BACKGROUND: All newborns admitted to the neonatal intensive care unit (NICU) experience pain during routine care and are at increased risk of long-term adverse effects. Endotracheal suctioning (ETS) is one of the most frequently performed procedures in the NICU, causing moderate-to-severe pain. Approximately 50% of extremely preterm neonates require intubation and repeated ETS.
OBJECTIVES: To evaluate the benefits and harms of pharmacological interventions for the prevention of pain during ETS in mechanically ventilated neonates.
SEARCH METHODS: We searched Cochrane CRS, MEDLINE, Embase, CINAHL and three trial registries, together with reference checking. The latest search date was August 2024.
SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-, cluster- and cross-over RCTs of neonates (term and preterm) who were mechanically ventilated via endotracheal or tracheostomy tube and required ETS. Pharmacological interventions were compared to placebo, no intervention, or standard care, or to non-pharmacological interventions.
DATA COLLECTION AND ANALYSIS: Critical outcome measures were validated by composite pain scores. Secondary outcomes included physiological and behavioural pain indicators. We used standard Cochrane methods. For continuous outcomes, we used a fixed-effect model and reported mean differences (MDs) with 95% confidence intervals (CIs). For categorical outcomes, we reported the typical risk ratio (RR) and risk difference (RD) and 95% CIs. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS: We included seven RCTs (1242 participants); six included preterm neonates; one included term neonates; four were included in a meta-analysis. Opioids (morphine, alfentanil, meperidine) versus placebo (four studies) The evidence is very uncertain for the following outcomes (all very low-certainty): morphine may have little to no effect on Premature Infant Pain Profile (PIPP) (MD -0.11; 95% CI -0.28 to 0.06; I= 93%; 4 studies, 1123 participants). The use of 20 µg/kg of alfentanil may reduce the pain score (CHEOPS) change from baseline (median = not specified (NS); IQR = NS; P = 0.031; 1 study; 10 participants). Results after 10 µg/kg of alfentanil were not reported. The use of 20 µg/kg of alfentanil may reduce heart rate change from baseline (median = NS; IQR = NS; P = 0.031; 1 study; 10 participants). Results after 10 µg/kg were not specified. Morphine may have little to no effect on the duration of mechanical ventilation (MD -4.70; 95% CI -11.07 to 1.67; I= not applicable (NA); 1 study, 45 participants). Meperidine may reduce behavioural pain score (BPS) (MD -2.7; P = 0.001; 1 study, 84 participants; low-certainty). Morphine may not increase the risk of arterial hypotension (RR 1.49; 95% CI 95% 0.88 to 2.51; I= 57%; 2 studies, 928 participants; low-certainty). Morphine probably does not reduce the incidence of severe intraventricular haemorrhage (IVH) (RR 1.13; 95% CI 0.80 to 1.61; I= 36%; I= 36%; 4 studies, 1065 participants; moderate-certainty). No studies reported adverse events (AE) associated with morphine and meperidine; severe muscle rigidity was observed with alfentanil. Opioids (morphine) versus sedatives (midazolam) (one study) The evidence is very uncertain for the following outcomes (all very low-certainty): morphine may have little to no effect on PIPP score (MD -1.00; 95% CI -2.66 to 0.66; I= NA; 1 study, 46 participants); CHEOPS not reported. Morphine may result in a large reduction in the duration of mechanical ventilation (MD -6.70; 95% CI -12.40 to -1.00; I= NA; 1 study, 46 participants). Morphine may not reduce the incidence of severe IVH (RR 0.08; 95% CI 0.00 to 1.43; 1 study, 46 participants; low-certainty). No studies reported on physiological and behavioural indicators or haemodynamic changes. No AEs were reported. Sedatives (ketamine, midazolam) versus placebo (two studies) Midazolam may reduce PIPP scores (MD -3.80; 95% CI -5.89 to -1.71; I= NA; 1 study, 45 participants; low-certainty). The evidence is very uncertain for the following outcomes (all very low-certainty). Ketamine 0.5 mg/kg and 2 mg/kg may have little to no effect on CHEOPS change from baseline (P = NS; 1 study, 16 participants). Ketamine 1 mg/kg may reduce CHEOPS change from baseline (P = 0.043; 1 study, 16 participants). Ketamine 0.5 mg/kg and 1 mg/kg may have little to no effect on heart rate change from baseline (P = NS; 1 study, 16 participants). Ketamine 2 mg/kg may increase heart rate change from baseline (P = 0.029; 1 study, 16 infants). The use of 0.5 mg/kg, 1 mg/kg and 2 mg/kg ketamine may have little to no effect on mean arterial blood pressure change from baseline (P = NS; 1 study, 16 participants; very low-certainty). Midazolam may have little to no effect on the duration of mechanical ventilation (MD 2.00; 95% CI -5.14 to 9.14; I= NA; 1 study, 43 participants), and may have little to no effect on the risk of severe grade IVH (RR 1.59; 95% CI 0.43 to 5.84; I= NA; 1 study, 43 participants). No studies reported behavioural indicators. No AEs reported. RoB assessment Four studies had low RoB; three had high RoB: one for reporting bias; two for risk of carry-over effects. 2 2 2 2 2 2 2 2 2 2
AUTHORS' CONCLUSIONS: Morphine may have little to no effect on PIPP or duration of ventilation (evidence very uncertain). Morphine may not increase the risk of hypotension and probably does not reduce the incidence of severe IVH. Alfentanil may reduce CHEOPS and heart rate change from baseline (evidence very uncertain). Meperidine may reduce BPS. Compared to midazolam, morphine may have little to no effect on PIPP scores, and may result in a large reduction in the duration of ventilation (evidence very uncertain). No studies reported on physiological and behavioural indicators or haemodynamic changes. Morphine may not reduce the incidence of severe IVH, compared to midazolam (low-certainty evidence). Compared to placebo, midazolam may reduce PIPP scores, and has little to no effect on the duration of ventilation or on the risk of severe IVH (low to very low-certainty evidence); ketamine may reduce CHEOPS change, and have little to no effect on heart rate change, or on mean arterial blood pressure (evidence very uncertain). No studies reported on behavioural indicators or haemodynamic outcomes.
