Opioids for newborn infants receiving mechanical ventilation.

BACKGROUND: Mechanical ventilation is a potentially painful and discomforting intervention that is widely used in neonatal intensive care. Newborn infants demonstrate increased sensitivity to pain, which may affect clinical and neurodevelopmental outcomes. The use of drugs that reduce pain might be important in improving survival and neurodevelopmental outcomes. OBJECTIVES: To determine the benefits and harms of opioid analgesics for neonates (term or preterm) receiving mechanical ventilation compared to placebo or no drug, other opioids, or other analgesics or sedatives. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9), in the Cochrane Library; MEDLINE via PubMed (1966 to 29 September 2020); Embase (1980 to 29 September 2020); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 29 September 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials comparing opioids to placebo or no drug, to other opioids, or to other analgesics or sedatives in newborn infants on mechanical ventilation. We excluded cross-over trials. We included term (≥ 37 weeks' gestational age) and preterm (< 37 weeks' gestational age) newborn infants on mechanical ventilation. We included any duration of drug treatment and any dosage given continuously or as bolus; we excluded studies that gave opioids to ventilated infants for procedures. DATA COLLECTION AND ANALYSIS: For each of the included trials, we independently extracted data (e.g. number of participants, birth weight, gestational age, types of opioids) using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria and assessed the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 23 studies (enrolling 2023 infants) published between 1992 and 2019. Fifteen studies (1632 infants) compared the use of morphine or fentanyl versus placebo or no intervention. Four studies included both term and preterm infants, and one study only term infants; all other studies included only preterm infants, with five studies including only very preterm infants. We are uncertain whether opioids have an effect on the Premature Infant Pain Profile (PIPP) Scale in the first 12 hours after infusion (MD -5.74, 95% confidence interval (CI) -6.88 to -4.59; 50 participants, 2 studies) and between 12 and 48 hours after infusion (MD -0.98, 95% CI -1.35 to -0.61; 963 participants, 3 studies) because of limitations in study design, high heterogeneity (inconsistency), and imprecision of estimates (very low-certainty evidence - GRADE). The use of morphine or fentanyl probably has little or no effect in reducing duration of mechanical ventilation (MD 0.23 days, 95% CI -0.38 to 0.83; 1259 participants, 7 studies; moderate-certainty evidence because of unclear risk of bias in most studies) and neonatal mortality (RR 1.12, 95% CI 0.80 to 1.55; 1189 participants, 5 studies; moderate-certainty evidence because of imprecision of estimates). We are uncertain whether opioids have an effect on neurodevelopmental outcomes at 18 to 24 months (RR 2.00, 95% CI 0.39 to 10.29; 78 participants, 1 study; very low-certainty evidence because of serious imprecision of the estimates and indirectness). Limited data were available for the other comparisons (i.e. two studies (54 infants) on morphine versus midazolam, three (222 infants) on morphine versus fentanyl, and one each on morphine versus diamorphine (88 infants), morphine versus remifentanil (20 infants), fentanyl versus sufentanil (20 infants), and fentanyl versus remifentanil (24 infants)). For these comparisons, no meta-analysis was conducted because outcomes were reported by one study. AUTHORS' CONCLUSIONS: We are uncertain whether opioids have an effect on pain and neurodevelopmental outcomes at 18 to 24 months; the use of morphine or fentanyl probably has little or no effect in reducing the duration of mechanical ventilation and neonatal mortality. Data on the other comparisons planned in this review (opioids versus analgesics; opioids versus other opioids) are extremely limited and do not allow any conclusions. In the absence of firm evidence to support a routine policy, opioids should be used selectively - based on clinical judgement and evaluation of pain indicators - although pain measurement in newborns has limitations.

Assessment and feasibility of the four landmarks of the aortic root in a cohort of very preterm infants.

BACKGROUND: The diameter of the aortic root is used as a parameter to calculate blood flow in very preterm infants. There are considerable differences in diameter of the four anatomical landmarks of the aortic root in children and adults, but limited data are available for the very preterm population. The aim of this study was to obtain reference and reliability data on two-dimensional measurements of the aortic root in very preterm infants <30 weeks gestation. MATERIALS AND METHODS: Fifty long axis echocardiograms were reviewed and re-analyzed for measurements at the four anatomical landmarks of the aortic root; the aortic annulus, sinus of Valsalva (SV), sinotubular junction, and the proximal ascending aorta (PAA). A subjective visual scoring system was developed to quantify image quality. A random sample of images was blindly re-measured to assess intra- and inter-observer reliability. RESULTS: Significant differences in diameter were found between the four landmarks, except between SV and PAA. Inter-observer coefficients showed marginal variation ranging from 5.0% to 8.2%, with slightly lower intra-observer variability. Overall image quality score was poorest for PAA on standard long axis images but improved when the probe was adjusted along the outflow tract. CONCLUSION: We present reliability and reference values for all four anatomic landmarks of the aortic root in very preterm infants and demonstrated the importance of standardizing and reporting cardiac output measurements in preterm infants.

The methodology of Doppler-derived central blood flow measurements in newborn infants.

Central blood flow (CBF) measurements are measurements in and around the heart. It incorporates cardiac output, but also measurements of cardiac input and assessment of intra- and extracardiac shunts. CBF can be measured in the central circulation as right or left ventricular output (RVO or LVO) and/or as cardiac input measured at the superior vena cava (SVC flow). Assessment of shunts incorporates evaluation of the ductus arteriosus and the foramen ovale. This paper describes the methodology of CBF measurements in newborn infants. It provides a brief overview of the evolution of Doppler ultrasound blood flow measurements, basic principles of Doppler ultrasound, and an overview of all used methodology in the literature. A general guide for interpretation and normal values with suggested cutoffs of CBFs are provided for clinical use.

Cardiorespiratory effects of changes in end expiratory pressure in ventilated newborns.

BACKGROUND: Positive pressure ventilation in premature infants can improve oxygenation but may diminish cerebral blood flow and cardiac output. Low superior vena cava (SVC) flow increases risk of intraventricular haemorrhage, and higher mean airway pressure is associated with low SVC flow. Whether this is a direct effect of positive pressure ventilation or a reflection of severity of lung disease is not known. This study aimed to determine if positive end expiratory pressure (PEEP) in ventilated newborns could be increased without clinically relevant cardiorespiratory changes. METHOD: Ventilated newborns were studied before and 10 min after increasing PEEP (5 cm H(2)O to 8 cmH(2)O) and again when PEEP returned to baseline. Echocardiographic and respiratory function measurements were collected during the intervention. RESULTS: In 50 infants, increased PEEP was associated with a non-significant difference in mean SVC flow of -5 ml/kg/min (95% CI -12 to 3 ml/kg/min) but a significant reduction in right ventricular output of 17 ml/kg/min (95% CI 5 to 28 ml/kg/min). The increase in lung compliance was non-significant (median difference 0.02 ml/cmH(2)O/kg) and the decrease in lung resistance (18 cmH(2)O/l/s; 95% CI 10 to 26 cm H(2)O/l/s) was significant. Changes (%) in lung compliance and SVC flow, when corrected for Paco(2), were positively associated (regression coefficient 0.4%; 95% CI 0.2% to 0.6%). CONCLUSION: A short-term increase in PEEP does not lead to significant changes in systemic blood flow, although 36% of infants in the present study had clinically important changes in flow (+/-25%). The intervention can improve dynamic lung function, especially airway resistance. Improvements in compliance tend to be associated with improvements in blood flow.