Background: Intrathecal hydrophilic opioids decrease systemic opioid consumption after abdominal surgery and potentially facilitate enhanced recovery. A meta-analysis is needed to quantify associated risks and benefits. Methods: A systematic search was performed to find RCTs investigating intrathecal hydrophilic opioids in abdominal surgery. Caesarean section and continuous regional or neuraxial techniques were excluded. Several subgroup analyses were prespecified. A conventional meta-analysis, meta-regression, trial sequential analysis, and provision of GRADE scores were planned. Results: The search yielded 40 trials consisting of 2500 patients. A difference was detected in 'i.v. morphine consumption' at Day 1 {mean difference [MD] À18.4 mg, (95% confidence interval [CI]: À22.3 to À14.4)} and Day 2 (MD À25.5 mg [95% CI: À30.2 to À20.8]), pain scores at Day 1 in rest (MD À0.9 [95% CI: À1.1 to À0.7]) and during movement (MD À1.2 [95% CI: À1.6 to À0.8]), length of stay (MD À0.2 days [95% CI: À0.4 to À0.1]) and pruritus (relative risk 4.3 [95% CI: 2.5e7.5]) but not in nausea or sedation. A difference was detected for respiratory depression (odds ratio 5.5 [95% CI: 2.1e14.2]) but not when two small outlying studies were excluded (odds ratio 1.4 [95% CI: 0.4e5.2]). The level of evidence was graded as high for morphine consumption, in part because the required information size was reached. Conclusions: This study showed important opioid-sparing effects of intrathecal hydrophilic opioids. Our data suggest a dose-dependent relationship between the risk of respiratory depression and the dose of intrathecal opioids. Excluding two high-dose studies, intrathecal opioids have a comparable incidence of respiratory depression as the control group. Clinical trial registration: PROSPERO-registry: CRD42018090682.

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Summary Phenylephrine is recommended for the management of hypotension after spinal anaesthesia in women undergoing caesarean section. Noradrenaline, an adrenergic agonist with weak β‐adrenergic activity, has been reported to have a more favourable haemodynamic profile than phenylephrine. However, there are concerns that noradrenaline may be associated with a higher risk of fetal acidosis, defined as an umbilical artery pH < 7.20. We performed a systematic review of trials comparing noradrenaline with phenylephrine, concentrating on primary outcomes of fetal acidosis and maternal hypotension. We identified 13 randomised controlled trials including 2002 patients. Heterogeneity among the studies was high, and there were too few data to calculate a pooled effect estimate. Fetal acidosis was assessed in four studies that had a low risk of bias and a low risk of confounding, that is, studies which used a prophylactic vasopressor and where women received the allocated vasopressor only. There were no significant differences between these studies. No significant differences were observed for hypotension. Two trials found a significantly lower incidence of bradycardia when using noradrenaline. Cardiac output was significantly higher after noradrenaline in two of three studies. For other secondary outcomes including nausea, vomiting and Apgar scores at 1 and 5 min, no studies found significant differences. The evidence so far is too limited to support an advantage of noradrenaline over phenylephrine. Concerns of a deleterious effect of noradrenaline on fetal blood gas status cannot currently be assuaged by the available data from randomised controlled studies.

There are data suggesting that intravenous dexamethasone has an effect on postoperative analgesia when given during single-shot spinal anaesthesia. However, the research literature is equivocal. We performed a systematic literature search followed by conventional meta-analysis (random effects model). We used trial sequential analysis to control for type-1 and -2 statistical errors. We also performed a leave-one-out metaanalysis for our primary outcome, the consumption of intravenous morphine in the first 24 postoperative hours. We applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the level of evidence. We obtained data from 1133 patients, reported in 17 trials. Reporting quality was high, with low risk of bias. Dexamethasone use was associated with a significant reduction in 24-h morphine consumption, the mean difference (95%CI) being À4.01 (À5.01 to À3.01) mg, 6 trials, 326 participants, I 2 = 0%. Trial sequential analysis showed that there was firm evidence for the primary outcome, and leave-one-out metaanalysis showed that our result was not driven by one single trial. The GRADE evaluation showed a high level of evidence, suggesting that further studies are unlikely to alter the result. The time to first analgesic request (95% CI) was significantly prolonged by 86.62 (10.62-162.62) min, I 2 = 93%, in the dexamethasone group. For other secondary outcomes including number of patients requiring rescue analgesia, or visual analogue scale pain scores, we found no evidence of a significant difference between the treatment arms. We report a high level of evidence that intravenous dexamethasone improves postoperative analgesia after spinal anaesthesia.

Summary Postoperative pain might be different after intravenous vs. oral paracetamol. We systematically reviewed randomised controlled trials in patients >15 years that compared intravenous with oral paracetamol for postoperative pain. We identified 14 trials with 1695 participants. There was inconclusive evidence for an effect of route of paracetamol administration on postoperative pain at 0–2 h (734 participants), 2–6 h (766 participants), 6–24 h (1115 participants) and >24 h (248 participants), with differences in standardised mean (95%CI) pain scores for intravenous vs. oral of −0.17 (−0.45 to 0.10), −0.09 (−0.24 to 0.06), 0.06 (−0.12 to 0.23) and 0.03 (−0.22 to 0.28), respectively. Trial sequential analyses suggested that a total of 3948 participants would be needed to demonstrate a meaningful difference in pain or its absence at 0–2 h. There were no differences in secondary outcomes. Intravenous paracetamol is more expensive than oral paracetamol. Substitution of oral paracetamol in half the patients given intravenous paracetamol in our hospital would save around £ 38,711 (€ 43,960 or US$ 47,498) per annum.

BACKGROUND Fluid loading is one of the recognised measures to prevent hypotension due to spinal anaesthesia in women scheduled for a caesarean section. OBJECTIVE We aimed to evaluate the current evidence on fluid loading in the prevention of spinal anaesthesia-induced hypotension. DESIGN Systematic review and network meta-analysis with trial sequential analysis and meta-regression. DATA SOURCES Medline, Epub, Embase.com (Embase and Medline), Cochrane Central, Web of Science and Google Scholar were used. ELIGIBILITY CRITERIA Only randomised controlled trials were used. Patients included women undergoing elective caesarean section who received either crystalloid or colloid fluid therapy as a preload or coload. The comparator was a combination of either a different fluid or time of infusion. RESULTS A total of 49 studies (4317 patients) were included. Network meta-analysis concluded that colloid coload and preload offered the highest chance of success (97 and 67%, respectively). Conventional meta-analysis showed that crystalloid preload is associated with a significantly higher incidence of maternal hypotension than colloid preload: risk ratio 1.48 (95% CI 1.29 to 1.69, P < 0.0001, I 2 = 60%). However, this result was not supported by Trial Sequential Analysis. There was a significant dose–response effect for crystalloid volume preload (regression coefficient = −0.073), which was not present in the analysis of only double-blind studies. There was no dose–response effect for the other fluid regimes. CONCLUSION Unlike previous meta-analysies, we found a lack of data obviating an evidence-based recommendation. In most studies, vasopressors were not given prophylactically as is recommended. Studies on the best fluid regimen in combination with prophylactic vasopressors are needed. Due to official european usage restrictions on the most studied colloid (HES), we recommend crystalloid coload as the most appropriate fluid regimen. TRIAL REGISTRATION CRD42018099347.