and 21 were >/= 33 weeks gestation) </= 48 hours of age were randomly assigned 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. One infant in the midazolam group was withdrawn because of major neurologic abnormality at 24 hours of age. Two infants from the midazolam group and two from the placebo group were withdrawn from the study within 72 hours due to rapid clinical improvement. Contamination was noted 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 the mean airway pressure (MAP) while ventilated and the fraction of inspired oxygen (FiO2) from the time of enrollment to the end of the study, were not significantly different between groups. Midazolam was administered as an infusion at 60 mcg/kg/hr for up to five days in infants > 33 weeks gestation, and at 60 mcg/kg/hr for one day followed by 30 mcg/kg/hr for up to a total of five days in infants </= 33 weeks gestation. Duration of the infusion was not reported. Weaning of sedatives was allowed after at least 48 hours of administration; a weaning protocol, however, was not specified. The primary outcome was adequacy of sedation as measured by a behavioral score adapted from the clinical neurologic and behavioral scoring system by Barrier (Barrier 1989), and changes in physiologic variables (heart rate and blood pressure). The sedation score consists of five items, assessing facial expression, sucking, spontaneous motor activity, excitability / responsiveness to stimulation, and excessive flexion, with score ranging from 0 (sedated) to 5 (inadequate sedation). The sedation score was performed four times per day during treatment, twice by nurses and twice by physicians. Secondary outcomes included days of ventilation support, days of supplemental oxygen use, surfactant use, duration of NICU stay, and common complications of preterm birth (pneumothorax, pulmonary interstitial emphysema, hypotension, chronic lung disease, necrotizing enterocolitis, intracranial hemorrhage, persistent pulmonary hypertension of the newborn, death). Outcomes were reported on all 46 infants.

In the multicenter pilot study by Anand et al (Anand 1999), 67 preterm infants of 24 to 32 weeks gestation who were </= 72 hours of age and who were ventilated for < 8 hours were randomly assigned 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, assessed by the clinical risk index for babies (CRIB) score (Cockburn 1993), did not show any significant difference among groups at birth (p = 0.24). However, severity of illness measured by the neonatal medical index (NMI) score (Korner 1993) using response variables during the hospital stay, showed significant differences in the distribution of risk categories among the three groups at discharge (p = 0.01). Midazolam was administered at 200 mcg/kg loading dose followed by an infusion of 20, 40, or 60 mcg/kg/hr for infants of gestational ages 24 - 26, 27 - 20, or 30 - 33 weeks, respectively. Morphine was administered at 100 mcg/kg loading dose followed by an infusion of 10, 20 or 30 mcg/kg/hr for infants of gestational ages 24-26, 27-29, or 30-33 weeks, respectively. Duration of the infusion was not different among groups (5.1 vs 3.4 vs 5.0 days in the midazolam, morphine and placebo groups, respectively, p = 0.37). Additional sedation, if necessary, was provided by boluses of morphine, and the frequency and amount given were documented as a measure of inadequate sedation. Weaning of sedatives was done according to a standardized protocol. Primary outcome was the incidence of adverse neurologic events (defined as neonatal death, grade III or IV intraventricular hemorrhage, or periventricular leukomalacia). Adequacy of sedation was measured by the COMFORT score, an 8-item behavioural and physiologic measurement of distress in the pediatric intensive care unit (Ambuel 1992). The score includes assessment of: Alertness, calmness/agitation, respiratory response, physical movement, mean arterial blood pressure, heart rate, muscle tone, and facial tension, with score ranging from 8 (sedated) to 40 (not adequately sedated). Adequacy of analgesia was measured by 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 score ranging from 0 (adequate analgesia) to 21 (inadequate analgesia). The two scores were performed on all infants at baseline, after 24 hours of infusion, and 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 outcome at 36 weeks corrected age using the Neurobehavioral Assessment of the Premature Infant examination cluster scores (NAPI) (Korner 1991). Outcomes were reported on all 67 infants.

In the study by Arya et al (Arya 2001), 33 infants with birth weight < 2000 grams and requiring mechanical ventilation during the first week of life were randomized 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), mean airway pressure (MAP), oxygenation index (OI), and the alveolar-arterial oxygen gradient (AaDO2), were similar between the two groups at the time of enrolment. Midazolam was administered intravenously at 200 mcg/kg loading dose followed by an infusion of 60 mcg/kg/hr. Infants in both groups also received morphine infusion at 10 mcg/kg/hr during the study period. The study concentrated on the first 48 hours of midazolam infusion and did not report on duration of benzodiazepine use and on the 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 the 48 hours of the study. Reasons for withdrawal were death (13 infants) and extubation (one infant). They were included 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 neurologic and behavioural scoring system by Barrier (Barrier 1989). This is the same scoring system used in the study by Jacqz-Aigrain et al (Jacqz-Aigrain 1994). The study infants were assessed for adequacy of sedation prior to midazolam administration and then every six hours over the 48-hour study period. Other outcomes measured include changes in physiologic variables (heart rate and blood pressure), changes in oxygen requirement (FiO2), ventilation requirement (PIP, PEEP, ventilator rate) and arterial blood gas as measured by mean daily values. Complications related to mechanical ventilation (air leak, intraventricular hemorrhage), potential adverse effect of midazolam (epileptiform movements, hypotension, tachycardia, and oliguria) were also documented. The duration of ventilation was reported. No long-term outcome was reported. Outcomes were reported on all 33 infants in the study.

Methodological quality of included studies

For details see: table of included studies

Jacqz-Aigrain et al (Jacqz-Aigrain 1994)
Infants were randomized using sealed envelopes in a box; however, adequacy of allocation concealment was unclear from the description of the study methodology. Blinding of intervention and outcome measures was ensured. Outcomes were reported on all infants who received the study drug.

Anand et al (Anand 1999)
Balanced randomization in blocks, stratified by each participating center of the NOPAIN trial, was performed via a 24 hour automated telephone response system. Blinding of randomization was ensured. The identity of the study drug was concealed, and blinding of both the intervention and the outcome measures was achieved. Outcomes were reported on all infants enrolled in the study.

Arya et al (Arya 2001)
Randomization was performed using opaque envelopes containing computer-generated random numbers. Blinding of intervention was ensured by providing placebo with colour and vial volume similar to midazolam. Blinding of outcome measures was achieved. Outcomes were reported on all infants enrolled in the study.

Sample size calculation was performed only in the study by Arya et al (Arya 2001), although the study by Anand et al (Anand 1999) was stated as a pilot trial. Statistical analyses were performed using an intention-to-treat approach in all three studies.

Results

COMPARISON 01: MIDAZOLAM INFUSION VS PLACEBO

In the study by Anand et al (Anand 1999), outcomes were evaluated by analysis of variance to detect statistically significant differences among the midazolam, morphine, and placebo groups. For this review we have performed comparisons between the midazolam group and the placebo group on relevant continuous outcome variables using the information available from the publication (sample size, mean, standard deviation, standard error of the mean).

Level of sedation

Jacqz-Aigrain et al (Jacqz-Aigrain 1994)
Sedation scores were not different between groups at baseline. The midazolam group had consistently lower scores (more sedated) than the placebo group on all days as assessed by both nurses and physicians (p < 0.05). Significant decreases in sedation scores from baseline [mean (SD) score 1.9 (0.4)] to day 1[score 1.1 (0.3), p < 0.01] , day 2 [score 0.8 (0.2), p < 0.01] and day 3 [score 1.1 (0.3), p < 0.05] were observed in the midazolam group (per nurses' score), while significant increases were observed in the placebo group from baseline [mean (SD) score 1.7 (0.3)] to day 1 [score 2.6 (0.3), p < 0.01] (per physicians' score). Heart rates and blood pressures did not differ between groups at baseline, but were significantly lower in the midazolam group than in the placebo group on days 1 and 2. These trends continued through to day five, although they were not statistically significant. One infant in the midazolam group and seven in the placebo group (p < 0.05) were inadequately sedated and required fentanyl and muscle relaxants within 72 hours. Two infants in the midazolam group received fentanyl within 72 hours.

Anand et al (Anand 1999)
Compared to the placebo group, statistically significantly lower COMFORT score (more sedated) was noted in the midazolam group during the infusion [mean (SD) score 14.9 (4.6) vs. 17.5 (4.2), p = 0.04], although there was no statistically significant difference in scores between these two groups before the infusion and 12 hours after stopping the infusion [mean (SD) score 15.9 (3.8) vs. 15.6 (3.2), p = 0.8, before the infusion and 15.8 (4.7) vs. 16.2 (4.1), p = 0.76, after the infusion]. In response to tracheal suctioning, the midazolam group had significantly lower PIPP scores (more sedated) during the infusion compared with the placebo group [mean (SD) score 8.9 (3.3) vs. 12.7 (3.8), p < 0.001]. The requirement for additional morphine was not statistically different between the midazolam and the placebo groups, but there was a trend of the midazolam group to require fewer additional morphine doses than the placebo group.

Arya et al (Arya 2001)
Sedation scores were not significantly different between the two groups at baseline. The midazolam group had statistically significantly lower sedation scores (more sedated) than the placebo group from 18 hours after starting infusion [median (range) score 0 (0-3) vs. 1 (0-4), p<0.05]. This trend continued for the study duration (up to 48 hours), with statistical significant difference noted at 36, 42, and 48 hours of the study drug infusion. Mean daily heart rates and blood pressures were not significantly different between the two groups throughout the study (data not reported).

Even though Jacqz-Aigrain et al (Jacqz-Aigrain 1994) and Arya et al (Arya 2001) both used the same sedation score, results on adequacy of sedation could not be combined by meta-analysis, as Arya et al (Arya 2001) presented the sedation scores as median and range.

Outcome 01.01: Intraventricular hemorrhage

Neither Jacqz-Agrain et al (Jacqz-Aigrain 1994) nor Anand et al (Anand 1999) found a statistically significant difference between the midazolam and placebo groups in the incidence of intraventricular hemorrhage (IVH). In the study by Arya et al (Arya 2001), no intracranial hemorrhage was observed during the 48-hour study period in all of the enrolled neonates. Meta-analysis of the results of the three studies showed no statistically significant difference in the incidence of IVH of any grade [relative risk (RR) 1.68, 95% CI 0.87, 3.24; risk difference (RD) 0.12, 95% CI -0.02, 0.26].

Outcome 01.02: Mortality

Neither Jacqz-Aigrain et al (Jacqz-Aigrain 1994) nor Anand et al (Anand 1999) found a statistically significant difference between the midazolam and placebo groups in mortality. Arya et al (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 the results of the three studies shows no evidence of effect (RR 0.79, 95% CI 0.40, 1.56; RD -0.05, 95% CI -0.18, 0.09).

Occurrence of adverse effects associated with midazolam administration:

Jacqz-Aigrain et al (Jacqz-Aigrain 1994)
No adverse neurologic effect was reported. However, one infant in the midazolam group was excluded from the study within 24 hours due to major neurological abnormalities. Details around the case were not described. There was no statistically significant difference in the incidence of hypotension requiring albumin or vasoactive drugs between groups (8/24 vs 6/22).

Anand et al (Anand 1999)
No adverse neurologic effect associated with midazolam administration was noted. The incidence of hypotension was not reported.

Arya et al (Arya 2001)
No adverse neurologic effect associated with midazolam administration was noted. Epileptiform movements of unknown cause were noted in two infants in the placebo group. Significant hypotension was not noted in any infant during the study period.

Outcomes 01.03 - 01.05: Pulmonary outcomes

Jacqz-Aigrain et al (Jacqz-Aigrain 1994)
No statistically significant difference was noted between groups in days of ventilation, days of supplemental oxygen use, incidence of pneumothorax, and incidence of pulmonary interstitial emphysema.

Anand et al (Anand 1999)
No statistically significant difference was noted between the midazolam group and the placebo group in days of ventilatory support, days of supplemental oxygen use, and incidence of pneumothorax.

Arya et al (Arya 2001)
Oxygenation status, ventilation parameters, and blood gas measurements were not significantly different between the two groups. Days of ventilation were similar between the two groups. Days of oxygen use were not reported. Pneumothorax was not observed in any infant during the study period.

Data on days of ventilation in the study by Arya et al (Arya 2001) were presented as median and range and therefore cannot be combined with data from the other two studies. Meta-analyses of the results of the studies by Jacqz-Aigrain et al (Jacqz-Aigrain 1994) and Anand et al (Anand 1999) showed no statistically significant difference in days of ventilation [weighted mean difference (WMD) 3.6 days, 95% CI -0.2, 7.4], and days of supplemental oxygen use (WMD 0.6 days, 95% CI -5.3, 6.6).
From the three studies, meta-analysis of the results on incidence of pneumothorax between the midazolam and placebo groups showed no evidence of effect (RR 1.08; 95% CI 0.41, 2.84; RD 0.01; 95% CI -0.10, 0.12).

Outcome 01.06: Length of NICU stay

In the study by Jacqz-Aigrain et al (Jacqz-Aigrain 1994) and Anand et al (Anand 1999), the length of NICU stay was not statistically significantly different between the midazolam group and the placebo group. Arya et al (Arya 2001) did not report on the length of NICU stay.

Meta-analysis of the data by Jacqz-Aigrain et al (Jacqz-Aigrain 1994) and Anand et al (Anand 1999) 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, 10.5).

Neurodevelopmental outcome:

Jacqz-Aigrain (Jacqz-Aigrain 1994)
Long-term neurodevelopmental outcome was not reported.

Anand et al (Anand 1999)
No statistically significant difference in NAPI score at 36 weeks corrected gestational age was noted between the midazolam group and the placebo group.

Arya et al (Arya 2001)
Long-term neurodevelopmental outcome was not reported.

Discussion

Since the introduction of midazolam into the NICU in the 1980's, little information has been published on its effectiveness and safety when administered to critically ill neonates. The majority of reports to date are case series and case reports of midazolam use in patients of diverse age groups (from three days to 18 years of age), in variable doses (from 0.025 to 0.3 mg/kg administered as a bolus, to 24 to 400 mcg/kg/hr administered as an infusion) (Hartwig 1991, Pellier 1999, Rosen 1991, Stenhammar 1994). The three studies included in this review (Jacqz-Aigrain 1994, Anand 1999, Arya 2001) are the only randomized, controlled trials on the use of midazolam infusion for sedation in infants to date.

There is a paucity of tools to measure level of sedation in preterm infants (AAP/CPS 2000). Sedation level in such infants is currently measured by scales previously validated in older infants and children. Whether these scales are appropriate in preterm infants are unknown. Therefore, in the three randomized, controlled trials included in this review (Jacqz-Aigrain 1994, Anand 1999, Arya 2001), although intravenous infusion of midazolam appeared to be an effective sedative compared to placebo, a definite conclusion on the its effectiveness as a sedative in preterm infants could not be drawn. Anand et al (Anand 1999) assessed level of sedation by the COMFORT score, a composite scale using eight behavioral and physiologic items to assess distress (Ambuel 1992). Although the items are applicable to preterm infants, the score has only been validated in older infants and children (mean age of 37.1 months). Jacqz-Aigrain et al (Jacqz-Aigrain 1994) and Arya et al (Arya 2001) both used a sedation scale adapted from the scoring system by Barrier (Barrier 1989), which was not validated in preterm infants, by choosing five of the 10 items from the scoring system. The validity of such adapted score in assessing sedation level in neonates is unknown.

The study by Jacqz-Aigrain et al (Jacqz-Aigrain 1994) showed similar incidence of intracranial hemorrhage between the midazolam and control groups. However, the midazolam-treated infant who was excluded within 24 hours for major neurologic abnormalities raises concern about the safety of midazolam. In the study by Anand et al (Anand 1999), the incidence of poor neurological outcome (death, severe intraventricular hemorrhage, periventricular leukomalacia) was higher in the midazolam group compared to the placebo group and the morphine group (32% vs. 24% vs. 4%, respectively, p=0.03). It should be noted, however, that the morphine group included a higher percentage of female infants with slightly higher birth weight and more mature gestational age. These baseline characteristics may have contributed to the difference in neurologic outcomes in the groups.

Adverse neurologic effects associated with midazolam in term and preterm neonates have been reported in the literature (Bergman 1991, Collins 1991, van den Anker 1992, Magny 1994, Adams 1997, Ng 2002). A variety of transient neurologic effects have been reported after boluses and/or infusions of midazolam, including impaired level of consciousness, lack of visual following, hypertonia, hypotonia, choreic movements, dyskinetic movements, myoclonus, and epileptiform activity. Abnormalities in electroencephalograms were also noted in some cases. In all of these cases, the effects were transient, although long term neurodevelopmental outcomes were not reported. Two studies (van Straaten 1992, Harte 1997) have found a significant decrease in middle cerebral artery blood flow velocity in preterm infants administered a single bolus injection of midazolam. This effect lasted up to one hour, and was directly related to a drop in the mean arterial blood pressure. Thus, it appears that the neurologic effects of midazolam may be at least partially related to transient cerebral hypoperfusion. The long-term sequalae of these effects are not known.

The mechanism of midazolam-induced hypotension was thought to be vasodilation related to levels of extravascular prostanoids and calcium (Modanlou 1997). In the study by Jacqz-Aigrain et al (Jacqz-Aigrain 1994), the number of infants with hemodynamic instability was not significantly different between the midazolam and the placebo groups (8 vs. 6), although infants in the midazolam group had significantly lower blood pressures than infants in the placebo group. Other investigators (Burtin 1991,van den Anker 1992, Ng 2002) have observed significant hypotension in several preterm infants after bolus doses and infusions of midazolam that required volume resuscitation or vasoactive drugs. In the majority of cases, fentanyl was administered concomitantly.

Reviewers' conclusions

Implications for practice

Definite conclusions about the effectiveness and safety of midazolam infusion (in the dose range of 30 to 60 mcg/kg/hr) as a sedative in preterm neonates cannot be made from this systematic review. The occurrence of adverse neurologic events, though they may be multifactorial in origin, were more frequently observed in the midazolam-treated infants in the studies included in this review. These adverse effects cannot be dismissed in light of previous case reports of serious neurologic and hemodynamic effects from non-randomized, uncontrolled studies, and studies on the effect of midazolam on cerebral artery blood flow velocity. The use of intravenous midazolam infusion, therefore, cannot currently be recommended in the preterm population.

Implications for research

There is a need to develop reliable, valid, and clinically useful scales to measure level of sedation in pre-verbal infants. With the development of such scales, further research on the effectiveness of sedatives such as midazolam infusion on term and preterm infants may be performed. With regards to the safety of midazolam use in infants, further studies on the short and long term adverse effects associated with the use of midazolam are needed.

Acknowledgements

Joseph Beyene, Biostatistician, University of Toronto, Ontario, Canada, for statistical analyses of the study by Anand et al (Anand 1999).

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Anand 1999	Multicenter randomized, double blind, placebo-controlled pilot study (NOPAIN trial). 1. Blinding of randomization - Yes 2. Blinding of intervention - Yes 3. Complete follow up - Yes 4. Blinding of outcome measure - Yes	Preterm infants from 24-32 weeks gestational age </= 72 hours postnatal age who were ventilated for < 8 hours were eligible for inclusion. Exclusion criteria: major congenital anomalies, severe intrapartum asphyxia (5 minute Apgar score </=3), and participation in other studies interfering with the NOPAIN trial procedures. 67 infants were randomized. Demographic data: Values presented as mean (SD). Midazolam group (n=22) Gestational age: 28.6 (2.5) wks Birth weight : 1245 (445) g Entry weight: 1224 (491) g Male (%): 54.5 Duration of infusion: 122.2 (122.1) hrs CRIB score: 5.7 (3.5) Morphine group (n=24) Gestational age: 29.2 (2.2) wks Birth weight: 1230 (475) g Entry weight: 1265 (501) g Male (%): 46.2 Duration of infusion: 81.0 (94.1) hrs CRIB score: 4.5 (3.1) Placebo (10% Dextrose) group (n=21) Gestation age: 28.1(2.2) wks Birth weight: 1049 (419) g Entry weight: 1188 (524) g Male (%): 57.1 Duration of infusion: 121.1(120.8) hrs CRIB score: 6.6 (4.0)	Midazolam was given as 200 mcg/kg loading dose followed by infusion of 20, 40, or 60 mcg/kg/hr for those whose gestational age were 24-26, 27-29, or 30-33 weeks, respectively. Morphine was given as 100 mcg/kg loading dose, followed by infusion of 10, 20, or 30 mcg/kg/hr for those whose gestational age were 24-26, 27-29, or 30-33 weeks, respectively. Additional analgesia was given, as needed, by intravenous morphine boluses at the discretion of the clinical team. The amount and frequency of additional morphine was recorded as an outcome measure. The infusions were weaned according to a set protocol. The maximum duration of study treatment was 14 days.	Severity of illness was measured by the CRIB score (Cockburn 1993), and the NMI (Korner 1994). Primary outcome: Incidence of adverse neurological event (neonatal death, grade III/IV intraventricular hemorrhage, periventricular leukmalacia). Secondary outcomes: Level of sedation, as measured by the COMFORT score (Ambuel 1992). Pain response to tracheal suctioning, as assessed by the PIPP (Stevens 1995). All of these scores were assessed before starting the study treatment, after 24 hours of infusion, and at 10-12 hours after treatment was discontinued. Incidence of pneumothorax, days of ventilatory support, continuous positive airway pressure, and oxygen, length of intensive care unit and hospital stay, and neurodevelopmental outcome measured by the Neurobeurobehavioral Assessment of the NAPI cluster scores (Korner 1991) at 36 weeks corrected gestational age.	Balanced randomization by blocks stratified by each participating center. Randomization performed by a 24 hour automated telephone response system. Reasons for nonenrollment were provided. Finnegan neonatal abstinence scale was performed at 12 and 24 hours after discontinuation of study infusion, and then daily.	A
Arya 2001	Randomized, double-blind, placebo controlled trial. 1. Blinding of randomization - Yes 2. Blinding of intervention - Yes 3. Complete follow up - Yes 4. Blinding of outcome measure - Yes	Newborn infants < 2000 g needing mechanical ventilation during first week of life were eligible for inclusion. Exclusion criteria: encephalopathy, birth asphyxia, major malformation, maternal benzodiazepine use prior to delivery. 33 infants were randomized. 3 in each group did not complete the first 24 hours of study; 4 in each group did not complete the first 48 hours of study. Reasons for withdrawal: death (13) and extubation (1). Demographic data: Values presented as mean (SD) unless indicated. Midazolam group (n=17) Gestational age: 31.5 (2.4) wks Birth weight: 1263 (326)g Male (%): 58.8 PIP at baseline: 19.9 (5.5) cm H2O MAP at baseline: 8.7 (3.2) cm H2O Median (range) OI at baseline: 5 (1-22) Median(range) AaDO2 at baseline: 205 (13-619) Placebo group (n=16) Gestational age: 32.3 (2.2) wks Birth weight: 1337 (297)g Male (%): 75.0 PIP at baseline: 21.2 (7.1) cm H2O MAP at baseline: 9.8 (4.3) cm H2O Median (range) OI at baseline: 5 (2-55) Median(range) AaDO2 at baseline: 234.5 (59-553)	Midazolam was given as 200mcg/kg loading dose followed by infusion of 60mcg/kg/hr. Duration of infusion and method of weaning not specified. Infants in both groups received morphine infusion at 10mcg/kg/hr during the study. The study duration was 48 hours of infusion.	Primary outcome: Adequacy of sedation as measured every 6 hours by a 5 item behavioural scale (facial expression, sucking, continuous motor activity, excitability and response to stimulation, excessive flexing); physiologic measures of sedation level included mean daily values of heart rate, blood pressure. Secondary outcomes: intracranial hemorrhage and epileptiform movement, hemodynamic instability (hypotension, tachycardia, oliguria) with need for volume expansion and/or vasoactive drugs, ventilation requirement (peak inspiratory and positive end-expiratory pressures, mean airway pressure and rate), days of ventilation, incidence of pulmonary air leak.	Randomization was performed using opaque envelopes containing computer-generated random numbers.	A
Jacqz-Aigrain 1994	Randomized, double-blind, placebo controlled trial. Randomization was stratified by 2 gestational age group (<33wks and >/=33 wks). 1. Blinding of randomization - Can't tell 2. Blinding of intervention - Yes 3. Complete follow up - Yes 4. Blinding of outcome measure - Yes	Newborn infants </= 48 hours of age who required intubation and ventilation for respiratory distress syndrome were eligible for inclusion. Exclusion criteria: previous exposure to benzodiazepines (maternal/infant), congenital anomalies, major neurological abnormalities, low Apgar score at 5 minutes (score not defined by authors). 48 preterm infants were enrolled. 1 received midazolam previously and 1 with 5 minute Apgar score of 0 were excluded. 46 infants (25 were </= 33 weeks, 21 were >33 weeks gestational age) were included in the analysis. Demographic data: Values presented as mean (SD). Midazolam group (n=24) Gestational age: 32.1(2.8) wks Birth weight: 1820 (647) g Male %: 58.3 5 minute Apgar score: 9.0 (1.2) MAP at enrollment: 12 (2) mmHg FiO2 at enrollment: 49 (13) % Duration of infusion: 78.7 (30.9) hrs Placebo group (n=22) Gestational age: 32.8 (2.6) wks Birth weight: 2000 (548) g Male %: 59.1 5 minute Apgar score: 8.1 (2.3) MAP at enrollment: 13 (2) mmHg FiO2 at enrollment: 51 (16) %	24 received midazolam infusion. For infants>/= 33weeks: 60mcg/kg/hr for up to 5 days. For infants<33 weeks: 60mcg/kg/hr for 1 day, then 30mcg/kg/hr for up to 5 days. Infusion may be stopped after 48 hours if no longer required. 22 infants received a manufactured placebo. Additional sedation with fentanyl or the use of muscle relaxant was permitted; the study protocol was interrupted in such cases, but data from these infants were used in the analysis.	Primary outcome: Adequacy of sedation as measured 4 times per day (twice by nurses and twice by physicians) by a 5 item behavioural scale (facial expression, sucking, spontaneous motor activity, excitability and response to stimulation, excessive flexing); physiologic measure of sedation level include mean daily values of hourly heart rate, systolic and diastolic blood pressures; Secondary outcomes include: Incidence of intracranial hemorrhage and epileptiform movement.; hemodynamic instability (need for fluid, albumin, vasoactive drugs); ventilation requirement (Peak inspiratory and positive end-expiratory pressures, mean airway pressure), days of ventilation, days of supplemental oxygen use, incidence of pneumothorax and pulmonary interstitial emphysema; total days of intensive care unit stay. Serum concentrations of midazolam were monitored before, 24 and 48 hours after infusion was started, and at the end of treatment.	Randomization was performed by picking of the next envelope in 2 boxes, one for each gestational age stratum. Protocol for weaning of study drug was not described.	B

AaDO2, alveolar-arterial oxygen gradient; CRIB, clinical risk index for babies; FiO2, fraction of inspired oxygen concentration; MAP, mean airway pressure; NAPI, neurobehavioral assessment of the premature infant; NMI, neonatal medical index; OI, oxygenation index; PIP, peak inspiratory pressure; PIPP, premature infant pain profile; SD, standard deviation

Characteristics of excluded studies

Study	Reason for exclusion
Kawakami 1998	A randomized, controlled trial comparing intravenous lidocaine (1.5mg/kg) to intravenous midazolam (0.1mg/kg) in addition to lidocaine for anesthetic induction in 27 neonates undergoing surgery. It was excluded because midazolam was given as a single bolus dose and was not used as a sedative.
McCarver-May 1996	A randomized crossover trial comparing intravenous midazolam (0.2mg/kg) to oral chloral hydrate (75mg/kg) for sedation during neuroimaging studies in seven full term neonates. It was excluded because midazolam was given as a single bolus dose.
Parkinson 1997	A randomized, controlled trial comparing oral chloral hydrate (25mg/kg to 50mg/kg) with promethazine (0.5mg/kg to 1.0mg/kg) to an intravenous midazolam infusion (50mcg/kg/hr to 300mcg/kg/hr) for sedation in the critically ill. It was excluded because the population studied included children from one day to 15 years of age, and that data for the neonates could not be extracted from the study.

References to studies

References to included studies

Anand 1999 {published data only}

Anand KJS, McIntosh N, Lagercrantz H, Pelausa E, Young TE, Vasa R. Analgesia and sedation in preterm neonates who require ventilatory support - results from the NOPAIN trial. Arch Pediatr Adolesc Med 1999;153:331-8.

Arya 2001 {published data only}

Arya V, Ramji S. Midazolam sedation in mechanically ventilated newborns: A double blind randomized placebo controlled trial. Indian Pediatr 2001;38:967-72.

Jacqz-Aigrain 1994 {published data only}

Jacqz-Aigrain E, Daoud P, Burtin P, Desplanques L, Beaufils F. Placebo-controlled trial of midazolam sedation in mechanically ventilated newborn babies. Lancet 1994;344:646-50.

References to excluded studies

Kawakami 1998 {published data only}

Kawakami K, Ohata J, Kadosaki M, et al. Midazolam for anesthetic induction in neonates. Masui-Japanese Journal of Anesthesiology 1998;47:570-5.

McCarver-May 1996 {published data only}

McCarver-May DG, Kang J, Aouthmany M, et al. Comparison of chloral hydrate and midazolam for sedation of neonates for neuroimaging studies. J Pediatr 1996;128:573-6.

Parkinson 1997 {published data only}

Parkinson L, Hughes J, Gill A, et al. A randomized controlled trial of sedation in the critically ill. Paediatr Anaesth 1997;7:405-10.

* indicates the primary reference for the study

Other references

Additional references

AAP/CPS 2000

American Academy of Pediatrics, Committee on Fetus and Newborn, Committee on Drugs, Sections on Anesthesiology, Section on Surgery; Canadian Paediatric Society, Fetus and Newborn Committee. Prevention and management of pain and stress in the neonate. Pediatrics 2000;105:454-61.

Adams 1997

Adams MM, Hahn JS, Benitz WE. A series of neonatal patients with paradoxical seizure-like reactions to bolus intravenous injections of midazolam. Pediatr Res 1997;41:134A.

Ambuel 1992

Ambuel B, Hamlett KW, Marx CM, Blumer JL. Assessing distress in pediatric intensive care environments: The COMFORT scale. J Pediatr Psychol 1992;17:95-109.

Anand 1987

Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321-9.

Anand 1992

Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1-9.

Barrier 1989

Barrier G, Attia J, Mayer MN, Amiel-Tison C, Shnider SM. Measurement of post-operative pain and narcotic administration in infants using a new clinical scoring system. Intensive Care Medicine 1989;15(Suppl 1):S37-9.

Bergman 1991

Bergman I, Steeves M, Burckart G, Thompson A. Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration. J Pediatr 1991;119:644-9.

Burtin 1991

Burtin P, Daoud P, Jacqz-Aigrain E, Mussat P, Moriette G. Hypotension with midazolam and fentanyl in the newborn. Lancet 1991;337:1545-6.

Cockburn 1993

Cockburn F, Cooke RWI, Gamsu HR, et al. The CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. The lancet 1993;342:193-8.

Collins 1991

Collins S, Carter JA. Resedation after bolus administration of midazolam to an infant and its reversal by flumazenil. Anaesthesia 1991;46:471-2.

Greenough 1983

Greenough A, Morley C, Davis J. Interaction of spontaneous respiration with artificial ventilation in preterm babies. J Pediatr 1983;103:769-73.

Harte 1997

Harte GJ, Gray PH, Lee TC, Steer PA, Charles BG. Haemodynamic responses and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates. J Paediatr Child Health 1997;33:335-8.

Hartwig 1991

Hartwig S, Roth B, Theisohn M. Clinical experience with continuous intravenous sedation using midazolam and fentanyl in the paediatric intensive care unit. Eur J Pediatr 1991;150:784-88.

Hebebrand 1988

Hebebrand J, Hofmann D, Reichelt R, et al. Early ontogeny of the central benzodiazepine receptor in human embryos and fetuses. Life Sciences 1988;43:2127-36.

Jacqz-Aigrain 1992

Jacqz-Aigrain E, Daoud P, Burtin P, Maherzi S, Beaufils F. Pharmacokinetics of midazolam during continuous infusion in critically ill neonates. Eur J Clin Pharmacol 1992;42:329-32.

Jacqz-Aigrain 1996

Jacqz-Aigrain E, Burtin P. Clinical pharmacokinetics of sedatives in neonates. Clin Pharmacokinet 1996;31:423-443.

Korner 1991

Korner AF, Constantinou J, Dimiceli S, Brown BW, Thom VA. Establishing the reliability and developmental validity of a neurobehavioural assessment for preterm infants: a methodological process. Child Development 1991;62:1200-8.

Korner 1993

Korner AF, Stevenson DK, Kraemer HC, et al. Prediction of the development of low birth weight preterm infants by a new neonatal medical index. J Dev Behav Pediatr 1993;14:106-11.

Lee 1999

Lee TC, Charles BG, Harte GJ, et al. Population phramacokinetic modeling in very premature infants receiving midazolam during mechanical ventilation. Anesthesiology 1999;90:451-7.

Magny 1994

Magny JF, d'Allest AM, Nedelcoux H, Zupan V, Dehan M. Midazolam and myoclonus in neonate. Eur J Pediatr 1994;153:389-92.

Modanlou 1997

Modanlou HD, Beharry K. Mechanism of midazolam-induced hypotension: possible role of prostanoids and calcium. Pediatr Res 1997;41:57A.

Ng 2002

Ng E, Klinger G, Shah V, Taddio A. Safety of benzodiazepines in newborns. Ann Pharmacother 2002;36:1150-5.

Papile 1978

Papile LA, Burstein J, Burstein R, et al.. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with weights less than 1500 grams. J Pediatr 1978;92:529-34.

Pellier 1999

Pellier I, Monrigal JP, Le Moine P, et al. Use of intravenous ketamine-midazolam association for pain procedure in children with cancer. A prospective study. Paediatr Anaesth 1999;9:61-68.

Perlman 1985

Perlman JM, Goodman S, Kreusser KL, Volpe JJ. Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood-flow velocity in preterm infants with respiratory distress syndrome. N Engl J Med 1985;312:1353-7.

Quinn 1993

Quinn MW, Wild J, Dean HG, et al. Randomised double-blind controlled trial of effect of morphine on catecholamine concentrations in ventilated pre-term babies. Lancet 1993;342:324-7.

Rosen 1991

Rosen DA, Rosen KR. Midazolam for sedation in the paediatric intensive care unit. Intensive Care Med 1991;17:S15-19.

Stenhammar 1994

Stenhammar L, Högberg L, Lewander P, Nordvall M, Tjellström B. Intravenous midazolam in small bowel biopsy. Arch Dis Child 1994;71:558.

Stevens 1996

Stevens BJ, Johnson CC, Petryshen P, Taddio A. Premature infant pain profile: development and initial validation. Clin J Pain 1996;12:13-22.

van den Anker 1992

van den Anker JN, Sauer PJJ. The use of midazolam in the preterm neonate. Eur J Pediatr 1992;151:152.

van Straaten 1992

van Straaten HLM, Rademaker CMA, de Vries LS. Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn. Dev Pharmacol Ther 1992;19:191-5.

Other published versions of this review

Ng 2000

Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. In: The Cochrane Database of Systematic Reviews, Issue 2, 2000.

Ng 2003

Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. In: The Cochrane Database of Systematic Reviews, Issue 1, 2003.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Midazolam versus placebo
01 Intraventricular hemorrhage (any grade)	3	122	RR (fixed), 95% CI	1.68 [0.87, 3.24]
02 Mortality	3	122	RR (fixed), 95% CI	0.79 [0.40, 1.56]
03 Days of ventilation	2	89	WMD (fixed), 95% CI	3.60 [-0.25, 7.44]
04 Days of supplemental oxygen use	2	89	WMD (fixed), 95% CI	0.64 [-5.30, 6.57]
05 Pneumothorax	3	122	RR (fixed), 95% CI	1.08 [0.41, 2.84]
06 Length of NICU stay (days)	2	89	WMD (fixed), 95% CI	5.44 [0.40, 10.49]

01 Midazolam versus placebo

01.01 Intraventricular hemorrhage (any grade)

01.02 Mortality

01.03 Days of ventilation

01.04 Days of supplemental oxygen use

01.05 Pneumothorax

01.06 Length of NICU stay (days)

Contact details for co-reviewers

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca

Dr Anna Taddio
Graduate Department of Pharmaceutical Sciences
Hospital for Sick Children Research Institute
555 University Avenue
Toronto
Ontario CANADA
M5G 1X8
Telephone 1: +1 416 813 6235
Facsimile: +1 416 813 5880
E-mail: anna.taddio@sickkids.ca

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2006 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.