An explorative analysis of pharmacovigilance data of oxytocin and its analogue carbetocin, with a focus on haemodynamic adverse effects.

BACKGROUND: Oxytocin and its analogue carbetocin are uterotonics whose prophylactic use is recommended to prevent postpartum haemorrhage, which is one of the leading causes of maternal deaths worldwide. However, both drugs can cause specific adverse effects and haemodynamic challenges. AIM: The aim of this work was to exploratively examine reports of adverse drug events of both drugs and to establish a comparative haemodynamic profile. METHOD: Using data extracted from the World Health Organization's pharmacovigilance database VigiBase, a descriptive analysis was performed of all reports for oxytocin and carbetocin as a suspected or interacting drug followed by a disproportionality analysis for haemodynamic events. Reporting odds ratios (ROR) of carbetocin for hypertension, hypotension, tachycardia, and bradycardia were calculated, with oxytocin-related reports serving as comparators. RESULTS: Oxytocin and carbetocin were mentioned as suspected or interacting drugs in 11,258 and 374 reports, respectively. Resulting RORs for carbetocin were 3.45 (95%CI: 1.72-6.92) for hypertension, 2.65 (1.64-4.28) for hypotension, 2.84 (1.79-4.49) for tachycardia, and 2.00 (0.87-4.60) for bradycardia, when compared to oxytocin. Of 231 patients for whom oxytocin-related tachycardia was reported, 2.6% died, and of 91 patients for whom bradycardia was reported, 2.2% died. No deaths were reported with carbetocin for any of the haemodynamic adverse events. CONCLUSION: Compared to oxytocin, carbetocin showed an elevated reporting for adverse hypertension, hypotension, and tachycardia in pharmacovigilance data. Clinicians should be aware of their patients' individual susceptibility and the possibility of haemodynamic deterioration until causal inferences are possible.

Accuracy of Spinal Anesthesia Drug Concentrations in Mixtures Prepared by Anesthetists.

OBJECTIVE: Medication errors include the indirect dosing of drugs. For spinal anesthesia mixtures of local anesthetics, opioids are drawn from ampoules and combined in a syringe, according to clinical practice. We set out to determine the accuracy of the drug mixtures. METHODS: Physicians of our department were invited to prepare the mixture used for spinal anesthesia for cesarean section, consisting of 10-mg hyperbaric bupivacaine (2-mL volume), 20-µg fentanyl (0.4-mL volume), and 100-µg morphine (0.1-mL volume). Concentrations of these drugs were determined by means of high performance liquid chromatography. Interindividual and intraindividual variations were assessed. RESULTS: We analyzed 96 samples from 31 physicians. Fifty-one percent of the measured bupivacaine concentrations were in ±10% deviation range of the intended concentration; 17% of the fentanyl and 24% of the morphine concentrations were in this range. A total of 2.1% of the samples had a bupivacaine concentration corresponding to a dose of 8 mg or less, and 11.5% of the samples had a morphine concentration corresponding to a dose of 150 µg or greater. Intraindividual variations were 10.9% for bupivacaine, 24.7% for fentanyl, and 38.9% for morphine. CONCLUSIONS: Our results show a high deviation of the obtained from the intended concentrations. Two percent of the samples had bupivacaine concentrations that probably resulted into an insufficient analgesia, and 11% of the samples had morphine concentrations that, according to guidelines, would require a longer monitoring period than with the intended dose.

Optimal uterotonic management.

Uterotonics play an important role in the management of postpartum haemorrhage (PPH), often caused by uterine atony. The World Health Organization (WHO) recommends the application of uterotonics for all births. Oxytocin, considered the first-line uterotonic, binds to a G protein-coupled receptor which is subject to down sensitization upon repeated or prolonged administration of oxytocin. Consequently, a uterotonic with a different mechanism of action should be chosen early when oxytocin does not restore uterine tone. Choice of the second-line uterotonic is determined by institutional preferences as well as by maternal co-morbidities since most uterotonics have cardiovascular side effects. Slow injection of all uterotonics is strongly recommended to blunt these reactions. Methylergometrine and carboprost should, therefore, be avoided in many cardiovascular pathologies. Carbetocin is a chemical modification of oxytocin with a longer half-time, and therefore one bolus of carbetocin is usually sufficient. Its heat stability makes it an ideal candidate in resource-restricted settings.

The Impact of a 22-Month Multistep Implementation Program on Speaking-Up Behavior in an Academic Anesthesia Department.

BACKGROUND: Speaking-up is a method of assertive communication that increases patient safety but often encounters barriers. Numerous studies describe programs introducing speaking-up with varying success; the common denominator seems to be the need for a multimodal and sustained approach to achieve the required change in behavior and culture for safer health care. METHODS: Before implementing a 22-month multistep program for establishing and strengthening speaking-up at our institution, we assessed perceived safety culture using the "Safety Attitudes Questionnaire." After program completion, participants completed parts of the same Safety Attitudes Questionnaire relevant to speaking-up, and preresult and postresult were compared. In addition, levels of speaking-up and assertive communication were compared with a Swiss benchmark using results from the "Speaking-up About Patient Safety Questionnaire." RESULTS: Safety Attitudes Questionnaire scores were significantly higher after program completion in 2 of 3 answered questions (median [first quartile, third quartile), 5.0 [4.0, 5.0] versus 4.0 [4.0, 5.0], P = 0.0002, and 5.0 [4.0, 5.0] versus 4.0 [4.0, 4.0] P = 0.002; n = 34). Our composite score on the Speaking-up About Patient Safety Questionnaire was significantly higher (mean ± SD, 5.9 ± 0.7 versus 5.2 ± 1.0; P < 0.001) than the benchmark (n = 65). CONCLUSIONS: A long-term multimodal program for speaking-up was successfully implemented. Attitude and climate toward safety generally improved, and postprogram perceived levels of assertive communication and speaking-up were higher than the benchmark. These results support current opinion that multimodal programs and continued effort are required, but that speaking-up can indeed be strengthened.

Flouroscopic versus conventional epidural blood patch in obstetrics: A retrospective cohort study.

BACKGROUND: Epidural blood patch is a common effective treatment for postdural puncture headache after accidental dural puncture during labor and may be done in conventional or fluoroscopy-guided methods. The aim of this study was to compare intensity of headache at the time of discharge from the hospital and to compare blood volumes injected in conventional epidural blood patches versus fluoroscopic-guided blood patches and evaluate the side effects of both method of treatment. METHODS: Between the years 2010 and 2020, 84 patients who were diagnosed with postdural puncture headache received either a conventional epidural blood patch or a fluoroscopic-guided blood patch. Blood volumes were compared and evaluation of side effects was made based on data collected during and after the procedure. RESULTS: Eighty-four patients were included in this study. Fifty-two women in the conventional epidural blood patch group and 32 in the fluoroscopic-guided blood patch group. Women in the conventional epidural blood patch group received statistically significantly higher doses of blood than women in the fluoroscopic-guided blood patch group: conventional method 29 ml IQR [23-36] versus fluoroscopic method 16 ml, IQR [12-18], p < .001 with no difference in headache pain intensity at hospital release. There was no difference between groups in hospital length of stay, or persistent PDPH. There was also no difference chronic headache or backache between the two groups. CONCLUSIONS: Women who received fluoroscopic epidural blood patch required a much lower volume of blood injected while there was no difference between groups in headache pain intensity at discharge.

The effect of prophylactic use of tranexamic acid for cesarean section.

AIM: Treatment with tranexamic acid (TxA) significantly reduces maternal death due to postpartum hemorrhage. There is increasing interest in whether it can also be used as prophylaxis for postpartum hemorrhage, especially during cesarean sections (CS). This impact study is aimed to determine the effect of routine prophylactic tranexamic acid during CS on maternal hemorrhage and the rate of the associated side effects. METHODS: This retrospective population-based cohort single-center impact study include 2000 women who delivered by CS divided into two groups with (n = 1000) and without (n = 1000) prophylactic administration of 1gram TxA prior to surgery. Primary outcomes were to determine the: (1) rate of women experiencing >10% or ≥2 g/dL hemoglobin drop from the preoperative concentration within 24 h after CS. (2) incidence of women having a hemoglobin drop of ≥2 g/dL. RESULTS: Women who did not receive TxA prophylactic had a higher rate of >10% hemoglobin decrease and a higher rate of ≥2 g/dL hemoglobin decrease Than those who received TxA prophylaxis (p < .0001, for both). Mean hospital stay (p = .002) and umbilical cord pH (p < .05) were higher among those who received TxA prophylaxis than in those who were not treated. CONCLUSIONS: The finding of our study suggest that prophylactic administration of TxA prior to CS improves maternal and neonatal outcomes.

Preoperative chest computed tomography in emergency surgery during COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic challenges the recommendations for patients' preoperative assessment for preventing severe acute respiratory syndrome coronavirus type 2 transmission and COVID-19-associated postoperative complications and morbidities. PURPOSE: To evaluate the contribution of chest computed tomography for preoperatively assessing patients who are not suspected of being infected with COVID-19 at the time of referral. METHODS: Candidates for emergency surgery screened via chest computed tomography from 8 to 27 April 2020 were retrospectively evaluated. Computed tomography images were analysed for the presence of COVID-19-associated intrapulmonary changes. When applicable, laboratory and recorded clinical symptoms were extracted. RESULTS: Eighty-eight patients underwent preoperative chest computed tomography; 24% were rated as moderately suspicious and 11% as highly suspicious on computed tomography. Subsequent reverse transcription polymerase chain reaction (RT-PCR) was performed for seven patients, all of whom tested negative for COVID-19. Seven patients showed COVID-19-associated clinical symptoms, and most were classified as being mildly to moderately severe as per the clinical classification grading system. Only one case was severe. Four cases underwent RT-PCR with negative results. CONCLUSION: In a cohort without clinical suspicion of COVID-19 infection upon referral, preoperative computed tomography during the COVID-19 pandemic can yield a high suspicion of infection, even if the patient lacks clinical symptoms and is RT-PCR-negative. No recommendations can be made based on our results but contribute to the debate.

Prognostic factors for chronic post-surgical pain after lung or pleural surgery: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Chronic post-surgical pain (CPSP) after lung or pleural surgery is a common complication and associated with a decrease in quality of life, long-term use of pain medication and substantial economic costs. An abundant number of primary prognostic factor studies are published each year, but findings are often inconsistent, methods heterogeneous and the methodological quality questionable. Systematic reviews and meta-analyses are therefore needed to summarise the evidence. METHODS AND ANALYSIS: The reporting of this protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist. We will include retrospective and prospective studies with a follow-up of at least 3 months reporting patient-related factors and surgery-related factors for any adult population. Randomised controlled trials will be included if they report on prognostic factors for CPSP after lung or pleural surgery. We will exclude case series, case reports, literature reviews, studies that do not report results for lung or pleural surgery separately and studies that modified the treatment or prognostic factor based on pain during the observation period. MEDLINE, Scopus, Web of Science, Embase, Cochrane, CINAHL, Google Scholar and relevant literature reviews will be searched. Independent pairs of two reviewers will assess studies in two stages based on the PICOTS criteria. We will use the Quality in Prognostic Studies tool for the quality assessment and the CHARMS-PF checklist for the data extraction of the included studies. The analyses will all be conducted separately for each identified prognostic factor. We will analyse adjusted and unadjusted estimated measures separately. When possible, evidence will be summarised with a meta-analysis and otherwise narratively. We will quantify heterogeneity by calculating the Q and I2 statistics. The heterogeneity will be further explored with meta-regression and subgroup analyses based on clinical knowledge. The quality of the evidence obtained will be evaluated according to the Grades of Recommendation Assessment, Development and Evaluation guideline 28. ETHICS AND DISSEMINATION: Ethical approval will not be necessary, as all data are already in the public domain. Results will be published in a peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42021227888.

Attentional processing of pain faces and other emotional faces in chronic pain-an eye-tracking study.

Altered attentional processing of pain-associated stimuli-which might take the form of either avoidance or enhanced vigilance-is thought to be implicated in the development and maintenance of chronic pain. In contrast to reaction time tasks like the dot probe, eye tracking allows for tracking the time course of visual attention and thus differentiating early and late attentional processes. Our study aimed at investigating visual attention to emotional faces in patients with chronic musculoskeletal pain (N = 20) and matched pain-free controls (N = 20). Emotional faces (pain, angry, happy) were presented in pairs with a neutral face for 2000 ms each. Three parameters were determined: First fixation probabilities, fixation durations (overall and divided in four 500 ms intervals) and a fixation bias score as the relative fixation duration of emotional faces compared to neutral faces. There were no group differences in any of the parameters. First fixation probabilities were lower for pain faces than for angry faces. Overall, we found longer fixation duration on emotional compared to neutral faces ('emotionality bias'), which is in accord with previous research. However, significant longer fixation duration compared to the neutral face was detected only for happy and angry but not for pain faces. In addition, fixation durations as well as bias scores yielded evidence for vigilant-avoidant processing of pain faces in both groups. These results suggest that attentional bias towards pain-associated stimuli might not generally differentiate between healthy individuals and chronic pain patients. Exaggerated attentional bias in patients might occur only under specific circumstances, e.g., towards stimulus material specifically relating to the specific pain of the patients under study or under high emotional distress.

Association Between Hyperbaric Bupivacaine Dose and Maternal Hypotension: Retrospective Database Study of 8226 Women Undergoing Cesarean Delivery Under Spinal Anesthesia.

BACKGROUND: Low-dose (≤8 mg) hyperbaric bupivacaine for spinal anesthesia during cesarean delivery results in reduced efficacy, yet as a secondary outcome was associated with reduced frequency of spinal-induced hypotension. Our primary aim was to investigate the relationship between hyperbaric bupivacaine dose and the occurrence of spinal-induced hypotension for cesarean delivery. METHODS: Retrospective study of cesarean delivery under spinal or combined spinal anesthesia with hyperbaric bupivacaine in 1 academic institution (2 centers-tertiary and district) from 2012 to 2018. Data were retrieved from the anesthesia information management systems (Metavision, iMDsoft, Tel Aviv, Israel) and the hospital information system, including potential confounding factors, maternal age and weight, hypertensive disease of pregnancy, single/multiple gestation, gestational age, vasopressor administration, planned/urgent surgery, position during anesthesia placement (sitting/lateral), and anesthesiologist seniority. Spinal-induced hypotension was defined as systolic blood pressure that either dropped >20% from baseline or <100 mm Hg. The primary outcome of interest was the incidence of spinal-induced hypotension according to hyperbaric bupivacaine dose. Logistic regression was used to characterize the association between the dose of hyberbaric bupivacaine and spinal-induced hypotension after adjusting for confounding factors. RESULTS: A total of 8226 women were identified. The hyperbaric bupivacaine dose administered was <9 mg for 2395 (29.1%), 9-9.5 mg for 1031 (12.5%), 10 mg for 4155 (50.5%), and >10 mg for 645 (7.8%). We used a cutoff (<10 vs ≥10 mg) to assess for the primary outcome, using multivariable logistic regression. The incidence of at least 1 spinal-induced hypotension episode was higher in patients who received ≥10 mg hyperbaric bupivacaine, 75.8% vs 62.9% for doses below 10 mg, P < .0001; however, even women with lower doses had hypotension. Hyperbaric bupivacaine dose <10 mg was associated with a lower incidence of spinal hypotension, adjusted odds ratio (OR) of 0.774, 95% confidence interval (CI), 0.669-0.897, and P = .0006, adjusted for confounding factors.Umbilical cord pH was available for 2684 (32.6%) cases. There were significantly more neonates with pH < 7.2, among women who received hyperbaric bupivacaine ≥10 mg (10.1%) versus women who received <10 mg (6.8%), P = .0032; however, in the adjusted model, hyperbaric bupivacaine dose ≥10 mg was not associated with pH < 7.2 and an OR of 0.955 (95% CI, 0.631-1.446, P = .829). CONCLUSIONS: Our major finding was that hypotension occurred at all doses of hyperbaric bupivacaine, yet occurrence of spinal hypotension was significantly associated with doses ≥10 mg after adjustment for potential confounders.

Perioperative mortality in older patients: a systematic review with a meta-regression analysis and meta-analysis of observational studies.

STUDY OBJECTIVE: Older patients have a higher probability of developing major complications during the perioperative period than other adult patients. Perioperative mortality depends on not only on a patient condition but also on the quality of perioperative care provided. We tested the hypothesis that the perioperative mortality rate among older patients has decreased over time and is related to a country's Human Development Index (HDI) status. DESIGN: A systematic review with a meta-regression and meta-analysis of observational studies that reported perioperative mortality rates in patients aged ≥60 years was performed. We searched the PubMed, EMBASE, LILACS and SciELO databases from inception to December 30, 2019. SETTING: Mortality rates up to the seventh postoperative day were evaluated. MEASUREMENTS: We evaluated the quality of the included studies. Perioperative mortality rates were analysed by time, country HDI status and baseline American Society of Anesthesiologists (ASA) physical status using meta-regression. Perioperative mortality and ASA status were analysed in low- and high-HDI countries during two time periods using proportion meta-analysis. MAIN RESULTS: We included 25 studies, which reported 4,412,100 anaesthesia procedures and 3568 perioperative deaths from 12 countries. Perioperative mortality rates in high-HDI countries decreased over time (P = 0.042). When comparing pre-1990 to 1990-2019, in high-HDI countries, the perioperative mortality rates per 10,000 anaesthesia procedures decreased 7.8-fold from 100.85 (95% CI 43.36 to 181.72) in pre-1990 to 12.98 (95% CI 6.47 to 21.70) in 1990-2019 (P < 0.0001). There were no studies from low-HDI countries pre-1990. In the period from 1990 to 2019, perioperative mortality rates did not differ between low- and high-HDI countries (P = 0.395) but the limited number of patients in low-HDI countries impaired the result. Perioperative mortality rates increased with increasing ASA status (P < 0.0001). There were more ASA III-V patients in high-HDI countries than in low-HDI countries (P < 0.0001), and the perioperative mortality rate increased 24-fold in ASA III-V patients compared with ASA I-II patients (P < 0.0001). CONCLUSION: The perioperative mortality rates in older patients have declined over the past 60 years in high-DHI countries, highlighting that perioperative safety in this population is increasing in these countries. Since data prior to 1990 were lacking in low-HDI countries, the evolution of their mortality rates could not be analysed. The perioperative mortality rate was similar in low- and high-HDI countries in the post-1990 period, but the low number of patients in the low-HDI countries does not allow a definitive conclusion.

Renal ischemic adverse drug events related to tranexamic acid in women of child-bearing age: an analysis of pharmacovigilance data.

PURPOSE: In response to a large trial, the World Health Organization broadened their recommendation on tranexamic acid to be used for post-partum hemorrhage. A 2013 French periodic safety update report warned of an abnormally high rate of renal cortical necrosis associated with tranexamic acid and other drugs for severe post-partum hemorrhage. We aimed to identify the reporting incidence of adverse thrombo-embolic events among women in child-bearing age who received tranexamic acid, with a focus on renal vascular and ischemic conditions. METHODS: We analyzed individual case safety reports (ICSRs) on renal vascular and ischemic conditions, pulmonary thrombotic and embolic conditions, and peripheral embolism and thrombosis from the database of the World Health Organization - Uppsala Monitoring Centre (WHO-UMC). ICSRs were restricted to reports including tranexamic acid as a suspected drug, sex reported as female, and reported age between 18 and 44 years. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated by comparing ICSRs on tranexamic acid to all other drugs in VigiBase. RESULTS: Within 2245 included ICSRs on tranexamic acid, we identified 29 reports of adverse renal vascular and ischemic conditions, 42 reports of pulmonary thrombotic and embolic conditions, and 41 reports of peripheral embolism and thrombosis. RORs were statistically significant by 32.6-fold (32.62, 95% CI: 22.50-47.29), 2.5-fold (2.52, 95% CI: 1.85-3.42), and 2.7-fold (2.67, 95% CI: 1.96-3.64), respectively, when compared to any other drug within VigiBase. CONCLUSION: Tranexamic acid might bear an increased risk for renal ischemic adverse drug events in women of child-bearing age.

The relationship between resited epidural catheters after secondary epidural catheter failure and vaginal delivery: A retrospective case-control study.

BACKGROUND: There are cases where epidural analgesia is initially effective but subsequently fails and needs to be resited. We evaluated the rate of normal vaginal delivery and operative delivery among parturients who had resited epidurals compared to parturients with epidurals that were not resited. METHODS: A retrospective electronic medical review of parturients with a singleton gestation attempting normal vaginal delivery under epidural analgesia between the years 2012-2016 was conducted. Resited epidurals were defined as epidurals that were considered effective but subsequently removed and reinserted. For each resited epidural, two previous and two consecutive deliveries of parturients with normally functioning epidural catheter inserted by the same anesthesiologist were matched controls (non-resited epidurals). RESULTS: There were 35,984 attempted vaginal deliveries with 118 resited epidurals and 472 non-resited epidurals. When adjusted for nulliparity, oxytocin administration, sex and weight of the baby, and maternal BMI, labor epidural catheter replacement was not associated with need for instrumental or caesarean delivery, (OR 1.5, 95% CI 0.91-2.49, P = .11). CONCLUSIONS: Need for labor epidural catheter replacement does not appear to be associated with need for operative delivery based on this single-centre cohort analysis.

Labor neuraxial analgesia and breastfeeding: An updated systematic review.

INTRODUCTION: There have been numerous reports studying the effect of neuraxial analgesia on breastfeeding success, but the results are inconsistent. METHODS: We performed a literature search in various databases for studies comparing neuraxial analgesia to non-neuraxial or no analgesia. Outcomes were the percentage of women breastfeeding fully or mixed with formula. Where possible, nulliparous parturients were analyzed separately. We conducted an analysis excluding studies of serious and critical risk of bias. Odds ratios and 95% confidence intervals were calculated. RESULTS: We included 15 studies (13 observational studies, 1 secondary analysis of a randomized controlled trial, 1 case-control study) with 16,112 participants. Overall, there were 6 studies that found no difference between groups, 6 studies that showed a significantly lower incidence of breastfeeding in the neuraxial group and 3 studies finding mixed results (at some time-points statistically significant and at some time-point statistically non-significant results). In nulliparous only studies, 2 found no difference between study groups, 1 found a lower breastfeeding rate in the neuraxial group and 3 studies showed mixed results. Excluding studies with a serious and critical risk of bias, 1 study found no difference between study groups, 3 studies found a decrease of breastfeeding rates in the neuraxial group, and 1 study showed mixed results. DISCUSSION: In our review we found a high disparity in results. One reason is probably the high potential of confounding (immediate skin to skin placement, maternity leave etc.). Education programs and breastfeeding support are likely more important in determining long term breastfeeding success.

Fluid loading therapy to prevent spinal hypotension in women undergoing elective caesarean section: Network meta-analysis, trial sequential analysis and meta-regression.

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 = 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.

Intrathecal hydrophilic opioids for abdominal surgery: a meta-analysis, meta-regression, and trial sequential analysis.

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] -18.4 mg, (95% confidence interval [CI]: -22.3 to -14.4)} and Day 2 (MD -25.5 mg [95% CI: -30.2 to -20.8]), pain scores at Day 1 in rest (MD -0.9 [95% CI: -1.1 to -0.7]) and during movement (MD -1.2 [95% CI: -1.6 to -0.8]), length of stay (MD -0.2 days [95% CI: -0.4 to -0.1]) and pruritus (relative risk 4.3 [95% CI: 2.5-7.5]) but not in nausea or sedation. A difference was detected for respiratory depression (odds ratio 5.5 [95% CI: 2.1-14.2]) but not when two small outlying studies were excluded (odds ratio 1.4 [95% CI: 0.4-5.2]). 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.

Sleep, Experimental Pain and Clinical Pain in Patients with Chronic Musculoskeletal Pain and Healthy Controls.

PURPOSE: Everyday variations in night sleep in healthy pain-free subjects are at most weakly associated with pain, whereas strong alterations (eg, sleep deprivation, insomnia) lead to hyperalgesic pain changes. Since it remains unclear how substantial sleep alterations need to be in order to affect the pain system and lead to a coupling of both functions, the present study aimed at providing sufficient variance for co-variance analyses by examining a sample consisting of both healthy subjects and chronic pain patients. METHODS: A sample of 20 chronic musculoskeletal pain patients and 20 healthy controls was examined. This sample was assumed to show high inter-individual variability in sleep and pain, as pain patients frequently report sleep disturbances, whereas healthy subjects were required to be pain-free and normal sleepers. Sleep of two non-consecutive nights was measured using portable polysomnography and questionnaires. Experimental pain parameters (pressure pain thresholds (PPT), temporal summation of pain (TSP), conditioned pain modulation (CPM)) and situational pain catastrophizing (SCQ) were assessed in laboratory sessions before and after sleep. Pain patients' clinical pain was assessed via questionnaire. RESULTS: As expected, both groups differed in several sleep parameters (reduced total sleep time and sleep efficiency, more time awake after sleep onset, lower subjective sleep quality in the patients) and in a few pain parameters (lower PPTs in the patients). In contrast, no differences were found in TSP, CPM, and SCQ. Contrary to our expectations, regression analyses indicated no prediction of overnight pain changes by sleep parameters. CONCLUSION: Since sleep parameters were hardly apt to predict overnight pain changes, this leaves the association of both systems mainly unproven when using between-subject variance for verification.