Surfactant therapy guided by tests for lung maturity in preterm infants at risk of respiratory distress syndrome.

BACKGROUND: Administration of various exogenous surfactant preparations has been shown to decrease lung injury and pneumothorax and improve survival in very preterm infants with respiratory distress syndrome (RDS). There is no consensus on the threshold for surfactant administration, to allow timely intervention and avoid over-treatment, also considering the invasiveness of the procedure and its cost. Rapid tests for lung maturity, which include the click test, lamellar body counts and stable microbubble test, might guide the identification of those infants needing surfactant administration. OBJECTIVES: To assess the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants at risk for or having RDS. Comparison 1: In preterm infants at risk for RDS, does surfactant treatment guided by rapid tests for surfactant deficiency compared to prophylactic surfactant administration to all high-risk infants minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality? Comparison 2: In preterm infants who require early respiratory support, does surfactant treatment guided by rapid tests for surfactant deficiency compared to surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality? SEARCH METHODS: We searched in October 2022 CENTRAL, PubMed, Embase and three additional trial registries. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs evaluating rapid tests after birth for surfactant deficiency in infants at high risk of RDS or requiring respiratory support. We specified two comparisons: 1)surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high-risk infants in extremely preterm (less than 28 weeks' gestation) and very preterm (28 to 32 weeks' gestation); 2)surfactant treatment guided by rapid tests for surfactant deficiency versus surfactant therapy provided to preterm infants (less than 37 weeks' gestation) with RDS diagnosed on clinical and radiologic criteria. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) and risk difference (RD), with their 95% confidence intervals (CIs) for dichotomous data. Our primary outcomes were: neonatal mortality, mortality prior to hospital discharge, bronchopulmonary dysplasia and the composite outcome bronchopulmonary dysplasia or mortality. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included three RCTs enrolling 562 newborn infants in this review. No studies compared surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high-risk infants. Comparing surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge: RR 1.25, 95% CI 0.65 to 2.41, RD 0.01, 95% CI -0.03 to 0.05, 562 participants, 3 studies; I² for RR and RD = 75% and 43%, respectively; very low-certainty evidence. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia: RR 0.90, 95% CI 0.61 to 1.32, RD -0.02, 95% CI -0.08 to 0.04, 562 participants, 3 studies; I² for RR and RD = 0%; low-certainty evidence. No studies reported the composite outcome bronchopulmonary dysplasia or mortality. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in surfactant utilization (RR 0.97, 95% CI 0.85 to 1.11, RD -0.02, 95% CI -0.10 to 0.06, 562 participants, 3 studies, I² for RR and RD = 63% and 65%, respectively, low-certainty evidence), and any pneumothorax (RR 0.53, 95% CI 0.15 to 1.92, RD -0.01, 95% CI -0.04 to 0.01, 506 participants, 2 studies, I² for RR and RD = 0%, low-certainty evidence) compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported moderate to severe neurodevelopmental impairment. We identified two large ongoing RCTs. AUTHORS' CONCLUSIONS: No studies compared surfactant treatment guided by rapid tests for surfactant deficiency to prophylactic surfactant administration to all high-risk infants. Low to very low-certainty evidence from three studies is available on surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality, the composite outcome 'bronchopulmonary dysplasia or mortality', or neurodevelopmental outcomes. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia, surfactant utilization and any pneumothorax. The findings of the two large ongoing trials identified in this review are likely to have an important impact on establishing the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants.

Opioids for procedural pain in neonates.

BACKGROUND: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. OBJECTIVES: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence): with one study reporting a concerning increase in severe apnea (RR 7.44, 95% CI 0.42 to 132.95; 31 participants, 1 study; very low-certainty). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). AUTHORS' CONCLUSIONS: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. The evidence is very uncertain about the effect of opioids on episodes of bradycardia, hypotension or severe apnea. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

Opioids for procedural pain in neonates.

BACKGROUND: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. OBJECTIVES: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). AUTHORS' CONCLUSIONS: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. No studies reported if any harms occurred. The evidence is very uncertain about the effect of opioids on episodes of bradycardia or hypotension. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

Cooling strategies during neonatal transport for hypoxic-ischaemic encephalopathy.

AIM: We reviewed the literature on cooling methods during transport of newborn infants with hypoxic-ischaemic encephalopathy (HIE) born in a non-tertiary centre and transferred to a neonatal intensive care unit for therapeutic hypothermia. METHODS: The electronic databases CENTRAL, MEDLINE, Embase, CINAHL, and Scopus were searched from inception up to 8 March 2022 for studies comparing cooling versus no cooling, active versus passive cooling, and servo-controlled versus non-servo-controlled cooling. Odds ratio and confidence of interval were calculated for dichotomous outcomes and mean difference and confidence interval for continuous outcomes. RESULTS: The final analysis included 14 studies, 1 randomised and 13 non-randomised, involving 1098 newborn infants. Compared with the other cooling methods, servo-controlled active cooling was more likely to maintain body temperature within the target range of 33°C-34°C on arrival at a neonatal intensive care unit: odds ratio 13.58, 95% confidence interval 4.32-42.66, risk difference 0.33, 95% confidence interval 0.19-0.46; 224 participants; three studies; I2 0%. The certainty of evidence was low. Only five studies reported mortality rates. CONCLUSION: Servo-controlled active cooling may be the preferred method during transport of newborn infants with HIE. A future area of focus should be long-term neurodevelopmental outcomes after servo-controlled active cooling.

Antileukotrienes for the prevention and treatment of chronic lung disease in very preterm newborns: a systematic review.

BACKGROUND: Very preterm infants are at high risk of developing chronic lung disease, which requires respiratory support and might have long-term sequelae. As lung inflammation plays an important role in pathogenesis, antileukotrienes have been explored in both clinical and animal studies. We aimed to assess the benefits and harms of antileukotrienes for the prevention and treatment of respiratory morbidity and mortality in very preterm newborns. METHODS: In this systematic review, we included randomized trials and non-randomized studies in humans and animals reporting the effects of antileukotrienes in very preterm infants or other mammals within 10 days of birth. Our pre-specified primary outcomes were all-cause mortality and any harm, and, for the clinical studies, incidence of chronic lung disease. Included studies underwent risk of bias-assessment and data extraction performed by two authors independently. There were no language restrictions. RESULTS: Fifteen studies totally met our inclusion criteria: one randomized trial and four non-randomized studies in humans and 10 animal studies (five in rodents, two in lambs and one in either guinea pigs, rabbits or caprinae). All five clinical studies used montelukast and had a small sample size, ranging from 4 to 77 infants. The randomized trial (n = 60) found no difference in the incidence of chronic lung disease between the groups. Only one clinical study, which enrolled four very preterm infants and had a critical overall risk of bias, reported long-term outcomes. All other studies had unclear or greater overall risk of bias and meta-analyses were therefore deemed unfeasible. Eight of ten animal studies used leukotriene receptor antagonists as antileukotriene (montelukast in three of ten studies) and seven had an experimental study design (i.e. some animals were not exposed to antileukotrienes but no randomization). Three of the ten animal studies assessed different doses. Animal studies found no effect on the outcomes mortality, growth, or lung function related surrogate outcomes. CONCLUSIONS: Use of antileukotrienes in very preterm infants to prevent or treat chronic lung disease is not supported by the available evidence. Large randomized trials focusing on outcomes relevant to patients, including long-term outcomes, are needed. Studies should also minimize risk of bias.

Addressing harms of screening - A review of outcomes in Cochrane reviews and suggestions for next steps.

OBJECTIVE: To investigate if Cochrane reviews that assess screening interventions address their major harms. STUDY DESIGN AND SETTING: A systematic search for Cochrane reviews that assess screening interventions was performed. Two authors independently screened abstracts, assessed full-texts, and extracted data from included reviews. For each review, two authors judged whether each predefined harm was relevant. When the harm was judged as of questionable relevance, the review was excluded from the denominator in our calculations. RESULTS: Forty-seven reviews were included. Overdiagnosis was addressed in 6 of 39 (15%), overtreatment in 7 of 43 (16%), and psychosocial consequences in 30 of 47 (64%) of reviews where this was judged relevant. When data on harms were included, they were generally not treated with the same methodological rigor as the benefits, with no assessment of the risk of bias or certainty of the evidence. About half of the Abstracts, Plain Language Summaries, and Summary of Findings tables did not include any harms. CONCLUSION: The underreporting of harms of screening in Cochrane reviews likely reflects primary research and is problematic. We call for broad collaboration to develop reporting guidelines and core outcome sets for studies of screening interventions.

Accuracy of continuous glucose monitoring in preterm infants: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Continuous glucose monitoring (CGM) could be a valuable instrument for measurement of glucose concentration in preterm neonate. We undertook a systematic review and meta-analysis to compare the diagnostic accuracy of CGM devices to intermittent blood glucose evaluation methods for the detection of hypoglycaemic or hypoglycaemic events in preterm infants. DATA SOURCES: A structured electronic database search was performed for studies that assessed the accuracy of CGM against any intermittent blood glucose testing methods in detecting episodes of altered glycaemia in preterm infants. No restrictions were used. Three review authors screened records and included studies. DATA EXTRACTION: Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. From individual patient data (IPD), sensitivity and specificity were determined using predefined thresholds. The mean absolute relative difference (MARD) of the studied CGM devices was assessed and if those satisfied the accuracy requirements (EN ISO 15197). IPD datasets were meta-analysed using a logistic mixed-effects model. A bivariate model was used to estimate the summary receiver operating characteristic curve (ROC) curve and extract the area under the curve (AUC). The overall level of certainty of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Among 4481 records, 11 were included. IPD datasets were obtained for five studies. Only two of the studies showed an MARD lower than 10%, with none of the five CGM devices studied satisfying the European Union (EU) ISO 15197 requirements. Pooled sensitivity and specificity of CGM devices for hypoglycaemia were 0.39 and 0.99, whereas for hyperglycaemia were 0.87 and 0.99, respectively. The AUC was 0.70 and 0.86, respectively. The certainty of the evidence was considered as low to moderate. Limitations primarily related to the lack of representative population, reference standard and CGM device. CONCLUSIONS: CGM devices demonstrated low sensitivity for detecting hypoglycaemia in preterm infants, however, provided high accuracy for detection of hyperglycaemia. PROSPERO REGISTRATION NUMBER: CRD42020152248.