Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation - an overview of systematic reviews

Abstract

Background: Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) may contribute to neonatal morbidity and mortality and result in long-term neurodevelopmental sequelae. Appropriate pain and sedation management in ventilated preterm infants may decrease the risk of GMH-IVH; however, it might be associated with harms.

Objectives: To summarize the evidence from systematic reviews regarding the effects and safety of pharmacological interventions related to pain and sedation management in order to prevent GMH-IVH in ventilated preterm infants.

Methods: We searched the Cochrane Library August 2022 for reviews on pharmacological interventions for pain and sedation management to prevent GMH-IVH in ventilated preterm infants (< 37 weeks' gestation). We included Cochrane Reviews assessing the following interventions administered within the first week of life: benzodiazepines, paracetamol, opioids, ibuprofen, anesthetics, barbiturates, and antiadrenergics. Primary outcomes were any GMH-IVH (aGMH-IVH), severe IVH (sIVH), all-cause neonatal death (ACND), and major neurodevelopmental disability (MND). We assessed the methodological quality of included reviews using the AMSTAR-2 tool. We used GRADE to assess the certainty of evidence.

Main results: We included seven Cochrane Reviews and one Cochrane Review protocol. The reviews on clonidine and paracetamol did not include randomized controlled trials (RCTs) matching our inclusion criteria. We included 40 RCTs (3791 infants) from reviews on paracetamol for patent ductus arteriosus (3), midazolam (3), phenobarbital (9), opioids (20), and ibuprofen (5). The quality of the included reviews was high. The certainty of the evidence was moderate to very low, because of serious imprecision and study limitations. Germinal matrix hemorrhage-intraventricular hemorrhage (any grade) Compared to placebo or no intervention, the evidence is very uncertain about the effects of paracetamol on aGMH-IVH (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.38 to 2.07; 2 RCTs, 82 infants; very low-certainty evidence); midazolam may result in little to no difference in the incidence of aGMH-IVH (RR 1.68, 95% CI 0.87 to 3.24; 3 RCTs, 122 infants; low-certainty evidence); the evidence is very uncertain about the effect of phenobarbital on aGMH-IVH (RR 0.99, 95% CI 0.83 to 1.19; 9 RCTs, 732 infants; very low-certainty evidence); opioids may result in little to no difference in aGMH-IVH (RR 0.85, 95% CI 0.65 to 1.12; 7 RCTs, 469 infants; low-certainty evidence); ibuprofen likely results in little to no difference in aGMH-IVH (RR 0.99, 95% CI 0.81 to 1.21; 4 RCTs, 759 infants; moderate-certainty evidence). Compared to ibuprofen, the evidence is very uncertain about the effects of paracetamol on aGMH-IVH (RR 1.17, 95% CI 0.31 to 4.34; 1 RCT, 30 infants; very low-certainty evidence). Compared to midazolam, morphine may result in a reduction in aGMH-IVH (RR 0.28, 95% CI 0.09 to 0.87; 1 RCT, 46 infants; low-certainty evidence). Compared to diamorphine, the evidence is very uncertain about the effect of morphine on aGMH-IVH (RR 0.65, 95% CI 0.40 to 1.07; 1 RCT, 88 infants; very low-certainty evidence). Severe intraventricular hemorrhage (grade 3 to 4) Compared to placebo or no intervention, the evidence is very uncertain about the effect of paracetamol on sIVH (RR 1.80, 95% CI 0.43 to 7.49; 2 RCTs, 82 infants; very low-certainty evidence) and of phenobarbital (grade 3 to 4) (RR 0.91, 95% CI 0.66 to 1.25; 9 RCTs, 732 infants; very low-certainty evidence); opioids may result in little to no difference in sIVH (grade 3 to 4) (RR 0.98, 95% CI 0.71 to 1.34; 6 RCTs, 1299 infants; low-certainty evidence); ibuprofen may result in little to no difference in sIVH (grade 3 to 4) (RR 0.82, 95% CI 0.54 to 1.26; 4 RCTs, 747 infants; low-certainty evidence). No studies on midazolam reported this outcome. Compared to ibuprofen, the evidence is very uncertain about the effects of paracetamol on sIVH (RR 2.65, 95% CI 0.12 to 60.21; 1 RCT, 30 infants; very low-certainty evidence). Compared to midazolam, the evidence is very uncertain about the effect of morphine on sIVH (grade 3 to 4) (RR 0.08, 95% CI 0.00 to 1.43; 1 RCT, 46 infants; very low-certainty evidence). Compared to fentanyl, the evidence is very uncertain about the effect of morphine on sIVH (grade 3 to 4) (RR 0.59, 95% CI 0.18 to 1.95; 1 RCT, 163 infants; very low-certainty evidence). All-cause neonatal death Compared to placebo or no intervention, the evidence is very uncertain about the effect of phenobarbital on ACND (RR 0.94, 95% CI 0.51 to 1.72; 3 RCTs, 203 infants; very low-certainty evidence); opioids likely result in little to no difference in ACND (RR 1.12, 95% CI 0.80 to 1.55; 5 RCTs, 1189 infants; moderate-certainty evidence); the evidence is very uncertain about the effect of ibuprofen on ACND (RR 1.00, 95% CI 0.38 to 2.64; 2 RCTs, 112 infants; very low-certainty evidence). Compared to midazolam, the evidence is very uncertain about the effect of morphine on ACND (RR 0.31, 95% CI 0.01 to 7.16; 1 RCT, 46 infants; very low-certainty evidence). Compared to diamorphine, the evidence is very uncertain about the effect of morphine on ACND (RR 1.17, 95% CI 0.43 to 3.19; 1 RCT, 88 infants; very low-certainty evidence). Major neurodevelopmental disability Compared to placebo, the evidence is very uncertain about the effect of opioids on MND at 18 to 24 months (RR 2.00, 95% CI 0.39 to 10.29; 1 RCT, 78 infants; very low-certainty evidence) and at five to six years (RR 1.6, 95% CI 0.56 to 4.56; 1 RCT, 95 infants; very low-certainty evidence). No studies on other drugs reported this outcome.

Authors' conclusions: None of the reported studies had an impact on aGMH-IVH, sIVH, ACND, or MND. The certainty of the evidence ranged from moderate to very low. Large RCTs of rigorous methodology are needed to achieve an optimal information size to assess the effects of pharmacological interventions for pain and sedation management for the prevention of GMH-IVH and mortality in preterm infants. Studies might compare interventions against either placebo or other drugs. Reporting of the outcome data should include the assessment of GMH-IVH and long-term neurodevelopment.