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

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Authors

Eugene Ng1, Anna Taddio2, Arne Ohlsson3

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


1Aubrey and Marla Dan Program for High Risk Mothers and Babies, Sunnybrook Health Sciences Centre, Toronto, Canada [top]
2Graduate Department of Pharmaceutical Sciences, Hospital for Sick Children Research Institute, Toronto, Canada [top]
3Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada [top]

Citation example: Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database of Systematic Reviews 2012, Issue 6. Art. No.: CD002052. DOI: 10.1002/14651858.CD002052.pub2.

Contact person

Eugene Ng

Aubrey and Marla Dan Program for High Risk Mothers and Babies
Sunnybrook Health Sciences Centre
Room M4-230A
Toronto Ontario M5S1B2
Canada

E-mail: eugene.ng@sunnybrook.ca

Dates

Assessed as Up-to-date: 21 March 2012
Date of Search: 19 March 2012
Next Stage Expected: 17 March 2014
Protocol First Published: Not specified
Review First Published: Issue 2, 2000
Last Citation Issue: Issue 6, 2012

What's new

Date / Event Description
22 March 2012
Updated

This updates the review "Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit' published in The Cochrane Database of Systematic Reviews (Ng 2003).

A literature search was performed in March 2012.

22 March 2012
New citation: conclusions not changed

No new trial was identified. No change to conclusions.

History

Date / Event Description
09 September 2009
Updated

This updates the review 'Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit' published in The Cochrane Library, Issue 1, 2003 (Ng 2003).

No new trials identified.

02 November 2008
Amended

Converted to new review format.

01 August 2006
Updated

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.

17 September 2002
New citation: conclusions changed

Substantive amendment. 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.

Abstract

Background

Proper sedation for neonates undergoing uncomfortable procedures may reduce stress and avoid complications. Midazolam is a short-acting benzodiazepine that is increasingly used in neonatal intensive care units (NICU). However, its effectiveness 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 or physiological measurements, or both, for critically ill neonates undergoing intensive care and to assess clinically significant short- and long-term adverse effects associated with its use.

Search methods

We performed a literature search according to the Cochrane Neonatal Review Group search strategy. Randomised and quasi-randomised 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, 2012), MEDLINE (1985 to 2012), EMBASE (1980 to 2012), CINAHL (1981 to 2012), reference lists of published studies, personal files, and abstracts published in The Pediatric Academic Societies Meeting Abstract Archives from 1990 to 2011.

Selection criteria

Randomised and quasi-randomised controlled trials of intravenous midazolam infusion in infants aged 28 days or less for sedation were selected for review.

Data collection and analysis

Data regarding the primary outcome of level of sedation were abstracted. Secondary outcomes such as intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), death, length of NICU stay, and adverse effects associated with midazolam were assessed. When appropriate, meta-analyses were performed using risk ratio (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 included in the review. Using different sedation scales, each study showed a statistically significantly higher sedation level in the midazolam group compared to the placebo group. However, since none of the sedation scales used have been validated in preterm infants, the effectiveness of midazolam in this population could not be ascertained. One study showed a statistically significant higher incidence of adverse neurological events (death, grade III or IV IVH, PVL), and meta-analysis of data from two studies showed a statistically significant longer duration of NICU stay in the midazolam group compared to the placebo group.

Authors' 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.

Plain language summary

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

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.

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Background

Description of the condition

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 or uncomfortable, or both, 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 haemorrhages (IVHs) may be prevented (Greenough 1983; Perlman 1985).

Description of the intervention

Benzodiazepines, administered as intravenous infusions or as intravenous boluses, are used to provide sedation, but not analgesia, in many clinical settings. Midazolam is a short-acting benzodiazepine that has increasingly been used in the NICU.

How the intervention might work

The benzodiazepines are a class of sedatives that acts on specific receptors in the central nervous system. These receptors, which are present in the foetus from seven weeks' gestation (Hebebrand 1988), potentiate the neuronal inhibitory pathways mediated by gamma-aminobutyric acid (GABA) (Jacqz-Aigrain 1996). 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.

Why it is important to do this review

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

Primary objective

  1. To assess the effectiveness of intravenous midazolam infusion for sedation, as evaluated by behavioural or physiological, or both, measurements of sedation levels, in critically ill neonates in the NICU.

Secondary objectives

  1. Incidence of IVH/periventricular leukomalacia (PVL).
  2. Mortality.
  3. Occurrence of adverse effects associated with the use of midazolam (hypotension, neurological 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.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials or quasi-randomised 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 aged 28 days or less 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 microgram/kg/hour to 60 microgram/kg/hour administered for at least 24 hours for sedation during mechanical ventilation and radiological 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 anaesthetic induction agent or as an anticonvulsant were also excluded.

Types of outcome measures

Primary outcomes

Primary outcome was level of sedation, evaluated by:

  1. Behavioural measures: facial actions, excitability, muscle tone, physical movements and respiratory behaviour, which may be evaluated by age-appropriate scoring systems; and
  2. Physiological 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
  1. IVH (defined by classification of Papile et al (Papile 1978)).
  2. PVL (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), neurological 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 methods for identification of studies

See: Cochrane Review Group Search Strategy.

Electronic searches

We identified randomised and quasi-randomised controlled trials of intravenous midazolam in infants from the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2012), MEDLINE (from 1985 to March 2012), EMBASE (1980 to 2012) and CINAHL (1980 to 2012) using the MeSH headings: midazolam; infant, newborn. We searched for abstracts published in Pediatric Academic Societies Meetings Abstract Archives from 1990 to 2011. We did not impose language restrictions. We attempted to contact investigators of studies meeting the inclusion criteria to gather additional data for analysis. We searched clinical trials registries for ongoing or recently completed trials (Clinical Trials; Controlled-Trials.com External Web Site Policy; and WHO Clinical Trials Registry External Web Site Policy). We searched the Web of Science to identify any trial that quoted the earliest study that we identified (Jacqz-Aigrain 1994).

Searching other resources

In addition, we manually searched bibliographies of articles and personal files. 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.

Data collection and analysis

We used the standard methodology for performing systematic reviews according to the Cochrane Neonatal Review Group (http://neonatal.cochrane.org/resources-review-authors External Web Site Policy).

Selection of studies

We included randomised or quasi-randomised controlled trials involving neonates aged 28 days or less with a treatment group and a placebo group. We accepted studies reporting outcome measures including physiological, behavioural, and hormonal changes, as well as adverse neurological outcomes for review

We excluded studies involving neonates and older infants and children if data for neonates could not be extracted.

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

Data extraction and management

We created a data collection form and the following data were abstracted from the included studies: demographics of the participants, age at enrolment into study, inclusion and exclusion criteria, sample size, treatment and control group regimens, and outcomes. Two review authors (EN, AT) independently abstracted the data and differences were resolved by consensus.

Assessment of risk of bias in included studies

Quality of the trials included was evaluated using the following criteria: 1) blinding of randomisation; 2) blinding of intervention 3) complete follow-up; 4) blinding of outcome measurement. This information was added to the table ' Characteristics of Included Studies'.

In addition, the following issues were evaluated and entered into the ' Risk of bias in included studies' table:

  1. Sequence generation: was the allocation sequence adequately generated?
  2. Allocation concealment: was allocation adequately concealed?
  3. Blinding of participants, personnel and outcome assessors: was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
  4. Incomplete outcome data: were incomplete outcome data adequately addressed?
  5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?
  6. Other sources of bias: was the study apparently free of other problems that could put it at a high risk of bias?

Measures of treatment effect

Statistical analyses were performed using Review Manager 5.1 software. Categorical data were analysed using risk ratio (RR), risk difference (RD) and the number needed to treat to benefit (NNTB) or to harm (NNTH). Continuous data were analysed using weighted mean difference (WMD). The 95% confidence interval (CI) was reported on all estimates.

Assessment of heterogeneity

We examined heterogeneity between trials by inspecting the forest plots (if at least 10 trials were included in one analysis) and quantifying the impact of heterogeneity using the I2 statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (e.g. differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses.

Data synthesis

When there were at least two randomised 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 5.1.4 (RevMan 2011). We used the Mantel-Haenszel method for estimates of typical RR and RD. We used the inverse variance method for measured quantities. We used the fixed-effect model for all meta-analyses.

Subgroup analysis and investigation of heterogeneity

No subgroup analyses were prospectively planned.

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Results

Description of studies

For details see: ' Characteristics of Included Studies' and ' Characteristics of excluded studies'.

Six randomised, 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 anaesthetic 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 (Anand 1999; Arya 2001; Jacqz-Aigrain 1994) reported on the effectiveness of midazolam infusion and included a total of 146 infants.
The literature searches conducted in September 2009 and March 2012 did not identify any additional trials.

In the study by Jacqz-Aigrain et al (Jacqz-Aigrain 1994), 46 preterm infants (25 were < 33 weeks' gestation and 21 were greater than/or equal to 33 weeks' gestation) less than/or equal to 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 neurological 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 enrolment to the end of the study, were not significantly different between groups.Midazolam was administered as an infusion at 60 microgram/kg/hour for up to five days in infants of 33 weeks' gestation or more, and at 60 microgram/kg/hour for one day followed by 30 microgram/kg/hour 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 behavioural score adapted from the clinical neurological and behavioural scoring system by Barrier (Barrier 1989), and changes in physiological variables (heart rate and blood pressure). The sedation score consisted 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, necrotising enterocolitis, intracranial haemorrhage, persistent pulmonary hypertension of the newborn, death). Outcomes were reported on all 46 infants.

In the multicentre pilot study by Anand et al (Anand 1999), 67 preterm infants of 24 to 32 weeks' gestation who were less than/or equal to 72 hours of age and who were ventilated for less than eight 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 (The International Neonatal Network), 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 microgram/kg loading dose followed by an infusion of 20 microgram/kg/hour, 40 microgram/kg/hour, or 60 microgram/kg/hour for infants of gestational ages 24 to 26 weeks, 27 to 20 weeks, or 30 to 33 weeks, respectively. Morphine was administered at 100 microgram/kg loading dose followed by an infusion of 10 microgram/kg/hour, 20 microgram/kg/hour, or 30 microgram/kg/hour for infants of gestational ages 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 versus 3.4 days versus 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 standardised protocol. Primary outcome was the incidence of adverse neurological events (defined as neonatal death, grade III or IV IVH, or PVL). Adequacy of sedation was measured by the COMFORT score, an eight-item behavioural and physiological measurement of distress in the paediatric 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 (NAPI) examination cluster scores (Korner 1991). Outcomes were reported on all 67 infants.

In the study by Arya et al (Arya 2001), 33 infants with birth weight < 2000 g and requiring mechanical ventilation during the first week of life were randomised 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), were similar between the two groups at the time of enrolment. Midazolam was administered intravenously at 200 microgram/kg loading dose followed by an infusion of 60 microgram/kg/hour. Infants in both groups also received morphine infusion at 10 microgram/kg/hour 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 neurological 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 included changes in physiological variables (heart rate and blood pressure), changes in oxygen requirement (FiO2), ventilation requirement (PIP, positive end-expiratory pressure (PEEP), ventilator rate), and arterial blood gas as measured by mean daily values. Complications related to mechanical ventilation (air leak, IVH), potential adverse effect of midazolam (epileptiform movements, hypotension, tachycardia, and oliguria) were also documented. The duration of ventilation was reported. No long-term outcomes were reported. Outcomes were reported on all 33 infants in the study.

Risk of bias in included studies

For details see ' Risk of bias in included studies' table.

Jacqz-Aigrain et al

Infants were randomised 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 (Jacqz-Aigrain 1994).

Anand et al

Balanced randomisation in blocks, stratified by each participating centre of the NOPAIN (Neonatal Outcome and Prolonged Analgesia In Neonates) trial, was performed via a 24-hour automated telephone response system. Blinding of randomisation 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 (Anand 1999).

Arya et al

Randomisation 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 (Arya 2001).

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.

Effects of interventions

Midazolam infusion versus placebo (comparison 1)

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 (SD), standard error of the mean).

Level of sedation
Jacqz-Aigrain et al

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 one [score 1.1 (0.3), P < 0.01], day two [score 0.8 (0.2), P < 0.01] and day three [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 one [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 one and two. 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 (Jacqz-Aigrain 1994).

Anand et al

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) versus 17.5 (4.2), P = 0.04], although there was no statistically significant difference in scores between the two groups before the infusion and 12 hours after stopping the infusion [mean (SD) score 15.9 (3.8) versus 15.6 (3.2), P = 0.8, before the infusion and 15.8 (4.7) versus 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) versus 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 (Anand 1999).

Arya et al

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 to 3) versus 1 (0 to 4), P < 0.05]. This trend continued for the study duration (up to 48 hours), with statistical significant difference noted at 36 [median (range) score 0 versus 1 (0 to 3), p < 0.05], 42 [0 (0-3) vs. 1 (0-3), p < 0.05], and 48 [0 (0 to 2) versus 1 (0 to 3), p < 0.05] hours of the study drug infusion (Arya 2001).

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 whereas Jacqz-Aigrain et al (Jacqz-Aigrain 1994) presented results as mean and SD.

Intraventricular haemorrhage (outcome 1.1)

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 the incidence of IVH. In the study by Arya et al (Arya 2001), no intracranial haemorrhage 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 (RR 1.68; 95% CI 0.87 to 3.24; RD 0.12; 95% CI -0.02 to 0.26).

Mortality (outcome 1.2)

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 to 1.56; RD -0.05; 95% CI -0.18 to 0.09).

Occurrence of adverse effects associated with midazolam administration
Jacqz-Aigrain et al

No adverse neurological effects were 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 versus 6/22) (Jacqz-Aigrain 1994).

Anand et al

No adverse neurological effects associated with midazolam administration were noted. The incidence of hypotension was not reported (Anand 1999).

Arya et al

No adverse neurological effects associated with midazolam administration were 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 (Arya 2001).

Pulmonary outcomes (outcomes 1.3 to 1.5)
Jacqz-Aigrain et al

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 (Jacqz-Aigrain 1994).

Anand et al

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 (Anand 1999).

Arya et al

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 (Arya 2001).

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 (WMD 3.6 days; 95% CI -0.2 to 7.4 days), and days of supplemental oxygen use (WMD 0.6 days; 95% CI -5.3 to 6.6 days).
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 to 2.84; RD 0.01; 95% CI -0.10 to 0.12).

Length of NICU stay (outcome 1.6)

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 to 10.5 days).

Neurodevelopmental outcome
Jacqz-Aigrain

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

Anand et al

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

Arya et al

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

Discussion

Since the introduction of the use of midazolam into the NICU in the 1980s, 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 mg/kg to 0.3 mg/kg administered as a bolus, to 24 microgram/kg/hour to 400 microgram/kg/hour administered as an infusion) (Hartwig 1991; Pellier 1999; Rosen 1991; Stenhammar 1994). The three studies included in this review (Anand 1999; Arya 2001; Jacqz-Aigrain 1994) are the only randomised, controlled trials on the use of midazolam infusion for sedation in infants to date. The repeat literature searches in September 2009 and March 2012 did not identify any additional trials.

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 is unknown. Therefore, in the three randomised, controlled trials included in this review (Anand 1999; Arya 2001; Jacqz-Aigrain 1994), 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 behavioural and physiological 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 an 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 haemorrhage between the midazolam and control groups. However, the midazolam-treated infant who was excluded within 24 hours for major neurological 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 IVH, PVL) was higher in the midazolam group compared to the placebo and the morphine groups (32% versus 24% versus 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 weights and more mature gestational age. These baseline characteristics may have contributed to the difference in neurological outcomes in the groups.

Adverse neurological effects associated with midazolam in term and preterm neonates have been reported in the literature (Adams 1997; Bergman 1991; Collins 1991; Magny 1994; Ng 2002; van den Anker 1992). A variety of transient neurological effects have been reported after boluses or infusions, or both, 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 (Harte 1997; van Straaten 1992) 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 neurological effects of midazolam may be at least partially related to transient cerebral hypoperfusion. The long-term sequelae 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 haemodynamic instability was not significantly different between the midazolam and the placebo groups (8 versus 6, respectively), although infants in the midazolam group had significantly lower blood pressures than infants in the placebo group. Other investigators (Burtin 1991; Ng 2002; van den Anker 1992) 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.

Authors' conclusions

Implications for practice

Definite conclusions about the effectiveness and safety of midazolam infusion (in the dose range of 30 microgram/kg/hour to 60 microgram/kg/hour) as a sedative in preterm neonates cannot be made from this systematic review. The occurrence of adverse neurological 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 following previous case reports of serious neurological and haemodynamic effects from non-randomised, 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).

Contributions of authors

E Ng:

  • development and writing of protocol,
  • literature search and identification of trials for inclusion,
  • evaluation of methodological quality of included trials,
  • abstraction of data independent of co-review author,
  • 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 methodological quality of included trials,
  • abstraction of data independent of co-review author,
  • verifying data entered into RevMan.

A Ohlsson:

  • development of protocol,
  • literature search and identification of trials for inclusion,
  • verifying data entered into RevMan,
  • revision of the final review and the 2009 update.

All authors participated in the completion of the 2009 update. However, only two review authors (E Ng, A Ohlsson) participated in the completion of the 2012 update.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Anand 1999

Methods

Multicentre randomised, double-blind, placebo-controlled pilot study (NOPAIN trial)

  1. Blinding of randomisation - yes
  2. Blinding of intervention - yes
  3. Complete follow-up - yes
  4. Blinding of outcome measure - yes
Participants

Preterm infants from 24 to 32 weeks' gestational age less than/or equal to 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 less than/or equal to 3), and participation in other studies interfering with the NOPAIN trial procedures

67 infants were randomised
Demographic data: values presented as mean (SD)
Midazolam group (n = 22)
Gestational age: 28.6 weeks (2.5 weeks)
Birth weight: 1245 g (445 g)
Entry weight: 1224 g (491 g)
Male: 54.5%
Duration of infusion: 122.2 hours (122.1 hours)
CRIB score: 5.7 (3.5)
Morphine group (n = 24)
Gestational age: 29.2 weeks (2.2 weeks)
Birth weight: 1230 g (475 g)
Entry weight: 1265 g (501 g)
Male: 46.2%
Duration of infusion: 81.0 hours (94.1 hours)
CRIB score: 4.5 (3.1)
Placebo (10% dextrose) group (n = 21)
Gestation age: 28.1 weeks (2.2 weeks)
Birth weight: 1049 g (419 g)
Entry weight: 1188 g (524 g)
Male: 57.1%
Duration of infusion: 121.1 hours (120.8 hours)
CRIB score: 6.6 (4.0)

Interventions

Midazolam was given as 200 microgram/kg loading dose followed by infusion of 20 microgram/kg/hour, 40 microgram/kg/hour, or 60 microgram/kg/hour for those whose gestational age were 24 to 26 weeks, 27 to 29 weeks, or 30 to 33 weeks, respectively

Morphine was given as 100 microgram/kg loading dose, followed by infusion of 10 microgram/kg/hour, 20 microgram/kg/hour, or 30 microgram/kg/hour for those whose gestational age were 24 to 26 weeks, 27 to 29 weeks, or 30 to 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

Outcomes

Severity of illness was measured by the CRIB score (The International Neonatal Network), and the NMI (Korner 1993)
Primary outcome:
Incidence of adverse neurological event (neonatal death, grade III or IV IVH, PVL)
Secondary outcomes:
Level of sedation, as measured by the COMFORT score (Ambuel 1992). Pain response to tracheal suctioning, as assessed by the PIPP (Stevens 1996). All of these scores were assessed before starting the study treatment, after 24 hours of infusion, and at 10 to 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 NAPI cluster scores (Korner 1991) at 36 weeks' corrected gestational age

Notes

Balanced randomisation by blocks stratified by each participating centre. Randomisation performed by a 24-hour automated telephone response system
Reasons for non-enrolment were provided
Finnegan Neonatal Abstinence scale (Finnegan 1975) was performed at 12 and 24 hours after discontinuation of study infusion, and then daily

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Balanced randomisation in blocks, stratified by each participating centre via a 24-hour automated telephone response system

Allocation concealment (selection bias) Low risk

Identity of study drug was concealed and blinding of both the intervention and the outcome measures was achieved

Selective reporting (reporting bias) Low risk

Outcomes were reported on all infants enrolled in the trial

Other bias Low risk

-

Arya 2001

Methods

Randomised, double-blind, placebo-controlled trial

  1. Blinding of randomisation - yes
  2. Blinding of intervention - yes
  3. Complete follow up - yes
  4. Blinding of outcome measure - yes
Participants

Newborn infants < 2000 g needing mechanical ventilation during first week of life were eligible for inclusion

Exclusion criteria: encephalopathy, birth asphyxia, major malformation, and maternal benzodiazepine use prior to delivery

33 infants were randomised
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 weeks (2.4 weeks)
Birth weight: 1263 g (326) g
Male: 58.8%
PIP at baseline: 19.9 cm h3O (5.5 cm h3O)
MAP at baseline: 8.7 cm h3O (3.2 cm h3O)
Median (range) OI at baseline: 5 (1 to 22)
Median(range) AaDO2 at baseline: 205 (13 to 619)

Placebo group (n = 16)
Gestational age: 32.3 weeks (2.2 weeks)
Birth weight: 1337 g (297 g)
Male: 75.0%
PIP at baseline: 21.2 cm h3O (7.1 cm h3O)
MAP at baseline: 9.8 cm h3O (4.3 cm h3O)
Median (range) OI at baseline: 5 (2 to 55)
Median(range) AaDO2 at baseline: 234.5 (59 to 553)

Interventions

Midazolam was given as 200 microgram/kg loading dose followed by infusion of 60 microgram/kg/hour
Duration of infusion and method of weaning not specified
Infants in both groups received morphine infusion at 10 microgram/kg/hour during the study
The study duration was 48 hours of infusion

Outcomes

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); physiological measures of sedation level included mean daily values of heart rate, blood pressure

Secondary outcomes:
intracranial haemorrhage and epileptiform movement, haemodynamic instability (hypotension, tachycardia, oliguria) with need for volume expansion or vasoactive drugs, or both, ventilation requirement (peak inspiratory and PEEP, MAP, and rate), days of ventilation, incidence of pulmonary air leak

Notes

Randomisation was performed using opaque envelopes containing computer-generated random numbers

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated random numbers placed in opaque envelopes

Allocation concealment (selection bias) Low risk

Placebo was manufactured with colour and vial volume similar to the study drug

Selective reporting (reporting bias) Low risk

-

Other bias Low risk

-

Jacqz-Aigrain 1994

Methods

Randomised, double-blind, placebo-controlled trial
Randomisation was stratified by 2 gestational age group (< 33 weeks and greater than/or equal to 33 weeks)

  1. Blinding of randomisation - cannot determine
  2. Blinding of intervention - yes
  3. Complete follow-up - yes
  4. Blinding of outcome measure - yes
Participants

Newborn infants less than/or equal to 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 study 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 less than/or equal to 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 weeks (2.8 weeks)
Birth weight: 1820 g (647 g)
Male: 58.3%
5-minute Apgar score: 9.0 (1.2)
MAP at enrolment: 12 mm Hg (2 mm Hg)
FiO2 at enrolment: 49% (13%)
Duration of infusion: 78.7 hours (30.9 hours)
Placebo group (n = 22)
Gestational age: 32.8 weeks (2.6 weeks)
Birth weight: 2000 g (548 g)
Male: 59.1%
5-minute Apgar score: 8.1 (2.3)
MAP at enrolment: 13 mmHg (2 mmHg)
FiO2 at enrolment: 51% (16%)

Interventions

24 infants received midazolam infusion
For infants greater than/or equal to 33 weeks: 60 microgram/kg/hour for up to 5 days
For infants < 33 weeks: 60 microgram/kg/hour for 1 day, then 30 microgram/kg/hour for up to 5 days
Infusion could have been 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

Outcomes

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); physiological measure of sedation level include mean daily values of hourly heart rate, systolic and diastolic blood pressures

Secondary outcomes included: incidence of intracranial haemorrhage and epileptiform movement; haemodynamic instability (need for fluid, albumin, vasoactive drugs); ventilation requirement (PIP, PEEP, MAP), days of ventilation, days of supplemental oxygen use, incidence of pneumothorax and pulmonary interstitial emphysema; total days of NICU stay
Serum concentrations of midazolam were monitored before, 24 and 48 hours after infusion was started, and at the end of treatment

Notes

Randomisation was performed by picking of the next envelope in 2 boxes, 1 for each gestational age stratum.
Protocol for weaning of study drug was not described

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information on sequence generation

Allocation concealment (selection bias) Unclear risk
Selective reporting (reporting bias) Low risk
Other bias Low risk
Footnotes

AaDO2: alveolar-arterial oxygen gradient; CRIB: Clinical Risk Index for Babies; FiO2: fraction of inspired oxygen concentration; IVH: intraventricular haemorrhage; MAP: mean airway pressure; NAPI: Neurobehavioral Assessment of the Premature Infant; NICU: neonatal intensive care unit; NMI: Neonatal Medical Index; NOPAIN: Neonatal Outcome and Prolonged Analgesia In Neonates; OI: oxygenation index; PEEP: positive end-expiratory pressures; PIP: peak inspiratory pressure; PIPP: Premature Infant Pain Profile; PVL: periventricular leukomalacia; SD: standard deviation.

Characteristics of excluded studies

Kawakami 1998

Reason for exclusion

A randomised, controlled trial comparing intravenous lidocaine (1.5 mg/kg) to intravenous midazolam (0.1 mg/kg) in addition to lidocaine for anaesthetic 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

Reason for exclusion

A randomised cross-over trial comparing intravenous midazolam (0.2 mg/kg) to oral chloral hydrate (75 mg/kg) for sedation during neuroimaging studies in 7 full-term neonates. It was excluded because midazolam was given as a single bolus dose

Parkinson 1997

Reason for exclusion

A randomised, controlled trial comparing oral chloral hydrate (25 mg/kg to 50 mg/kg) with promethazine (0.5 mg/kg to 1.0 mg/kg) to an intravenous midazolam infusion (50 microgram/kg/hour to 300 microgram/kg/hour) for sedation in critically ill children. It was excluded because the population studied included children from 1 day to 15 years of age, and that data for the neonates could not be extracted from the study

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References to studies

Included studies

Anand 1999

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. Archives of Pediatrics and Adolescent Medicine 1999;153:331-8.

Arya 2001

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

Jacqz-Aigrain 1994

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.

Excluded studies

Kawakami 1998

Kawakami K, Ohata J, Kadosaki M, Saito I, Iwasawa K, Mitono H. Midazolam for anesthetic induction in neonates. Masui-Japanese Journal of Anesthesiology 1998;47:570-5.

McCarver-May 1996

McCarver-May DG, Kang J, Aouthmany M, Elton R, Mowery JL, Slovis TL, et al. Comparison of chloral hydrate and midazolam for sedation of neonates for neuroimaging studies. Journal of Pediatrics 1996;128:573-6.

Parkinson 1997

Parkinson L, Hughes J, Gill A, Billingham I, Ratcliffe J, Choonara I. A randomized controlled trial of sedation in the critically ill. Paediatric Anaesthesia 1997;7:405-10.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

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. Pediatric Research 1997;41:134A.

Ambuel 1992

Ambuel B, Hamlett KW, Marx CM, Blumer JL. Assessing distress in pediatric intensive care environments: the COMFORT scale. Journal of Pediatric Psychology 1992;17:95-109.

Anand 1987

Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. New England Journal of Medicine 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. New England Journal of Medicine 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. Journal of Pediatrics 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.

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.

Finnegan 1975

Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addictive Diseases 1975;2(1-2):141-58.

Greenough 1983

Greenough A, Morley C, Davis J. Interaction of spontaneous respiration with artificial ventilation in preterm babies. Journal of Pediatrics 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. Journal of Paediatrics and 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. European Journal of Pediatrics 1991;150:784-8.

Hebebrand 1988

Hebebrand J, Hofmann D, Reichelt R, Schnarr S, Knapp M, Propping P, 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. European Journal of Clinical Pharmacology 1992;42:329-32.

Jacqz-Aigrain 1996

Jacqz-Aigrain E, Burtin P. Clinical pharmacokinetics of sedatives in neonates. Clinical Pharmacokinetics 1996;31:423-43.

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, Spiker D, Scott DT, Constantinou J, et al. Prediction of the development of low birth weight preterm infants by a new neonatal medical index. Journal of Developmental and Behavioral Pediatrics 1993;14:106-11.

Lee 1999

Lee TC, Charles BG, Harte GJ, Gray PH, Steer PA, Flenady VJ. Population pharmacokinetic 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. European Journal of Pediatrics 1994;153:389-92.

Modanlou 1997

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

Ng 2002

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

Papile 1978

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

Pellier 1999

Pellier I, Monrigal JP, Le Moine P, Rod B, Rialland X, Granry JC. Use of intravenous ketamine-midazolam association for pain procedure in children with cancer. A prospective study. Paediatric Anaesthesia 1999;9:61-8.

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. New England Journal of Medicine 1985;312:1353-7.

Quinn 1993

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

RevMan 2011

Review Manager (RevMan) [Computer program]. Version 5.1.4. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.

Rosen 1991

Rosen DA, Rosen KR. Midazolam for sedation in the paediatric intensive care unit. Intensive Care Medicine 1991;17:S15-9.

Stenhammar 1994

Stenhammar L, Högberg L, Lewander P, Nordvall M, Tjellström B. Intravenous midazolam in small bowel biopsy. Archives of Disease in Childhood 1994;71:558.

Stevens 1996

Stevens BJ, Johnson CC, Petryshen P, Taddio A. Premature Infant Pain Profile: development and initial validation. Clinical Journal of Pain 1996;12:13-22.

The International Neonatal Network

The International Neonatal Network. 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.

van den Anker 1992

van den Anker JN, Sauer PJJ. The use of midazolam in the preterm neonate. European Journal of Pediatrics 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. Developmental Pharmacology and Therapeutics 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. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD002052. DOI: 10.1002/14651858.CD002052.

Ng 2003

Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002052. DOI: 10.1002/14651858.CD002052.

Classification pending references

  • None noted.

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Data and analyses

1 Midazolam versus placebo

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Intraventricular haemorrhage (any grade) 3 122 Risk Ratio (M-H, Fixed, 95% CI) 1.68 [0.87, 3.24]
1.2 Mortality 3 122 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.40, 1.56]
1.3 Days of ventilation 2 89 Mean Difference (IV, Fixed, 95% CI) 3.60 [-0.25, 7.44]
1.4 Days of supplemental oxygen use 2 89 Mean Difference (IV, Fixed, 95% CI) 0.64 [-5.30, 6.57]
1.5 Pneumothorax 3 122 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.41, 2.84]
1.6 Length of NICU stay (days) 2 89 Mean Difference (IV, Fixed, 95% CI) 5.44 [0.40, 10.49]

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Sources of support

Internal sources

  • Sunnybrook Health Sciences Centre, Toronto, Canada
  • The Hospital for Sick Children, Toronto, Canada
  • Mount Sinai Hospital, Toronto, Canada

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

This review is published as a Cochrane review in The Cochrane Library, Issue 6, 2012 (see http://www.thecochranelibrary.com External Web Site Policy 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.