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This trial assessed the pharmacokinetics, pharmacodynamics, and safety of liposomal bupivacaine given via ultrasound-guided popliteal sciatic nerve block with or without immediate-release bupivacaine hydrochloride in adults having bunionectomies. Forty-five adults were enrolled into four sequential cohorts: (1) liposomal bupivacaine 266 mg with bupivacaine hydrochloride 50 mg; (2) liposomal bupivacaine 133 mg with bupivacaine hydrochloride 50 mg; (3) liposomal bupivacaine 266 mg; or (4) bupivacaine hydrochloride 100 mg. Outcomes included pharmacokinetics (e.g., bupivacaine maximum plasma concentration [C max ]), onset and duration of motor and sensory nerve block, and safety. Liposomal bupivacaine admixed with bupivacaine hydrochloride produced biphasic bupivacaine plasma disposition profiles with two distinct peaks. Geometric mean C max of the early peak ranged from 235 to 421 ng/mL and the geometric mean of the late C max was ∼30%-50% lower than the early peak. Median time to sensory block onset was 18 to 29 min in all cohorts. Sensory blocks lasted about twice as long with liposomal bupivacaine (median, 119-167 h) than with bupivacaine hydrochloride alone (median, 67 h). There were no serious adverse events. In conclusion, liposomal bupivacaine provided prolonged sensory nerve block when given as popliteal sciatic nerve blocks with or without bupivacaine hydrochloride, and bupivacaine plasma concentrations were well below the lower bound of the toxicity threshold of 2000 ng/mL for all cohorts., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Intraoperative controlled hypotension improves surgical field visibility by reducing blood loss (efficacy) but poses potential risks linked to organ hypoperfusion (safety). The use of controlled hypotension persists despite increasing evidence of associations between intraoperative inadvertent hypotension and adverse outcomes. Therefore, we tested the hypothesis that the focus and results of intraoperative controlled hypertension research differ across anaesthesia and surgery investigators because of differing priorities., Methods: We systematically reviewed randomised trials comparing controlled hypotension with usual care with trials categorised by investigators' affiliation., Results: We identified 48 eligible trials, of which 37 were conducted by anaesthesia investigators and 11 by surgery investigators. For the primary outcome, 54% of the anaesthesia-led trials focused on safety, whereas all (100%) surgery-led trials focused on efficacy (P=0.004). Compared with usual care, mean arterial pressure in controlled hypotension was 23% (95% confidence interval [CI] 17-29%) lower in anaesthesia trials and 30% (95% CI 14-37%) lower in surgery trials; estimated blood loss was 44% (95% CI 30-55%) less in anaesthesia trials and 38% (95% CI 30-49%) less in surgery trials. Overall, blood loss was reduced by 43% (95% CI 32-53%), and trial sequential analysis supported an efficacy conclusion. Mean arterial pressure and estimated blood loss reductions were associated (R 2 =0.41, P=0.002). All trials were underpowered for safety outcomes, and none adequately evaluated myocardial or renal injury., Conclusions: Anaesthesia researchers prioritised safety outcomes, whereas surgery researchers emphasised efficacy in controlled hypotension trials. Controlled hypotension significantly reduces blood loss. In contrast, safety outcomes were poorly studied. Given increasing observational evidence linking inadvertent hypotension to myocardial and renal injury, the safety of controlled hypotension remains to be addressed., Systematic Review Protocol: PROSPERO (CRD42023450397)., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Purpose: There are different techniques for ultrasound-guided central venous catheter (CVC) insertion. When using the conventional syringe-on-needle technique, the syringe needs to be removed from the needle after venous puncture to pass the guidewire through the needle into the vein. When, alternatively, using the wire-in-needle technique, the needle is preloaded with the guidewire, and the guidewire-after venous puncture-is advanced into the vein under real-time ultrasound guidance. We tested the hypothesis that the wire-in-needle technique reduces the time to successful guidewire insertion in the internal jugular vein compared with the syringe-on-needle technique in adults., Methods: We randomized 250 patients to the wire-in-needle or syringe-on-needle technique. Our primary endpoint was the time to successful guidewire insertion in the internal jugular vein., Results: Two hundred and thirty eight patients were analyzed. The median (25th percentile, 75th percentile) time to successful guidewire insertion was 22 (16, 38) s in patients assigned to the wire-in-needle technique and 25 (19, 34) s in patients assigned to the syringe-on-needle technique (estimated location shift: 2 s; 95%-confidence-interval: - 1 to 5 s, p = 0.165). CVC insertion was successful on the first attempt in 103/116 patients (89%) assigned to the wire-in-needle technique and in 113/122 patients (93%) assigned to the syringe-on-needle technique. CVC insertion-related complications occurred in 8/116 patients (7%) assigned to the wire-in-needle technique and 19/122 patients (16%) assigned to the syringe-on-needle technique., Conclusion: The wire-in-needle technique-compared with the syringe-on-needle technique-did not reduce the time to successful guidewire insertion in the internal jugular vein. Clinicians can consider either technique for ultrasound-guided CVC insertion in adults., (© 2024. The Author(s).)

Background: Glycyrrhiza glabrata (licorice) is used in traditional medicine and herbal remedies and reduces sore throats consequent to intubation, but whether it is protective for more intense pain after oropharyngeal surgery remains unclear. We thus tested the joint hypothesis that gargling with licorice, which has anti-inflammatory and antioxidant properties, reduces postoperative pain and morphine consumption., Methods: We enrolled patients having elective oropharyngeal surgery. Participants were randomly allocated to gargle with either 1 g licorice or a sugar placebo before and for up to three days after surgery. A numerical rating scale (NRS) for pain along with morphine consumption was evaluated every 30 min during the post-anesthesia care unit (PACU) stay and then three times daily for three days. We pre-specified that licorice gargling would be deemed better than sugar gargling only if found non-inferior on both morphine consumption and pain score and superior on at least one of the two., Results: 65 patients were randomized to the licorice group and 61 to placebo. We found noninferiority (NI) in pain scores with an estimated mean difference of -0.09 (95.2% CI: -0.88, 0.70; p = 0.001; NI delta = 1) between licorice and placebo gargling. There were no adverse events reported in either group that required treatment discontinuation., Conclusions: Gargling with licorice did not significantly or meaningfully reduce postoperative pain or morphine consumption in patients recovering from oropharyngeal surgery. While higher doses might prove more effective, our results suggest that other topical analgesics should be considered.

Background: The incidence of central venous catheter-related thrombosis and the long-term effects of thrombosis on catheterized veins in neonates is unknown. We therefore determined the incidence of central venous thrombosis, identified associated risk factors, and evaluated outcomes at 6 months., Methods: We enrolled neonates aged less than 28 days scheduled for major intestinal or cardiac surgery whom we expected to require central venous catheters for at least 48 hours. Catheter size, insertion method, and puncture site were determined by the attending anesthesiologist. The duration of catheterization was also determined by clinical need. Central venous thrombi were diagnosed by color Doppler ultrasound imaging within 48 hours after catheter removal; results were not shared with clinicians. Ultrasound examinations were repeated 1, 3, and 6 months after discharge., Results: We enrolled 188 neonates over 2 years. The median duration of catheter insertion was 12 days. 128 (68%) of the neonates had central venous thrombi at the catheter site, all of which were asymptomatic. Among patients with thrombi, 29 (23%) had complete vessel occlusion and 5 (4%) had venous stenosis at 6 months after discharge. Thrombi therefore spontaneously resolved by 6 months in 73% of the neonates. CVC/vein diameter ratio, duration of catheterization, and catheter dysfunction were independent risk factors for vessel thrombus. Complete vessel occlusion was most common in patients whose thrombus occupied more than 58% of the vessel at the initial assessment., Conclusions: Covert central venous thrombosis is frequent in neonates who have central venous catheters, and complications are most common in patients who have large intravascular thrombi. Neonates with large intravascular thrombi should be followed, and considered for anticoagulation., Competing Interests: Competing interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: Minimally invasive thoracic surgery is associated with substantial pain that can impair pulmonary function. Fascial plane blocks may offer a favorable alternative to opioids, but conventional local anesthetics provide a limited duration of analgesia. We therefore tested the primary hypothesis that a mixture of liposomal bupivacaine and plain bupivacaine improves the overall benefit of analgesia score (OBAS) during the first three postoperative days compared to bupivacaine alone. Secondarily, we tested the hypotheses that liposomal bupivacaine improves respiratory mechanics, and decreases opioid consumption., Methods: Adults scheduled for robotically or video-assisted thoracic surgery with combined ultrasound-guided pectoralis II and serratus anterior plane block were randomized to bupivacaine or bupivacaine combined with liposomal bupivacaine. OBAS was measured on postoperative days 1-3 and was analyzed with a linear mixed regression model. Postoperative respiratory mechanics were estimated using a linear mixed model. Total opioid consumption was estimated with a simple linear regression model., Results: We analyzed 189 patients, of whom 95 were randomized to the treatment group and 94 to the control group. There was no significant treatment effect on total OBAS during the initial three postoperative days, with an estimated geometric mean ratio of 0.93 (95% CI: 0.76, 1.14; p = 0.485). There was no observed treatment effect on respiratory mechanics, total opioid consumption, or pain scores. Average pain scores were low in both groups., Conclusions: Liposomal bupivacaine did not improve OBAS during the initial postoperative three days following minimally invasive thoracic procedures. Furthermore, there was no improvement in respiratory mechanics, no reduction in opioid consumption, and no decrease in pain scores. Thus, the data presented here does not support the use of liposomal bupivacaine over standard bupivacaine to enhance analgesia after minimally invasive thoracic surgery., Summary Statement: For minimally invasive thoracic procedures, addition of liposomal bupivacaine to plain bupivacaine for thoracic fascial plane blocks does not improve OBAS, reduce opioid requirements, improve postoperative respiratory mechanics, or decrease pain scores., Competing Interests: Declaration of competing interest Sudish Murthy is a consultant for Advanced Medical Solutions, LLC, an advisor for Lazzaro Medical, and received honoraria from Intuitive Surgical and Medtronic; Alparslan Turan is a consultant for Civco medical and received a research grant from Pacira Pharmaceuticals. Daniel I Sessler - is a consultant for Pacira Pharmaceuticals. Other authors have no conflicts of interest to declare. Sudish Murthy is a consultant for Advanced Medical Solutions, LLC, an advisor for Lazzaro Medical, and received honoraria from Intuitive Surgical and Medtronic; Alparslan Turan is a consultant for Civco medical and received a research grant from Pacira Pharmaceuticals. All other authors declare no conflicts of interest. Pacira Pharmaceuticals was not involved in the data collection, data analysis, preparation of paper, or the decision to submit. The manuscript was not shared with the sponsor., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The efficacy of superficial cervical plexus blocks for reducing persistent pain after craniotomies remains unclear. We therefore tested the primary hypothesis that preoperative ultrasound-guided superficial cervical plexus blocks reduce persistent pain 3 months after suboccipital craniotomies., Methods: We conducted a single-center randomized and blinded parallel-group trial. Eligible patients having suboccipital craniotomies were randomly allocated to superficial cervical plexus blocks with 10 ml of 0.5% ropivacaine or a comparable amount of normal saline. Injections were into the superficial layer of prevertebral fascia. The primary outcome was the incidence of persistent pain three months after surgery., Results: From Nov 2021 to August 2023, 292 qualifying patients were randomly allocated to blocks with ropivacaine (n=146) or saline (n=146). The average ± SD age of participating patients was 45±12 years and the duration of surgery was 4.2±1.3 hours. Persistent pain 3 months after surgery was reported by 48 (34%) of patients randomized to ropivacaine versus 73 (51%) in those assigned to saline (relative risk 0.66; 95% CI, 0.50 to 0.88; P = 0.003) in the per-protocol population, and by 53 (36%) of patients randomized to ropivacaine versus 77 (53%) in those assigned to saline (relative risk 0.69, 95% CI, 0.53 to 0.90; P = 0.005) in the intention-to-treat population., Conclusion: Superficial cervical plexus blocks reduce the incidence of persistent incisional pain by about a third in patients recovering from suboccipital craniotomies., Competing Interests: Conflicts of Interest: The authors declare no relevant competing interests., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Three linked clinical observations prompted our current understanding of perioperative heat balance. The first was the extraordinarily rapid decrease in core temperature after induction of general anesthesia which led to an understanding of redistribution hypothermia. The second was the linear reduction in core temperature during the subsequent 2-3 h which led to an understanding of anesthetic effects on metabolic heat production and factors that influence cutaneous heat loss. And the third was the observation that core temperature reaches a plateau at about 34.5 °C which led to the understanding that thermoregulatory vasoconstriction re-emerges when patients become sufficiently hypothermic, and that arteri-venous shunt constriction constrains metabolic heat to the core thermal compartment., Competing Interests: Declaration of competing interest Dr. Sessler occasionally consults for temperature-related companies and donates all fees to charity., (Copyright © 2023. Published by Elsevier Inc.)

Background: The Hypotension Prediction Index (the index) software is a machine learning algorithm that detects physiologic changes that may lead to hypotension. The original validation used a case control (backward) analysis that has been suggested to be biased. This study therefore conducted a cohort (forward) analysis and compared this to the original validation technique., Methods: A retrospective analysis of data from previously reported studies was conducted. All data were analyzed identically with two different methodologies, and receiver operating characteristic curves were constructed. Both backward and forward analyses were performed to examine differences in area under the receiver operating characteristic curves for the Hypotension Prediction Index and other hemodynamic variables to predict a mean arterial pressure (MAP) less than 65 mmHg for at least 1 min 5, 10, and 15 min in advance., Results: The analysis included 2,022 patients, yielding 4,152,124 measurements taken at 20-s intervals. The area under the curve for the index predicting hypotension analyzed by backward and forward methodologies respectively was 0.957 (95% CI, 0.947 to 0.964) versus 0.923 (95% CI, 0.912 to 0.933) 5 min in advance, 0.933 (95% CI, 0.924 to 0.942) versus 0.923 (95% CI, 0.911 to 0.933) 10 min in advance, and 0.929 (95% CI, 0.918 to 0.938) versus 0.926 (95% CI, 0.914 to 0.937) 15 min in advance. No variable other than MAP had an area under the curve greater than 0.7. The areas under the curve using forward analysis for MAP predicting hypotension 5, 10, and 15 min in advance were 0.932 (95% CI, 0.920 to 0.940), 0.929 (95% CI, 0.918 to 0.938), and 0.932 (95% CI, 0.921 to 0.940), respectively. The R2 for the variation in the index due to MAP was 0.77., Conclusions: Using an updated methodology, the study found that the utility of the Hypotension Prediction Index to predict future hypotensive events is high, with an area under the receiver operating characteristics curve similar to that of the original validation method., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Study Objective: The use of hydroxyethyl starch 130/0.4 has been linked to renal injury in critically ill patients, but its impact on surgical patients remains uncertain., Design: A retrospective cohort study., Setting: This study was conducted at one tertiary care hospital in China., Patients: We evaluated the records of 51,926 Chinese adults who underwent noncardiac surgery from 2013 to 2022. Patients given a combination of hydroxyethyl starch 130/0.4 and crystalloids were propensity-matched at a 1: 1 ratio of baseline characteristics to patients given only crystalloids (11,725 pairs)., Interventions: Eligible patients were divided into those given a combination of hydroxyethyl starch 130/0.4 and crystalloid during surgery and a reference crystalloid group consisting of patients who were not given any colloid., Measurements: The primary outcome was the incidence of acute kidney injury. Secondarily, acute kidney injury stage, need for renal replacement therapy, intensive care unit transfer rate, and duration of postoperative hospitalization were considered., Main Results: After matching, hydroxyethyl starch use [8.5 (IQR: 7.5-10.0) mL/kg] did not increase the incidence of acute kidney injury compared with that in the crystalloid group [2.0 vs. 2.2%, OR: 0.90 (0.74-1.08), P = 0.25]. Nor did hydroxyethyl starch use worsen acute kidney injury stage [OR 0.90 (0.75-1.08), P = 0.26]. No significant differences between the fluid groups were observed in renal replacement therapy [OR 0.60 (0.41-0.90), P = 0.02)] or intensive care unit transfers [OR 1.02 (0.95-1.09), P = 0.53] after Bonferroni correction. Even in a subset of patients at high risk of renal injury, hydroxyethyl starch use was not associated with worse outcomes., Conclusions: Hydroxyethyl starch 130/0.4 use was not significantly associated with a greater incidence of postoperative acute kidney injury compared to receiving crystalloid solutions only., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Troponin elevation after noncardiac surgery is associated with an elevated risk of 30-day mortality. Little is known about relative merit of using a high-sensitivity Troponin T (hsTnT), the fifth-generation assay, vs the nonhigh sensitivity Troponin T (non-hsTnT), the fourth-generation assay, in the noncardiac surgery setting. We aimed to identify whether hsTnT can identify additional patients at risk that would have gone undetected with non-hsTnT measurement., Methods: The VISION Study included 40,004 noncardiac surgery patients with postoperative troponin measurements. Among them, 1,806 patients had both fourth-generation non-hsTnT and fifth-generation hsTnT concomitant measurements (4,451 paired results). We compared the absolute concentrations, the timing, and the impact of different thresholds on predicting 30-day major cardiovascular complications (composite of death, nonfatal cardiac arrest, coronary revascularization, and congestive heart failure)., Results: Based on the manufacturers' threshold of 14 ng/L, 580 (32.1%) patients had postoperative hsTnT concentrations greater than the threshold, while their non-hsTnT concentrations were below the manufacturer's threshold. These 580 patients had higher risk of major cardiovascular events (OR 2.33; CI 95% 1.04-5.23; P = .049) than patients with hsTnT concentrations below the manufacturer threshold. Among patients with myocardial injury after noncardiac surgery, only 50% would be detected by the fourth-generation non-hsTnT assay at 6 to 12 hours postoperative as compared to 85% with the fifth-generation hsTnT assay (P-value < .001)., Conclusions: Within the first 3 postoperative days, fifth-generation hsTnT identified at least 1 in 3 patients with troponin elevation that would have gone undetected by fourth-generation non-hsTnT using published thresholds in this setting. Furthermore, fifth-generation hsTnT identified patients with an elevation earlier than fourth-generation non-hsTnT, indicating potential to improve postoperative risk stratification., Competing Interests: Disclosures FKB holds a Research Early Career Award from Hamilton Health Sciences, and has received grants from Roche Diagnostics and SIEMENS for investigator initiated research grants, and honorarium for lectures or participation in as advisory board from Roche Diagnostics and Novartis. ED reports research grants for investigator-initiated studies and honoraria for participation in advisory board from Roche Diagnostics and research grant for investigator-initiated study from Abbott Laboratories. PK has received grants/reagents/consultant/advisor/ honoraria from Abbott Laboratories, Abbott Point of Care, Beckman Coulter, Ortho Clinical Diagnostics, Quidel, Randox Laboratories, Roche Diagnostics, Siemens Healthcare Diagnostics, and Thermo Fisher Scientific . McMaster University has filed patents with PK listed as an inventor in the acute cardiovascular biomarker field. OB Received research grants from AstraZeneca, Pfizer, Bayer, Amgen, Servier, Novartis, BMS and Boeheringer-Ingelheim unrelated to the submitted work PJD reports grants from Canadian Institutes of Health Research and from Ontario Strategy for Patient Oriented Research Support Unit/Ministry of Health and Long-Term Care during the conduct of the study; and grants from Abbott Diagnostics, Roche Diagnostics, and Siemens, CloudDX, Philips Healthcare, outside the submitted work. Declares to be consultant for Abbott Canada, Renibus, Roche Canada and Trimedic. Declares be a member of advisory board of Bayer, Quidel and speaker for Velocit. DIS, MT, AP, YL, DH, SS, WC, CC, SNO, SP, AK, AT and ACT declare no conflict of interest, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Clinically important perioperative atrial fibrillation (POAF) is a common cardiac complication after noncardiac surgery. Little is known about how patients with POAF are managed acutely and whether practices have changed over time., Methods: We conducted an observational substudy of patients who had POAF, were at elevated cardiovascular risk, and were enrolled in the PeriOperative Ischemic Evaluation (POISE)-1, 2 and 3 trials between 2002 and 2021. POAF was defined as new, clinically important atrial fibrillation occurring within 30 days after surgery. We assessed the use of rhythm-control and anticoagulation treatment in response to POAF, at hospital discharge and at 30 days after surgery. We assessed for temporal trends using multivariable logistic regression., Results: Of the 27,896 patients included, 545 (1.9%) developed clinically important POAF. Patients received rhythm-control treatment in 48.6% of cases. The level of use of rhythm-control treatment increased over the course of the trials (POISE-1 vs POISE-2 vs POISE-3; 40.9% vs 49.5% vs 59.1%). A later randomization date was associated independently with use of rhythm-control treatment (odds ratio, 1.05 per year; 95% confidence interval, 1.01-1.09). Anticoagulation treatment was prescribed in 21% of POAF cases. The level of anticoagulation treatement use was higher in POISE-3, compared to that in the 2 previous trials (POISE-1 vs POISE-2 vs POISE-3-16.4% vs 16.5% vs 33.6%). A later randomization date was associated independently with use of anticoagulation treatment (odds ratio, 1.06 per year; 95% confidence interval, 1.02-1.11)., Conclusions: Despite the absence of randomized controlled trials, the level of use of rhythm-control and anticoagulation treatment for POAF is rising. High-quality trials are needed urgently to determine whether these interventions are safe and effective in this population., (© 2024 The Authors.)

Introduction: Complex Regional Pain Syndrome (CRPS) is a debilitating neuropathic condition often refractory to conventional treatments. N-methyl-D-aspartate (NMDA) receptor antagonists have a well-established role in the development and modulation of chronic neuropathic pain. Nitrous oxide is widely used and generally safe anesthetic gas with NMDA receptor antagonist activity. We therefore tested the hypothesis that brief periods of nitrous oxide exposure reduce pain in patients with CRPS., Methods: Patients with a diagnosis of CRPS were randomized to either 2 hours of nitrous oxide exposure on three alternating days (Nitrous Oxide) versus a placebo air/oxygen mixture (Air-Oxygen). Our primary outcome was patient-reported pain scores at 1 week and 1 month. Secondary and exploratory outcomes were physical and mental health (PRMOIS-29 v2 survey), specific neuropathic pain symptoms (McGill short-form questionnaire), and opioid consumption., Results: 44 patients participated in the study; 20 were randomized to Nitrous Oxide and 24 were assigned to Air-Oxygen. Pain scores did not differ significantly, with the estimated difference in means (Nitrous Oxide-Air-Oxygen) of -0.57 (95% CI: -1.42 to 0.28) points, p=0.19. There were also no differences detected in secondary outcomes, with the estimated difference in mean Z-scores for physical health (Nitrous Oxide-Air-Oxygen) of 0.13 (95% CI: -0.16 to 0.43), mental health 0.087 (95% CI: -0.31 to 0.48), and Patient Global Impression of Change score -0.7 (95% CI: -1.85 to 0.46)., Conclusions: Compared with air/oxygen, 2 hours of nitrous oxide/oxygen exposure for three sessions did not provide meaningful therapeutic potential for patients with chronic CRPS. Our results do not support using nitrous oxide for the treatment of CRPS., Competing Interests: Competing interests: DIS is a consultant for Edwards Lifesciences, Sensifree, and Perceptive Medical. None of the conflicts are related to the submitted study. AT was a speaker for Pfizer and consultant for Consentric Medical. None of the conflicts are related to the submitted study. None of the other authors declare competing interests., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objective: To investigate the timing of peak blood concentrations and potential toxicity when using a combination of plain and liposomal bupivacaine for thoracic fascial plane blocks., Design: Pharmacokinetic analysis., Setting: Operating room., Patients: Eighteen adult patients undergoing robotically-assisted mitral valve surgery., Interventions: Ultrasound-guided pecto-serratus and serratus anterior plane blocks using a mixture of 0.5% bupivacaine HCl up to 2.5 mg/kg and liposomal bupivacaine up to 266 mg., Measurements: Arterial plasma bupivacaine concentration., Main Results: Samples from 13 participants were analyzed. There was substantial inter-patient variability in plasma concentrations. A geometric mean maximum bupivacaine concentration was 1492 ng/ml (range 660 to 4650 ng/ml) at median time of 30 min after injection. In 4/13 (31%) patients, plasma bupivacaine concentrations exceeded our predefined 2000 ng/ml toxic threshold. A second much smaller peak was observed about 32 h after the injection. No obvious signs of local anesthetic toxicity were observed., Conclusions: Combined injection of plain and liposomal bupivacaine for pecto-serratus/serratus anterior plane blocks produced a biphasic pattern, with the highest arterial plasma concentrations observed within 30 min. Maximum concentrations exceeded the potential toxic threshold in nearly a third of patients, but without clinical evidence of toxicity. Clinicians should not assume that routine combinations of plain and liposomal bupivacaine for thoracic fascial plane blocks are inherently safe., Competing Interests: Declaration of competing interest Daniel I Sessler - is a consultant for Pacira Pharmaceuticals. Other authors have no conflicts of interest to declare. DIS is a consultant for Pacira Pharmaceuticals. The Division of Multi-specialty Anesthesiology conducts other research funded by Pacira, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Objective: Processed electroencephalography (pEEG) may help clinicians optimize depth of general anesthesia. Avoiding excessive depth of anesthesia may reduce intraoperative hypotension and the need for vasopressors. We tested the hypothesis that pEEG-guided - compared to non-pEEG-guided - general anesthesia reduces the amount of norepinephrine needed to keep intraoperative mean arterial pressure above 65 mmHg in patients having vascular surgery., Design: Randomized controlled clinical trial., Setting: University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Patients: 110 patients having vascular surgery., Interventions: pEEG-guided general anesthesia., Measurements: Our primary endpoint was the average norepinephrine infusion rate from the beginning of induction of anesthesia until the end of surgery., Main Result: 96 patients were analyzed. The mean ± standard deviation average norepinephrine infusion rate was 0.08 ± 0.04 μg kg -1  min -1 in patients assigned to pEEG-guided and 0.12 ± 0.09 μg kg -1  min -1 in patients assigned to non-pEEG-guided general anesthesia (mean difference 0.04 μg kg -1  min -1 , 95% confidence interval 0.01 to 0.07 μg kg -1  min -1 , p = 0.004). Patients assigned to pEEG-guided versus non-pEEG-guided general anesthesia, had a median time-weighted minimum alveolar concentration of 0.7 (0.6, 0.8) versus 0.8 (0.7, 0.8) (p = 0.006) and a median percentage of time Patient State Index was <25 of 12 (1, 41) % versus 23 (3, 49) % (p = 0.279)., Conclusion: pEEG-guided - compared to non-pEEG-guided - general anesthesia reduced the amount of norepinephrine needed to keep mean arterial pressure above 65 mmHg by about a third in patients having vascular surgery. Whether reduced intraoperative norepinephrine requirements resulting from pEEG-guided general anesthesia translate into improved patient-centered outcomes remains to be determined in larger trials., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KKT has no conflicts of interest to declare. DIS has received research funding from Edwards Lifesciences; he also is an advisor and has equity interest in Perceptive Medical (Newport Beach, CA, USA). LK has no conflicts of interest to declare. PH has no conflicts of interest to declare. BO has no conflicts of interest to declare. TK has no conflicts of interest to declare. VC has no conflicts of interest to declare. AB has no conflicts of interest to declare. MF is a consultant for Edwards Lifesciences (Irvine, CA, USA) and has received honoraria for consulting and giving lectures from CNSystems Medizintechnik (Graz, Austria). KK is a consultant for and has received honoraria for giving lectures from Edwards Lifesciences (Irvine, CA, USA). KK is a consultand for Vygon (Aachen, Germany). CZ has no conflict of interest to declare. LS-U has no conflicts of interest to declare. BS has received honoraria for giving lectures from Masimo (Neuchâtel, Switzerland). BS is a consultant for and has received institutional restricted research grants and honoraria for giving lectures from Edwards Lifesciences (Irvine, CA, USA). BS is a consultant for Philips North America (Cambridge, MA, USA) and has received honoraria for giving lectures from Philips Medizin Systeme Böblingen (Böblingen, Germany). BS has received institutional restricted research grants and honoraria for giving lectures from Baxter (Deerfield, IL, USA). BS is a consultant for and has received institutional restricted research grants and honoraria for giving lectures from GE Healthcare (Chicago, IL, USA). BS has received institutional restricted research grants and honoraria for giving lectures from CNSystems Medizintechnik (Graz, Austria). BS is a consultant for Maquet Critical Care (Solna, Sweden). BS has received honoraria for giving lectures from Getinge (Gothenburg, Sweden). BS is a consultant for and has received institutional restricted research grants and honoraria for giving lectures from Pulsion Medical Systems (Feldkirchen, Germany). BS is a consultant for and has received institutional restricted research grants and honoraria for giving lectures from Vygon (Aachen, Germany). BS is a consultant for and has received institutional restricted research grants from Retia Medical (Valhalla, NY, USA). BS is a consultant for Dynocardia (Cambridge, MA, USA). BS has received institutional restricted research grants from Osypka Medical (Berlin, Germany). BS was a consultant for and has received institutional restricted research grants from Tensys Medical (San Diego, CA, USA). BS is an Editor of the British Journal of Anesthesia., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It is unclear whether optimising intraoperative cardiac index can reduce postoperative complications. We tested the hypothesis that maintaining optimised postinduction cardiac index during and for the first 8 h after surgery reduces the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery., Methods: In three German and two Spanish centres, high-risk patients having elective major open abdominal surgery were randomised to cardiac index-guided therapy to maintain optimised postinduction cardiac index (cardiac index at which pulse pressure variation was <12%) during and for the first 8 h after surgery using intravenous fluids and dobutamine or to routine care. The primary outcome was the incidence of a composite outcome of moderate or severe complications within 28 days after surgery., Results: We analysed 318 of 380 enrolled subjects. The composite primary outcome occurred in 84 of 152 subjects (55%) assigned to cardiac index-guided therapy and in 77 of 166 subjects (46%) assigned to routine care (odds ratio: 1.87, 95% confidence interval: 1.03-3.39, P=0.038). Per-protocol analyses confirmed the results of the primary outcome analysis., Conclusions: Maintaining optimised postinduction cardiac index during and for the first 8 h after surgery did not reduce, and possibly increased, the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. Clinicians should not strive to maintain optimised postinduction cardiac index during and after surgery in expectation of reducing complications., Clinical Trial Registration: NCT03021525., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Test the hypothesis that one-lung ventilation with variable tidal volume improves intraoperative oxygenation and reduces postoperative pulmonary complications after lung resection., Background: Constant tidal volume and respiratory rate ventilation can lead to atelectasis. Animal and human ARDS studies indicate that oxygenation improves with variable tidal volumes. Since one-lung ventilation shares characteristics with ARDS, we tested the hypothesis that one-lung ventilation with variable tidal volume improves intraoperative oxygenation and reduces postoperative pulmonary complications after lung resection., Design: Randomized trial., Setting: Operating rooms and a post-anesthesia care unit., Patients: Adults having elective open or video-assisted thoracoscopic lung resection surgery with general anesthesia were randomly assigned to intraoperative ventilation with fixed (n = 70) or with variable (n = 70) tidal volumes., Interventions: Patients assigned to fixed ventilation had a tidal volume of 6 ml/kgPBW, whereas those assigned to variable ventilation had tidal volumes ranging from 6 ml/kg PBW ± 33% which varied randomly at 5-min intervals., Measurements: The primary outcome was intraoperative oxygenation; secondary outcomes were postoperative pulmonary complications, mortality within 90 days of surgery, heart rate, and SpO 2 /FiO 2 ratio., Results: Data from 128 patients were analyzed with 65 assigned to fixed-tidal volume ventilation and 63 to variable-tidal volume ventilation. The time-weighted average PaO 2 during one-lung ventilation was 176 (86) mmHg in patients ventilated with fixed-tidal volume and 147 (72) mmHg in the patients ventilated with variable-tidal volume, a difference that was statistically significant (p < 0.01) but less than our pre-defined clinically meaningful threshold of 50 mmHg. At least one composite complication occurred in 11 (17%) of patients ventilated with variable-tidal volume and in 17 (26%) of patients assigned to fixed-tidal volume ventilation, with a relative risk of 0.67 (95% CI 0.34-1.31, p = 0.24). Atelectasis in the ventilated lung was less common with variable-tidal volumes (4.7%) than fixed-tidal volumes (20%) in the initial three postoperative days, with a relative risk of 0.24 (95% CI 0.01-0.8, p = 0.02), but there were no significant late postoperative differences. No other secondary outcomes were both statistically significant and clinically meaningful., Conclusion: One-lung ventilation with variable tidal volume does not meaningfully improve intraoperative oxygenation, and does not reduce postoperative pulmonary complications., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest. None of the authors received compensation to perform this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The amount of same-day surgery has increased markedly worldwide in recent decades, but there remains limited evidence on chronic postsurgical pain in this setting., Methods: This study assessed pain 90 days after ambulatory surgery in an international, multicenter prospective cohort study of patients at least 45 yr old with comorbidities or at least 65 yr old. Pain was assessed using the Brief Pain Inventory. Chronic postsurgical pain was defined as a change of more than 1 point in self-rated average pain at the surgical site between baseline and 90 days, and moderate to severe chronic postsurgical pain was defined as a score greater than 4 in self-rated average pain at the surgical site at 90 days. Risk factors for chronic postsurgical pain were identified using multivariable logistic regression., Results: Between November 2021 and January 2023, a total of 2,054 participants were included, and chronic postsurgical pain occurred in 12% of participants, of whom 93.1% had new chronic pain at the surgical site (i.e., participants without pain before surgery). Moderate to severe chronic postsurgical pain occurred in 9% of overall participants. Factors associated with chronic postsurgical pain were active smoking (odds ratio, 1.82; 95% CI, 1.20 to 2.76), orthopedic surgery (odds ratio, 4.7; 95% CI, 2.24 to 9.7), plastic surgery (odds ratio, 4.3; 95% CI, 1.97 to 9.2), breast surgery (odds ratio, 2.74; 95% CI, 1.29 to 5.8), vascular surgery (odds ratio, 2.71; 95% CI, 1.09 to 6.7), and ethnicity (i.e., for Hispanic/Latino ethnicity, odds ratio, 3.41; 95% CI, 1.68 to 6.9 and for First Nations/native persons, odds ratio, 4.0; 95% CI, 1.05 to 15.4)., Conclusions: Persistent postsurgical pain after same-day surgery is common, is usually moderate to severe in nature, and occurs mostly in patients without chronic pain before surgery., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Arterial pressure monitoring and management are mainstays of haemodynamic therapy in patients having surgery. This article presents updated consensus statements and recommendations on perioperative arterial pressure management developed during the 11th POQI PeriOperative Quality Initiative (POQI) consensus conference held in London, UK, on June 4-6, 2023, which included a diverse group of international experts. Based on a modified Delphi approach, we recommend keeping intraoperative mean arterial pressure ≥60 mm Hg in at-risk patients. We further recommend increasing mean arterial pressure targets when venous or compartment pressures are elevated and treating hypotension based on presumed underlying causes. When intraoperative hypertension is treated, we recommend doing so carefully to avoid hypotension. Clinicians should consider continuous intraoperative arterial pressure monitoring as it can help reduce the severity and duration of hypotension compared to intermittent arterial pressure monitoring. Postoperative hypotension is often unrecognised and might be more important than intraoperative hypotension because it is often prolonged and untreated. Future research should focus on identifying patient-specific and organ-specific hypotension harm thresholds and optimal treatment strategies for intraoperative hypotension including choice of vasopressors. Research is also needed to guide monitoring and management strategies for recognising, preventing, and treating postoperative hypotension., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Patients with high-grade gliomas often have severe brain edema. Goal-directed fluid management protects neurological function, but whether reduces postoperative brain edema remains unknown., Methods: Patients having elective resection of supratentorial malignant gliomas were randomly assigned to goal-directed versus routine fluid management. Patients assigned to goal-directed management group were given 3 mL kg-1 hydroxyethyl starch solution when stroke volume variation exceeded 15% for 5 minutes. Fluid was managed per routine by attending anesthesiologists in reference patients. The primary outcome was cerebral edema volume after surgery as assessed by computerized tomography., Results: A total of 480 eligible patients were randomly assigned to the goal-directed (n = 240) or the routine fluid management group (n = 240). The amounts of crystalloid (5.4 vs. 7.0 ml kg-1 hour-1, P < 0.001), colloid (1.1 vs. 1.7 ml kg-1 hour-1, P < 0.001), and overall fluid balance (0.3 vs. 1.9 ml kg-1 hour-1, P < 0.001) were significantly lower in goal-directed fluid management. There was no significant difference in postoperative brain edema volume between groups (36.0 cm3 vs. 38.9 cm3, mean difference: 0.18cm3, 95% CI: -5.7 to 5.9). Goal-directed patients had lower intraoperative dural tension (risk ratio: 0.63, 95% CI: 0.50 to 0.80, P < 0.001). There was no significant difference in Karnofsky Performance Status between the two groups at 30 days after surgery., Conclusions: Goal-directed fluid therapy substantially reduced intravenous fluid volumes, but did not reduce postoperative brain edema in patients having brain tumor resections., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Surgical patients are often transfused to manage bleeding and anemia. Best practices for red blood cell (RBC) transfusion administration in patient having noncardiac surgery remains controversial and a robust evaluation and description of perioperative transfusion practices is lacking. We characterized perioperative hemoglobin concentrations and transfusion practices from the prospective VISION cohort which included 39,222 patients aged ≥45 years who had inpatient noncardiac surgery. Variations in transfusion practices were analyzed using hierarchical mixed models, and associations with mortality and complications were evaluated using a nested frailty survival model. Within the cohort, 16.1% (n = 6296) were given perioperative RBC transfusions, with the fraction declining from 20% to 13% over the 6-year study period. The proportion of patients transfused varied by surgery type from 6.4% for low-risk operations (i.e., minor surgery) to 31.5% for orthopedic surgeries. Variations were largely associated with patient hemoglobin concentrations, but also with center (range: 3.7%-27.3%) and country (0.4%-25.3%). Even after adjusting for baseline hemoglobin, comorbidities and type of surgery, both center and country were significant sources of variation in transfusion practices. Among transfused participants, 60.4% (n = 3728/6170) had at least 1 hemoglobin concentration ≤80g/L and 86.0% (n = 5305/6170) had at least 1 hemoglobin concentration ≤90g/L, suggesting that relatively restrictive transfusion strategies were used in most. The proportion of patients receiving at least 1 RBC transfusion declined from 20% to 13% over 6 years. However, there was considerable unexplained variation in transfusion practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The cause of postoperative delirium is unknown, but it is thought to result at least in part from inflammation. Metformin, besides its hypoglycemic properties, demonstrates anti-inflammatory effects systemically and in the brain. We tested the primary hypothesis that chronic metformin use in adults with type 2 diabetes is associated with less delirium during the first 5 days after major noncardiac surgery. Secondary outcomes were a composite of serious complications (myocardial infarction, cardiac arrest, stage 2-3 acute kidney injury [AKI], and mortality) and time to discharge alive., Methods: We considered adults with type 2 diabetes who did or did not routinely use metformin daily and had noncardiac surgery. Delirium was assessed by Confusion Assessment Method for Intensive Care Unit (CAM-ICU) or brief Confusion Assessment Method (bCAM) for 5 postoperative days. Postoperative AKI was defined by Kidney Disease Improving Global Guidelines. Logistic regression and generalized estimating equation models accounted for within-patient correlation across multiple surgeries and explored the association between metformin use and postoperative delirium and complications. Inverse propensity score weighting and propensity score calibration (PSC) adjusted for confounding variables., Results: No significant difference was observed in the incidence of postoperative delirium between the 2 groups, with 260 of 4744 cases (5.5%) among metformin users and 502 of 5918 cases (8.5%) cases in nonmetformin users, for an odds ratio of 0.88 (95% confidence interval [CI], 0.73-1.05; P = .155), number-needed-to-expose = 118 patients. Similarly, there were fewer composite complications in metformin users (3.3%) than in nonusers (11.7%); However, the common-effect odds ratio of 0.67 was not statistically significant (97.5% CI, 0.39-1.17; P = .106). Discharge from the hospital was significantly faster in patients who took metformin (3 [interquartile range, IQR, 1-5] days for metformin users and 3 [IQR, 2-6] days for nonmetformin users), with a hazard ratio of 1.07 for early discharge, and tight CIs (1.01-1.13)., Conclusions: Chronic metformin use was associated with slightly and nonsignificantly less delirium. However, patients who used metformin had clinically meaningfully fewer major complications, mostly stage 2 to 3 kidney injury. While not statistically significant, the reduction was substantial and warrants further investigation because there is currently no effective preventive measure for perioperative renal injury. Benefit would be especially meaningful if it could be produced by acute perioperative treatment. Finally, metformin was associated with faster hospital discharge, although not by a clinically meaningful amount., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Background: Pressure ulcers account for a substantial fraction of hospital-acquired pathology, with consequent morbidity and economic cost. Treatments are largely focused on preventing further injury, whereas interventions that facilitate healing remain limited. Intermittent electrical stimulation (IES) increases local blood flow and redistributes pressure from muscle-bone interfaces, thus potentially reducing ulcer progression and facilitating healing., Methods: The Pressure Injury Treatment by Intermittent Electrical Stimulation (PROTECT-2) trial will be a parallel-arm multicenter randomized trial to test the hypothesis that IES combined with routine care reduces sacral and ischial pressure injury over time compared to routine care alone. We plan to enroll 548 patients across various centers. Hospitalized patients with stage 1 or stage 2 sacral or ischial pressure injuries will be randomized to IES and routine care or routine care alone. Wound stage will be followed until death, discharge, or the development of an exclusion criteria for up to 3 months. The primary endpoint will be pressure injury score measured over time., Discussion: Sacral and ischial pressure injuries present a burden to hospitalized patients with both clinical and economic consequences. The PROTECT-2 trial will evaluate whether IES is an effective intervention and thus reduces progression of stage 1 and stage 2 sacral and ischial pressure injuries., Trial Registration: ClinicalTrials.gov NCT05085288 Registered October 20, 2021., (© 2024. The Author(s).)

Study Objective: Postoperative delirium is associated with morbidity and mortality, and its incidence varies widely. Using known predisposing and precipitating factors, we sought to develop postoperative delirium prediction models for noncardiac surgical patients., Design: Retrospective prediction model study., Setting: Major quaternary medical center., Patients: Our January 2016 to June 2020 training dataset included 51,677 patients of whom 2795 patients had delirium. Our July 2020 to January 2022 validation dataset included 14,438 patients of whom 912 patients had delirium., Interventions: None., Measurements: We trained and validated two static prediction models and one dynamic delirium prediction model. For the static models, we used random survival forests and traditional Cox proportional hazard models to predict postoperative delirium from preoperative variables, or from a combination of preoperative and intraoperative variables. We also used landmark modeling to dynamically predict postoperative delirium using preoperative, intraoperative, and postoperative variables before onset of delirium., Main Results: In the validation analyses, the static random forest model had a c-statistic of 0.81 (95% CI: 0.79, 0.82) and a Brier score of 0.04 with preoperative variables only, and a c-statistic of 0.86 (95% CI: 0.84, 0.87) and a Brier score of 0.04 when preoperative and intraoperative variables were combined. The corresponding Cox models had similar discrimination metrics with slightly better calibration. The dynamic model - using all available data, i.e., preoperative, intraoperative and postoperative data - had an overall c-index of 0.84 (95% CI: 0.83, 0.85)., Conclusions: Using preoperative and intraoperative variables, simple static models performed as well as a dynamic delirium prediction model that also included postoperative variables. Baseline predisposing factors thus appear to contribute far more to delirium after noncardiac surgery than intraoperative or postoperative variables. Improved postoperative data capture may help improve delirium prediction and should be evaluated in future studies., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Endotracheal tubes are typically inserted in the operating room using direct laryngoscopy. Video laryngoscopy has been reported to improve airway visualization; however, whether improved visualization reduces intubation attempts in surgical patients is unclear., Objective: To determine whether the number of intubation attempts per surgical procedure is lower when initial laryngoscopy is performed using video laryngoscopy or direct laryngoscopy., Design, Setting, and Participants: Cluster randomized multiple crossover clinical trial conducted at a single US academic hospital. Patients were adults aged 18 years or older having elective or emergent cardiac, thoracic, or vascular surgical procedures who required single-lumen endotracheal intubation for general anesthesia. Patients were enrolled from March 30, 2021, to December 31, 2022. Data analysis was based on intention to treat., Interventions: Two sets of 11 operating rooms were randomized on a 1-week basis to perform hyperangulated video laryngoscopy or direct laryngoscopy for the initial intubation attempt., Main Outcomes and Measures: The primary outcome was the number of operating room intubation attempts per surgical procedure. Secondary outcomes were intubation failure, defined as the responsible clinician switching to an alternative laryngoscopy device for any reason at any time, or by more than 3 intubation attempts, and a composite of airway and dental injuries., Results: Among 8429 surgical procedures in 7736 patients, the median patient age was 66 (IQR, 56-73) years, 35% (2950) were women, and 85% (7135) had elective surgical procedures. More than 1 intubation attempt was required in 77 of 4413 surgical procedures (1.7%) randomized to receive video laryngoscopy vs 306 of 4016 surgical procedures (7.6%) randomized to receive direct laryngoscopy, with an estimated proportional odds ratio for the number of intubation attempts of 0.20 (95% CI, 0.14-0.28; P < .001). Intubation failure occurred in 12 of 4413 surgical procedures (0.27%) using video laryngoscopy vs 161 of 4016 surgical procedures (4.0%) using direct laryngoscopy (relative risk, 0.06; 95% CI, 0.03-0.14; P < .001) with an unadjusted absolute risk difference of -3.7% (95% CI, -4.4% to -3.2%). Airway and dental injuries did not differ significantly between video laryngoscopy (41 injuries [0.93%]) vs direct laryngoscopy (42 injuries [1.1%])., Conclusion and Relevance: In this study among adults having surgical procedures who required single-lumen endotracheal intubation for general anesthesia, hyperangulated video laryngoscopy decreased the number of attempts needed to achieve endotracheal intubation compared with direct laryngoscopy at a single academic medical center in the US. Results suggest that video laryngoscopy may be a preferable approach for intubating patients undergoing surgical procedures., Trial Registration: ClinicalTrials.gov Identifier: NCT04701762.

Objective: To determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression., Design: Randomised, double blind, placebo controlled trial with two parallel arms., Setting: Five tertiary care hospitals in China, 19 June 2020 to 3 August 2022., Participants: 364 mothers aged ≥18 years who had at least mild prenatal depression as indicated by Edinburgh postnatal depression scale scores of ≥10 (range 0-30, with higher scores indicating worse depression) and who were admitted to hospital for delivery., Interventions: Participants were randomly assigned 1:1 to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth once the umbilical cord had been clamped., Main Outcome Measures: The primary outcome was prevalence of a major depressive episode at 42 days post partum, diagnosed using the mini-international neuropsychiatric interview. Secondary outcomes included the Edinburgh postnatal depression scale score at seven and 42 days post partum and the 17 item Hamilton depression rating scale score at 42 days post partum (range 0-52, with higher scores indicating worse depression). Adverse events were monitored until 24 hours after childbirth., Results: A total of 364 mothers (mean age 31.8 (standard deviation 4.1) years) were enrolled and randomised. At 42 days post partum, a major depressive episode was observed in 6.7% (12/180) of participants in the esketamine group compared with 25.4% (46/181) in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P<0.001). Edinburgh postnatal depression scale scores were lower in the esketamine group at seven days (median difference -3, 95% CI -4 to -2; P<0.001) and 42 days (-3, -4 to -2; P<0.001). Hamilton depression rating scale scores at 42 days post partum were also lower in the esketamine group (-4, -6 to -3; P<0.001). The overall incidence of neuropsychiatric adverse events was higher in the esketamine group (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than a day and none required drug treatment., Conclusions: For mothers with prenatal depression, a single low dose of esketamine after childbirth decreases major depressive episodes at 42 days post partum by about three quarters. Neuropsychiatric symptoms were more frequent but transient and did not require drug intervention., Trial Registration: ClinicalTrials.gov NCT04414943., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the National Natural Science Foundation of China, National High Level Hospital Clinical Research Funding, Peking University First Hospital, and Zhejiang University; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine timing and risk factors associated with readmission within 30 days of discharge following noncardiac surgery., Background: Hospital readmission after noncardiac surgery is costly. Data on the drivers of readmission have largely been derived from single-center studies focused on a single surgical procedure with uncertainty regarding generalizability., Methods: We undertook an international (28 centers, 14 countries) prospective cohort study of a representative sample of adults ≥45 years of age who underwent noncardiac surgery. Risk factors for readmission were assessed using Cox regression (ClinicalTrials.gov, NCT00512109)., Results: Of 36,657 eligible participants, 2744 (7.5%; 95% confidence interval [CI], 7.2-7.8) were readmitted within 30 days of discharge. Rates of readmission were highest in the first 7 days after discharge and declined over the follow-up period. Multivariable analyses demonstrated that 9 baseline characteristics (eg, cancer treatment in past 6 months; adjusted hazard ratio [HR], 1.44; 95% CI, 1.30-1.59), 5 baseline laboratory and physical measures (eg, estimated glomerular filtration rate or on dialysis; HR, 1.47; 95% CI, 1.24-1.75), 7 surgery types (eg, general surgery; HR, 1.86; 95% CI, 1.61-2.16), 5 index hospitalization events (eg, stroke; HR, 2.21; 95% CI, 1.24-3.94), and 3 other factors (eg, discharge to nursing home; HR, 1.61; 95% CI, 1.33-1.95) were associated with readmission., Conclusions: Readmission following noncardiac surgery is common (1 in 13 patients). We identified perioperative risk factors associated with 30-day readmission that can help frontline clinicians identify which patients are at the highest risk of readmission and target them for preventive measures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: Postoperative delirium is a common and impactful neuropsychiatric complication in patients undergoing coronary artery bypass grafting surgery. Cognitive training may enhance cognitive reserve, thereby reducing postoperative delirium., Objective: To determine whether preoperative cognitive training reduces the incidence of delirium in patients undergoing coronary artery bypass grafting., Design, Setting, and Participants: This prospective, single-blind, randomized clinical trial was conducted at 3 university teaching hospitals in southeastern China with enrollment between April 2022 and May 2023. Eligible participants included those scheduled for elective coronary artery bypass grafting who consented and enrolled at least 10 days before surgery., Interventions: Participating patients were randomly assigned 1:1, stratified by site, to either routine care or cognitive training, which included substantial practice with online tasks designed to enhance cognitive functions including memory, imagination, reasoning, reaction time, attention, and processing speed., Main Outcomes and Measures: The primary outcome was occurrence of delirium during postoperative days 1 to 7 or until hospital discharge, diagnosed using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Units. Secondary outcomes were postoperative cognitive dysfunction, delirium characteristics, and all-cause mortality within 30 days following the operation., Results: A total of 218 patients were randomized and 208 (median [IQR] age, 66 [58-70] years; 64 female [30.8%] and 144 male [69.2%]) were included in final analysis, with 102 randomized to cognitive training and 106 randomized to routine care. Of all participants, 95 (45.7%) had only a primary school education and 54 (26.0%) had finished high school. In the cognitive training group, 28 participants (27.5%) developed delirium compared with 46 participants (43.4%) randomized to routine care. Those receiving cognitive training were 57% less likely to develop delirium compared with those receiving routine care (adjusted odds ratio [aOR] 0.43; 95% CI, 0.23-0.77; P = .007). Significant differences were observed in the incidence of severe delirium (aOR, 0.46; 95% CI, 0.25-0.82; P = .01), median (IQR) duration of delirium (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .008), and median (IQR) number of delirium-positive days (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .007). No other secondary outcomes differed significantly., Conclusions and Relevance: In this randomized trial of 208 patients undergoing coronary artery bypass grafting, preoperative cognitive training reduced the incidence of postoperative delirium. However, our primary analysis was based on fewer than 75 events and should therefore be considered exploratory and a basis for future larger trials., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200058243.

Background: Relaxation and distraction provided by virtual reality presentations might be analgesic and reduce the need for opioid analgesia. We tested the hypothesis that a virtual reality program (AppliedVR) decreases acute postoperative pain and opioid requirements in patients recovering from hip arthroplasty. We also evaluated whether virtual reality distraction improves patient mobility and reduces the need for antiemetics., Methods: We evaluated 106 adults who were recovering from elective primary total hip arthroplasty. Participating patients were randomized to 2- to 8-minute-long 3-dimensional immersive virtual reality relaxation and distraction video presentations (eg, guided breathing exercises, games, mindfulness) or to 2-dimensional presentations of nature short films (eg, forest wildlife) with neutral music that was chosen to be neither overly relaxing nor distracting, presented through identical headsets. Our primary outcome was pain after virtual reality or sham video presentations, adjusted for pretreatment scores. Secondary outcomes included total opioid consumption, pain scores obtained per routine by nurse staff, perception of video system usability, and pain 1 week after hospital discharge., Results: Fifty-two patients were randomized to virtual reality distraction and relaxation, and 54 were assigned to 2-dimensional sham presentations. Virtual reality presentations were not found to affect pain scores before and after presentations, with an estimated difference in means (virtual reality minus sham video) of -0.1 points (95% confidence interval [CI], -0.5 to 0.2; P = .391) on a 0 to 10 scale, with 10 being the worst. The mean (standard error [SE]) after-intervention pain score was estimated to be 3.4 (0.3) in the virtual reality group and 3.5 (0.2) in the reference group. Virtual reality treatment was not found to affect postoperative opioid consumption in morphine milligram equivalents, with an estimated ratio of geometric means (virtual reality/sham video) of 1.2 (95% CI, 0.6-2.1; P = .608). Virtual reality presentations were not found to reduce pain scores collected every 4 hours by nursing staff, with an estimated difference in means of 0.1 points (95% CI, -0.9 to 0.7; P = .768)., Conclusions: We did not observe statistically significant or clinically meaningful reductions in average pain scores or opioid consumption. As used in our trial, virtual reality did not reduce acute postoperative pain., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Background: Obesity distorts airways and slightly complicates intubations in adults, but whether obesity complicates pediatric intubations remains unclear. We, therefore, tested the primary hypothesis that increasing age- and sex-specific body mass index (BMI) percentile is associated with difficult intubation, defined as >1 intubation attempt., Methods: We conducted a retrospective analysis of pediatric patients between 2 and 18 years of age who had noncardiac surgery with oral endotracheal intubation. We assessed the association between BMI percentile and difficult intubation, defined as >1 intubation attempt, using a confounder-adjusted multivariable logistic regression model. Secondarily, we assessed whether the main association depended on preoperative substantial airway abnormality status or age group., Results: A total of 9339 patients were included in the analysis. Median [quartiles] age- and sex-specific BMI percentile was 70 [33, 93], and 492 (5.3%) patients had difficult intubation. There was no apparent association between age- and sex-specific BMI percentile and difficult intubation. The estimated odds ratio (OR) for having difficult intubation for a 10-unit increase in BMI percentile was 0.98 (95% confidence interval [CI], 0.95-1.005) and was consistent across the 3 age groups of early childhood, middle childhood, and early adolescence (interaction P = .53). Patients with preoperative substantial airway abnormalities had lower odds of difficult intubation per 10-unit increase in BMI percentile, with OR (95% CI) of 0.83 (0.70-0.98), P = .01., Conclusions: Age- and sex-specific BMI percentile was not associated with difficult intubation in children between 2 and 18 years of age. As in adults, obesity in children does not much complicate intubation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Background: The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis., Methods: In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC., Results: The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667., Conclusions: Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2024 International Anesthesia Research Society.)

The major goal of translational research is to evaluate the efficacy and effectiveness of treatments and interventions that have emerged from exhaustive preclinical evidence. In 2007, a major clinical trial was started to investigate the impact of paravertebral analgesia on breast cancer recurrence. The trial was based on preclinical evidence demonstrating that spinal anesthesia suppressed metastatic dissemination by inhibiting surgical stress, boosting the immunological response, avoiding volatile anesthetics, and reducing opioid use. However, that trial and three more recent randomized trials with a total of 4,770 patients demonstrate that regional analgesia does not improve survival outcomes after breast, lung, and abdominal cancers. An obvious question is why there was an almost complete disconnect between the copious preclinical investigations suggesting benefit and robust clinical trials showing no benefit? The answer is complex but may result from preclinical research being mechanistically driven and based on reductionist models. Both basic scientists and clinical investigators underestimated the limitations of various preclinical models, leading to the apparently incorrect hypothesis that regional anesthesia reduces cancer recurrence. This article reviews factors that contributed to the discordance between the laboratory science, suggesting that regional analgesia might reduce cancer recurrence and clinical trials showing that it does not-and what can be learned from the disconnect., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: The effects of spinal versus general anesthesia on long-term outcomes have not been well studied. This study tested the hypothesis that spinal anesthesia is associated with better long-term survival and functional recovery than general anesthesia., Methods: A prespecified analysis was conducted of long-term outcomes of a completed randomized superiority trial that compared spinal anesthesia versus general anesthesia for hip fracture repair. Participants included previously ambulatory patients 50 yr of age or older at 46 U.S. and Canadian hospitals. Patients were randomized 1:1 to spinal or general anesthesia, stratified by sex, fracture type, and study site. Outcome assessors and investigators involved in the data analysis were masked to the treatment arm. Outcomes included survival at up to 365 days after randomization (primary); recovery of ambulation among 365-day survivors; and composite endpoints for death or new inability to ambulate and death or new nursing home residence at 365 days. Patients were included in the analysis as randomized., Results: A total of 1,600 patients were enrolled between February 12, 2016, and February 18, 2021; 795 were assigned to spinal anesthesia, and 805 were assigned to general anesthesia. Among 1,599 patients who underwent surgery, vital status information at or beyond the final study interview (conducted at approximately 365 days after randomization) was available for 1,427 (89.2%). Survival did not differ by treatment arm; at 365 days after randomization, there were 98 deaths in patients assigned to spinal anesthesia versus 92 deaths in patients assigned to general anesthesia (hazard ratio, 1.08; 95% CI, 0.81 to 1.44, P = 0.59). Recovery of ambulation among patients who survived a year did not differ by type of anesthesia (adjusted odds ratio for spinal vs. general, 0.87; 95% CI, 0.67 to 1.14; P = 0.31). Other outcomes did not differ by treatment arm., Conclusions: Long-term outcomes were similar with spinal versus general anesthesia., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Competing Interests: The author declares no conflicts of interest.

Purpose of Review: This review examines advances in clinical trial methodologies relevant to cardiac anesthesia. It focuses on innovative approaches, including factorial randomization, composite outcomes, and cluster randomized trials, which enhance the efficiency, practical relevance, and generalizability of trial outcomes., Recent Findings: Factorial randomization is becoming popular because the approach allows investigators to simultaneously evaluate two or more interventions. Furthermore, factorial designs can evaluate interactions among treatments which is highly relevant information that cannot be obtained from separate trials. Composite outcomes are also increasingly utilized, combining multiple individual outcomes into a single measure, which increases statistical power and can better represent relevant physiology. Designing valid composites requires careful consideration of component outcome severity and incidence. Cluster randomized trials, including stepped wedge and multiple crossover designs, address the challenges of group-level effects and shared environments., Summary: The evolution of clinical trial designs is marked by a shift towards methodologies that enhance efficiency and provide more nuanced insights into treatment effects. These include factorial designs for simultaneous intervention assessment, composite outcomes for comprehensive physiological representation, and cluster trials for group-level effect analysis. Such advancements are shaping the future of clinical research, making it more relevant, efficient, and broadly applicable., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Previous studies report that intraoperative hypotension worsens outcomes after aneurysmal subarachnoid hemorrhage (aSAH). However, the hypotensive harm threshold for major adverse cardiovascular events (MACE) remains unclear., Methods: The authors included aSAH patients who had general anesthesia for aneurysmal clipping/coiling. MACE were defined by a composite of acute myocardial injury, acute myocardial infarction, and other cardiovascular complications identified by electrocardiogram and echocardiography. The authors initially used logistic regression and change-point analysis based on the second derivative to identify mean arterial pressure (MAP) of 75 mmHg as the harm threshold. Thereafter, our major exposure was MAP below 75 mmHg characterized by area, duration, and time-weighted average. The area below 75 mmHg represents the severity and duration of exposure and was defined as the sum of all areas below a specified threshold using the trapezoid rule. Time-weighted average MAP was derived by dividing area below the threshold by the duration of anesthesia. All analyses were adjusted for baseline risk factors including age greater than 70 years, female sex, severity of intracerebral hemorrhage, history of cardiovascular disease, and preoperative elevated myocardial enzymes., Results: Among 1029 patients enrolled, 254 (25%) developed postoperative MACE. Patients who experienced MACE were slightly older (59±11 vs. 54±11 years), were slightly more often women (69 vs. 58%), and had a higher prevalence of cardiovascular history (65 vs. 47%). Adjusted cardiovascular risk increased nearly linearly over the entire range of observed MAP. However, there was a slight inflexion at MAP of 75 mmHg. MACE was significantly associated with area [adjusted odds ratios (aOR) 1.004 per 10 mmHg.min, 95% CI: 1.001-1.007, P =0.002), duration (aOR 1.031 per 10 min, 95% CI: 1.009-1.054, P =0.006), and time-weighted average (aOR 3.516 per 10 mmHg, 95% CI: 1.818-6.801, P <0.001) of MAP less than 75 mmHg., Conclusions: Lower blood pressures were associated with cardiovascular complications over the entire observed range, but worsened when MAP was less than 75 mmHg. Pending trial data to establish causality, it may be prudent to keep MAP above 75 mmHg in patients having surgical aSAH repairs to reduce the risk of MACE., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Study Objectives: Tranexamic acid (TXA) is an antifibrinolytic that is widely used to reduce surgical bleeding. However, TXA occasionally causes seizures and the risk might be especially great after neurosurgery. We therefore tested the hypothesis that TXA does not meaningfully increase the risk of postoperative seizures within 7 days after intracranial tumor resections., Design: Randomized, double-blind, placebo-controlled, non-inferiority trial., Setting: Beijing Tiantan Hospital, Capital Medical University., Patients: 600 patients undergoing supratentorial meningioma resection were included from October 2020 to August 2022., Interventions: Patients were randomly assigned to a single dose of 20 mg/kg of TXA after induction (n = 300) or to the same volume of normal saline (n = 300)., Measurement: The primary outcome was postoperative seizures occurring within 7 days after surgery, analyzed in both the intention-to-treat and per-protocol populations. Non-inferiority was defined by an upper limit of the 95% confidence interval for the absolute difference being <5.5%. Secondary outcomes included incidence of non-epileptic complication within 7 days, changes in hemoglobin concentration, estimated intraoperative blood loss. Post hoc analyses included the types and timing of seizures, oozing assessment, and a sensitivity analysis for the primary outcome in patients with pathologic diagnosis of meningioma., Main Results: All 600 enrolled patients adhered to the protocol and completed the follow-up for the primary outcome. Postoperative seizures occurred in 11 of 300 (3.7%) of patients randomized to normal saline and 13 of 300 (4.3%) patients assigned to tranexamic acid (mean risk difference, 0.7%; 1-sided 97.5% CI, -∞ to 4.3%; P = 0.001 for noninferiority). No significant differences were observed in any secondary outcome. Post hoc analysis indicated similar amounts of oozing, calculated blood loss, recurrent seizures, and timing of seizures., Conclusion: Among patients having supratentorial meningioma resection, a single intraoperative dose of TXA did not significantly reduce bleeding and was non-inferior with respect to postoperative seizures after surgery., Registry Information: This trial was registered at clinicaltrials.gov (NCT04595786) on October 22, 2020, by Dr.Yuming Peng., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Purpose of Review: Randomized clinical trials, now commonplace and regarded as top-tier evidence, are actually a recent development. The first randomized trial took place in 1948, just six decades ago. As anticipated from a relatively young field, rapid progress continues in response to an ever-increasing number of medical questions that demand answers. We examine evolving methodologies in cardiac anesthesia clinical trials, focusing on the transition towards larger sample sizes, increasing use of pragmatic trial designs, and the innovative adoption of real-time automated enrollment and randomization. We highlight how these changes enhance the reliability and feasibility of clinical trials., Recent Findings: Recent understanding in clinical trial methodology acknowledges the importance of large sample sizes, which increase the reliability of findings. As illustrated by P value fragility, small trials can mislead despite statistical significance. Pragmatic trials have gained prominence, offering real-world insights into the effectiveness of various treatments. Additionally, the use of real-time automated enrollment and randomization, particularly in situations where obtaining prior consent is impractical, is an important methodological advance., Summary: The landscape of cardiac anesthesia clinical trials is rapidly evolving, with a clear trend towards large sample sizes and innovative approaches to enrollment. Recent developments enhance the quality and applicability of research findings, thus providing robust guidance to clinicians., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery., Methods: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis., Results: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr)., Conclusions: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)