Analgesia and sedation in premature infants receiving invasive ventilation: a systematic scoping review.

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Fiona Moultrie, Xavier Durrmeyer, Gerbrich E. van den Bosch, Manon Tauzin, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5519389/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The purpose of this scoping review is to assess the risks and benefits of providing analgesic and sedative drugs to ventilated premature infants. We sourced primary empirical research reporting outcomes related to the use of pharmacological analgesics and sedatives in ventilated premature infants. We included articles published in any language in peer-reviewed journals before February 2024 from MEDLINE, Embase, Web of Science, Cochrane Library, and Google scholar databases. Morphine was the most studied drug (39 studies), followed by fentanyl (19 studies). Midazolam (8 studies) and dexmedetomidine (3 studies) were the most frequently studied sedatives. Analgesic efficacy was more consistently reported for fentanyl than morphine. The sedative effect of opioids was rarely assessed. Respiratory, cardiovascular, gastrointestinal, neurological and neurodevelopmental risks were unclear for all opioids. Alternative synthetic opioids and midazolam appear to be associated with significant risks in the absence of clear benefits. Dexmedetomidine shows encouraging but limited results and merits further investigation as an opioid-sparing adjunct. Overall, fentanyl appears to have the best efficacy and safety profile for analgosedation in this patient population. This scoping review will support clinicians in their analgosedative management of ventilated premature infants and identifies research gaps and priorities. pain pediatrics preterm infants ventilated analgesic sedation Figures Figure 1 Impact This systematic scoping review provides a comprehensive summary of the evidence of the risks and benefits of analgesics and sedatives in ventilated premature infants. Although morphine is the most extensively studied and used drug, its analgesic effect has been less consistently reported than that of fentanyl. Sedation has rarely been assessed and dexmedetomidine seems a promising sedative adjunct as midazolam use is not supported by evidence. Introduction Invasive mechanical ventilation has the potential to cause pain and distress 1 – 3 . Over the past decade, despite a dramatic increase in the use of non-invasive ventilation in neonatal care, the majority of very premature infants continue to receive mechanical ventilation during parts of their NICU stay: 84% of infants born before 29 weeks in the USA 4 and 98% of infants born before 28 weeks in the UK 5 . Given the cumulative evidence of pain in infants 6 , and growing concerns regarding the potential long-term neurodevelopmental effects of pain and distress in early life 7 , the provision of appropriate and effective analgesia and sedation is paramount. However, there is ongoing controversy regarding the use of analgesics and sedatives in the context of mechanical ventilation in premature infants 8 , 9 . As such, there is substantial variability, both within and between countries in the use of analgosedatives and their dosage in NICUs 10 , 11 . This is likely due to a lack of knowledge regarding effective analgesic doses, the optimal degree of sedation, and uncertainty regarding associated acute adverse effects and long-term safety, including negative neurodevelopmental effects 12 . A lack of consensus on the provision, type and dosage of analgosedatives will inevitably result in some premature infants enduring untreated pain or others experiencing adverse effects from unnecessary treatment, with both outcomes having potential long-term consequences 13 . Clinical decision-making requires a comprehensive understanding of the balance of benefits and risks of any potential treatment from the best available evidence. Therefore, the aim of this systematic scoping review was to identify which analgosedative drugs have been studied in ventilated premature infants and to objectively report their benefits and risks to guide future clinical management of this patient population and motivate further research. Methods Study design The protocol for this review was developed in accordance with the PRISMA-P 2015 guidelines and checklist 14 , and was publicly registered on 15th June 2022 on OSF, prior to data extraction ( https://doi.org/10.17605/OSF.IO/YNHGS ). This systematic scoping review aimed to assess the benefits and harms of pharmacological analgesics and sedatives used in premature neonates receiving invasive ventilation. We included all study designs from primary empirical research that were full peer-reviewed publications. A full list of eligibility criteria is provided in the Supplementary Information S.1. (Tables S1 and S2). Objectives We conducted this scoping review to report the short and long-term beneficial and harmful outcomes associated with the use of analgesics and sedatives during invasive ventilation in premature infants. We sought to examine the results in the context of doses and open-label treatments and to identify gaps in our knowledge and research priorities. Search strategy We searched five bibliographic databases to identify potentially relevant records on February 15th, 2022, with the assistance of an academic librarian: Embase (Embase.com), MEDLINE (Ovid Technologies, Inc), Web of Science Core Collection (Web of Knowledge), Cochrane Central Register of Controlled Trials (John Wiley & Sons), and the first 200 search results from Google Scholar (Publish or Perish). Additionally, we performed backward citation searching for all studies identified at the end of the screening process. The search was updated on February 12th, 2024. All search strategies are provided in full in the Supplementary Information S.2. Report selection Search results were curated and de-duplicated in EndNote and uploaded to EPPI-Reviewer Web 15 for review. Study selection was a two-stage process: screening on title and abstract followed by screening on full text. Screening was carried out in duplicate by two independent reviewers and disagreements settled by discussion between reviewers. Remaining disagreements were resolved by a third reviewer. To ensure standardized study selection process, an initial piloting stage was performed. Data extraction Due to the high volume of reports eligible for data extraction (n = 80), the data extraction process was distributed among five reviewers (n = 15–16 reports each). Each reviewer’s data extraction results were validated by a second reviewer. Any disagreements were settled by discussion between reviewers. To ensure a standardized data extraction process, an initial piloting stage was performed. The standardized data extraction form listing all extracted data items is available via OSF ( https://osf.io/xyjb4 ) and a summary of data items are listed in the Supplementary Information S.3. Results Summary of included studies Our bibliographic database search yielded 1766 records, with 593 duplicates. 1173 records were screened on title and abstract. 136 reports were sought for retrieval. 82 relevant studies were identified via full text screening; 75 in English, others in Chinese 16 , 17 , French 18 , 19 , Portuguese 20 and German 21 , 22 , translated for data extraction. Some articles 21 , 23 reported the same study, with considerable overlap of results. Therefore, only data from one 23 were considered in the review. Similarly, the same patients and data were reported by two articles 20 , 24 , therefore only data extracted from the later publication were included. The study selection process is outlined in Fig. 1 . Summary of characteristics of the 80 studies included is presented in Table 1. Studies were published between 1981 and 2023. Only 10% (n = 8) were conducted in the last five years. Most studies reported research conducted in Europe (n = 46; 57%). Others were based in North America (n = 12; 15%), Asia (n = 7; 9%), Australia (n = 4; 5%), and South America (n = 2; 3%). 10% of studies were international (n = 8); one study did not disclose a location 25 . Study designs were largely randomized controlled trials (RCTs), including 25 double-blind (31%), 5 open (6%), 1 pilot double-blind (1%) and 7 follow-up studies of RCTs (9%). The rest comprised of 19 cohort studies (24%), 15 case-control studies (19%), and eight case reports (10%). Most studies were primary (n = 52; 65%), monocentric (n = 56; 70%) and included only premature infants (n = 59; 74%). The most common study aims were assessment of analgesia and/or sedation (n = 25). Other aims included respiratory (n = 21), cardiovascular (n = 19), neurological (n = 19), stress hormone (n = 10), safety (n = 8), pharmacological (n = 7), gastrointestinal (n = 7), death (n = 3), and renal outcomes (n = 1). Many studies included a placebo group for comparison (29 of 55 studies that included a comparator group). The most frequently studied drugs were morphine (n = 34; 42%) and fentanyl (n = 16; 20%). Other studies investigated the effects of alternative synthetic opioids (n = 12; 15%) such as remifentanil, alfentanil, sufentanil, diamorphine, meperidine, or sedative agents (n = 13; 16%) including dexmedetomidine, lorazepam, midazolam, diazepam and phenobarbitone. Five studies included a mixture of narcotics and/or sedatives (n = 5; 6%). Sample sizes ranged from single case report studies to large observational case-control studies with 2672 patients 26 , and included infants as young as 22 weeks’ gestation 27 through to term. We have classified the studies by drug, reporting the results within the categories of morphine, fentanyl, other synthetic opioids, sedatives, and mixed studies of narcotics and/or sedatives. For each of these categories, we have summarized the significant benefits and risks reported (Tables 2–6). Characteristics of studies of morphine Morphine was studied in premature infants receiving mechanical ventilation in 39 studies: 12 primary RCTs, 13 secondary reports of RCTs, 7 cohort studies, 5 case-control studies and 2 case reports (Table 2). All studies were of intravenous administration except one 25 in which oral morphine was included. A loading dose was administered in 19 of the 23 primary studies, ranging widely between 25 and 200µg/kg. The most common loading dose was 100 µg/kg (12 studies). Continuous morphine was also administered in 16 primary studies at a rate ranging 5–100µg/kg/h. Only two primary studies used infusion rates greater than 30 µg/kg/h 28,29 , all of which were conducted in the 1990s. Six primary studies administered a maximum infusion rate of 10 µg/kg/h 16,30–34 , and 10–30 µg/kg/h was given in a further eight studies 25 , 35 – 41 . Five primary studies were open label, of which 4 were RCTs, and all but one study 36 provided specific doses of rescue medication. Most studies compared morphine solely to a placebo (18/29) primary and secondary studies with comparator. Other comparisons included a control group (n = 3); fentanyl (n = 2); pancuronium (n = 1); pancuronium or placebo (n = 1); diamorphine (n = 1); midazolam (n = 1); midazolam or placebo (n = 1); remifentanil (n = 1); phenobarbitone (n = 1). Morphine: Analgosedation Eleven out of twelve primary studies assessed the analgesic efficacy of morphine and used a validated pain score. The most frequently used score was the Premature Infant Pain Profile (PIPP) (5/11 studies); three studies used multiple different pain scores. Only two studies assessed the reliability of this scoring. Two primary RCTs comparing morphine solely to placebo reported a reduction in pain scores 16 , 37 . Another RCT reported a significant but clinically irrelevant effect 42 . Three trials reported no difference 31 , 35 , 43 . Others reported no difference in analgesia compared to fentanyl 39 or to remifentanil 33 . Only four studies reported sedation as an outcome, three of which used COMFORT, a validated sedation score 15 , 30 , 33 , 35 . One RCT 16 compared sedation to placebo and reported a significant reduction in score. Another RCT 36 comparing morphine with midazolam and placebo found increased scores after stopping morphine. Two others found no difference when comparing morphine with remifentanil 33 or diamorphine 38 , although diamorphine induced quicker sedation. Morphine: risks Higher mortality was described in three (case control studies) 41 , 44 , 45 of 13 studies reporting mortality. One observational cohort study reported lower mortality in premature infants treated with standard morphine 34 , but RCTs could not confirm this finding. There was minimal evidence of adverse respiratory effects. Minor changes in ventilatory parameters were reported in a few studies (n = 4; negative changes in FiO 2 ; triggered breaths; functional residual capacity). Most studies reported no increase in duration of ventilation, and none reported an increase in pneumothoraces (5 placebo RCT; 2 other RCT) or bronchopulmonary dysplasia (4 placebo RCTs). There was also conflicting evidence of cardiovascular effects: three placebo RCTs reported no significant difference in blood pressure 16 , 30 , 35 , but two reported increase in hypotension 46 , 47 and one reported lower blood pressure after the loading dose 37 . In addition, there was no reported difference in blood pressure compared to fentanyl 39 , pancuronium 29 or remifentanil 33 . Compared to diamorphine, lower blood pressure was reported after a loading dose 38 . Studies reported no difference in heart rate or patent ductus arteriosus. Minimal evidence of adverse neurological effects of morphine was observed. Of the 12 RCTs that reported the incidence of intraventricular hemorrhage (IVH), only one placebo RCT reported an increase in IVH and this was specifically in infants born at 27–29 weeks of gestation 37 . In this trial an increase in combined outcome of IVH/PVL (Periventricular leukomalacia)/death associated with use of open label morphine was identified. One study reported increased cerebral blood volume after morphine administration 32 . Long-term neurological outcomes were assessed between 5–8 years in four RCT follow-up studies 48 – 51 , which reported no difference in IQ, neuropsychological functioning or thermal detection and pain thresholds. An association between opioid exposure and brain volume was reported in one study 51 . Consistent with other studies beyond the scope of this review, suppression of brain activity, characterized by an increase in burst interval on amplitude-integrated EEG, was reported in one study compared to no sedation 44 . There was mixed evidence of gastrointestinal effects of morphine. Of the studies that reported gastrointestinal outcomes, three reported an increased time to feed 34 , 37 , 52 but three reported no difference 36 , 39 , 53 . Of six studies reporting necrotizing enterocolitis (NEC) as an outcome measure, none reported an increase associated with morphine administration 16 , 34 , 39 , 47 , 52 , 54 . Lastly, there was no evidence of an effect of morphine on sepsis (2 RCTs, 2 case control studies). Urinary retention was reported in one case report 25 , while one cohort study and two RCTs did not find an increased risk 37 , 39 , 54 . Morphine benefits Apart from potential analgosedative effects, no major clinically relevant benefits were reported for morphine. One RCT observed increased mechanical ventilator synchrony in infants treated with morphine compared to placebo 30 . Four RCTs reported stress hormone outcomes. Only one study was placebo-controlled and it only reported a significant reduction in noradrenaline 47 . Two other RCTs reported a significant reduction in noradrenaline compared to pancuronium 29 and diamorphine 38 . Characteristics of studies of fentanyl Fentanyl was the second most studied drug for analgosedation in ventilated preterm infants (Table 3). Seventeen studies were identified including nine RCTs (8 primary) 24 , 27 , 39 , 55 – 59 , two cohort studies 23 , 60 , three case-control studies 41 , 61 , 62 and three case reports 18 , 19 , 63 . Fentanyl was administered intravenously in all studies. A loading dose was given in 11 primary studies, ranging from 1 to 12.5 µg/kg. A continuous infusion was administered in 13 primary studies, ranging from 0.5 to 2 µg/kg/h. The most common infusion rate was ~ 1 µg/kg/h. Only 1 study was open label 27 , 58 . Most trials were placebo controlled RCTs (7 trials and one follow-up). Other comparators included bolus versus continuous administration 64 , low or no dose 61 , morphine 41 , midazolam/pentobarbital 23 and dexmedetomidine 62 . Fentanyl: Analgosedation Nine studies assessed the analgesic efficacy of fentanyl. Six used a validated clinical pain score. The PIPP score was most frequently used (4/6 studies 17 , 27 , 41 , 57 ). Three studies reported multiple different pain scores 24 , 27 , 64 . Three placebo RCTs reported significantly lower PIPP scores with fentanyl 27 , 57 , 59 ; one reported no difference using the Neonatal Facial Coding System 24 . One cohort study reported higher PIPP scores with fentanyl compared to morphine 41 . Four studies reported sedation or adjunctive sedative use as an outcome. One placebo-controlled trial reported lower non-validated sedation scores with fentanyl 56 , another reported low NPASS and NIPS scores with both continuous and bolus fentanyl administration 64 . One study reported decreased adjunctive sedation compared to morphine 23 , and another reported increased adjunctive sedation compared to dexmedetomidine 62 . Fentanyl: additional benefits and risks There was no increase in mortality with fentanyl administration in the three placebo RCTs that reported this outcome. There was no clear evidence of respiratory adverse effects. Two placebo RCTs reported increased ventilatory parameters with fentanyl 27 , 55 whereas two reported no increase 24 , 56 . Three placebo RCTs reported no difference in the duration of mechanical ventilation 27 , 39 , 56 ; one trial reported slower weaning 55 . A cohort study reported increased duration of ventilation compared to dexmedetomidine 62 . Three placebo RCTs reported no difference in oxygenation 24 , 56 , 59 ; three found no difference in the development of bronchopulmonary dysplasia 27 , 55 , 56 . There was no evidence of decreased blood pressure in five placebo RCTs 24 , 27 , 39 , 55 , 59 , 64 or two observational studies 23 , 62 , and no difference in vasoactive treatment use in three placebo RCTs 27 , 39 , 55 . Additionally, three placebo RCTs reported no difference in patent ductus arteriosus 27 , 55 , 56 . Three placebo RCTs reported a decrease in heart rate that remained within the normal range 24 , 55 , 59 . Fentanyl was not associated with increased time to feeding (3 placebo RCTs 27 , 39 , 56 ), sepsis (2 placebo RCTs 39 , 55 ), urinary retention (2 placebo RCTs 27 , 39 ) or risk of withdrawal (2 placebo RCTs 54 , 56 , 1 cohort study 23 ). Withdrawal was less frequent with fentanyl than with morphine in one observational study 41 , but more frequent than with dexmedetomidine in another 62 . Three placebo RCTs reported differences in stress-related hormones 24 , 39 , 55 . There was no evidence of neurological adverse effects of fentanyl. All four placebo RCTs reporting IVH found no significant difference 27 , 39 , 55 , 56 . In terms of neurodevelopmental outcomes, one RCT follow-up study reported a significant reduction in hand and eye coordination scores but not in developmental quotient after adjusting for confounders at 24 months 58 . Another RCT found no difference between fentanyl and placebo for mental developmental index (MDI) and psychomotor developmental index (PDI) at 3, 6, 9 and 12 months of age 59 . A case-control study reported no significant impact of cumulated fentanyl dose on Bayley III composite scores at this age after adjusting for confounders 61 . Studies of other synthetic opioids A variety of synthetic opioids were studied in premature infants receiving mechanical ventilation, including remifentanil (4 studies); diamorphine (3 studies); alfentanil (3 studies); sufentanil (2 studies); and meperidine (1 study). This included five RCTs (all of which were primary), six cohort studies, one case-control study and one case report (Table 4). There were only two placebo-controlled trials, one of meperidine 65 and one of alfentanil 66 . All synthetic opioids were administered intravenously with infusion rates ranging as follows for different drugs: remifentanil 0.075–0.94 µg/kg/h; diamorphine 15 µg/kg/h; alfentanil 10–20µg/kg loading dose; sufentanil 0.05-1 µg/kg/h. Synthetic opioids: analgosedation There was no clear evidence of analgesic efficacy among synthetic opioids. A pain score was reported in eight studies but only three studies of remifentanil used validated pain scores (NIPS and COMFORT 33 , 53 , 67 ), including a RCT comparing remifentanil to morphine 33 , which found no significant difference in effects, a cohort study 67 that reported reduction in pain score 1-hour post-administration, and a case report 53 . One study used meperidine, a RCT which reported significant difference in an unvalidated pain score compared to placebo 65 . None of the studies of alfentanil 66 , 68 , 69 or sufentanil 22 , 70 assessed analgesia or sedation with a validated score. No studies of diamorphine assessed analgesia. One RCT assessed sedation with an unvalidated score and did not find a difference in sedation compared to morphine over 24 hours 38 , but reported reduced time to sedation with diamorphine. Limited evidence was available on the sedative effect of synthetic opioids. Only three studies assessed sedation, two using COMFORT 33 , 67 , a validated score, to assess the effect of remifentanil. One RCT reported no difference in sedation compared to morphine 33 and a cohort study reported deep sedation in all patients 67 . Synthetic opioids: additional benefits and risks There is very little evidence for the added benefits or risks of remifentanil. In a RCT with morphine, remifentanil administration was associated with increased mean airway pressures but reduced time to extubation 33 . There was also no difference in blood pressure or time to feed compared to morphine. No significant harms were reported. However, they did report infants developing respiratory depression 22 , hypoxaemia 69 , severe muscle rigidity 66 , 69 and thoracic rigidity 22 . They also reported an increased incidence of IVH in infants who received diamorphine 38 . In a RCT of high and low dose diamorphine, 2/14 infants who received high dose required resuscitation after receiving the loading dose 71 . There were no significant changes in arterial blood pressure, heart rate, plasma-endorphin, cortisol, or glucose concentrations between meperidine and placebo 65 . Characteristics of studies of sedatives Several sedative agents have been studied in premature infants receiving mechanical ventilation (Table 5). The most frequently studied sedatives were midazolam (8 studies) and dexmedetomidine (3 studies). Other agents with single studies included phenobarbitone, lorazepam and diazepam. Midazolam was studied in 3 placebo RCTs, 1 RCT compared to morphine, 3 cohort studies and a case report. It was administered intravenously with an infusion loading dose ranging 100–200 µg, and continuous infusion rates widely ranging 20–200µg/kg/h, with only one open label study 72 . Only two studies used a validated pain score; one was a placebo RCT that reported significantly lower PIPP scores with midazolam compared to placebo 36 . Four studies assessed sedation with midazolam; only one used a validated score. There was no difference in COMFORT scores following drug administration 36 . Studies of dexmedetomidine included 1 case-control comparison to fentanyl, 1 dose-escalation trial and a case report. Dexmedetomidine was administered intravenously with an infusion loading dose ranging 0.05–0.5 µg and continuous infusion rates of 0.05–1.2µg/kg/h. Only one study was open label 62 . The primary endpoint of both the dose escalation trial and case-control study with fentanyl was the need for rescue sedation. In the dose escalation trial, premature infants were adequately sedated at all doses (based on NPASS scores and clinical judgement) and did not require additional sedatives 73 . However, some infants (17%) did require administration of rescue analgesia. In the study comparing dexmedetomidine to fentanyl, significantly less rescue sedation and analgesia was required in patients who received dexmedetomidine 62 . Sedatives: additional benefits and risks There was little evidence of neurological effects with no difference in PVL and IVH in the three placebo RCTs 36 , 74 , 75 and two observational studies 72 , 76 . However, one RCT reported an increased risk of combined IVH, PVL or death in the midazolam group compared to morphine, but no difference in Neurobehavioral Assessment of the Preterm (NAPI) scores at 36 weeks 36 . One RCT 32 and one cohort study 76 also reported decrease in cerebral blood flow with midazolam. There was no evidence of an effect of midazolam on gastrointestinal outcomes, sepsis, withdrawal and mortality, but very few studies reported these outcomes (see table). There was no clear evidence of respiratory effects of midazolam. The three placebo RCTs reported no significant difference in mechanical ventilation duration 36 , 74 , 75 , O 2 duration 74 or ventilation parameters 74 , 75 . One case-control study reported increased duration of mechanical ventilation 72 . One placebo RCT 74 , one RCT comparing midazolam to morphine 32 and three cohort studies 76 – 78 reported a lower BP and hypotension in the midazolam group. One placebo RCT did not find this difference in BP 75 . There was mixed evidence of an effect on heart rate, with one placebo RCT 74 and two cohort studies 77 , 78 reporting reduction, whereas two RCTs 32 , 75 and two cohort studies 76 , 79 did not find a difference with midazolam. For dexmedetomidine, there was very little data for added benefits and risks. In the dose escalation study, an average decrease in heart rate and blood pressure values was described and one case of diastolic hypotension was reported, none of which required intervention 73 . In the case control study with fentanyl as comparison, shorter duration of mechanical ventilation, shorter time to full feeds and a decrease in culture positive sepsis were reported 62 . Studies of mixed narcotics/sedatives We also identified studies of mixed narcotics and/or sedatives including four case-control studies and one propensity score matched cohort study (Table 6). These large studies (two retrospective and three prospective) provide an insight into outcomes related to the use of narcotics and/or sedatives versus non-exposed patients. None of them reported on analgesic or sedative efficacy of these drugs. Four studies reported on duration of mechanical ventilation, with no differences between treated or non-treated patients in two 80 , 81 and an increased duration of mechanical ventilation in treated groups in the remaining 26 , 82 . Only one study reported on cardiovascular outcomes with no difference in heart rate and blood pressure 81 . 3/4 studies reported an increased incidence of severe IVH in treated groups 26 , 81 , 82 , and one, an increased incidence of severe ROP 26 . One study reported no difference in survival without moderate to severe neurological disabilities at 2 years 80 . A higher incidence of death was reported by two studies 26 , 82 ; another study reported the opposite 80 . These conflicting results likely reflect various designs, drugs and adjustments in these observational studies. Discussion We undertook a systematic scoping review of the analgosedative agents studied in premature infants receiving mechanical ventilation to explore the benefits and risks associated with their use. Morphine, fentanyl, a variety of other synthetic opioids, and a selection of sedatives including midazolam and dexmedetomidine have been studied in this clinical context. Here, we discuss the overall benefits and risks reported for each of these drugs, identify associated gaps in our knowledge, and recommend priorities for future research. Morphine is the most studied drug for analgosedation in ventilated preterm infants (39 studies in three decades), but its efficacy in terms of analgesia and sedation remain unclear. Morphine is considered a standard for analgosedation in children and adults; these findings lead us to question whether morphine is not as effective in this patient population, or in the way it has been tested. All nine primary placebo RCTs identified in this review were conducted prior to 2014. Despite conflicting results of efficacy, over the past decade the focus has shifted to observational drug or dosing regimen comparisons and follow-up studies of the primary RCTs. Dosage of both loading boluses and continuous infusions of morphine have ranged broadly across studies. However, high doses (> 100 µg/kg loading) have been particularly used in RCTs involving drug-drug comparisons, such as morphine and diamorphine 38 , and morphine and remifentanil 33 . Interestingly, studies which reported positive analgesic efficacy results were not studies administering the highest doses. The variability in dosage likely reflects the lack of appropriate dose-finding studies in this patient population. Furthermore, half of the placebo RCTs of morphine included open-label administration of rescue opioids complicating the assessment of analgesic efficacy. Rescue medication is an ethical imperative as infants who appear in pain cannot be ignored by the clinician. However, this non-randomized intervention can have a significant impact on the results of a trial. The administration of rescue morphine to infants receiving placebo has created an ‘as needed’ group comparison, reducing the chance of identifying a significant difference in analgesic efficacy. Equally, the administration of rescue medication to a significant proportion of infants in the morphine treatment group in several studies suggests that the drug was not providing adequate pain relief 31 , 37 . Studies of morphine which reported pain outcomes used validated scores for premature infants such as PIPP, COMFORT and NIPS. However, only two studies reported the reliability of their assessments. Given the subjective nature of these scales, adequate training, use of multiple raters, and reporting of inter- and intra-rater reliability should be conducted as standard. All studies but one 16 assessed acute pain in response to tracheal suctioning. Interestingly, this placebo RCT measured continuous pain (in the absence of suction) using a validated scale for premature infants (COMFORT) and reported a significant reduction in pain at two and twelve hours 16 . Tracheal suctioning is a common painful 83 procedure in NICU but given that variability in catheter size, pressure, depth, duration, and indication could potentially impact the distress and physiological instability caused by the procedure 84 , we should question whether this non-standardized procedure is the optimal way to test analgesia during mechanical ventilation. There is minimal data suggesting morphine causes significant respiratory or cardiovascular adverse effects in ventilated premature infants. Some data indicated a prolonged time to establish enteral feeding 37 , 52 , which could have an impact on the postnatal functional adaptation of the gut, its microbial colonisation 85 and infectious complications due to prolongation of parenteral nutrition 86 . There were no reports of an increased incidence of NEC or sepsis. A potential increase in mortality was only reported in case-control studies. There were also no major neurological effects, except in extremely premature infants (27–29 GA), in whom intermittent boluses may be associated with an increased risk of IVH/PVL/death 37 . Data from follow-up studies of RCTs, do not indicate long-term effects of morphine on cognitive development. However, a growing body of literature regarding the effects of cumulative morphine exposure during neonatal hospitalization, beyond the scope of this review, notably provides concerning evidence of potential long-term neurodevelopmental effects 87 . Overall, it is difficult to identify clear benefits or risks of routine morphine administration in ventilated premature infants. Fentanyl, the second most studied drug in ventilated premature infants, reported positive analgesic efficacy, with three of four placebo-controlled trials using validated pain scores reporting significantly lower scores following administration. However, there is little data regarding the sedative effect of fentanyl, as no placebo RCTs assessed this outcome. One study comparing bolus and continuous administration of fentanyl reported deep sedation in their participants using NPASS 64 . Considering fentanyl is significantly more potent than morphine (50-100x) and the impact of prolonged deep sedation on the developing brain is unknown, optimal degree of sedation should be investigated in future studies. One observational cohort study compared fentanyl to morphine, but the authors used an unconventional method of assessing analgesic efficacy, limiting its utility 41 . There is some data to suggest that an increase in ventilatory parameters may be required following administration 27 , 55 but one of these studies used a larger loading dose 55 . Reassuringly, multiple placebo RCTs reported no associated increase in the duration of mechanical ventilation. Given current concerns over potential neurological effects of opioids, it is also reassuring to note that there was no increase in IVH in the placebo RCTs which reported this outcome. However, the only RCT that assessed later neurodevelopmental outcomes reports a poorer performance in tests of coordination and cognition at 24 months in infants who received fentanyl 58 . Further research is needed to address optimal dosing and long-term safety of fentanyl in premature infants, particularly in infants requiring prolonged periods of mechanical ventilation. The rapid development of tolerance is a significant issue 88 , which has not yet been addressed in this patient population and unfortunately may considerably limit its prolonged use in practice. Other highly potent synthetic opioids such as remifentanil, alfentanil and sufentanil have also been studied in preterm ventilated infants. There is limited data to assess their efficacy in this population, and no placebo-controlled trials employing a validated score to determine analgesic or sedative efficacy. The risks associated with their administration, which included reports of severe muscle rigidity and respiratory depression, clearly outweigh any potential benefits. Notably, all studies were conducted prior to 2010, and further investigations have not been undertaken likely due to the considerable risks reported. However, remifentanil and sufentanil have been studied more recently for analgosedation in term infants and in the context of surgical anesthesia and procedural analgesia, and chest wall rigidity appears to be a common and limiting adverse effect 89 – 91 . Midazolam and dexmedetomidine are sedatives which have been most studied in ventilated premature infants. Given their classification as sedative drugs, it is surprising that only one RCT has assessed the sedative efficacy of midazolam in ventilated premature infants using a validated score (COMFORT), and it did not demonstrate any sedative effect 36 . In animal models the sedative effect of midazolam is not observed until maturation of supraspinal centers; paradoxical excitation has been reported in young rats 92 , calling into question the potential efficacy of this drug in premature infants. Clinical data on midazolam in premature infants also raise concerns over the cardiovascular and neurological effects of the benzodiazepine including hypotension, decreased cerebral blood flow, myoclonus and increased risk of combined death/IVH/PVL in extremely premature infants. Until recently, midazolam was the most frequently used sedative in NICUs 10 . However, with pre-clinical studies describing neuroapoptotic effects 93 , 94 and clinical studies reporting potential harmful neurodevelopmental effects 95 , 96 , there has been a reduction in the use of midazolam, with some countries introducing dexmedetomidine in its place 97 , 98 . Dexmedetomidine is a highly selective, centrally-acting α2 adrenergic agonist, more commonly used for sedation in older children 99 . Although there are no randomized clinical trials of dexmedetomidine in ventilated preterm infants, a stepwise dose-escalation trial of dexmedetomidine provides promising initial results in this population 73 . None of the premature infants in the study required rescue sedative medication at any drug dose level tested, as determined by NPASS scoring/clinical judgement. However, some infants (3/18) did require administration of fentanyl as rescue analgesia. Dexmedetomidine has potential opioid sparing properties and could be efficacious as an adjunct, maximizing the efficacy of analgosedation whilst minimizing adverse effects. Encouragingly, unlike midazolam, pre-clinical data also suggest that this sedative may have neuroprotective effects 100 , which merit further investigation in clinical trials with long-term follow-up. In summary, we have provided an overview of the data available from studies of analgosedatives in ventilated premature infants. Overall, fentanyl appears to have the best efficacy and safety profile for analgosedation in this patient population, with a positive balance of benefits and risks. The data for morphine is less clear. Alternative synthetic opioids and midazolam are associated with significant risks in the absence of clear benefits. Dexmedetomidine may hold early promise as an opioid-sparing adjunct sedative, meriting further investigation. These results are clearly limited by the scoping nature of the review and a subsequent full systematic review with risk of bias assessment could yield further detailed conclusions. The provision of analgosedation varies greatly worldwide and is no longer routinely administered to ventilated premature infants. Only ~ 20% of units surveyed in a recent global, prospective, cross-sectional study administer analgosedatives in more than 80% of these patients. Although opioids remain the most frequently administered agents, fentanyl use has now overtaken morphine use overall 103 , which is encouraging given the data reviewed here. However, in England and Wales, although the use of fentanyl has increased, it remains significantly less frequently administered than morphine (fentanyl 18% vs morphine 60% of premature infants born < 32 weeks) 82 .Despite NICE guidance more than half of UK units continue to routinely give morphine 104 . Further research is required to fully establish the optimal use of fentanyl and the longer-term effects of repeated administration during extended periods of mechanical ventilation. All studies identified in this review investigated the use of pre-emptive analgosedation. Guidelines are increasingly recommending the administration of analgosedatives only ‘as required’ based on cot-side assessment of pain and sedation 105 . This is complicated by challenges posed by inconsistent and subjective assessment of pain and distress using behaviorally focused scores. Encouragingly, most studies that used non-validated pain scores were conducted prior to 2000. Novel studies of responsive administration of analgosedatives are now needed in premature infants to justify this emerging approach to analgosedation. The rigorous use of validated objective developmentally appropriate assessments of pain will be essential In conclusion, based on the current data, fentanyl appears to have the most favorable efficacy and safety profile compared to morphine for use in ventilated preterm infants. Further comparative trials of responsive administration using optimal drug doses, adjunctive sedatives and long-term neurodevelopmental follow-up are needed to determine the best approach to analgosedation in this patient population. Declarations Data availability The datasets generated and analyzed during the current review are available from the corresponding author on reasonable request. Acknowledgments The authors wish to thank Dr. Maarten F.M. Engel, biomedical information specialist from the Medical Library of the Erasmus MC Rotterdam, the Netherlands for developing and updating the search strategies. Funding No financial assistance was received in support of the study. RS is funded by a Senior Wellcome Research Fellowship (207457/Z/17/Z). Author contributions Substantial contributions to conception and design (XD, RS, FM, GvdB, MT, MC, LB, AB, JMR, SS); acquisition of data or analysis and interpretation of data (FM,XD, GvdB, MT, JMR, MMC, AB, EO); Drafting the article or revising it critically for important intellectual content (FM, XD, MT, GvdB, JMR, SS, LB); Final approval of the version to be published (all authors). Competing interests The authors declare no conflict of interest. Consent statement Patient consent was not required. References Aranda JV et al (2005) Analgesia and sedation during mechanical ventilation in neonates. Clin Ther 27:877–899 Topulos GP, Lansing RW, Banzett RB (1993) The experience of complete neuromuscular blockade in awake humans. J Clin Anesth 5:369–374 Gélinas C, Fortier M, Viens C, Fillion L, Puntillo K (2004) Pain Assessment and Management in Critically Ill Intubated Patients: a Retrospective Study. 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Arch Dis Child Fetal Neonatal Ed fetalneonatal-2024-327458 10.1136/archdischild-2024-327458 Ancora G et al (2019) Evidence-based clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation. Acta Paediatr 108:208–217 Tables Tables 1 to 6 are available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Analgosedationsupplement.docx Supplementary Information - Analgesic and sedation practices in premature infants receiving invasive ventilation: a systematic scoping review Analgosedationtables.docx Tables - Analgesic and sedation practices in premature infants receiving invasive ventilation: a systematic scoping review Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5519389","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":382274957,"identity":"d31cde0c-fe99-41b1-bd88-9c0044c603f8","order_by":0,"name":"Fiona Moultrie","email":"","orcid":"","institution":"Department of Paediatrics, University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Fiona","middleName":"","lastName":"Moultrie","suffix":""},{"id":382274958,"identity":"639f76f9-c69a-45b2-ba49-22491022bb71","order_by":1,"name":"Xavier Durrmeyer","email":"","orcid":"","institution":"Centre Hospitalier Intercommunal de Créteil, Créteil, France; Faculté de Médecine de Créteil, Université Paris Est Créteil","correspondingAuthor":false,"prefix":"","firstName":"Xavier","middleName":"","lastName":"Durrmeyer","suffix":""},{"id":382274959,"identity":"cfab12ad-03cd-4663-a5e3-5e835d780c6b","order_by":2,"name":"Gerbrich E. van den Bosch","email":"","orcid":"","institution":"Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children’s Hospital, Rotterdam, the Netherlands","correspondingAuthor":false,"prefix":"","firstName":"Gerbrich","middleName":"E. van den","lastName":"Bosch","suffix":""},{"id":382274960,"identity":"9e94aab5-5fc3-4b5f-a278-193f29fd9d95","order_by":3,"name":"Manon Tauzin","email":"","orcid":"","institution":"Centre Hospitalier Intercommunal de Créteil, Créteil, France","correspondingAuthor":false,"prefix":"","firstName":"Manon","middleName":"","lastName":"Tauzin","suffix":""},{"id":382274961,"identity":"9d2eefa3-2198-44c2-82c8-561b121524e4","order_by":4,"name":"Jean Michel Roué","email":"","orcid":"","institution":"Department of Neonatal and Pediatric Critical Care, Brest University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jean","middleName":"Michel","lastName":"Roué","suffix":""},{"id":382274962,"identity":"6f6f7bfa-7f37-4380-98f1-206da6985d8d","order_by":5,"name":"Emma Olsson","email":"","orcid":"","institution":"Faculty of Medicine and Health, School of Health Sciences, Örebro University","correspondingAuthor":false,"prefix":"","firstName":"Emma","middleName":"","lastName":"Olsson","suffix":""},{"id":382274963,"identity":"4407bedf-a820-4a68-acaf-da4f17524dde","order_by":6,"name":"Maria M Cobo","email":"","orcid":"","institution":"Department of Paediatrics, University of Oxford; Colegio de Ciencias Biologicas y Ambientales, Universidad San Francisco de Quito USFQ","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"M","lastName":"Cobo","suffix":""},{"id":382274964,"identity":"55a9df8c-b78d-4575-ba16-9d0921c58aff","order_by":7,"name":"Luke Baxter","email":"","orcid":"","institution":"Department of Paediatrics, University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Luke","middleName":"","lastName":"Baxter","suffix":""},{"id":382282820,"identity":"4198c328-e9a5-4870-acbf-7e5e968aaff7","order_by":8,"name":"Samyuktha Iyer","email":"","orcid":"","institution":"Department of Paediatrics, University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Samyuktha","middleName":"","lastName":"Iyer","suffix":""},{"id":382274965,"identity":"9c7caed0-d862-4f33-8322-12662a0e3531","order_by":9,"name":"Aomesh Bhatt","email":"","orcid":"","institution":"Department of Paediatrics, University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Aomesh","middleName":"","lastName":"Bhatt","suffix":""},{"id":382274966,"identity":"7dba15bb-8053-4973-9d0c-da44bf0c6fb1","order_by":10,"name":"Sinno H.P. Simons","email":"","orcid":"","institution":"Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, the Netherlands","correspondingAuthor":false,"prefix":"","firstName":"Sinno","middleName":"H.P.","lastName":"Simons","suffix":""},{"id":382274967,"identity":"5d0f5302-0e40-416d-884d-80a62868726a","order_by":11,"name":"Rebeccah Slater","email":"data:image/png;base64,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","orcid":"","institution":"Department of Paediatrics, University of Oxford","correspondingAuthor":true,"prefix":"","firstName":"Rebeccah","middleName":"","lastName":"Slater","suffix":""}],"badges":[],"createdAt":"2024-11-25 10:36:37","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5519389/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5519389/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70130552,"identity":"f6df3932-2c9c-4a71-a6c0-a44f59cdd62c","added_by":"auto","created_at":"2024-11-28 15:54:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23651,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA flow diagram.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"PRISMAflowdiagram.png","url":"https://assets-eu.researchsquare.com/files/rs-5519389/v1/c1189f5e7617e4d32f213e5a.png"},{"id":70132239,"identity":"43937b40-9164-467d-bcbd-b56648bcaa64","added_by":"auto","created_at":"2024-11-28 16:10:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":693784,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5519389/v1/2d206f1e-b639-448a-b7d7-9b84f4249034.pdf"},{"id":70130550,"identity":"d93fbd50-71ca-4a60-8f2f-c6c4125cf623","added_by":"auto","created_at":"2024-11-28 15:54:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34490,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Information - Analgesic and sedation practices in premature infants receiving invasive ventilation: a systematic scoping review\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Analgosedationsupplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-5519389/v1/cee989337d6d8623ad0beca8.docx"},{"id":70130558,"identity":"2aa4dc9a-4a9d-437b-8480-37095c269302","added_by":"auto","created_at":"2024-11-28 15:54:35","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2478615,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTables\u003c/strong\u003e - \u003cstrong\u003eAnalgesic and sedation practices in premature infants receiving invasive ventilation: a systematic scoping review\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Analgosedationtables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5519389/v1/08ef8bc3e9fcbb5ac7528e3a.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eAnalgesia and sedation in premature infants receiving invasive ventilation: a systematic scoping review.\u003c/p\u003e","fulltext":[{"header":"Impact","content":"\u003cul\u003e\n \u003cli\u003eThis systematic scoping review provides a comprehensive summary of the evidence of the risks and benefits of analgesics and sedatives in ventilated premature infants.\u003c/li\u003e\n \u003cli\u003eAlthough morphine is the most extensively studied and used drug, its analgesic effect has been less consistently reported than that of fentanyl.\u003c/li\u003e\n \u003cli\u003eSedation has rarely been assessed and dexmedetomidine seems a promising sedative adjunct as midazolam use is not supported by evidence.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eInvasive mechanical ventilation has the potential to cause pain and distress\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Over the past decade, despite a dramatic increase in the use of non-invasive ventilation in neonatal care, the majority of very premature infants continue to receive mechanical ventilation during parts of their NICU stay: 84% of infants born before 29 weeks in the USA\u003csup\u003e4\u003c/sup\u003e and 98% of infants born before 28 weeks in the UK\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Given the cumulative evidence of pain in infants\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, and growing concerns regarding the potential long-term neurodevelopmental effects of pain and distress in early life\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, the provision of appropriate and effective analgesia and sedation is paramount. However, there is ongoing controversy regarding the use of analgesics and sedatives in the context of mechanical ventilation in premature infants\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. As such, there is substantial variability, both within and between countries in the use of analgosedatives and their dosage in NICUs\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. This is likely due to a lack of knowledge regarding effective analgesic doses, the optimal degree of sedation, and uncertainty regarding associated acute adverse effects and long-term safety, including negative neurodevelopmental effects\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA lack of consensus on the provision, type and dosage of analgosedatives will inevitably result in some premature infants enduring untreated pain or others experiencing adverse effects from unnecessary treatment, with both outcomes having potential long-term consequences\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Clinical decision-making requires a comprehensive understanding of the balance of benefits and risks of any potential treatment from the best available evidence. Therefore, the aim of this systematic scoping review was to identify which analgosedative drugs have been studied in ventilated premature infants and to objectively report their benefits and risks to guide future clinical management of this patient population and motivate further research.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe protocol for this review was developed in accordance with the PRISMA-P 2015 guidelines and checklist\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, and was publicly registered on 15th June 2022 on OSF, prior to data extraction (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.17605/OSF.IO/YNHGS\u003c/span\u003e\u003cspan address=\"10.17605/OSF.IO/YNHGS\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). This systematic scoping review aimed to assess the benefits and harms of pharmacological analgesics and sedatives used in premature neonates receiving invasive ventilation. We included all study designs from primary empirical research that were full peer-reviewed publications. A full list of eligibility criteria is provided in the Supplementary Information S.1. (Tables S1 and S2).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eObjectives\u003c/h3\u003e\n\u003cp\u003eWe conducted this scoping review to report the short and long-term beneficial and harmful outcomes associated with the use of analgesics and sedatives during invasive ventilation in premature infants. We sought to examine the results in the context of doses and open-label treatments and to identify gaps in our knowledge and research priorities.\u003c/p\u003e\n\u003ch3\u003eSearch strategy\u003c/h3\u003e\n\u003cp\u003eWe searched five bibliographic databases to identify potentially relevant records on February 15th, 2022, with the assistance of an academic librarian: Embase (Embase.com), MEDLINE (Ovid Technologies, Inc), Web of Science Core Collection (Web of Knowledge), Cochrane Central Register of Controlled Trials (John Wiley \u0026amp; Sons), and the first 200 search results from Google Scholar (Publish or Perish). Additionally, we performed backward citation searching for all studies identified at the end of the screening process. The search was updated on February 12th, 2024. All search strategies are provided in full in the Supplementary Information S.2.\u003c/p\u003e\n\u003ch3\u003eReport selection\u003c/h3\u003e\n\u003cp\u003eSearch results were curated and de-duplicated in EndNote and uploaded to EPPI-Reviewer Web\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e for review. Study selection was a two-stage process: screening on title and abstract followed by screening on full text. Screening was carried out in duplicate by two independent reviewers and disagreements settled by discussion between reviewers. Remaining disagreements were resolved by a third reviewer. To ensure standardized study selection process, an initial piloting stage was performed.\u003c/p\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eDue to the high volume of reports eligible for data extraction (n\u0026thinsp;=\u0026thinsp;80), the data extraction process was distributed among five reviewers (n\u0026thinsp;=\u0026thinsp;15\u0026ndash;16 reports each). Each reviewer\u0026rsquo;s data extraction results were validated by a second reviewer. Any disagreements were settled by discussion between reviewers. To ensure a standardized data extraction process, an initial piloting stage was performed. The standardized data extraction form listing all extracted data items is available via OSF (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://osf.io/xyjb4\u003c/span\u003e\u003cspan address=\"https://osf.io/xyjb4\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and a summary of data items are listed in the Supplementary Information S.3.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSummary of included studies\u003c/h2\u003e \u003cp\u003eOur bibliographic database search yielded 1766 records, with 593 duplicates. 1173 records were screened on title and abstract. 136 reports were sought for retrieval. 82 relevant studies were identified via full text screening; 75 in English, others in Chinese\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, French\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, Portuguese\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and German\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, translated for data extraction. Some articles\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e reported the same study, with considerable overlap of results. Therefore, only data from one\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e were considered in the review. Similarly, the same patients and data were reported by two articles\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, therefore only data extracted from the later publication were included. The study selection process is outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Summary of characteristics of the 80 studies included is presented in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eStudies were published between 1981 and 2023. Only 10% (n\u0026thinsp;=\u0026thinsp;8) were conducted in the last five years. Most studies reported research conducted in Europe (n\u0026thinsp;=\u0026thinsp;46; 57%). Others were based in North America (n\u0026thinsp;=\u0026thinsp;12; 15%), Asia (n\u0026thinsp;=\u0026thinsp;7; 9%), Australia (n\u0026thinsp;=\u0026thinsp;4; 5%), and South America (n\u0026thinsp;=\u0026thinsp;2; 3%). 10% of studies were international (n\u0026thinsp;=\u0026thinsp;8); one study did not disclose a location\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Study designs were largely randomized controlled trials (RCTs), including 25 double-blind (31%), 5 open (6%), 1 pilot double-blind (1%) and 7 follow-up studies of RCTs (9%). The rest comprised of 19 cohort studies (24%), 15 case-control studies (19%), and eight case reports (10%). Most studies were primary (n\u0026thinsp;=\u0026thinsp;52; 65%), monocentric (n\u0026thinsp;=\u0026thinsp;56; 70%) and included only premature infants (n\u0026thinsp;=\u0026thinsp;59; 74%). The most common study aims were assessment of analgesia and/or sedation (n\u0026thinsp;=\u0026thinsp;25). Other aims included respiratory (n\u0026thinsp;=\u0026thinsp;21), cardiovascular (n\u0026thinsp;=\u0026thinsp;19), neurological (n\u0026thinsp;=\u0026thinsp;19), stress hormone (n\u0026thinsp;=\u0026thinsp;10), safety (n\u0026thinsp;=\u0026thinsp;8), pharmacological (n\u0026thinsp;=\u0026thinsp;7), gastrointestinal (n\u0026thinsp;=\u0026thinsp;7), death (n\u0026thinsp;=\u0026thinsp;3), and renal outcomes (n\u0026thinsp;=\u0026thinsp;1). Many studies included a placebo group for comparison (29 of 55 studies that included a comparator group).\u003c/p\u003e \u003cp\u003eThe most frequently studied drugs were morphine (n\u0026thinsp;=\u0026thinsp;34; 42%) and fentanyl (n\u0026thinsp;=\u0026thinsp;16; 20%). Other studies investigated the effects of alternative synthetic opioids (n\u0026thinsp;=\u0026thinsp;12; 15%) such as remifentanil, alfentanil, sufentanil, diamorphine, meperidine, or sedative agents (n\u0026thinsp;=\u0026thinsp;13; 16%) including dexmedetomidine, lorazepam, midazolam, diazepam and phenobarbitone. Five studies included a mixture of narcotics and/or sedatives (n\u0026thinsp;=\u0026thinsp;5; 6%). Sample sizes ranged from single case report studies to large observational case-control studies with 2672 patients\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, and included infants as young as 22 weeks\u0026rsquo; gestation\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e through to term.\u003c/p\u003e \u003cp\u003eWe have classified the studies by drug, reporting the results within the categories of morphine, fentanyl, other synthetic opioids, sedatives, and mixed studies of narcotics and/or sedatives. For each of these categories, we have summarized the significant benefits and risks reported (Tables\u0026nbsp;2\u0026ndash;6).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCharacteristics of studies of morphine\u003c/h3\u003e\n\u003cp\u003eMorphine was studied in premature infants receiving mechanical ventilation in 39 studies: 12 primary RCTs, 13 secondary reports of RCTs, 7 cohort studies, 5 case-control studies and 2 case reports (Table\u0026nbsp;2). All studies were of intravenous administration except one\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e in which oral morphine was included. A loading dose was administered in 19 of the 23 primary studies, ranging widely between 25 and 200\u0026micro;g/kg. The most common loading dose was 100 \u0026micro;g/kg (12 studies). Continuous morphine was also administered in 16 primary studies at a rate ranging 5\u0026ndash;100\u0026micro;g/kg/h. Only two primary studies used infusion rates greater than 30 \u0026micro;g/kg/h\u003csup\u003e28,29\u003c/sup\u003e, all of which were conducted in the 1990s. Six primary studies administered a maximum infusion rate of 10 \u0026micro;g/kg/h\u003csup\u003e16,30\u0026ndash;34\u003c/sup\u003e, and 10\u0026ndash;30 \u0026micro;g/kg/h was given in a further eight studies\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan additionalcitationids=\"CR36 CR37 CR38 CR39 CR40\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Five primary studies were open label, of which 4 were RCTs, and all but one study\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e provided specific doses of rescue medication. Most studies compared morphine solely to a placebo (18/29) primary and secondary studies with comparator. Other comparisons included a control group (n\u0026thinsp;=\u0026thinsp;3); fentanyl (n\u0026thinsp;=\u0026thinsp;2); pancuronium (n\u0026thinsp;=\u0026thinsp;1); pancuronium or placebo (n\u0026thinsp;=\u0026thinsp;1); diamorphine (n\u0026thinsp;=\u0026thinsp;1); midazolam (n\u0026thinsp;=\u0026thinsp;1); midazolam or placebo (n\u0026thinsp;=\u0026thinsp;1); remifentanil (n\u0026thinsp;=\u0026thinsp;1); phenobarbitone (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMorphine: Analgosedation\u003c/h2\u003e \u003cp\u003eEleven out of twelve primary studies assessed the analgesic efficacy of morphine and used a validated pain score. The most frequently used score was the Premature Infant Pain Profile (PIPP) (5/11 studies); three studies used multiple different pain scores. Only two studies assessed the reliability of this scoring. Two primary RCTs comparing morphine solely to placebo reported a reduction in pain scores\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Another RCT reported a significant but clinically irrelevant effect\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Three trials reported no difference\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Others reported no difference in analgesia compared to fentanyl\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e or to remifentanil\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Only four studies reported sedation as an outcome, three of which used COMFORT, a validated sedation score\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. One RCT\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e compared sedation to placebo and reported a significant reduction in score. Another RCT\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e comparing morphine with midazolam and placebo found increased scores after stopping morphine. Two others found no difference when comparing morphine with remifentanil\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e or diamorphine\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, although diamorphine induced quicker sedation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMorphine: risks\u003c/h2\u003e \u003cp\u003eHigher mortality was described in three (case control studies)\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e of 13 studies reporting mortality. One observational cohort study reported lower mortality in premature infants treated with standard morphine\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, but RCTs could not confirm this finding.\u003c/p\u003e \u003cp\u003eThere was minimal evidence of adverse respiratory effects. Minor changes in ventilatory parameters were reported in a few studies (n\u0026thinsp;=\u0026thinsp;4; negative changes in FiO\u003csub\u003e2\u003c/sub\u003e; triggered breaths; functional residual capacity). Most studies reported no increase in duration of ventilation, and none reported an increase in pneumothoraces (5 placebo RCT; 2 other RCT) or bronchopulmonary dysplasia (4 placebo RCTs). There was also conflicting evidence of cardiovascular effects: three placebo RCTs reported no significant difference in blood pressure\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, but two reported increase in hypotension\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e and one reported lower blood pressure after the loading dose\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. In addition, there was no reported difference in blood pressure compared to fentanyl\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, pancuronium\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e or remifentanil\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Compared to diamorphine, lower blood pressure was reported after a loading dose\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Studies reported no difference in heart rate or patent ductus arteriosus.\u003c/p\u003e \u003cp\u003eMinimal evidence of adverse neurological effects of morphine was observed. Of the 12 RCTs that reported the incidence of intraventricular hemorrhage (IVH), only one placebo RCT reported an increase in IVH and this was specifically in infants born at 27\u0026ndash;29 weeks of gestation\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. In this trial an increase in combined outcome of IVH/PVL (Periventricular leukomalacia)/death associated with use of open label morphine was identified. One study reported increased cerebral blood volume after morphine administration\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Long-term neurological outcomes were assessed between 5\u0026ndash;8 years in four RCT follow-up studies\u003csup\u003e\u003cspan additionalcitationids=\"CR49 CR50\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e, which reported no difference in IQ, neuropsychological functioning or thermal detection and pain thresholds. An association between opioid exposure and brain volume was reported in one study\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. Consistent with other studies beyond the scope of this review, suppression of brain activity, characterized by an increase in burst interval on amplitude-integrated EEG, was reported in one study compared to no sedation\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere was mixed evidence of gastrointestinal effects of morphine. Of the studies that reported gastrointestinal outcomes, three reported an increased time to feed\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e but three reported no difference\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. Of six studies reporting necrotizing enterocolitis (NEC) as an outcome measure, none reported an increase associated with morphine administration\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. Lastly, there was no evidence of an effect of morphine on sepsis (2 RCTs, 2 case control studies). Urinary retention was reported in one case report\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, while one cohort study and two RCTs did not find an increased risk\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eMorphine benefits\u003c/h2\u003e \u003cp\u003eApart from potential analgosedative effects, no major clinically relevant benefits were reported for morphine. One RCT observed increased mechanical ventilator synchrony in infants treated with morphine compared to placebo\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Four RCTs reported stress hormone outcomes. Only one study was placebo-controlled and it only reported a significant reduction in noradrenaline\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Two other RCTs reported a significant reduction in noradrenaline compared to pancuronium\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e and diamorphine\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of studies of fentanyl\u003c/h2\u003e \u003cp\u003eFentanyl was the second most studied drug for analgosedation in ventilated preterm infants (Table\u0026nbsp;3). Seventeen studies were identified including nine RCTs (8 primary)\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan additionalcitationids=\"CR56 CR57 CR58\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e, two cohort studies\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e, three case-control studies\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e and three case reports\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e. Fentanyl was administered intravenously in all studies. A loading dose was given in 11 primary studies, ranging from 1 to 12.5 \u0026micro;g/kg. A continuous infusion was administered in 13 primary studies, ranging from 0.5 to 2 \u0026micro;g/kg/h. The most common infusion rate was ~\u0026thinsp;1 \u0026micro;g/kg/h. Only 1 study was open label\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. Most trials were placebo controlled RCTs (7 trials and one follow-up). Other comparators included bolus versus continuous administration\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e, low or no dose\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e, morphine\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, midazolam/pentobarbital\u003csup\u003e23\u003c/sup\u003e and dexmedetomidine\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eFentanyl: Analgosedation\u003c/h2\u003e \u003cp\u003eNine studies assessed the analgesic efficacy of fentanyl. Six used a validated clinical pain score. The PIPP score was most frequently used (4/6 studies\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e). Three studies reported multiple different pain scores\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e. Three placebo RCTs reported significantly lower PIPP scores with fentanyl\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e; one reported no difference using the Neonatal Facial Coding System\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. One cohort study reported higher PIPP scores with fentanyl compared to morphine\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Four studies reported sedation or adjunctive sedative use as an outcome. One placebo-controlled trial reported lower non-validated sedation scores with fentanyl\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e, another reported low NPASS and NIPS scores with both continuous and bolus fentanyl administration\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e. One study reported decreased adjunctive sedation compared to morphine\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, and another reported increased adjunctive sedation compared to dexmedetomidine\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eFentanyl: additional benefits and risks\u003c/h2\u003e \u003cp\u003eThere was no increase in mortality with fentanyl administration in the three placebo RCTs that reported this outcome.\u003c/p\u003e \u003cp\u003eThere was no clear evidence of respiratory adverse effects. Two placebo RCTs reported increased ventilatory parameters with fentanyl\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e whereas two reported no increase\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. Three placebo RCTs reported no difference in the duration of mechanical ventilation\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e; one trial reported slower weaning\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. A cohort study reported increased duration of ventilation compared to dexmedetomidine\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e. Three placebo RCTs reported no difference in oxygenation\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e; three found no difference in the development of bronchopulmonary dysplasia\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. There was no evidence of decreased blood pressure in five placebo RCTs\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e,\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e or two observational studies\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e, and no difference in vasoactive treatment use in three placebo RCTs\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Additionally, three placebo RCTs reported no difference in patent ductus arteriosus\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. Three placebo RCTs reported a decrease in heart rate that remained within the normal range\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFentanyl was not associated with increased time to feeding (3 placebo RCTs\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e), sepsis (2 placebo RCTs\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e), urinary retention (2 placebo RCTs\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e) or risk of withdrawal (2 placebo RCTs\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e, 1 cohort study\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e). Withdrawal was less frequent with fentanyl than with morphine in one observational study\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, but more frequent than with dexmedetomidine in another\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e. Three placebo RCTs reported differences in stress-related hormones\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere was no evidence of neurological adverse effects of fentanyl. All four placebo RCTs reporting IVH found no significant difference\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. In terms of neurodevelopmental outcomes, one RCT follow-up study reported a significant reduction in hand and eye coordination scores but not in developmental quotient after adjusting for confounders at 24 months\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. Another RCT found no difference between fentanyl and placebo for mental developmental index (MDI) and psychomotor developmental index (PDI) at 3, 6, 9 and 12 months of age\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e. A case-control study reported no significant impact of cumulated fentanyl dose on Bayley III composite scores at this age after adjusting for confounders\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudies of other synthetic opioids\u003c/h2\u003e \u003cp\u003eA variety of synthetic opioids were studied in premature infants receiving mechanical ventilation, including remifentanil (4 studies); diamorphine (3 studies); alfentanil (3 studies); sufentanil (2 studies); and meperidine (1 study). This included five RCTs (all of which were primary), six cohort studies, one case-control study and one case report (Table\u0026nbsp;4). There were only two placebo-controlled trials, one of meperidine\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e and one of alfentanil\u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e. All synthetic opioids were administered intravenously with infusion rates ranging as follows for different drugs: remifentanil 0.075\u0026ndash;0.94 \u0026micro;g/kg/h; diamorphine 15 \u0026micro;g/kg/h; alfentanil 10\u0026ndash;20\u0026micro;g/kg loading dose; sufentanil 0.05-1 \u0026micro;g/kg/h.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSynthetic opioids: analgosedation\u003c/h2\u003e \u003cp\u003eThere was no clear evidence of analgesic efficacy among synthetic opioids. A pain score was reported in eight studies but only three studies of remifentanil used validated pain scores (NIPS and COMFORT\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e,\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e), including a RCT comparing remifentanil to morphine\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, which found no significant difference in effects, a cohort study\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e that reported reduction in pain score 1-hour post-administration, and a case report\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. One study used meperidine, a RCT which reported significant difference in an unvalidated pain score compared to placebo\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e. None of the studies of alfentanil\u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e,\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e,\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e or sufentanil\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e assessed analgesia or sedation with a validated score. No studies of diamorphine assessed analgesia. One RCT assessed sedation with an unvalidated score and did not find a difference in sedation compared to morphine over 24 hours\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, but reported reduced time to sedation with diamorphine. Limited evidence was available on the sedative effect of synthetic opioids. Only three studies assessed sedation, two using COMFORT\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e, a validated score, to assess the effect of remifentanil. One RCT reported no difference in sedation compared to morphine\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e and a cohort study reported deep sedation in all patients\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eSynthetic opioids: additional benefits and risks\u003c/h2\u003e \u003cp\u003eThere is very little evidence for the added benefits or risks of remifentanil. In a RCT with morphine, remifentanil administration was associated with increased mean airway pressures but reduced time to extubation\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. There was also no difference in blood pressure or time to feed compared to morphine. No significant harms were reported.\u003c/p\u003e \u003cp\u003eHowever, they did report infants developing respiratory depression\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, hypoxaemia\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e, severe muscle rigidity\u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e,\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e and thoracic rigidity\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. They also reported an increased incidence of IVH in infants who received diamorphine\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. In a RCT of high and low dose diamorphine, 2/14 infants who received high dose required resuscitation after receiving the loading dose\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere were no significant changes in arterial blood pressure, heart rate, plasma-endorphin, cortisol, or glucose concentrations between meperidine and placebo\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of studies of sedatives\u003c/h2\u003e \u003cp\u003eSeveral sedative agents have been studied in premature infants receiving mechanical ventilation (Table\u0026nbsp;5). The most frequently studied sedatives were midazolam (8 studies) and dexmedetomidine (3 studies). Other agents with single studies included phenobarbitone, lorazepam and diazepam.\u003c/p\u003e \u003cp\u003eMidazolam was studied in 3 placebo RCTs, 1 RCT compared to morphine, 3 cohort studies and a case report. It was administered intravenously with an infusion loading dose ranging 100\u0026ndash;200 \u0026micro;g, and continuous infusion rates widely ranging 20\u0026ndash;200\u0026micro;g/kg/h, with only one open label study\u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e. Only two studies used a validated pain score; one was a placebo RCT that reported significantly lower PIPP scores with midazolam compared to placebo\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Four studies assessed sedation with midazolam; only one used a validated score. There was no difference in COMFORT scores following drug administration\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Studies of dexmedetomidine included 1 case-control comparison to fentanyl, 1 dose-escalation trial and a case report. Dexmedetomidine was administered intravenously with an infusion loading dose ranging 0.05\u0026ndash;0.5 \u0026micro;g and continuous infusion rates of 0.05\u0026ndash;1.2\u0026micro;g/kg/h. Only one study was open label\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e. The primary endpoint of both the dose escalation trial and case-control study with fentanyl was the need for rescue sedation. In the dose escalation trial, premature infants were adequately sedated at all doses (based on NPASS scores and clinical judgement) and did not require additional sedatives\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e. However, some infants (17%) did require administration of rescue analgesia. In the study comparing dexmedetomidine to fentanyl, significantly less rescue sedation and analgesia was required in patients who received dexmedetomidine\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eSedatives: additional benefits and risks\u003c/h2\u003e \u003cp\u003eThere was little evidence of neurological effects with no difference in PVL and IVH in the three placebo RCTs\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e,\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e and two observational studies\u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e,\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u003c/sup\u003e. However, one RCT reported an increased risk of combined IVH, PVL or death in the midazolam group compared to morphine, but no difference in Neurobehavioral Assessment of the Preterm (NAPI) scores at 36 weeks\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. One RCT\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e and one cohort study\u003csup\u003e\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u003c/sup\u003e also reported decrease in cerebral blood flow with midazolam. There was no evidence of an effect of midazolam on gastrointestinal outcomes, sepsis, withdrawal and mortality, but very few studies reported these outcomes (see table).\u003c/p\u003e \u003cp\u003eThere was no clear evidence of respiratory effects of midazolam. The three placebo RCTs reported no significant difference in mechanical ventilation duration\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e,\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e, O\u003csub\u003e2\u003c/sub\u003e duration\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e or ventilation parameters\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e,\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e. One case-control study reported increased duration of mechanical ventilation\u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e. One placebo RCT\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e, one RCT comparing midazolam to morphine\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e and three cohort studies\u003csup\u003e\u003cspan additionalcitationids=\"CR77\" citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u003c/sup\u003e reported a lower BP and hypotension in the midazolam group. One placebo RCT did not find this difference in BP\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e. There was mixed evidence of an effect on heart rate, with one placebo RCT\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e and two cohort studies\u003csup\u003e\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e,\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u003c/sup\u003e reporting reduction, whereas two RCTs\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e and two cohort studies\u003csup\u003e\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e,\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e did not find a difference with midazolam.\u003c/p\u003e \u003cp\u003eFor dexmedetomidine, there was very little data for added benefits and risks. In the dose escalation study, an average decrease in heart rate and blood pressure values was described and one case of diastolic hypotension was reported, none of which required intervention\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e. In the case control study with fentanyl as comparison, shorter duration of mechanical ventilation, shorter time to full feeds and a decrease in culture positive sepsis were reported\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eStudies of mixed narcotics/sedatives\u003c/h2\u003e \u003cp\u003eWe also identified studies of mixed narcotics and/or sedatives including four case-control studies and one propensity score matched cohort study (Table\u0026nbsp;6). These large studies (two retrospective and three prospective) provide an insight into outcomes related to the use of narcotics and/or sedatives versus non-exposed patients. None of them reported on analgesic or sedative efficacy of these drugs. Four studies reported on duration of mechanical ventilation, with no differences between treated or non-treated patients in two\u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e,\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u003c/sup\u003e and an increased duration of mechanical ventilation in treated groups in the remaining\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e. Only one study reported on cardiovascular outcomes with no difference in heart rate and blood pressure\u003csup\u003e\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u003c/sup\u003e. 3/4 studies reported an increased incidence of severe IVH in treated groups\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e,\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e, and one, an increased incidence of severe ROP\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. One study reported no difference in survival without moderate to severe neurological disabilities at 2 years\u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u003c/sup\u003e. A higher incidence of death was reported by two studies\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e; another study reported the opposite\u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u003c/sup\u003e. These conflicting results likely reflect various designs, drugs and adjustments in these observational studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe undertook a systematic scoping review of the analgosedative agents studied in premature infants receiving mechanical ventilation to explore the benefits and risks associated with their use. Morphine, fentanyl, a variety of other synthetic opioids, and a selection of sedatives including midazolam and dexmedetomidine have been studied in this clinical context. Here, we discuss the overall benefits and risks reported for each of these drugs, identify associated gaps in our knowledge, and recommend priorities for future research.\u003c/p\u003e \u003cp\u003eMorphine is the most studied drug for analgosedation in ventilated preterm infants (39 studies in three decades), but its efficacy in terms of analgesia and sedation remain unclear. Morphine is considered a standard for analgosedation in children and adults; these findings lead us to question whether morphine is not as effective in this patient population, or in the way it has been tested. All nine primary placebo RCTs identified in this review were conducted prior to 2014. Despite conflicting results of efficacy, over the past decade the focus has shifted to observational drug or dosing regimen comparisons and follow-up studies of the primary RCTs. Dosage of both loading boluses and continuous infusions of morphine have ranged broadly across studies. However, high doses (\u0026gt;\u0026thinsp;100 \u0026micro;g/kg loading) have been particularly used in RCTs involving drug-drug comparisons, such as morphine and diamorphine\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, and morphine and remifentanil\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Interestingly, studies which reported positive analgesic efficacy results were not studies administering the highest doses. The variability in dosage likely reflects the lack of appropriate dose-finding studies in this patient population. Furthermore, half of the placebo RCTs of morphine included open-label administration of rescue opioids complicating the assessment of analgesic efficacy. Rescue medication is an ethical imperative as infants who appear in pain cannot be ignored by the clinician. However, this non-randomized intervention can have a significant impact on the results of a trial. The administration of rescue morphine to infants receiving placebo has created an \u0026lsquo;as needed\u0026rsquo; group comparison, reducing the chance of identifying a significant difference in analgesic efficacy. Equally, the administration of rescue medication to a significant proportion of infants in the morphine treatment group in several studies suggests that the drug was not providing adequate pain relief\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStudies of morphine which reported pain outcomes used validated scores for premature infants such as PIPP, COMFORT and NIPS. However, only two studies reported the reliability of their assessments. Given the subjective nature of these scales, adequate training, use of multiple raters, and reporting of inter- and intra-rater reliability should be conducted as standard. All studies but one\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e assessed acute pain in response to tracheal suctioning. Interestingly, this placebo RCT measured continuous pain (in the absence of suction) using a validated scale for premature infants (COMFORT) and reported a significant reduction in pain at two and twelve hours\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Tracheal suctioning is a common painful\u003csup\u003e\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u003c/sup\u003e procedure in NICU but given that variability in catheter size, pressure, depth, duration, and indication could potentially impact the distress and physiological instability caused by the procedure\u003csup\u003e\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u003c/sup\u003e, we should question whether this non-standardized procedure is the optimal way to test analgesia during mechanical ventilation.\u003c/p\u003e \u003cp\u003eThere is minimal data suggesting morphine causes significant respiratory or cardiovascular adverse effects in ventilated premature infants. Some data indicated a prolonged time to establish enteral feeding\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e, which could have an impact on the postnatal functional adaptation of the gut, its microbial colonisation\u003csup\u003e\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u003c/sup\u003e and infectious complications due to prolongation of parenteral nutrition\u003csup\u003e\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u003c/sup\u003e. There were no reports of an increased incidence of NEC or sepsis. A potential increase in mortality was only reported in case-control studies. There were also no major neurological effects, except in extremely premature infants (27\u0026ndash;29 GA), in whom intermittent boluses may be associated with an increased risk of IVH/PVL/death\u003csup\u003e37\u003c/sup\u003e. Data from follow-up studies of RCTs, do not indicate long-term effects of morphine on cognitive development. However, a growing body of literature regarding the effects of cumulative morphine exposure during neonatal hospitalization, beyond the scope of this review, notably provides concerning evidence of potential long-term neurodevelopmental effects\u003csup\u003e\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e\u003c/sup\u003e. Overall, it is difficult to identify clear benefits or risks of routine morphine administration in ventilated premature infants.\u003c/p\u003e \u003cp\u003eFentanyl, the second most studied drug in ventilated premature infants, reported positive analgesic efficacy, with three of four placebo-controlled trials using validated pain scores reporting significantly lower scores following administration. However, there is little data regarding the sedative effect of fentanyl, as no placebo RCTs assessed this outcome. One study comparing bolus and continuous administration of fentanyl reported deep sedation in their participants using NPASS\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e. Considering fentanyl is significantly more potent than morphine (50-100x) and the impact of prolonged deep sedation on the developing brain is unknown, optimal degree of sedation should be investigated in future studies. One observational cohort study compared fentanyl to morphine, but the authors used an unconventional method of assessing analgesic efficacy, limiting its utility\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. There is some data to suggest that an increase in ventilatory parameters may be required following administration\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e but one of these studies used a larger loading dose\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Reassuringly, multiple placebo RCTs reported no associated increase in the duration of mechanical ventilation. Given current concerns over potential neurological effects of opioids, it is also reassuring to note that there was no increase in IVH in the placebo RCTs which reported this outcome. However, the only RCT that assessed later neurodevelopmental outcomes reports a poorer performance in tests of coordination and cognition at 24 months in infants who received fentanyl\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. Further research is needed to address optimal dosing and long-term safety of fentanyl in premature infants, particularly in infants requiring prolonged periods of mechanical ventilation. The rapid development of tolerance is a significant issue\u003csup\u003e\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e\u003c/sup\u003e, which has not yet been addressed in this patient population and unfortunately may considerably limit its prolonged use in practice.\u003c/p\u003e \u003cp\u003eOther highly potent synthetic opioids such as remifentanil, alfentanil and sufentanil have also been studied in preterm ventilated infants. There is limited data to assess their efficacy in this population, and no placebo-controlled trials employing a validated score to determine analgesic or sedative efficacy. The risks associated with their administration, which included reports of severe muscle rigidity and respiratory depression, clearly outweigh any potential benefits. Notably, all studies were conducted prior to 2010, and further investigations have not been undertaken likely due to the considerable risks reported. However, remifentanil and sufentanil have been studied more recently for analgosedation in term infants and in the context of surgical anesthesia and procedural analgesia, and chest wall rigidity appears to be a common and limiting adverse effect\u003csup\u003e\u003cspan additionalcitationids=\"CR90\" citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMidazolam and dexmedetomidine are sedatives which have been most studied in ventilated premature infants. Given their classification as sedative drugs, it is surprising that only one RCT has assessed the sedative efficacy of midazolam in ventilated premature infants using a validated score (COMFORT), and it did not demonstrate any sedative effect\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. In animal models the sedative effect of midazolam is not observed until maturation of supraspinal centers; paradoxical excitation has been reported in young rats\u003csup\u003e\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e\u003c/sup\u003e, calling into question the potential efficacy of this drug in premature infants. Clinical data on midazolam in premature infants also raise concerns over the cardiovascular and neurological effects of the benzodiazepine including hypotension, decreased cerebral blood flow, myoclonus and increased risk of combined death/IVH/PVL in extremely premature infants. Until recently, midazolam was the most frequently used sedative in NICUs\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. However, with pre-clinical studies describing neuroapoptotic effects\u003csup\u003e\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e,\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e\u003c/sup\u003e and clinical studies reporting potential harmful neurodevelopmental effects\u003csup\u003e\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e,\u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e\u003c/sup\u003e, there has been a reduction in the use of midazolam, with some countries introducing dexmedetomidine in its place\u003csup\u003e\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e,\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e\u003c/sup\u003e. Dexmedetomidine is a highly selective, centrally-acting α2 adrenergic agonist, more commonly used for sedation in older children\u003csup\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e\u003c/sup\u003e. Although there are no randomized clinical trials of dexmedetomidine in ventilated preterm infants, a stepwise dose-escalation trial of dexmedetomidine provides promising initial results in this population\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e. None of the premature infants in the study required rescue sedative medication at any drug dose level tested, as determined by NPASS scoring/clinical judgement. However, some infants (3/18) did require administration of fentanyl as rescue analgesia. Dexmedetomidine has potential opioid sparing properties and could be efficacious as an adjunct, maximizing the efficacy of analgosedation whilst minimizing adverse effects. Encouragingly, unlike midazolam, pre-clinical data also suggest that this sedative may have neuroprotective effects\u003csup\u003e\u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e\u003c/sup\u003e, which merit further investigation in clinical trials with long-term follow-up.\u003c/p\u003e \u003cp\u003eIn summary, we have provided an overview of the data available from studies of analgosedatives in ventilated premature infants. Overall, fentanyl appears to have the best efficacy and safety profile for analgosedation in this patient population, with a positive balance of benefits and risks. The data for morphine is less clear. Alternative synthetic opioids and midazolam are associated with significant risks in the absence of clear benefits. Dexmedetomidine may hold early promise as an opioid-sparing adjunct sedative, meriting further investigation. These results are clearly limited by the scoping nature of the review and a subsequent full systematic review with risk of bias assessment could yield further detailed conclusions.\u003c/p\u003e \u003cp\u003eThe provision of analgosedation varies greatly worldwide and is no longer routinely administered to ventilated premature infants. Only\u0026thinsp;~\u0026thinsp;20% of units surveyed in a recent global, prospective, cross-sectional study administer analgosedatives in more than 80% of these patients. Although opioids remain the most frequently administered agents, fentanyl use has now overtaken morphine use overall\u003csup\u003e\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e\u003c/sup\u003e, which is encouraging given the data reviewed here. However, in England and Wales, although the use of fentanyl has increased, it remains significantly less frequently administered than morphine (fentanyl 18% vs morphine 60% of premature infants born\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks)\u003csup\u003e\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e.Despite NICE guidance more than half of UK units continue to routinely give morphine\u003csup\u003e\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e\u003c/sup\u003e. Further research is required to fully establish the optimal use of fentanyl and the longer-term effects of repeated administration during extended periods of mechanical ventilation.\u003c/p\u003e \u003cp\u003eAll studies identified in this review investigated the use of pre-emptive analgosedation. Guidelines are increasingly recommending the administration of analgosedatives only \u0026lsquo;as required\u0026rsquo; based on cot-side assessment of pain and sedation\u003csup\u003e\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e\u003c/sup\u003e. This is complicated by challenges posed by inconsistent and subjective assessment of pain and distress using behaviorally focused scores. Encouragingly, most studies that used non-validated pain scores were conducted prior to 2000. Novel studies of responsive administration of analgosedatives are now needed in premature infants to justify this emerging approach to analgosedation. The rigorous use of validated objective developmentally appropriate assessments of pain will be essential\u003c/p\u003e \u003cp\u003eIn conclusion, based on the current data, fentanyl appears to have the most favorable efficacy and safety profile compared to morphine for use in ventilated preterm infants. Further comparative trials of responsive administration using optimal drug doses, adjunctive sedatives and long-term neurodevelopmental follow-up are needed to determine the best approach to analgosedation in this patient population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current review are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank Dr. Maarten F.M. Engel, biomedical information specialist from the Medical Library of the Erasmus MC Rotterdam, the Netherlands for developing and updating the\u0026nbsp;search\u0026nbsp;strategies.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNo financial assistance was received in support of the study. RS is funded by a Senior Wellcome Research Fellowship (207457/Z/17/Z).\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eSubstantial contributions to conception and design (XD, RS, FM, GvdB, MT, MC, LB, AB, JMR, SS); acquisition of data or analysis and interpretation of data (FM,XD, GvdB, MT, JMR, MMC, AB, EO); Drafting the article or revising it critically for important intellectual content (FM, XD, MT, GvdB, JMR, SS, LB); Final approval of the version to be published (all authors).\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003eConsent statement\u003c/p\u003e\n\u003cp\u003ePatient consent was not required.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAranda JV et al (2005) Analgesia and sedation during mechanical ventilation in neonates. 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Acta Paediatr 108:208\u0026ndash;217\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"d8f70bce-1f44-470c-a1da-c5daab593985","identifier":"10.13039/100010269","name":"Wellcome Trust","awardNumber":"(207457/Z/17/Z)","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Oxford","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"pain, pediatrics, preterm infants, ventilated, analgesic, sedation","lastPublishedDoi":"10.21203/rs.3.rs-5519389/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5519389/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe purpose of this scoping review is to assess the risks and benefits of providing analgesic and sedative drugs to ventilated premature infants. We sourced primary empirical research reporting outcomes related to the use of pharmacological analgesics and sedatives in ventilated premature infants. We included articles published in any language in peer-reviewed journals before February 2024 from MEDLINE, Embase, Web of Science, Cochrane Library, and Google scholar databases. Morphine was the most studied drug (39 studies), followed by fentanyl (19 studies). Midazolam (8 studies) and dexmedetomidine (3 studies) were the most frequently studied sedatives. Analgesic efficacy was more consistently reported for fentanyl than morphine. The sedative effect of opioids was rarely assessed. Respiratory, cardiovascular, gastrointestinal, neurological and neurodevelopmental risks were unclear for all opioids. Alternative synthetic opioids and midazolam appear to be associated with significant risks in the absence of clear benefits. Dexmedetomidine shows encouraging but limited results and merits further investigation as an opioid-sparing adjunct. Overall, fentanyl appears to have the best efficacy and safety profile for analgosedation in this patient population. This scoping review will support clinicians in their analgosedative management of ventilated premature infants and identifies research gaps and priorities.\u003c/p\u003e","manuscriptTitle":"Analgesia and sedation in premature infants receiving invasive ventilation: a systematic scoping review.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-28 15:54:29","doi":"10.21203/rs.3.rs-5519389/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3b73b292-573f-46ee-97c5-f592be15f905","owner":[],"postedDate":"November 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-28T15:54:29+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-28 15:54:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5519389","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5519389","identity":"rs-5519389","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}