Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit
There are insufficient data for the use of intravenous midazolam alone as a sedative for neonates. This review raises serious concerns about the safety of midazolam alone in preterm infants.
RHL Commentary Murki S, Reddy A
1. INTRODUCTION
In neonates, the prevention of pain (and response to it) should be the goal of all caregivers. Studies have documented that neonates younger than 32 weeks of gestation are exposed to 10–15 painful or discomforting procedures each day, and to almost 80% of newborns in intensive care no treatment for pain control is offered (1). Pain and stress can interact negatively with mechanical ventilation, leading to unsynchronized breathing and suboptimal ventilation. Infants' response to pain may compromise clinically important factors such as heart rate, respiration rate, blood pressure, intracranial pressure and oxygen saturation. There is also evidence of an endocrine stress response which leads to increased secretion of steroids, catecholamines, and glucagon as well as to a rise in the rate of catabolism (2). Metabolic and immune changes have also been reported. Neonates demonstrate a heightened sensitivity to repetitive noxious stimuli that leads to chronic pain and discomfort (3). These responses may affect long-term clinical and neurodevelopmental outcomes.
Adequate sedation during mechanical ventilation may decrease stress and help in effective ventilation so that complications such as pneumothorax and intraventricular hemorrhage are avoided. Benzodiazepines are effective sedatives, but they are not effective analgesics and potentiate the neurological inhibitory path mediated by gamma amino butyric acid (GABA). Midazolam is a short-acting sedative and is preferred over other benzodiazepines because of its water solubility and rapid clearance. This Cochrane review examined the effectiveness and adverse effects of intravenous midazolam infusion in critically ill neonates undergoing intensive care (4).
2. METHODS OF THE REVIEW
The review authors sought to include randomized or quasi-randomized controlled trials involving neonates (less than or equal to 28 days of age) allocated to a treatment or a placebo group. The treatment group should have either received continuous intravenous infusion of midazolam (20–60 µg/kg/hour for at least 24 hours) for sedation during mechanical ventilation or undergone radiological investigation procedures. Studies using combination of midazolam with analgesics, intravenous bolus doses, midazolam as an anesthetic or anticonvulsant were excluded. Studies were retrieved from the Cochrane Central Register of Controlled Trials, Medline (1985–2006), Embase (1980–2000), and abstracts published in Pediatric Research from 1990 to 2006. The quality of the included trials was evaluated based on blinding of randomization, blinding of the intervention, completeness of follow-up and blinding of outcome measurements. The primary outcome measure was level of sedation evaluated by behavioral measures and physiological parameters. Secondary outcomes were intraventricular hemorrhage, periventricular leukmalacia, mortality, adverse effects associated with the use of midazolam, days of mechanical ventilation, pneumothorax, days of stay in an intensive care unit, and neurodevelopmental outcomes.
3. RESULTS OF THE REVIEW
Three trials (with a total of 146 infants) met the inclusion criteria. All three were judged to be of good quality, although in one trial the concealment of allocation procedure was unclear. Even though all the studies had used objective sedation scores, each of them had used a different scale and none had used scoring systems that had been validated in newborns. Each trial had individually reported significantly greater sedation during infusion of midazolam in the intervention group compared with the placebo group. However, owing to the use of different types of sedation measurement score and non-availability of mean and standard deviation values, the review authors were unable to provide a combined estimate of the level of sedation achieved. Combined estimates for mortality [relative risk (RR) 0.79; 95% confidence interval (CI) 0.40–1.56], intraventricular hemorrhage (RR 1.68; 95% CI 0.87–3.24) and pneumothorax (RR 1.08; 95% CI 0.41–2.84) were not different in midazolam and placebo groups. In one study, blood pressure was significantly lower in the midazolam group, although there was no difference in the incidence of hypotension requiring albumin or vasoactive drugs (8/26 versus 6/22). Another study reported a higher incidence of adverse neurological events (death, grades III–IV intraventricular hemorrhage, periventricular leucomalacia) in the midazolam group compared with other groups (morphine and placebo). Infants receiving midazolam spent more days in the intensive care unit compared with those in the placebo group [weighted mean difference (WMD) 5.4 days; 95% CI 0.4–10.5 days]. None of the three trials addressed the long-term effects of midazolam on neurodevelopment.
4. DISCUSSION
4.1 Applicability of the results
The review authors conclude that there are insufficient data to recommend the use of intravenous midazolam alone as a sedative for neonates. This review also raises doubts about the safety of midazolam in preterm infants owing to the adverse effects of midazolam (lower blood pressures, higher incidence of adverse neurological events and increased stay in a neonatal intensive care unit). The findings of this review are applicable to all settings.
4.2 Implementation of the intervention
Pain relief for neonates is essential, especially for decreasing stress during interventions performed in intensive care units. This review clearly states that midazolam as a sedative should not be used, even though it is easily available and affordable. Other pharmacological preparations such as opiates, fentanyl or morphine may be considered for selective use, as these offer analgesia in addition to sedation for neonates undergoing ventilation or other painful procedures (5).
In all settings, the most effective way of preventing and relieving pain/stress is to reduce by as much as possible the number of painful procedures, bundle the required interventions, eliminate unnecessary laboratory and radiological interventions, use non-invasive measurements/treatments (SpO2, transcutaneous PO2-PCO2, nasal continuous positive airway pressure). Moreover, effort should be made to minimize the number of repeat procedures after failed attempts. Also, the use of non-pharmacological pain/stress prevention and pain relief techniques, such as oral sucrose/glucose, breastfeeding, nonnutritive sucking, kangaroo care, facilitated tucking, swaddling and developmental care (limiting environmental stimuli, lateral positioning, use of supportive bedding, attention to behavioral clues), should be promoted (6).
4.3 Implications for research
Although the current evidence suggests that clinicians should exercise caution in the use of midazolam, there is a need for further research on this drug. Future studies should also target non-pharmacological interventions for pain relief and stress prevention in critically ill neonates.
References
- Barker DP, Rutter N. Exposure to invasive procedures in neonatal intensive care unit admissions. Archives of Disease in Childhood – Fetal Neonatal Edition 1995;72:F47-F48.
- Anand KJ, HIceky RR. Pain and its effects in the human neonate and fetus. New England Journal of Medicine 1987;317:1321-1329.
- Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain 1989;39:31–6.
- 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.
- Bellù R, de Waal KA, Zanini R. Opioids for neonates receiving mechanical ventilation. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD004212; DOI: 10.1002/14651858.CD004212.pub3.
- Batton DG, Barrington KJ, Wallman C. American Academy of Pediatrics Committee on Fetus and Newborn; American Academy of Pediatrics Section on Surgery; Canadian Paediatric Society Fetus and Newborn Committee. Prevention and management of pain in the neonate: an update. Pediatrics 2006;118:2231-2241.
This document should be cited as: Murki S and Reddy A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit: RHL commentary (last revised: 1 December 2010). The WHO Reproductive Health Library; Geneva: World Health Organization.