Koert de Waal

Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis

Objective To evaluate the effect of opioid analgesics, compared to placebo, no drug, or other non-opioid analgesics or sedatives, on pain, duration of mechanical ventilation, mortality, growth and neurodevelopmental outcomes in newborn infants on mechanical ventilation. Methods This was a systematic review and meta-analysis of randomised controlled trials (RCTs). Data sources used were Cochrane, MEDLINE, EMBASE and CINAHL databases, and references from review articles. RCTs or quasi-RCTs comparing opioids to a control, or to other analgesics or sedatives in newborn infants on mechanical ventilation were reviewed. Results A total of 13 studies on 1505 infants were included. Infants given opioids showed reduced Premature Infant Pain Profile (PIPP) scores compared to the control group (weighted mean difference (WMD) −1.71, 95% CI −3.18 to −0.24). Heterogeneity was significantly high in all analyses of pain. Meta-analyses of mortality, duration of mechanical ventilation and long-term and short-term neurodevelopmental outcomes showed no statistically significant differences. Very preterm infants given morphine took significantly longer to reach full enteral feeding than those in control groups (WMD 2.10 days, 95% CI 0.35 to 3.85). One study that compared morphine with midazolam showed similar pain scores, but fewer adverse effects with morphine. Conclusions There is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Opioids should be used selectively, when indicated by clinical judgment and evaluation of pain indicators. If sedation is required, morphine is safer than midazolam.

The definition of a haemodynamic significant duct in randomized controlled trials: a systematic literature review

Aim:  A patent ductus arteriosus (PDA) is associated with morbidity in preterm infants. Treatment is prescribed for a haemodynamically significant duct (HSDA), but its definition varies. We systematically reviewed the clinical and ultrasound criteria used for the definition of an HSDA.

Functional echocardiography; from physiology to treatment.

Functional echocardiography (fECHO) is the bedside use of ultrasound to longitudinally assess myocardial function, systemic and pulmonary blood flow, and intra and extracardiac shunts. This review will focus on fECHO as a tool for the clinician to assess the hemodynamic condition of sick neonates and describe situations where fECHO can help determine a pathophysiological choice for cardiovascular support. The very low birth weight infant with hypotension during the first 24h of life, assessment and monitoring of the ductus arteriosus, assessment and response to treatment of infants with pulmonary hypertension, the infant with perinatal asphyxia and the infant with sepsis and cardiovascular compromise are reviewed. Close cooperation with pediatric cardiology, proper logistics and training programs are mandatory to achieve a 24h a day fECHO service run by bedside clinicians.

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 H2O to 8 cmH2O) 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/cmH2O/kg) and the decrease in lung resistance (18 cmH2O/l/s; 95% CI 10 to 26 cm H2O/l/s) was significant. Changes (%) in lung compliance and SVC flow, when corrected for Paco2, 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.

Hemodynamics in Preterm Infants with Late-Onset Sepsis

OBJECTIVE To describe the hemodynamic changes with time in preterm infants with clinical sepsis. STUDY DESIGN Blood pressure, right ventricular output (RVO), left ventricular output (LVO), and superior vena cava (SVC) flow of infants who had a suspected infection and showed signs of cardiovascular compromise were measured every 12 hours or until there was considered clinical improvement. RESULTS Twenty infants with a median gestational age of 27 weeks (range, 25-32 weeks) and weight of 995 g (range, 650-1980 g) were examined. Five patients died. The mean (SD) RVO, LVO, and SVC flow at the first measurement were 555 (133), 441 (164), and 104 (39) mL/kg/min, respectively. The calculated systemic vascular resistance (SVR) was 0.08 (0.04) mm Hg/mL/kg/min. There was no significant change in flow in the 15 surviving infants. Blood pressure and SVR increased from the first to the last measurement (mean difference: blood pressure, 8 mm Hg; 95% CI 3 to -13; systemic vascular resistance, 0.02 mm Hg/mL/kg/min; 95% CI, 0.01 to -0.04). Flows decreased and SVR increased in the 5 non-surviving infants (mean difference: RVO, -318 mL/kg/min; 95% CI, -463 to -174; LVO, -292 mL/kg/min; 95% CI, -473 to -111; SVC flow, -46 mL/kg/min; 95% CI, -77 to -16). CONCLUSION Preterm neonates with sepsis have relatively high left and right cardiac outputs and low SVRs. A decrease in RVO or LVO >50% compared with the initial measurement is associated with mortality.

Delayed versus Immediate Cord Clamping in Preterm Infants

Background The preferred timing of umbilical‐cord clamping in preterm infants is unclear. Methods We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late‐onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention‐to‐treat basis, accounting for multiple births. Results Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed‐clamping group and 9.0% in the immediate‐clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088.)

Effect of lung recruitment on pulmonary, systemic, and ductal blood flow in preterm infants

OBJECTIVE To determine the effect of lung recruitment on pulmonary, systemic, and ductal blood flow in preterm infants treated with primary high-frequency ventilation (HFV). STUDY DESIGN Thirty-four infants (median gestational age, 28 weeks) were included in this prospective cohort study. Changes in oxygenation in response to stepwise changes in the continuous distending pressure (CDP) were used to monitor lung recruitment during HFV. For each individual patient, the opening pressure (CDPo), closing pressure (CDPc), and optimal pressure (CDPopt) were determined. Ultrasound measurements of right ventricular output (RVO), superior vena cava (SVC), and ductus arteriosus (DA) flow were performed at the start of recruitment (CDPs), CDPo, and CDPopt. RESULTS Increasing the CDP from 8 (CDPs) to 20 (CDPo) cmH(2)O resulted in a decreased RVO (mean difference, -17%; 95% CI, -24, -10%) and unchanged SVC flow and ductal shunting. Transient low RVO and SVC flow values at CDPo were seen in 3 and 2 infants, respectively. CONCLUSIONS Lung recruitment during HFV in preterm infants does not appear to result in clinically relevant changes in pulmonary, systemic, and ductal blood flow.

Targeted Oxygen in the Resuscitation of Preterm Infants, a Randomized Clinical Trial

BACKGROUND AND OBJECTIVES: Lower concentrations of oxygen (O2) (≤30%) are recommended for preterm resuscitation to avoid oxidative injury and cerebral ischemia. Effects on long-term outcomes are uncertain. We aimed to determine the effects of using room air (RA) or 100% O2 on the combined risk of death and disability at 2 years in infants <32 weeks’ gestation. METHODS: A randomized, unmasked study designed to determine major disability and death at 2 years in infants <32 weeks’ gestation after delivery room resuscitation was initiated with either RA or 100% O2 and which were adjusted to target pulse oximetry of 65% to 95% at 5 minutes and 85% to 95% until NICU admission. RESULTS: Of 6291 eligible patients, 292 were recruited and 287 (mean gestation: 28.9 weeks) were included in the analysis (RA: n = 144; 100% O2: n = 143). Recruitment ceased in June 2014, per the recommendations of the Data and Safety Monitoring Committee owing to loss of equipoise for the use of 100% O2. In non-prespecified analyses, infants <28 weeks who received RA resuscitation had higher hospital mortality (RA: 10 of 46 [22%]; than those given 100% O2: 3 of 54 [6%]; risk ratio: 3.9 [95% confidence interval: 1.1–13.4]; P = .01). Respiratory failure was the most common cause of death (n = 13). CONCLUSIONS: Using RA to initiate resuscitation was associated with an increased risk of death in infants <28 weeks’ gestation. This study was not a prespecified analysis, and it was underpowered to address this post hoc hypothesis reliably. Additional data are needed.

Speckle tracking echocardiography in very preterm infants: Feasibility and reference values

BACKGROUND Speckle tracking echocardiography (STE) applies computer software analysis on images generated by conventional ultrasound to define and follow a cluster of speckles from frame to frame and calculates parameters of motion (velocity, displacement) and deformation (strain, strain rate). We explored STE of the left ventricle in stable very preterm infants. METHODS Apical 4 chamber clips (4CH) and short axis clips (SAX) at the level of the papillary muscle were analyzed using TomTec software with manual tracing of cardiac borders. The software automatically segmented the ventricle into 6 equidistant segments and provided segmental and global analysis of deformation parameters. Tracking accuracy was scored visually. RESULTS Seventy-four clips from 51 infants with a median gestational age of 28weeks were analyzed. Feasibility of 4CH was 95.5% for longitudinal and 96.2% for radial parameters. The reliability of longitudinal and circumferential deformation parameters was good, but radial parameters were less reliable. 4CH mean (SD) global peak systolic longitudinal and radial strain (%) and strain rate (s(-1)) were -18.7(2.6), -1.73(0.28), 23.6(9.1) and 1.94(0.65), and SAX circumferential and radial strain and strain rate were -19.5(3.7), -1.97(0.46), 32.1(14.4) and 2.37(0.80). CONCLUSION STE is feasible in preterm infants. Optimal image acquisition is paramount. Longitudinal parameters in 4CH and circumferential in SAX were most robust.

Transitional hemodynamics in preterm infants with a respiratory management strategy directed at avoidance of mechanical ventilation.

BACKGROUND Early respiratory management of very low birth weight infants has changed over recent years to a practice of early use of CPAP with early selective surfactant administration, and decreased use of mechanical ventilation. One strategy is to use the combination of surfactant and prompt extubation to nasal continuous positive airway pressure (INtubate, SURfactant, Extubate, or INSURE). The aim of this study is to describe blood flow and ductal flow in a prospective cohort during the transitional period when this respiratory management strategy is used. METHODS Inborn infants <29week gestation underwent INSURE within 30min of birth using 200mg/kg Curosurf. Blood pressure and blood flow parameters (RVO, LVO, SVC flow, ductus arteriosus) were measured at 6, 24 and 72h of age and information on morbidity was collected. RESULTS Sixty-eight infants with a median (range) weight of 940 (450-1380) g were studied. 13 (19%) patients needed mechanical ventilation within 72h of life (INSURE failure). Blood flows and blood pressure were within reported ranges. Eleven (16%) patients had a blood pressure <gestational age and 9 (13%) patients had low blood flow. CONCLUSION These data show a low prevalence of low blood pressure and low blood flow in the first 3days after INSURE as compared to cohorts where mechanical ventilation was preferred during transition. We speculate that altered ventilation strategies have helped decrease the incidence of low blood flow and low blood pressure.