Does opioid therapy enhance quality of life in patients suffering from chronic non-malignant pain? A systematic review and meta-analysis.

Background and objective: Chronic pain is associated with a poor health-related quality of life (HRQL). Whereas the prescription rate of opioids increased during the last decades, their use in chronic non-malignant pain remains unclear. However, there is currently no clinical consensus or evidence-based guidelines that consider the long-term effects of opioid therapy on HRQL in patients with chronic non-cancer pain. This systematic review aims to address the question of whether opioid therapy improves HRQL in patients with chronic non-malignant pain and provide some guidance to practitioners. Databases and data treatment: PubMed, EMBASE and CENTRAL were searched in June 2020 for double-blind, randomized trials (RCTs), comparing opioid therapy to placebo and assessed a HRQL questionnaire. The review comprises a qualitative vote counting approach and a meta-analysis of the Short Form Health Survey (SF-36), EQ-5D questionnaire and the pain interference scale of the Brief pain inventory (BPI). Results: 35 RCTs were included, of which the majority reported a positive effect of opioids for the EQ-5D, the BPI and the physical component score (PCS) of the SF-36 compared to placebo. The meta-analysis of the PCS showed a mean difference of 1.82 [confidence interval: 1.32, 2.32], the meta-analysis of the EQ-5D proved a significant advantage of 0.06 [0.00, 0.12]. In the qualitative analysis of the mental component score (MCS) of the SF-36, no positive or negative trend was seen. No significant differences were seen in the MCS (MD: 0.65 [-0.43, 1.73]). A slightly higher premature dropout rate was found in the opioid group (risk difference: 0.04 [0.00, 0.07], p = .07). The body of evidence is graded as low to medium. Conclusion: Opioids have a statistically significant, but small and clinical not relevant effect on the physical dimensions of HRQL, whereas there is no effect on mental dimensions of HRQL in patients with chronic non-malignant pain during the initial months of treatment. In clinical practice, opioid prescriptions for chronic non-cancer pain should be individually assessed as their broad efficacy in improving quality of life is not confirmed. The duration of opioid treatment should be determined carefully, as this review primarily focuses on the initial months of therapy.

Population kinetic/pharmacodynamic modelling of the haemodynamic effects of cafedrine/theodrenaline (Akrinor) under general anaesthesia.

AIMS: The 20:1 combination of cafedrine and theodrenaline (C/T) is widely used in Germany for the treatment of arterial hypotension. Since there is little knowledge about the impact of covariates on the effect, the aim was to develop a kinetic/pharmacodynamic covariate model describing mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), and heart rate (HR) for 30 min after the administration of C/T. METHODS: Data of patients receiving C/T from the HYPOTENS study (NCT02893241, DRKS00010740) were analysed using nonlinear mixed-effects modelling techniques. RESULTS: Overall, 16 579 measurements from 315 patients were analysed. The combination of two kinetic compartments and a delayed effect model, coupled with distinct Emax models for HR, SBP and DBP, described the data best. The model included age, sex, body mass index (BMI), antihypertensive medication, American Society of Anaesthesiologists (ASA) physical status classification grade, baseline SBP at the time of hypotension and pre-surgery HR as covariates (all P < .001). A higher baseline SBP led to a lower absolute increase in MAP. Patients with higher age, higher BMI and lower ASA grade showed smaller increases in MAP. The initial increase was similar for male and female patients. The long-term effect was higher in women. Concomitant antihypertensive medication caused a delayed effect and a lower maximum MAP. The HR increased only slightly (median increase 2.6 bpm, P < .001). CONCLUSIONS: Seven covariates with an impact on the effect of C/T could be identified. The results will enable physicians to optimize the dose with respect to individual patients.

Pharmacologic interventions for the therapy of postanesthetic shivering in adults: a systematic review and network meta-analysis.

INTRODUCTION: Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare but can occur due to increased oxygen consumption. Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons. The objective of this manuscript was a quantitative synthesis of evidence on pharmacological interventions to treat postanesthetic shivering. EVIDENCE ACQUSITION: Systematic review and frequentist network meta-analysis using the R package netmeta. Endpoints were the risk ratio (RR) of persistent shivering at one, five and 10 minutes after treatment with saline/placebo as the comparator. Data were retrieved from Medline, Embase, Central and Web of Science up to January 2022. Eligibility criteria were: randomized, controlled, and blinded trials comparing pharmacological interventions to treat shivering after general anesthesia. Studies on shivering during or after any type of regional anesthesia were excluded as well as sedated patients after cardiac surgery. EVIDENCE SYNTHESIS: Thirty-two trials were eligible for data synthesis, including 28 pharmacological interventions. The largest network included 1431 patients. The network geometry was two-centered with most comparisons linked to saline/placebo or pethidine. The best interventions were after one minute: doxapram 2 mg/kg, tramadol 2 mg/kg and nefopam 10 mg, after 5 minutes: tramadol 2 mg/kg, nefopam 10 mg and clonidine 150 µg and after 10 minutes: nefopam 10 mg, methylphenidate 20 mg and tramadol 1 mg/kg, all reaching statistical significance. Pethidine 25 mg and clonidine 75 µg also performed well and with statistical significance in all networks. CONCLUSIONS: Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering.

The effect of adjuvants added to local anaesthetics for single-injection upper extremity peripheral regional anaesthesia: A systematic review with network meta-analysis of randomised trials.

BACKGROUND: Peripheral regional anaesthesia is frequently used for upper extremity surgery. To prolong the duration of analgesia, adjuvants can be added to single-injection local anaesthetics. Despite attempts to compare several adjuvants in pairwise meta-analyses, a comprehensive comparison is still missing. OBJECTIVE: The objective of this network meta-analysis was to determine the effectiveness of adjuvants in upper extremity peripheral nerve blocks. DESIGN: A systematic review of randomised controlled trials with network meta-analyses. DATA SOURCES: A literature search in Embase, CENTRAL, MEDLINE and Web of Science was performed up to March 2023. ELIGIBILITY CRITERIA: Randomised trials comparing different adjuvants injected perineurally in peripheral upper extremity nerve blocks were eligible. Frequentist network meta-analysis was conducted using a random effects model with physiological saline as the comparator. The primary endpoint was the ratio of means (ROM) of the duration of analgesia. RESULTS: The review included 242 randomised controlled trials with a total of 17 391 patients. Twenty-eight adjuvants were compared in the largest networks. Most network estimations consisted of a high proportion of direct evidence. Fourteen adjuvants increased the duration of analgesia significantly by the following factors, ROM [95% confidence interval (CI)]: dexamethasone 1.95 (1.79 to 2.13), buprenorphine 1.83 (1.51 to 2.24), butorphanol 1.84 (1.41 to 2.39), potassium chloride 1.89 (1.15 to 3.11), dexmedetomidine 1.70 (1.59 to 1.81), sufentanil 1.70 (1.27 to 2.29), ketorolac 1.68 (1.24 to 2.27), midazolam 1.55 (1.24 to 1.94), tramadol 1.52 (1.32 to 1.75), nalbuphine 1.50 (1.30 to 1.72), morphine 1.43 (1.09 to 1.88), magnesium sulfate 1.42 (1.20 to 1.67), clonidine 1.36 (1.24 to 1.50) and fentanyl 1.23 (1.08 to 1.40). Inconsistency in network meta-analysis was substantial. Overall side effect rates were low with all adjuvants. CONCLUSION: The best interventions to prolong the duration of analgesia were dexamethasone, followed by dexmedetomidine, opioids, electrolytes, ketorolac and midazolam. There are general concerns about the quality of underlying studies and the risk of publication bias. TRIAL REGISTRATION: PROSPERO 2018 CRD42018115722.

A randomized open label, parallel-group study to evaluate the hemodynamic effects of Cafedrine/Theodrenaline vs Noradrenaline in the treatment of intraoperative hypotension after induction of general anesthesia: the "HERO" study design and rationale.

OBJECTIVE: Intraoperative arterial hypotension (IOH) is associated with poor patient outcome. This study aims to compare the hemodynamic effects of Cafedrine/Theodrenaline (C/T) and Noradrenaline (NA) for the treatment of hypotension in patients who develop IOH after anesthesia induction. RESEARCH DESIGN AND METHODS: This is a national, randomized, parallel-group, multicenter, and open-label study. Adult patients (≥50 years, ASA-classification III-IV) who undergo elective surgery will be included. When IOH (MAP <70 mmHg) develops, C/T or NA will be given as a bolus injection ("bolus phase", 0-20 min after initial application) and subsequently as continuous infusion ("infusion phase", 21-40 min after initial application) to achieve MAP = 90 mmHg. Hemodynamic data are captured in real time by advanced hemodynamic monitoring. RESULTS: Primary endpoints, i.e. the treatment-related difference in average mean arterial pressure (MAP) during the "infusion phase" and the treatment-related difference in average cardiac index during the "bolus phase" are assessed (fixed-sequence method). Non-inferiority of C/T compared to NA in achieving 90 mmHg (MAP) when applied as continuous infusion is hypothesized. In addition, superiority of C/T over NA, applied as bolus injection, in increasing cardiac index is postulated. It is estimated that 172 patients are required to establish statistical significance with a power of 90%. After adjusting for ineligibility and dropout rate, 220 patients will be screened. CONCLUSION: This clinical trial will yield evidence for marketing authorization of C/T applied as continuous infusion. Additionally, the effects of C/T compared to NA on cardiac index will be assessed. First results of the "HERO"-study are expected in 2024. DRKS identifier: DRKS00028589. EudraCT identifier: 2021-001954-76.

Efficacy of Adjuvants in Ophthalmic Regional Anesthesia: A Systematic Review and Network Meta-analysis.

PURPOSE: This network meta-analysis aims to determine the differences between adjuvants that are used in combination with local anesthetics for ophthalmic regional anesthesia. DESIGN: Systematic review and network meta-analysis. METHODS: A systematic literature search for randomized controlled trials, comparing the impact of adjuvants in ophthalmic regional anesthesia, in Embase, CENTRAL, MEDLINE and Web of Science was performed. Risk of bias was evaluated using the Cochrane risk of bias tool. Frequentist network meta-analysis was performed using a random effects model with saline as the comparator. Primary endpoints were the onset and the duration of sensory block and globe akinesia, as well as the duration of analgesia. Summary measure was the ratio of means (ROM). Secondary endpoints were the rates of side effects and adverse events. RESULTS: A total of 39 trials were identified as eligible for network meta-analysis, including 3046 patients. In all, 17 adjuvants were compared in the most extensive network (onset of globe akinesia). The addition of fentanyl (F), clonidine (C), or dexmedetomidine (D) showed the best overall results. Onset of sensory block was as follows: F 0.58 (CI = 0.47-0.72), C 0.75 (0.63-0.88), D 0.71 (0.61-0.84); onset of globe akinesia: F 0.71 (0.61-0.82), C 0.70 (0.61-0.82), D 0.81 (0.71-0.92); duration of sensory block: F 1.20 (1.14-1.26), C 1.22 (1.18-1.27), D 1.44 (1.34-1.55); duration of globe akinesia: F 1.38 (1.22-1.57), C 1.45 (1.26-1.67), D 1.41 (1.24-1.59); and duration of analgesia: F 1.46 (1.33-1.60), C 1.78 (1.63-1.96), D 1.41 (1.28-1.56). CONCLUSIONS: The addition of fentanyl, clonidine, or dexmedetomidine showed beneficial effects regarding onset and duration of sensory block and globe akinesia.

Therapeutic drug monitoring of linezolid: HPLC-based assays for routine quantification of linezolid in human serum and cerebrospinal fluid.

OBJECTIVE: Therapeutic drug monitoring (TDM) of linezolid can prevent over- and under-dosing in critically ill patients and can be crucial to successful antibiotic treatment. Quick and simple high-performance liquid chromatography (HPLC) assays for the detection of linezolid in human serum and cerebrospinal fluid (CSF) were developed in this study. METHODS: The methods used an Atlantis T3 5.0 µm stationary phase. The mobile phase A contained water (99.4% m/m) and formic acid (0.6% m/m) (pH 2.30). The mobile phase B contained acetonitrile (93.6% m/m), water (6% m/m) and formic acid (0.4% m/m). The methods were isocratic, using 23% of mobile phase B and 77% of mobile phase A. Ultraviolet absorbance detection at 252 nm was used. For sample preparation an internal standard was added, and acetonitrile/methanol was added for protein precipitation. RESULTS: The methods were investigated for linearity, specificity, accuracy, and precision. Stability of linezolid and internal standard was assessed. The retention times of linezolid were 8.5 min and 8.1 min, and the single run time was 15 min. Linezolid was quantified from the lower limit of quantification (0.2 mg/L) to the upper limit of quantification (50 mg/L, 75 mg/L, and 100 mg/L). In routine analysis a high variability of serum and CSF levels was observed and the mean CSF/serum ratio was 0.71±0.16. CONCLUSION: The developed assays enable the study of correlations between the applied dosage, serum concentration and CSF concentration. Additionally, studies with a higher number of samples can be performed to investigate the penetration of linezolid into the central nervous system.

Equianalgesic potency ratios of opioids used in patient-controlled analgesia: A network meta-analysis.

OBJECTIVE: To determine equianalgesic potency ratios for opioids with an -evidence-based approach without the use of pre-existing potency tables. DESIGN: Frequentist network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing opioids in patient-controlled analgesia (PCA). SETTING: A systematic review. DATA SOURCES: A systematic search of MEDLINE, EMBASE, the Cochrane Library (CENTRAL), and Web of Science identified relevant RCTs from start of recording to 2019. ELIGIBILITY CRITERIA: RCTs comparing opioids via intravenous PCA in acute pain, with comparable resulting pain scores and identical treatment with coanalgesics at study level. The quality of studies was assessed using the Cochrane risk of bias tool with six items. RESULTS: 52 RCTs were identified with data for 16 opioids. Primary endpoint was the inverted ratio of means of the total consumption administered via PCA, which resembles the analgesic potency. The calculated analgesic potencies were sufentanil 423 [95 percent CI 334.99; 532.96], fentanyl 58 [48.22; 68.60], buprenorphine 37 [26.66; 50.81], remifentanil 13 [9.37; 19.13], alfentanil 7 [4.02; 11.01], hydromorphone 6 [4.96; 8.43], oxymorphone 6 [4.46; 8.84], butorphanol 4.5 [3.05; 6.73], diamorphine 2.2 [1.16; 4.10], morphine 1, oxycodone 0.9 [0.65; 1.34], piritramide 0.9 [0.55; 1.56], nalbuphine 0.7 [0.54; 0.95], pethidine 0.12 [0.10; 0.15], meptazinol 0.08 [0.03; 0.20], and tramadol 0.08 [0.07; 0.10]. CONCLUSIONS: The results in part contradict the values from the literature, which have been criticized for their imprecision. From clinical experience however, our findings seem very plausible. Short-acting opioids are less potent compared to longer acting drugs, eg, morphine, probably due to shorter intervals for -readministration.

Study protocol for a randomised, patient- and observer-blinded evaluation of P6 acustimulation for the prevention of nausea and vomiting in the postoperative period in patients receiving routine pharmacological prophylaxis (P6NV-Trial).

BACKGROUND: The efficacy of pericardium 6 (P6) acupoint stimulation to reduce the incidence of postoperative nausea and vomiting (PONV) has been proven in several randomised controlled clinical trials. However, little is known about the effectiveness in daily practice and its use in combination with traditional pharmacologic approaches. METHODS: The primary objective of the P6NV study is to determine whether intraoperative acustimulation (acupuncture or acupressure) at the point P6 provides additional benefit when applied along with customary prophylactic intravenous antiemetics administered according to the local standard operating procedures (SOP). The primary endpoint is the incidence and severity of PONV within the first 24 h postoperatively reported with a validated postoperative nausea and vomiting intensity scale. The patient-reported outcome of perioperative quality of life (using the PPP33-questionnaire) and the detection of antiemetic-related side effects as well as the severity of PONV (via a standardised questionnaire) are secondary study objectives. P6NV is a national, multicentre, randomised, prospective, patient- and examiner-blinded interventional study and will be performed on 3500 adult patients with ASA classification I-III undergoing elective surgery under general anaesthesia and hospitalised for at least 24 h. Participating anaesthesiologists commit themselves to administer customised conventional antiemetic prophylaxis according to the local SOP by signing a statement before randomisation. The intervention group receives bilateral acupuncture or acupressure at P6. The control group receives no intervention. Before extubation, acustimulation is removed. DISCUSSION: Since P6 acustimulation is performed by a wide range of anaesthesiologists receiving written and verbal information on acustimulation beforehand, this trial will provide information on the effectiveness of an ad hoc implementation of P6 stimulation techniques in anaesthesia departments using traditional pharmacologic PONV prophylaxis. TRIAL REGISTRATION: DRKS DRKS00015272 . Registered on August 15, 2018.

[Update on PONV-What is new in prophylaxis and treatment of postoperative nausea and vomiting? : Summary of recent consensus recommendations and Cochrane reviews on prophylaxis and treatment of postoperative nausea and vomiting]. / Update PONV ­ Was gibt es Neues bei der Prophylaxe und Therapie von postoperativer Übelkeit und postoperativem Erbrechen? : Zusammenfassung rezenter Konsensusempfehlungen sowie Cochrane-Reviews zu Prophylaxe und Therapie postoperativer Übelkeit und postoperativen Erbrechens.

The prophylaxis and treatment of postoperative pain to enhance patient comfort has been a primary goal of anesthesiologists for the last decades; however, avoiding postoperative nausea and vomiting (PONV) is, from a patient's perspective, a highly relevant and equally important goal of anesthesia. Recent consensus-based guidelines suggest the assessment of risk factors including female gender, postoperative opioid administration, non-smoking status, a history of PONV or motion sickness, young patient age, longer duration of anesthesia, volatile anesthetics and the type of surgery and reducing the patient's baseline risk (e.g. through the use of regional anesthesia and administration of non-opioid analgesics as part of a multimodal approach). In general, a liberal PONV prophylaxis is encouraged for adult patients and children, which should also be administered when no risk assessment is made. The basis for every adult patient should be a standard prophylaxis with two antiemetics, such as dexamethasone in combination with a 5-HT3 receptor antagonist. In patients at high risk, this should be supplemented by a third and potentially a fourth antiemetic prophylaxis with a different mechanism of action. A recently published comprehensive Cochrane meta-analysis comparing available antiemetic prophylaxes reported the highest effectiveness to prevent PONV for the NK1 receptor antagonist aprepitant (relative risk, RR 0.26), followed by ramosetron (RR 0.44), granisetron (RR 0.45), dexamethasone (RR 0.51) and ondansetron (RR 0.55), thereby revising the dogma that every antiemetic is equally effective. Adverse events of antiemetics were generally rare and reported in less than half of the included studies, yielding a low quality of evidence for these end points. In general, combinations of different antiemetics were more effective than single prophylaxes. In children above 3 years of age, the same principles should be applied as in adults. For these patients, there is a high degree of evidence for the combination of dexamethasone and 5­HT3 receptor antagonists. When PONV occurs, the consensus guidelines suggest that antiemetics from a class different than given as prophylaxis should be administered. To decrease the incidence of PONV and increase the quality of care, the importance of the implementation of institutional-level guidelines and protocols as well as assessment of PONV prophylaxis and PONV incidence is highly recommended.

Drugs for preventing postoperative nausea and vomiting in adults after general anesthesia: An abridged Cochrane network meta-analysis.

OBJECTIVE: In this abridged version of the recently published Cochrane review on antiemetic drugs, we summarize its most important findings and discuss the challenges and the time needed to prepare what is now the largest Cochrane review with network meta-analysis in terms of the number of included studies and pages in its full printed form. METHODS: We conducted a systematic review with network meta-analyses to compare and rank single antiemetic drugs and their combinations belonging to 5HT3-, D2-, NK1-receptor antagonists, corticosteroids, antihistamines, and anticholinergics used to prevent postoperative nausea and vomiting in adults after general anesthesia. RESULTS: 585 studies (97 516 participants) testing 44 single drugs and 51 drug combinations were included. The studies' overall risk of bias was assessed as low in only 27% of the studies. In 282 studies, 29 out of 36 drug combinations and 10 out of 28 single drugs lowered the risk of vomiting at least 20% compared to placebo. In the ranking of treatments, combinations of drugs were generally more effective than single drugs. Single NK1 receptor antagonists were as effective as other drug combinations. Of the 10 effective single drugs, certainty of evidence was high for aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron, while moderate for fosaprepitant and droperidol. For serious adverse events (SAEs), any adverse event (AE), and drug-class specific side effects evidence for intervention effects was mostly not convincing. CONCLUSIONS: There is high or moderate evidence for at least seven single drugs preventing postoperative vomiting. However, there is still considerable lack of evidence regarding safety aspects that does warrant investigation.

The analgesic efficacy of liposomal bupivacaine compared with bupivacaine hydrochloride for the prevention of postoperative pain: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND/IMPORTANCE: Liposomal bupivacaine (LB) is a prolonged release formulation of conventional bupivacaine designed for prolonging local or peripheral regional single injection anesthesia. To this day, the benefit of the new substance on relevant end points is discussed controversial. OBJECTIVE: The objective was to determine whether there is a difference in postoperative pain scores and morphine consumption between patients treated with LB and bupivacaine hydrochloride in a systematic review and meta-analysis. EVIDENCE REVIEW: Randomized controlled trials (RCT) were identified in Embase, CENTRAL, MEDLINE and Web of Science up to May 2020. Risk of bias was assessed using Cochrane methodology. Primary end points were the mean pain score difference and the relative morphine equivalent (MEQ) consumption expressed as the ratio of means (ROM) 24 and 72 hours postoperatively. FINDINGS: 23 RCTs including 1867 patients were eligible for meta-analysis. The mean pain score difference at 24 hours postoperatively was significantly lower in the LB group, at -0.37 (95% CI -0.56 to -0.19). The relative MEQ consumption after 24 hours was also significantly lower in the LB group, at 0.85 (0.82 to 0.89). At 72 hours, the pain score difference was not significant at -0.25 (-0.71 to 0.20) and the MEQ ratio was 0.85 (0.77 to 0.95). CONCLUSION: The beneficial effect on pain scores and opioid consumption was small but not clinically relevant, despite statistical significance. The effect was stable among all studies, indicating that it is independent of the application modality.

Treatment of spinal anaesthesia-induced hypotension with cafedrine/theodrenaline versus ephedrine during caesarean section: Results from HYPOTENS, a national, multicentre, prospective, noninterventional study.

BACKGROUND: In Germany, hypotension induced by spinal anaesthesia is commonly treated with a combination of cafedrine hydrochloride (C, 200 mg) and theodrenaline hydrochloride (T, 10 mg) in 2 ml. We compared the effectiveness of C/T with ephedrine. OBJECTIVES: The primary objectives were to assess the speed of onset and the ability to restore blood pressure without an increase in heart rate. Secondary objectives were to evaluate maternal/foetal outcomes and the number of required additional boluses or other additional measures. DESIGN: HYPOTENS was a national, multicentre, prospective, open-label, two-armed, noninterventional study comparing C/T with ephedrine in two prospectively defined cohorts. This study relates to the cohort of patients receiving spinal anaesthesia for caesarean section. SETTING: German hospitals using either C/T or ephedrine in their routine clinical practice. PATIENTS: Women aged at least 18 years receiving spinal anaesthesia for caesarean section. INTERVENTIONS: Bolus administration of C/T or ephedrine at the discretion of the attending anaesthesiologist. MAIN OUTCOME MEASURES: Endpoints within 15 min after initial administration of C/T or ephedrine were area under the curve between the observed SBP and the minimum target SBP; and incidence of newly occurring heart rate of at least 100 beats min-1. RESULTS: Although effective blood pressure stabilisation was achieved with both treatments, this effect was faster and more pronounced with C/T (P < 0.0001). The incidence of tachycardia and changes in heart rate were higher with ephedrine (P < 0.01). Fewer additional boluses (P < 0.01) were required with C/T. Although favourable neonatal outcomes were reported in both groups, base deficit and lactate values were greater with ephedrine (P < 0.01). Physician satisfaction was higher with C/T. CONCLUSIONS: After C/T, tachycardia was not a problem, providing an advantage over ephedrine. Fewer additional boluses were required with C/T, suggesting greater effectiveness. An increased base deficit with ephedrine suggests reduced oxygen supply or increased demands in foetal circulation. TRIALS REGISTRATION: Clinicaltrials.gov: NCT02893241, German Clinical Trials Register: DRKS00010740.

Context-sensitive decrement times for inhaled anesthetics in obese patients explored with Gas Man®.

Anesthesia care providers and anesthesia decision support tools use mathematical pharmacokinetic models to control delivery and especially removal of anesthetics from the patient's body. However, these models are not able to reflect alterations in pharmacokinetics of volatile anesthetics caused by obesity. The primary aim of this study was to refine those models for obese patients. To investigate the effects of obesity on the elimination of desflurane, isoflurane and sevoflurane for various anesthesia durations, the Gas Man® computer simulation software was used. Four different models simulating patients with weights of 70 kg, 100 kg, 125 kg and 150 kg were constructed by increasing fat weight to the standard 70 kg model. For each modelled patient condition, the vaporizer was set to reach quickly and then maintain an alveolar concentration of 1.0 minimum alveolar concentration (MAC). Subsequently, the circuit was switched to an open (non-rebreathing) circuit model, the inspiratory anesthetic concentration was set to 0 and the time to the anesthetic decrements by 67% (awakening times), 90% (recovery times) and 95% (resolution times) in the vessel-rich tissue compartment including highly perfused tissue of the central nervous system were determined. Awakening times did not differ greatly between the simulation models. After volatile anesthesia with sevoflurane and isoflurane, awakening times were lower in the more obese simulation models. With increasing obesity, recovery and resolution times were higher. The additional adipose tissue in obese simulation models did not prolong awakening times and thus may act more like a sink for volatile anesthetics. The results of these simulations should be validated by comparing the elimination of volatile anesthetics in obese patients with data from our simulation models.

Hypertonic Saline Versus Mannitol for Traumatic Brain Injury: A Systematic Review and Meta-analysis With Trial Sequential Analysis.

BACKGROUND: Mannitol and hypertonic saline are widely used to treat raised intracranial pressure (ICP) after traumatic brain injury (TBI), but the clinical superiority of one over the other has not been demonstrated. METHODS: According to the PRISMA statement, this meta-analysis reports on randomized controlled trials investigating hypertonic saline compared with mannitol in the treatment of elevated ICP following TBI. The protocol for the literature searches (Medline, Embase, Central databases), quality assessment, endpoints (mortality, favorable outcome, brain perfusion parameters), and statistical analysis plan (including a trial sequential analysis) were prospectively specified and registered on the PROSPERO database (CRD42017057112). RESULTS: A total of 12 randomized controlled trials with 464 patients were eligible for inclusion in this analysis. Although there was a nonsignificant trend in favor of hypertonic saline, there were no significant differences in mortality between the 2 treatments (relative risk [RR]: 0.69, 95% confidence interval [CI]: 0.45, 1.04; P=0.08). There were also no significant differences in favorable neurological outcome between hypertonic saline (HS) and mannitol (RR: 1.28, 95% CI: 0.86, 1.90; P=0.23). There was no difference in ICP at 30 to 60 minutes after treatment (mean difference [MD]: -0.19 mm Hg, 95% CI: -0.54, 0.17; P=0.30), whereas ICP was significantly lower after HS compared with mannitol at 90 to 120 minutes (MD: -2.33 mm Hg, 95% CI: -3.17, -1.50; P<0.00001). Cerebral perfusion pressure was higher between 30 to 60 and 90 to 120 minutes after treatment with HS compared with after treatment with mannitol (MD: 5.48 mm Hg, 95% CI: 4.84, 6.12; P<0.00001 and 9.08 mm Hg, 95% CI: 7.54, 10.62; P<0.00001, respectively). Trial sequential analysis showed that the number of cases was insufficient to produce reliable statements on long-term outcomes. CONCLUSION: There are indications that HS might be superior to mannitol in the treatment of TBI-related raised ICP. However, there are insufficient data to reach a definitive conclusion, and further studies are warranted.

Risk-adapted strategy or universal multimodal approach for PONV prophylaxis?

The issue of postoperative nausea and vomiting (PONV) remains important in surgical practice, contributing to patient distress, slower recovery, and increased use of healthcare resources. Many surgical patients report it to be a worse problem than pain. Numerous findings of research indicate that PONV significantly affects patients' well-being and is among the important determinants of patient satisfaction with perioperative care. Numerous investigations have confirmed the efficacy of combining pharmacological interventions indicating that PONV is a clinical complication that is in principle avoidable. Nonetheless, PONV continues to be bothersome for too many patients. Thus, perhaps the biggest challenge across the field is to achieve a uniformly high standard of PONV management using the currently available resources. Although a risk-adapted approach has been advocated in the past, the current trend incorporated in clinical guidelines support a more liberal approach of multimodal antiemetic prevention. The current article emphasizes pros and cons of the various approaches to PONV prophylaxis and depicts most promising strategies to achieve a "PONV-free hospital."

Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common adverse effect of anaesthesia and surgery. Up to 80% of patients may be affected. These outcomes are a major cause of patient dissatisfaction and may lead to prolonged hospital stay and higher costs of care along with more severe complications. Many antiemetic drugs are available for prophylaxis. They have various mechanisms of action and side effects, but there is still uncertainty about which drugs are most effective with the fewest side effects. OBJECTIVES: • To compare the efficacy and safety of different prophylactic pharmacologic interventions (antiemetic drugs) against no treatment, against placebo, or against each other (as monotherapy or combination prophylaxis) for prevention of postoperative nausea and vomiting in adults undergoing any type of surgery under general anaesthesia • To generate a clinically useful ranking of antiemetic drugs (monotherapy and combination prophylaxis) based on efficacy and safety • To identify the best dose or dose range of antiemetic drugs in terms of efficacy and safety SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and reference lists of relevant systematic reviews. The first search was performed in November 2017 and was updated in April 2020. In the update of the search, 39 eligible studies were found that were not included in the analysis (listed as awaiting classification). SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing effectiveness or side effects of single antiemetic drugs in any dose or combination against each other or against an inactive control in adults undergoing any type of surgery under general anaesthesia. All antiemetic drugs belonged to one of the following substance classes: 5-HT3 receptor antagonists, D2 receptor antagonists, NK1 receptor antagonists, corticosteroids, antihistamines, and anticholinergics. No language restrictions were applied. Abstract publications were excluded. DATA COLLECTION AND ANALYSIS: A review team of 11 authors independently assessed trials for inclusion and risk of bias and subsequently extracted data. We performed pair-wise meta-analyses for drugs of direct interest (amisulpride, aprepitant, casopitant, dexamethasone, dimenhydrinate, dolasetron, droperidol, fosaprepitant, granisetron, haloperidol, meclizine, methylprednisolone, metoclopramide, ondansetron, palonosetron, perphenazine, promethazine, ramosetron, rolapitant, scopolamine, and tropisetron) compared to placebo (inactive control). We performed network meta-analyses (NMAs) to estimate the relative effects and ranking (with placebo as reference) of all available single drugs and combinations. Primary outcomes were vomiting within 24 hours postoperatively, serious adverse events (SAEs), and any adverse event (AE). Secondary outcomes were drug class-specific side effects (e.g. headache), mortality, early and late vomiting, nausea, and complete response. We performed subgroup network meta-analysis with dose of drugs as a moderator variable using dose ranges based on previous consensus recommendations. We assessed certainty of evidence of NMA treatment effects for all primary outcomes and drug class-specific side effects according to GRADE (CINeMA, Confidence in Network Meta-Analysis). We restricted GRADE assessment to single drugs of direct interest compared to placebo. MAIN RESULTS: We included 585 studies (97,516 randomized participants). Most of these studies were small (median sample size of 100); they were published between 1965 and 2017 and were primarily conducted in Asia (51%), Europe (25%), and North America (16%). Mean age of the overall population was 42 years. Most participants were women (83%), had American Society of Anesthesiologists (ASA) physical status I and II (70%), received perioperative opioids (88%), and underwent gynaecologic (32%) or gastrointestinal surgery (19%) under general anaesthesia using volatile anaesthetics (88%). In this review, 44 single drugs and 51 drug combinations were compared. Most studies investigated only single drugs (72%) and included an inactive control arm (66%). The three most investigated single drugs in this review were ondansetron (246 studies), dexamethasone (120 studies), and droperidol (97 studies). Almost all studies (89%) reported at least one efficacy outcome relevant for this review. However, only 56% reported at least one relevant safety outcome. Altogether, 157 studies (27%) were assessed as having overall low risk of bias, 101 studies (17%) overall high risk of bias, and 327 studies (56%) overall unclear risk of bias. Vomiting within 24 hours postoperatively Relative effects from NMA for vomiting within 24 hours (282 RCTs, 50,812 participants, 28 single drugs, and 36 drug combinations) suggest that 29 out of 36 drug combinations and 10 out of 28 single drugs showed a clinically important benefit (defined as the upper end of the 95% confidence interval (CI) below a risk ratio (RR) of 0.8) compared to placebo. Combinations of drugs were generally more effective than single drugs in preventing vomiting. However, single NK1 receptor antagonists showed treatment effects similar to most of the drug combinations. High-certainty evidence suggests that the following single drugs reduce vomiting (ordered by decreasing efficacy): aprepitant (RR 0.26, 95% CI 0.18 to 0.38, high certainty, rank 3/28 of single drugs); ramosetron (RR 0.44, 95% CI 0.32 to 0.59, high certainty, rank 5/28); granisetron (RR 0.45, 95% CI 0.38 to 0.54, high certainty, rank 6/28); dexamethasone (RR 0.51, 95% CI 0.44 to 0.57, high certainty, rank 8/28); and ondansetron (RR 0.55, 95% CI 0.51 to 0.60, high certainty, rank 13/28). Moderate-certainty evidence suggests that the following single drugs probably reduce vomiting: fosaprepitant (RR 0.06, 95% CI 0.02 to 0.21, moderate certainty, rank 1/28) and droperidol (RR 0.61, 95% CI 0.54 to 0.69, moderate certainty, rank 20/28). Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol showed clinically important benefit, but low doses showed no clinically important benefit. Aprepitant was used mainly at high doses, ramosetron at recommended doses, and fosaprepitant at doses of 150 mg (with no dose recommendation available). Frequency of SAEs Twenty-eight RCTs were included in the NMA for SAEs (10,766 participants, 13 single drugs, and eight drug combinations). The certainty of evidence for SAEs when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to low. Droperidol (RR 0.88, 95% CI 0.08 to 9.71, low certainty, rank 6/13) may reduce SAEs. We are uncertain about the effects of aprepitant (RR 1.39, 95% CI 0.26 to 7.36, very low certainty, rank 11/13), ramosetron (RR 0.89, 95% CI 0.05 to 15.74, very low certainty, rank 7/13), granisetron (RR 1.21, 95% CI 0.11 to 13.15, very low certainty, rank 10/13), dexamethasone (RR 1.16, 95% CI 0.28 to 4.85, very low certainty, rank 9/13), and ondansetron (RR 1.62, 95% CI 0.32 to 8.10, very low certainty, rank 12/13). No studies reporting SAEs were available for fosaprepitant. Frequency of any AE Sixty-one RCTs were included in the NMA for any AE (19,423 participants, 15 single drugs, and 11 drug combinations). The certainty of evidence for any AE when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to moderate. Granisetron (RR 0.92, 95% CI 0.80 to 1.05, moderate certainty, rank 7/15) probably has no or little effect on any AE. Dexamethasone (RR 0.77, 95% CI 0.55 to 1.08, low certainty, rank 2/15) and droperidol (RR 0.89, 95% CI 0.81 to 0.98, low certainty, rank 6/15) may reduce any AE. Ondansetron (RR 0.95, 95% CI 0.88 to 1.01, low certainty, rank 9/15) may have little or no effect on any AE. We are uncertain about the effects of aprepitant (RR 0.87, 95% CI 0.78 to 0.97, very low certainty, rank 3/15) and ramosetron (RR 1.00, 95% CI 0.65 to 1.54, very low certainty, rank 11/15) on any AE. No studies reporting any AE were available for fosaprepitant. Class-specific side effects For class-specific side effects (headache, constipation, wound infection, extrapyramidal symptoms, sedation, arrhythmia, and QT prolongation) of relevant substances, the certainty of evidence for the best and most reliable anti-vomiting drugs mostly ranged from very low to low. Exceptions were that ondansetron probably increases headache (RR 1.16, 95% CI 1.06 to 1.28, moderate certainty, rank 18/23) and probably reduces sedation (RR 0.87, 95% CI 0.79 to 0.96, moderate certainty, rank 5/24) compared to placebo. The latter effect is limited to recommended and high doses of ondansetron. Droperidol probably reduces headache (RR 0.76, 95% CI 0.67 to 0.86, moderate certainty, rank 5/23) compared to placebo. We have high-certainty evidence that dexamethasone (RR 1.00, 95% CI 0.91 to 1.09, high certainty, rank 16/24) has no effect on sedation compared to placebo. No studies assessed substance class-specific side effects for fosaprepitant. Direction and magnitude of network effect estimates together with level of evidence certainty are graphically summarized for all pre-defined GRADE-relevant outcomes and all drugs of direct interest compared to placebo in http://doi.org/10.5281/zenodo.4066353. AUTHORS' CONCLUSIONS: We found high-certainty evidence that five single drugs (aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron) reduce vomiting, and moderate-certainty evidence that two other single drugs (fosaprepitant and droperidol) probably reducevomiting, compared to placebo. Four of the six substance classes (5-HT3 receptor antagonists, D2 receptor antagonists, NK1 receptor antagonists, and corticosteroids) were thus represented by at least one drug with important benefit for prevention of vomiting. Combinations of drugs were generally more effective than the corresponding single drugs in preventing vomiting. NK1 receptor antagonists were the most effective drug class and had comparable efficacy to most of the drug combinations. 5-HT3 receptor antagonists were the best studied substance class. For most of the single drugs of direct interest, we found only very low to low certainty evidence for safety outcomes such as occurrence of SAEs, any AE, and substance class-specific side effects. Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol were more effective than low doses for prevention of vomiting. Dose dependency of side effects was rarely found due to the limited number of studies, except for the less sedating effect of recommended and high doses of ondansetron. The results of the review are transferable mainly to patients at higher risk of nausea and vomiting (i.e. healthy women undergoing inhalational anaesthesia and receiving perioperative opioids). Overall study quality was limited, but certainty assessments of effect estimates consider this limitation. No further efficacy studies are needed as there is evidence of moderate to high certainty for seven single drugs with relevant benefit for prevention of vomiting. However, additional studies are needed to investigate potential side effects of these drugs and to examine higher-risk patient populations (e.g. individuals with diabetes and heart disease).

Preoperative anxiety in adults - a cross-sectional study on specific fears and risk factors.

BACKGROUND: Preoperative anxiety comprising anesthesia and surgery related anxiety is common and perceived by many patients as the worst aspect of the surgical episode. The aim of this study was to identify independent predictors of these three anxieties dimensions and to quantify the relevance of specific fears particularly associated with anesthesia. METHODS: This study was part of a cross-sectional survey in patients scheduled to undergo elective surgery. Anxiety levels were measured with the Amsterdam Preoperative Anxiety and Information Scale (APAIS). Modified numeric rating scales (mNRS, range 0-10) were used to assess the severity of eight selected specific fears which were predominantly analyzed descriptively. Multivariate stepwise linear regression was applied to determine independent predictors of all three anxiety dimensions (APAIS anxiety subscales). RESULTS: 3087 of the 3200 enrolled patients were analyzed. Mean (SD) total preoperative anxiety (APAIS-A-T, range 4-20) was 9.9 (3.6). High anxiety (APAIS-A-T > 10) was reported by 40.5% of subjects. Mean (SD) levels of concern regarding the eight studied specific fears ranged from 3.9 (3.08) concerning "Anesthesiologist error" to 2.4 (2.29) concerning "Fatigue and drowsiness" with an average of 3.2 (2.84) concerning all specific fears. Ranking of all specific fears according to mean mNRS scores was almost identical in patients with high versus those with low anxiety. Among nine independent predictors of anxiety, only 3 variables (female gender, negative and positive anesthetic experience) independently predicted all three APAIS anxiety subscales. Other variables had a selective impact on one or two APAIS anxiety subscales only. Female gender had the strongest impact on all three APAIS anxiety subscales. Adjusted r2 values of the three models were all below 13%. CONCLUSIONS: The high variability of importance assigned to all specific fears suggests an individualized approach is advisable when support of anxious patients is intended. Considering independent predictors of anxiety to estimate each patient's anxiety level is of limited use given the very low predictive capacity of all three models. The clinical benefit of dividing patients into those with high and low anxiety is questionable. TRIAL REGISTRATION: German Registry of Clinical Trials (DRKS00016725), retrospectively registered.

An overview of intravenous amisulpride as a new therapeutic option for the prophylaxis and treatment of postoperative nausea and vomiting.

Introduction: Current therapies of postoperative nausea and vomiting (PONV) are based on a combination of antiemetics from different pharmacological classes. Dopamine receptor antagonists are one of the cornerstones of such multimodal antiemetic approach, with droperidol being the best studied representative of this group. Droperidol's use has significantly declined after the FDA's black-box warning in 2001 due to its QT-prolonging properties. Amisulpride is a promising antiemetic agent which could fill this gap.Areas covered: In this review, the authors discuss the pharmacological profile as well as clinical safety and efficacy of intravenous amisulpride and its relevance in the management of PONV. The article is based on a Medline, ClinicalTrials.gov, and Cochrane Library search for studies on amisulpride conducted so far.Expert opinion: Promising clinical results on Barhemsys®, an intravenous formulation of amisulpride, make it a potential future drug of choice from the dopamine receptor antagonist group, replacing droperidol after its safety concerns. Amisulpride's success on the market will mostly be determined by its cost-effectiveness and it will likely find a brighter use on the US-market, where the black-box warning led to droperidol's withdrawal, while in many European countries, droperidol is still being used as an antiemetic.