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Background Early mobilization is incorporated into many enhanced recovery pathways. Inadequate analgesia or excessive opioids may restrict postoperative mobilization. The authors tested the hypotheses that in adults recovering from abdominal surgery, postoperative pain and opioid consumption are inversely related to postoperative mobilization, and that postoperative mobilization is associated with fewer potentially related complications. Methods The authors conducted a subanalysis of two trials that enrolled adults recovering from abdominal surgery. Posture and movement were continuously monitored for 48 postoperative hours using noninvasive untethered monitors. Mobilization was defined as the fraction of monitored time spent sitting or standing. Results A total of 673 patients spent a median [interquartile range] of 7% [3 to 13%] of monitored time sitting or standing. Mobilization time was 1.9 [1.0 to 3.6] h/day for patients with average pain scores 3 or lower, but only 1.2 [0.5 to 2.6] h/day in those with average scores 6 or greater. Each unit increase in average pain score was associated with a decrease in mobilization time of 0.12 (97.5% CI, 0.02 to 0.24; P = 0.009) h/day. In contrast, there was no association between postoperative opioid consumption and mobilization time. The incidence of the composite of postoperative complications was 6.0% (10 of 168) in the lower mobilization quartile, 4.2% (7 of 168) in the second quartile, and 0% among 337 patients in the highest two quartiles (P = 0.009). Conclusions Patients recovering from abdominal surgery spent only 7% of their time mobilized, which is considerably less than recommended. Lower pain scores are associated with increased mobility, independently of opioid consumption. Complications were more common in patients who mobilized poorly. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Colloids are thought to sustain blood pressure and cardiac index better than crystalloids. However, the relative effects of intraoperative hydroxyethyl starch and crystalloid administration on the cardiac index and blood pressure remain unclear. This study therefore tested in this subanalysis of a previously published large randomized trial the hypothesis that intraoperative goal-directed colloid administration increases the cardiac index more than goal-directed crystalloid administration. Further, the effects of crystalloid and colloid boluses on blood pressure were evaluated. Methods This planned subanalysis of a previous trial analyzed data from 973 patients, of whom 480 were randomized to colloids and 493 were randomized to crystalloids. Fluid administration was guided by esophageal Doppler. The primary outcome was the time-weighted average cardiac index during surgery between the colloid and crystalloid group. The secondary outcomes were the cardiac index just after bolus administration, time elapsed between boluses, and the average real variability during surgery. The study recorded cardiac index, corrected flow time, and blood pressure at 10-min intervals, as well as before and after each bolus. Results Time-weighted average of cardiac index over the duration of anesthesia was only slightly greater in patients given colloid than crystalloid, with the difference being just 0.20 l · min–1 · m–2 (95% CI, 0.11 to 0.29; P < 0.001). However, the hazard for needing additional boluses was lower after colloid administration (hazard ratio [95% CI], 0.60 [0.55 to 0.66]; P < 0.001) in a frailty time-to-event model accounting for within-subject correlation. The median [quartiles] number of boluses per patient was 4 [2, 6] for colloids and 6 [3, 8] for crystalloids, with a median difference (95% CI) of –1.5 (–2 to –1; P < 0.001). The average real mean arterial pressure variability did not differ significantly between the groups (difference in means [95% CI] of –0.03 (–0.07 to 0.02) mmHg, P = 0.229). Conclusions There were not clinically meaningful differences in the cardiac index or mean pressure variability in patients given goal-directed colloid and crystalloids. As might be expected from longer intravascular dwell time, the interval between boluses was longer with colloids. However, on a case basis, the number of boluses differed only slightly. Colloids do not appear to provide substantial hemodynamic benefit. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Volatile anesthetics are increasingly used for sedation in intensive care units. The most common administration system is AnaConDa-100 mL (ACD-100; Sedana Medical, Uppsala, Sweden), which reflects volatile anesthetics in open ventilation circuits. AnaConDa-50 mL (ACD-50) is a new device with half the volumetric dead space. Carbon dioxide (CO2) can be retained with both devices. We therefore compared the CO2 elimination and isoflurane reflection efficiency of both devices.A test lung constantly insufflated with CO2 was ventilated with a tidal volume of 500 mL at 10 breaths/min. End-tidal CO2 (EtCO2) partial pressure was measured using 3 different devices: a heat-and-moisture exchanger (HME, 35 mL), ACD-100, and ACD-50 under 4 different experimental conditions: ambient temperature pressure (ATP), body temperature pressure saturated (BTPS) conditions, BTPS with 0.4 Vol% isoflurane (ISO-0.4), and BTPS with 1.2 Vol% isoflurane. Fifty breaths were recorded at 3 time points (n = 150) for each device and each condition. To determine device dead space, we adjusted the tidal volume to maintain normocapnia (n = 3), for each device. Thereafter, we determined reflection efficiency by measuring isoflurane concentrations at infusion rates varying from 0.5 to 20 mL/h (n = 3), for each device.EtCO2 was consistently greater with ACD-100 than with ACD-50 and HME (ISO-0.4, mean ± standard deviations: ACD-100, 52.4 ± 0.8; ACD-50, 44.4 ± 0.8; HME, 40.1 ± 0.4 mm Hg; differences of means of EtCO2 [respective 95% confidence intervals]: ACD-100 - ACD-50, 8.0 [7.9-8.1] mm Hg, P.001; ACD-100 - HME, 12.3 [12.2-12.4] mm Hg, P.001; ACD-50 - HME, 4.3 [4.2-4.3] mm Hg, P.001). It was greatest under ATP, less under BTPS, and least with ISO-0.4 and BTPS with 1.2 Vol% isoflurane. In addition to the 100 or 50 mL "volumetric dead space" of each AnaConDa, "reflective dead space" was 40 mL with ACD-100 and 25 mL with ACD-50 when using isoflurane. Isoflurane reflection was highest under ATP. Under BTPS with CO2 insufflation and isoflurane concentrations around 0.4 Vol%, reflection efficiency was 93% with ACD-100 and 80% with ACD-50.Isoflurane reflection remained sufficient with the ACD-50 at clinical anesthetic concentrations, while CO2 elimination was improved. The ACD-50 should be practical for tidal volumes as low as 200 mL, allowing lung-protective ventilation even in small patients.

Background Regional anesthesia and analgesia reduce the stress response to surgery and decrease the need for volatile anesthesia and opioids, thereby preserving cancer-specific immune defenses. This study therefore tested the primary hypothesis that combining epidural anesthesia–analgesia with general anesthesia improves recurrence-free survival after lung cancer surgery. Methods Adults scheduled for video-assisted thoracoscopic lung cancer resections were randomized 1:1 to general anesthesia and intravenous opioid analgesia or combined epidural–general anesthesia and epidural analgesia. The primary outcome was recurrence-free survival (time from surgery to the earliest date of recurrence/metastasis or all-cause death). Secondary outcomes included overall survival (time from surgery to all-cause death) and cancer-specific survival (time from surgery to cancer-specific death). Long-term outcome assessors were blinded to treatment. Results Between May 2015 and November 2017, 400 patients were enrolled and randomized to general anesthesia alone (n = 200) or combined epidural–general anesthesia (n = 200). All were included in the analysis. The median follow-up duration was 32 months (interquartile range, 24 to 48). Recurrence-free survival was similar in each group, with 54 events (27%) with general anesthesia alone versus 48 events (24%) with combined epidural–general anesthesia (adjusted hazard ratio, 0.90; 95% CI, 0.60 to 1.35; P = 0.608). Overall survival was also similar with 25 events (13%) versus 31 (16%; adjusted hazard ratio, 1.12; 95% CI, 0.64 to 1.96; P = 0.697). There was also no significant difference in cancer-specific survival with 24 events (12%) versus 29 (15%; adjusted hazard ratio, 1.08; 95% CI, 0.61 to 1.91; P = 0.802). Patients assigned to combined epidural–general had more intraoperative hypotension: 94 patients (47%) versus 121 (61%; relative risk, 1.29; 95% CI, 1.07 to 1.55; P = 0.007). Conclusions Epidural anesthesia–analgesia for major lung cancer surgery did not improve recurrence-free, overall, or cancer-specific survival compared with general anesthesia alone, although the CI included both substantial benefit and harm. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Experimental and observational research suggests that combined epidural–general anesthesia may improve long-term survival after cancer surgery by reducing anesthetic and opioid consumption and by blunting surgery-related inflammation. This study therefore tested the primary hypothesis that combined epidural–general anesthesia improves long-term survival in elderly patients. Methods This article presents a long-term follow-up of patients enrolled in a previous trial conducted at five hospitals. Patients aged 60 to 90 yr and scheduled for major noncardiac thoracic and abdominal surgeries were randomly assigned to either combined epidural–general anesthesia with postoperative epidural analgesia or general anesthesia alone with postoperative intravenous analgesia. The primary outcome was overall postoperative survival. Secondary outcomes included cancer-specific, recurrence-free, and event-free survival. Results Among 1,802 patients who were enrolled and randomized in the underlying trial, 1,712 were included in the long-term analysis; 92% had surgery for cancer. The median follow-up duration was 66 months (interquartile range, 61 to 80). Among patients assigned to combined epidural–general anesthesia, 355 of 853 (42%) died compared with 326 of 859 (38%) deaths in patients assigned to general anesthesia alone: adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408. Cancer-specific survival was similar with combined epidural–general anesthesia (327 of 853 [38%]) and general anesthesia alone (292 of 859 [34%]): adjusted hazard ratio, 1.09; 95% CI, 0.93 to 1.28; P = 0.290. Recurrence-free survival was 401 of 853 [47%] for patients who had combined epidural–general anesthesia versus 389 of 859 [45%] with general anesthesia alone: adjusted hazard ratio, 0.97; 95% CI, 0.84 to 1.12; P = 0.692. Event-free survival was 466 of 853 [55%] in patients who had combined epidural–general anesthesia versus 450 of 859 [52%] for general anesthesia alone: adjusted hazard ratio, 0.99; 95% CI, 0.86 to 1.12; P = 0.815. Conclusions In elderly patients having major thoracic and abdominal surgery, combined epidural–general anesthesia with epidural analgesia did not improve overall or cancer-specific long-term mortality. Nor did epidural analgesia improve recurrence-free survival. Either approach can therefore reasonably be selected based on patient and clinician preference. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

BACKGROUND Catheter-based endovascular neurointerventions require deep neuromuscular blocks during the procedure and rapid subsequent recovery of strength to facilitate neurological evaluation. We tested the primary hypothesis that sugammadex reverses deep neuromuscular blocks faster than neostigmine reverses moderate neuromuscular blocks. METHODS Patients having catheter-based cerebral neurointerventional procedures were randomized to: (1) deep rocuronium neuromuscular block with posttetanic count 1 to 2 and 4-mg/kg sugammadex as the reversal agent or (2) moderate rocuronium neuromuscular block with train-of-four (TOF) count 1 during the procedure and neuromuscular reversal with 0.07-mg/kg neostigmine to a maximum of 5 mg. Recovery of diaphragmatic function was assessed by ultrasound at baseline before the procedure and 90 minutes thereafter. The primary outcome-time to reach a TOF ratio ≥0.9 after administration of the designated reversal agent-was analyzed with a log-rank test. Secondary outcomes included time to successful tracheal extubation and the difference between postoperative and preoperative diaphragmatic contraction speed and distance. RESULTS Thirty-five patients were randomized to sugammadex and 33 to neostigmine. Baseline characteristics and surgical factors were well balanced. The median time to reach TOF ratio ≥0.9 was 3 minutes (95% confidence interval [CI], 2-3 minutes) in patients given sugammadex versus 8 minutes (95% CI, 6-10 minutes) in patients given neostigmine. Sugammadex was significantly faster by a median of 5 minutes (95% CI, 3-6 minutes; P < .001). However, times to tracheal extubation and diaphragmatic function at 90 minutes did not differ significantly. CONCLUSIONS Sugammadex reversed deep rocuronium neuromuscular blocks considerably faster than neostigmine reversed moderate neuromuscular blocks. However, times to extubation did not differ significantly, apparently because extubation was largely determined by the time required for awaking from general anesthesia and because clinicians were willing to extubate before full neuromuscular recovery. Sugammadex may nonetheless be preferable to procedures that require a deep neuromuscular block and rapid recovery.

Tumor hypoxia is correlated with increased resistance to chemotherapy and poor overall prognoses across a number of cancer types. We present here a cancer cell-selective and hypoxia-responsive probe (fol-BODIPY) designed on the basis of density functional theory (DFT)-optimized quantum chemical calculations. The fol-BODIPY probe was found to provide a rapid fluorescence "off-on" response to hypoxia relative to controls, which lack the folate or nitro-benzyl moieties. In vitro confocal microscopy and flow cytometry analyses, as well as in vivo near-infrared optical imaging of CT26 solid tumor-bearing mice, provided support for the contention that fol-BODIPY is more readily accepted by folate receptor-positive CT26 cancer cells and provides a superior fluorescence "off-on" signal under hypoxic conditions than the controls. Based on the findings of this study, we propose that fol-BODIPY may serve as a tumor-targeting, hypoxia-activatable probe that allows for direct cancer monitoring both in vitro and in vivo.

Published data suggest that the type of general anaesthesia used during surgical resection for cancer may impact on patient long-term outcome. However, robust prospective clinical evidence is essential to guide a change in clinical practice. We explored the feasibility of conducting a randomised controlled trial to investigate the impact of total intravenous anaesthesia with propofol vs. inhalational volatile anaesthesia on postoperative outcomes of patients undergoing major cancer surgery. We undertook a randomised, double-blind feasibility and pilot study of propofol total intravenous anaesthesia or volatile-based maintenance anaesthesia during cancer resection surgery at three tertiary hospitals in Australia and the USA. Patients were randomly allocated to receive propofol total intravenous anaesthesia or volatile-based maintenance anaesthesia. Primary outcomes for this study were successful recruitment to the study and successful delivery of the assigned anaesthetic treatment as per randomisation arm. Of the 217 eligible patients approached, 146 were recruited, a recruitment rate of 67.3% (95%CI 60.6-73.5%). One hundred and forty-five patients adhered to the randomised treatment arm, 99.3% (95%CI 96.2-100%). Intra-operative patient characteristics and postoperative complications were comparable between the two intervention groups. This feasibility and pilot study supports the viability of the protocol for a large, randomised controlled trial to investigate the effect of anaesthesia technique on postoperative cancer outcomes. The volatile anaesthesia and peri-operative outcomes related to cancer (VAPOR-C) study that is planned to follow this feasibility study is an international, multicentre trial with the aim of providing evidence-based guidelines for the anaesthetic management of patients undergoing major cancer surgery.

We report a chemiluminescent probe (CLPT1) that permits the paired detection of tyrosinase (Tyr) and biological thiols. Tyr only leads to a poor chemiluminescence response, a finding ascribed to the formation of a stable o-benzoquinone intermediate. The addition of glutathione (GSH), or ascorbate to the o-benzoquinone intermediate results in thiol conjugation or reduction to this intermediate, respectively. This produces a strong chemiluminescence response. Thiol co-dependence was demonstrated in live cells using the cell permeable analogue, CLPT3. The present chemiluminescence-based strategy allows the concurrent detection of tyrosinase activity and biological thiols.

Crystalline supramolecular architectures mediated by cations, anions, ion pairs or neutral guest species are well established. However, the robust crystallization of a well-designed receptor mediated by labile anionic solvate clusters remains unexplored. Herein, we describe the synthesis and crystalline behaviors of a trimacrocyclic hexasubstituted benzene 2 in the presence of guanidium halide salts and chloroform. Halide hexasolvate clusters, viz. [Cl(CHCl3)6]−, [Br(CHCl3)6]−, and [I(CHCl3)6]−, were found to be critical to the crystallization process, as suggested by the single-crystal structures, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS), and NMR spectroscopy. This study demonstrates the hitherto unexpected role that labile ionic solvate clusters can play in stabilizing supramolecular architectures., We report the synthesis and robust crystallization of a trimacrocyclic hexasubstituted benzene and guanidium mediated by unprecedented labile halide hexasolvate clusters, viz. [Cl(CHCl3)6]−, [Br(CHCl3)6]−, [I(CHCl3)6]−, and [Br(CHBr3)6]−.

Supplemental Digital Content is Available in the Text. A 6-day ambulatory continuous peripheral nerve block reduces phantom limb pain and pain-induced physical and emotional dysfunction for at least 4 weeks after treatment., Phantom limb pain is thought to be sustained by reentrant neural pathways, which provoke dysfunctional reorganization in the somatosensory cortex. We hypothesized that disrupting reentrant pathways with a 6-day-long continuous peripheral nerve block reduces phantom pain 4 weeks after treatment. We enrolled patients who had an upper- or lower-limb amputation and established phantom pain. Each was randomized to receive a 6-day perineural infusion of either ropivacaine or normal saline. The primary outcome was the average phantom pain severity as measured with a Numeric Rating Scale (0-10) at 4 weeks, after which an optional crossover treatment was offered within the following 0 to 12 weeks. Pretreatment pain scores were similar in both groups, with a median (interquartile range) of 5.0 (4.0, 7.0) for each. After 4 weeks, average phantom limb pain intensity was a mean (SD) of 3.0 (2.9) in patients given local anesthetic vs 4.5 (2.6) in those given placebo (difference [95% confidence interval] 1.3 [0.4, 2.2], P = 0.003). Patients given local anesthetic had improved global impression of change and less pain-induced physical and emotional dysfunction, but did not differ on depression scores. For subjects who received only the first infusion (no self-selected crossover), the median decrease in phantom limb pain at 6 months for treated subjects was 3.0 (0, 5.0) vs 1.5 (0, 5.0) for the placebo group; there seemed to be little residual benefit at 12 months. We conclude that a 6-day continuous peripheral nerve block reduces phantom limb pain as well as physical and emotional dysfunction for at least 1 month.

Background The Hypotension Prediction Index is a commercially available algorithm, based on arterial waveform features, that predicts hypotension defined as mean arterial pressure less than 65 mmHg for at least 1 min. We therefore tested the primary hypothesis that index guidance reduces the duration and severity of hypotension during noncardiac surgery. Methods We enrolled adults having moderate- or high-risk noncardiac surgery with invasive arterial pressure monitoring. Participating patients were randomized to hemodynamic management with or without index guidance. Clinicians caring for patients assigned to guidance were alerted when the index exceeded 85 (range, 0 to 100) and a treatment algorithm based on advanced hemodynamic parameters suggested vasopressor administration, fluid administration, inotrope administration, or observation. Primary outcome was the amount of hypotension, defined as time-weighted average mean arterial pressure less than 65 mmHg. Secondary outcomes were time-weighted mean pressures less than 60 and 55 mmHg. Results Among 214 enrolled patients, guidance was provided for 105 (49%) patients randomly assigned to the index guidance group. The median (first quartile, third quartile) time-weighted average mean arterial pressure less than 65 mmHg was 0.14 (0.03, 0.37) in guided patients versus 0.14 (0.03, 0.39) mmHg in unguided patients: median difference (95% CI) of 0 (–0.03 to 0.04), P = 0.757. Index guidance therefore did not reduce amount of hypotension less than 65 mmHg, nor did it reduce hypotension less than 60 or 55 mmHg. Post hoc, guidance was associated with less hypotension when analysis was restricted to episodes during which clinicians intervened. Conclusions In this pilot trial, index guidance did not reduce the amount of intraoperative hypotension. Half of the alerts were not followed by treatment, presumably due to short warning time, complex treatment algorithm, or clinicians ignoring the alert. In the future we plan to use a lower index alert threshold and a simpler treatment algorithm that emphasizes prompt treatment. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Surgical bleeding is associated with postoperative cardiovascular complications. The efficacy and safety of tranexamic acid (TXA) in noncardiac surgery are still uncertain. Statins may prevent perioperative cardiovascular complications. We conducted a pilot to assess the feasibility of a perioperative trial of TXA and rosuvastatin. Methods Using a factorial design, we randomized patients at cardiovascular risk undergoing noncardiac surgery to intravenous TXA (1 g at the start and end of surgery) or placebo, and oral rosuvastatin (40 mg before and 20 mg daily for 30 days after surgery) or placebo. Feasibility outcomes included recruitment rates, follow-up, and compliance to interventions. Clinical outcomes were secondarily explored. Results After 3 months, we changed the design to a partial factorial due to the difficult recruitment of statin-naive patients. Over 6 months, 100 patients were randomized in the TXA trial (49 TXA, 51 placebo), 34 in the rosuvastatin trial (18 rosuvastatin, 16 placebo). Ninety-two percent (95% CI 80–98) of TXA and 86% (95% CI 74–94) of TXA-placebo patients received the 2 study doses. Thirty-three percent (95% CI 13–59) of rosuvastatin patients and 37% (95% CI 15–65) of rosuvastatin-placebo patients discontinued the study drug. A major cardiovascular complication occurred at 30 days in 1 TXA and 6 TXA-placebo patients, and 1 rosuvastatin and no rosuvastatin-placebo patients. Conclusions Our pilot study supports the feasibility of a perioperative TXA trial in noncardiac surgery. Feasibility of a perioperative rosuvastatin trial is uncertain because of a high prevalence of statin use in the target population and concerns about compliance. Trial registration ClinicalTrials.govNCT02546648.

Background Various multimodal analgesic approaches have been proposed for spine surgery. The authors evaluated the effect of using a combination of four nonopioid analgesics versus placebo on Quality of Recovery, postoperative opioid consumption, and pain scores. Methods Adults having multilevel spine surgery who were at high risk for postoperative pain were double-blind randomized to placebos or the combination of single preoperative oral doses of acetaminophen 1,000 mg and gabapentin 600 mg, an infusion of ketamine 5 µg/kg/min throughout surgery, and an infusion of lidocaine 1.5 mg/kg/h intraoperatively and during the initial hour of recovery. Postoperative analgesia included acetaminophen, gabapentin, and opioids. The primary outcome was the Quality of Recovery 15-questionnaire (0 to 150 points, with 15% considered to be a clinically important difference) assessed on the third postoperative day. Secondary outcomes were opioid use in morphine equivalents (with 20% considered to be a clinically important change) and verbal-response pain scores (0 to 10, with a 1-point change considered important) over the initial postoperative 48 h. Results The trial was stopped early for futility per a priori guidelines. The average duration ± SD of surgery was 5.4 ± 2.1 h. The mean ± SD Quality of Recovery score was 109 ± 25 in the pathway patients (n = 150) versus 109 ± 23 in the placebo group (n = 149); estimated difference in means was 0 (95% CI, –6 to 6, P = 0.920). Pain management within the initial 48 postoperative hours was not superior in analgesic pathway group: 48-h opioid consumption median (Q1, Q3) was 72 (48, 113) mg in the analgesic pathway group and 75 (50, 152) mg in the placebo group, with the difference in medians being –9 (97.5% CI, –23 to 5, P = 0.175) mg. Mean 48-h pain scores were 4.8 ± 1.8 in the analgesic pathway group versus 5.2 ± 1.9 in the placebo group, with the difference in means being –0.4 (97.5% CI; –0.8, 0.1, P = 0.094). Conclusions An analgesic pathway based on preoperative acetaminophen and gabapentin, combined with intraoperative infusions of lidocaine and ketamine, did not improve recovery in patients who had multilevel spine surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Perioperative hyperoxia has been recommended by the World Health Organization and the Centers for Disease Control and Prevention for the prevention of surgical site infections. Based on animal studies and physiological concerns, the kidneys and heart may be at risk from hyperoxia. We therefore conducted 2 unplanned subanalyses of a previous alternating cohort trial in which patients having colorectal surgery were assigned to either 30% or 80% inspired intraoperative oxygen. Specifically, we tested 2 coprimary hypotheses: (1) hyperoxia increases the incidence of acute kidney injury (AKI) within 7 postoperative days (PODs); and (2) hyperoxia worsens a composite of myocardial injury, in-hospital cardiac arrest, and 30-day mortality. Methods The underlying controlled trial included 5749 colorectal surgeries in 4481 patients, with the exposure alternating between 30% and 80% fraction of inspired oxygen (FIO2) during general anesthesia at 2-week intervals over a period of 39 months. AKI was defined as a 1.5-fold increase in creatinine from the preoperative level to the highest value measured during the initial 7 PODs. Myocardial injury was defined by fourth-generation troponin-T level >0.03 ng/mL. We assessed the effect of 80% vs 30% oxygen on the outcomes using generalized estimating equation (GEE) logistic models that adjusted for the possible within-patient correlation across multiple potential operations for a patient on different visits. Results For the AKI outcome, 2522 surgeries were allocated to 80% oxygen and 2552 to 30% oxygen. Hyperoxia had no effect on the primary outcome of postoperative AKI, with an incidence of 7.7% in the 80% oxygen group and 7.7% in the 30% oxygen group (relative risk = 0.99; 95% confidence interval [CI], 0.82-1.2; P = .95). One thousand six hundred forty-seven surgeries (all with scheduled troponin monitoring) were analyzed for the composite cardiovascular outcome. Hyperoxia had no effect on the collapsed composite of myocardial injury, cardiac arrest, and 30-day mortality, nor on any of its components (estimated relative risk = 0.71; 95% CI, 0.44-1.16; P = .17). Conclusions We found no evidence that intraoperative hyperoxia causes AKI or cardiovascular complications in adults undergoing colorectal surgery. Consequently, we suggest that clinicians select intraoperative inspired oxygen fraction based on other considerations.

Background Both saline and lactated Ringer’s solutions are commonly given to surgical patients. However, hyperchloremic acidosis consequent to saline administration may provoke complications. The authors therefore tested the primary hypothesis that a composite of in-hospital mortality and major postoperative complications is less common in patients given lactated Ringer’s solution than normal saline. Methods The authors conducted an alternating cohort controlled trial in which adults having colorectal and orthopedic surgery were given either lactated Ringer’s solution or normal saline in 2-week blocks between September 2015 and August 2018. The primary outcome was a composite of in-hospital mortality and major postoperative renal, respiratory, infectious, and hemorrhagic complications. The secondary outcome was postoperative acute kidney injury. Results Among 8,616 qualifying patients, 4,187 (49%) were assigned to lactated Ringer’s solution, and 4,429 (51%) were assigned to saline. Each group received a median 1.9 l of fluid. The primary composite of major complications was observed in 5.8% of lactated Ringer’s versus 6.1% of normal saline patients, with estimated average relative risk across the components of the composite of 1.16 (95% CI, 0.89 to 1.52; P = 0.261). The secondary outcome, postoperative acute kidney injury, Acute Kidney Injury Network stage I–III versus 0, occurred in 6.6% of lactated Ringer’s patients versus 6.2% of normal saline patients, with an estimated relative risk of 1.18 (99.3% CI, 0.99 to 1.41; P = 0.009, significance criterion of 0.007). Absolute differences between the treatment groups for each outcome were less than 0.5%, an amount that is not clinically meaningful. Conclusions In elective orthopedic and colorectal surgery patients, there was no clinically meaningful difference in postoperative complications with lactated Ringer’s or saline volume replacement. Clinicians can reasonably use either solution intraoperatively. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

BACKGROUND Volatile anesthetics potentially trigger malignant hyperthermia crises in susceptible patients. We therefore aimed to identify preparation procedures for the Draeger Primus that minimize residual concentrations of desflurane and sevoflurane with and without activated charcoal filtration. METHODS A Draeger Primus test workstation was primed with 7% desflurane or 2.5% sevoflurane for 2 hours. Residual anesthetic concentrations were evaluated with five preparation procedures, three fresh gas flow rates, and three distinct applications of activated charcoal filters. Finally, non-exchangeable and autoclaved parts of the workstation were tested for residual emission of volatile anesthetics. Concentrations were measured by multicapillary column-ion mobility spectrometry with limits of detection/quantification being

Objectives To evaluate the effect of esophageal stimulation on nutritional adequacy in critically ill patients at risk for enteral feeding intolerance. Design A multicenter randomized sham-controlled clinical trial. Setting Twelve ICUs in Canada. Patients We included mechanically ventilated ICU patients who were given moderate-to-high doses of opioids and expected to remain alive and ventilated for an additional 48 hours and who were receiving enteral nutrition or expected to start imminently. Interventions Patients were randomly assigned 1:1 to esophageal stimulation via an esophageal stimulating catheter (E-Motion Tube; E-Motion Medical, Tel Aviv, Israel) or sham treatment. All patients were fed via these catheters using a standardized feeding protocol. Measurements and main results The co-primary outcomes were proportion of caloric and protein prescription received enterally over the initial 7 days following randomization. Among 159 patients randomized, the modified intention-to-treat analysis included 155 patients: 73 patients in the active treatment group and 82 in the sham treatment group. Over the 7-day study period, the percent of prescribed caloric intake (± SE) received by the enteral route was 64% ± 2 in the active group and 65% ± 2 in sham patients for calories (difference, -1; 95% CI, -8 to 6; p = 0.74). For protein, it was 57% ± 3 in the active group and 60% ± 3 in the sham group (difference, -3; 95% CI, -10 to 3; p = 0.30). Compared to the sham group, there were more serious adverse events reported in the active treatment group (13 vs 6; p = 0.053). Clinically important arrhythmias were detected by Holter monitoring in 36 out of 70 (51%) in the active group versus 22 out of 76 (29%) in the sham group (p = 0.006). Conclusions Esophageal stimulation via a special feeding catheter did not improve nutritional adequacy and was associated with increase risk of harm in critically ill patients.

SUMMARY Large randomized trials provide the highest level of clinical evidence. However, enrolling large numbers of randomized patients across numerous study sites is expensive and often takes years. There will never be enough conventional clinical trials to address the important questions in medicine. Efficient alternatives to conventional randomized trials that preserve protections against bias and confounding are thus of considerable interest. A common feature of novel trial designs is that they are pragmatic and facilitate enrollment of large numbers of patients at modest cost. This article presents trial designs including cluster designs, real-time automated enrollment, and practitioner-preference approaches. Then various adaptive designs that improve trial efficiency are presented. And finally, the article discusses the advantages of embedding randomized trials within registries.

There is intense debate around the use of altered and waived consent for pragmatic trials. Those in favor argue that traditional consent compromises the internal and external validity of these trials. Those against, warn that the resultant loss of autonomy compromises respect for persons and could undermine trust in the research enterprise. This article examines whether international ethical guidelines and the policy frameworks in three countries—the United States, England, and Australia—permit altered and waived consent for minimal-risk pragmatic trials conducted outside the emergency setting. Provisions for both are clearly articulated in U.S. regulations, but many countries do not have equivalent frameworks. Investigators should not assume that all consent models permitted in the United States are legal in their jurisdictions, even if they are deemed ethically defensible. The authors summarize ethical and regulatory considerations and present a framework for investigators contemplating trials with altered or waived consent.

Background Dexmedetomidine promotes normal sleep architecture; the drug also improves analgesia. We therefore tested the hypothesis that supplementing intravenous analgesia with dexmedetomidine reduces delirium in older patients recovering from orthopedic surgery. Methods In this double-blinded randomized controlled trial, we enrolled 712 older (aged 65–90 years) patients scheduled for major orthopedic surgery. Postoperative analgesia was provided by patient-controlled intravenous sufentanil, supplemented by randomly assigned dexmedetomidine (1.25 μg/mL) or placebo, for up to three days. The primary outcome was the incidence of delirium assessed twice daily with the Confusion Assessment Method. Among secondary outcomes, pain severity was assessed twice daily and sleep quality once daily, each with an 11-point scale where 0 = no pain/the best possible sleep and 10 = the worst pain/the worst possible sleep. Results The incidence of postoperative delirium was 7.3% (26 of 354) with placebo and 4.8% (17 of 356) with dexmedetomidine; relative risk 0.65, 95% CI 0.36 to 1.18; P = 0.151. Dexmedetomidine reduced pain both at rest (median difference -1 to 0 points, P ≤ 0.001) and with movement (-1 points, P P = 0.007; day two 0 point (-1 to 0), P = 0.010; and day three 0 point (-1 to 0), P = 0.003. The incidence of adverse events was similar in each group. Conclusions Supplementing sufentanil intravenous analgesia with low-dose dexmedetomidine did not significantly reduce delirium, but improved analgesia and sleep quality without provoking adverse events. Trial registration www.chictr.org.cn: ChiCTR1800017182 (Date of registration: July 17, 2018); ClinicalTrials.gov:NCT03629262 (Date of registration: August 14, 2018).

Background Delirium is a common and serious postoperative complication, especially in the elderly. Epidural anesthesia may reduce delirium by improving analgesia, reducing opioid consumption, and blunting stress response to surgery. This trial therefore tested the hypothesis that combined epidural–general anesthesia reduces the incidence of postoperative delirium in elderly patients recovering from major noncardiac surgery. Methods Patients aged 60 to 90 yr scheduled for major noncardiac thoracic or abdominal surgeries expected to last 2 h or more were enrolled. Participants were randomized 1:1 to either combined epidural–general anesthesia with postoperative epidural analgesia or general anesthesia with postoperative intravenous analgesia. The primary outcome was the incidence of delirium, which was assessed with the Confusion Assessment Method for the Intensive Care Unit twice daily during the initial 7 postoperative days. Results Between November 2011 and May 2015, 1,802 patients were randomized to combined epidural–general anesthesia (n = 901) or general anesthesia alone (n = 901). Among these, 1,720 patients (mean age, 70 yr; 35% women) completed the study and were included in the intention-to-treat analysis. Delirium was significantly less common in the combined epidural–general anesthesia group (15 [1.8%] of 857 patients) than in the general anesthesia group (43 [5.0%] of 863 patients; relative risk, 0.351; 95% CI, 0.197 to 0.627; P < 0.001; number needed to treat 31). Intraoperative hypotension (systolic blood pressure less than 80 mmHg) was more common in patients assigned to epidural anesthesia (421 [49%] vs. 288 [33%]; relative risk, 1.47, 95% CI, 1.31 to 1.65; P < 0.001), and more epidural patients were given vasopressors (495 [58%] vs. 387 [45%]; relative risk, 1.29; 95% CI, 1.17 to 1.41; P < 0.001). Conclusions Older patients randomized to combined epidural-general anesthesia for major thoracic and abdominal surgeries had one third as much delirium but 50% more hypotension. Clinicians should consider combining epidural and general anesthesia in patients at risk of postoperative delirium, and avoiding the combination in patients at risk of hypotension. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Three perioperative factors impair host defence against recurrence during cancer surgery: the surgical stress response, use of volatile anaesthetic, and opioids for analgesia. All factors are ameliorated by regional anaesthesia-analgesia. We tested the primary hypothesis that breast cancer recurrence after potentially curative surgery is lower with regional anaesthesia-analgesia using paravertebral blocks and the anaesthetic propofol than with general anaesthesia with the volatile anaesthetic sevoflurane and opioid analgesia. A second hypothesis was that regional anaesthesia-analgesia reduces persistent incisional pain.We did a randomised controlled trial at 13 hospitals in Argentina, Austria, China, Germany, Ireland, New Zealand, Singapore, and the USA. Women (age85 years) having potentially curative primary breast cancer resections were randomised by computer to either regional anaesthesia-analgesia (paravertebral blocks and propofol) or general anaesthesia (sevoflurane) and opioid analgesia. The primary outcome was local or metastatic breast cancer recurrence. The secondary outcome was incisional pain at 6 months and 12 months. Primary analyses were done under intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT00418457. The study was stopped after a preplanned futility boundary was crossed.Between Jan 30, 2007, and Jan 18, 2018, 2132 women were enrolled to the study, of whom 24 were excluded before surgery. 1043 were assigned to regional anaesthesia-analgesia and 1065 were allocated to general anaesthesia. Baseline characteristics were well balanced between study groups. Median follow-up was 36 (IQR 24-49) months. Among women assigned regional anaesthesia-analgesia, 102 (10%) recurrences were reported, compared with 111 (10%) recurrences among those allocated general anaesthesia (hazard ratio 0·97, 95% CI 0·74-1·28; p=0·84). Incisional pain was reported by 442 (52%) of 856 patients assigned to regional anaesthesia-analgesia and 456 (52%) of 872 patients allocated to general anaesthesia at 6 months, and by 239 (28%) of 854 patients and 232 (27%) of 852 patients, respectively, at 12 months (overall interim-adjusted odds ratio 1·00, 95% CI 0·85-1·17; p=0·99). Neuropathic breast pain did not differ by anaesthetic technique and was reported by 87 (10%) of 859 patients assigned to regional anaesthesia-analgesia and 89 (10%) of 870 patients allocated to general anaesthesia at 6 months, and by 57 (7%) of 857 patients and 57 (7%) of 854 patients, respectively, at 12 months.In our study population, regional anaesthesia-analgesia (paravertebral block and propofol) did not reduce breast cancer recurrence after potentially curative surgery compared with volatile anaesthesia (sevoflurane) and opioids. The frequency and severity of persistent incisional breast pain was unaffected by anaesthetic technique. Clinicians can use regional or general anaesthesia with respect to breast cancer recurrence and persistent incisional pain.Sisk Healthcare Foundation (Ireland), Eccles Breast Cancer Research Fund, British Journal of Anaesthesia International, College of Anaesthetists of Ireland, Peking Union Medical College Hospital, Science Fund for Junior Faculty 2016, Central Bank of Austria, and National Healthcare Group.

Continuous blood pressure monitoring may facilitate early detection and prompt treatment of hypotension. We tested the hypothesis that area under the curve (AUC) mean arterial pressure (MAP)65 mm Hg is reduced by continuous invasive arterial pressure monitoring.Adults having noncardiac surgery were randomly assigned to continuous invasive arterial pressure or intermittent oscillometric blood pressure monitoring. Arterial catheter pressures were recorded at 1-minute intervals; oscillometric pressures were typically recorded at 5-minute intervals. We estimated the arterial catheter effect on AUC-MAP65 mm Hg using a multivariable proportional odds model adjusting for imbalanced baseline variables and duration of surgery. Pressures65 mm Hg were categorized as 0, 1-17, 18-91, and91 mm Hg × minutes of AUC-MAP65 mm Hg (ie, no hypotension and 3 equally sized groups of increasing hypotension).One hundred fifty-two patients were randomly assigned to arterial catheter use and 154 to oscillometric monitoring. For various clinical reasons, 143 patients received an arterial catheter, while 163 were monitored oscillometrically. There were a median [Q1, Q3] of 246 [187, 308] pressure measurements in patients with arterial catheters versus 55 (46, 75) measurements in patients monitored oscillometrically. In the primary intent-to-treat analysis, catheter-based monitoring increased detection of AUC-MAP65 mm Hg, with an estimated proportional odds ratio (ie, odds of being in a worse hypotension category) of 1.78 (95% confidence interval [CI], 1.18-2.70; P = .006). The result was robust over an as-treated analysis and for sensitivity analyses with thresholds of 60 and 70 mm Hg.Intraoperative blood pressure monitoring with arterial catheters detected nearly twice as much hypotension as oscillometric measurements.

Perioperative investigators and professionals increasingly seek to evaluate whether implementing systematic practice changes improves outcomes compared to a previous routine. Cluster randomized trials are the optimal design to assess a systematic practice change but are often impractical; investigators, therefore, often select a before-after design. In this Statistical Grand Rounds, we first discuss biases inherent in a before-after design, including confounding due to periods being completely separated by time, regression to the mean, the Hawthorne effect, and others. Many of these biases can be at least partially addressed by using appropriate designs and analyses, which we discuss. Our focus is on segmented regression of an interrupted time series, which does not require a concurrent control group; we also present alternative designs including difference-in-difference, stepped wedge, and cluster randomization. Conducting segmented regression well requires a sufficient number of time points within each period, along with a robust set of potentially confounding variables. This method compares preintervention and postintervention changes over time, divergences in the outcome when an intervention begins, and trends observed with the intervention compared to trends projected without it. Difference-in-difference methods add a concurrent control, enabling yet stronger inference. When done well, the discussed methods permit robust inference on the effect of an intervention, albeit still requiring assumptions and having limitations. Methods are demonstrated using an interrupted time series study in which anesthesiologists took responsibility for an adult medical emergency team from internal medicine physicians in an attempt to improve outcomes.

This paper develops a practice-based Theory of Generative Interactions across diversity that builds on empirical findings and conceptual frameworks from multiple fields of study. This transdisciplinary review (Montuori in World Futures 69:200–230, 2013) draws on the disciplines of sociology, social psychology, organization studies, and communications. The Theory of Generative Interactions suggests that in order to facilitate inclusion, multiple types of exclusionary dynamics (self-segregation, communication apprehension, and stereotyping and stigmatizing) must be overcome through adaptive cognitive processing and skill development, and engagement in positive interactions must occur in order to facilitate inclusion that is created and sustained by contextually relevant sets of organizational practices. The organizational practices provide the following conditions for generative interactions: pursuing an important, shared organizational purpose, mixing diverse members frequently over protracted periods of time, enabling differing groups to have equal standing and insider status in contributing to success, and providing collaborative interdependence, interpersonal comfort, and self-efficacy. These interactions are generative in that they help to challenge the guiding assumptions of the organizational culture, reconsider taken-for-granted aspects, and raise fundamental questions about organizations (Gergen in Person Soc Psychol 36:1344–1360, 1978). We assert that such interactions, properly structured, can help organizations more fully address all stakeholders in creating value ethically, and ultimately creating equity for individuals and groups in the organization.

Background Perioperative arterial blood pressure management is a physiologically complex challenge influenced by multiple factors. Methods A multidisciplinary, international working subgroup of the Third Perioperative Quality Initiative (POQI) consensus meeting reviewed the (patho)physiology and measurement of arterial pressure as applied to perioperative medicine. We addressed predefined questions by undertaking a modified Delphi analysis, in which primary clinical research and review articles were identified using MEDLINE. Strength of recommendations, where applicable, were graded by National Institute for Health and Care Excellence (NICE) guidelines. Results Multiple physiological factors contribute to the perioperative physiological importance of arterial pressure: (i) arterial pressure is the input pressure to organ blood flow, but is not the sole determinant of perfusion pressure; (ii) blood flow is often independent of changes in perfusion pressure because of autoregulatory changes in vascular resistance; (iii) microvascular dysfunction uncouples microvascular blood flow from arterial pressure (haemodynamic incoherence). From a practical clinical perspective, we identified that: (i) ambulatory measurement is the optimal method to establish baseline arterial pressure; (ii) automated and invasive arterial pressure measurements have inherent physiological and technical limitations; (iii) individualised arterial pressure targets may change over time, especially in the perioperative period. There remains a need for research in non-invasive, continuous arterial pressure measurements, macro- and micro-circulatory control, regional perfusion pressure measurement, and the development of sensitive, specific, and continuous measures of cellular function to evaluate blood pressure management in a physiologically coherent manner. Conclusion The multivariable, complex physiology contributing to dynamic changes in perioperative arterial pressure may be underappreciated clinically. The frequently unrecognised dissociation between arterial pressure, organ blood flow, and microvascular and cellular function requires further research to develop a more refined, contextualised clinical approach to this routine perioperative measurement.

EDITOR’S PERSPECTIVE What We Already Know about This Topic Intraoperative triple-low events (mean arterial pressure less than 75 mmHg, Bispectral Index less than 45, and minimum alveolar fraction of anesthetic less than 0.8) have been found to be associated with increased risk of mortality What This Article Tells Us That Is New A randomized electronic alert of triple-low events to treating clinicians did not reduce 90-day mortality The alerts minimally influenced clinician responses, assessed as vasopressor administration or reduction in end-tidal volatile anesthetic partial pressure, and there was no association between response to alerts and mortality Triple-low events predict mortality but do not appear to be causally related Background Triple-low events (mean arterial pressure less than 75 mmHg, Bispectral Index less than 45, and minimum alveolar fraction less than 0.8) are associated with mortality but may not be causal. This study tested the hypothesis that providing triple-low alerts to clinicians reduces 90-day mortality. Methods Adults having noncardiac surgery with volatile anesthesia and Bispectral Index monitoring were electronically screened for triple-low events. Patients having triple-low events were randomized in real time, with clinicians either receiving an alert, “consider hemodynamic support,” or not. Patients were blinded to treatment. Helpful responses to triple-low events were defined by administration of a vasopressor within 5 min or a 20% reduction in end-tidal volatile anesthetic concentration within 15 min. Results Of the qualifying patients, 7,569 of 36,670 (20%) had triple-low events and were randomized. All 7,569 were included in the primary analysis. Ninety-day mortality was 8.3% in the alert group and 7.3% in the nonalert group. The hazard ratio (95% CI) for alert versus nonalert was 1.14 (0.96, 1.35); P = 0.12, crossing a prespecified futility boundary. Clinical responses were helpful in about half the patients in each group, with 51% of alert patients and 47% of nonalert patients receiving vasopressors or having anesthetics lowered after start of triple low (P < 0.001). There was no relationship between the response to triple-low events and adjusted 90-day mortality. Conclusions Real-time alerts to triple-low events did not lead to a reduction in 90-day mortality, and there were fewer responses to alerts than expected. However, similar mortality with and without responses suggests that there is no strong relationship between responses to triple-low events and mortality.

BACKGROUND Serratus anterior plane blocks (SAPBs) and thoracic paravertebral blocks (TPVBs) can both be used for video-assisted thoracic surgery. However, it remains unknown whether the analgesic efficacy of a SAPB is comparable to that of a TPVB. OBJECTIVE We tested the primary hypothesis that SAPBs provide noninferior analgesia compared with TPVBs for video-assisted thoracic surgery. DESIGN A noninferiority randomised trial. SETTING Shanghai Chest Hospital, between August 2018 and November 2018. PATIENTS Ninety patients scheduled for video-assisted thoracic lobectomy or segmentectomy were randomised. Patients were excluded if they were unable to perform the visual analogue pain scale, or surgery was converted to thoracotomy. INTERVENTIONS Blocks were performed after induction of general anaesthesia. The three groups were paravertebral blocks (n = 30); serratus anterior plane blocks (n = 29); and general anaesthesia alone (n = 30). PRIMARY OUTCOME MEASURES Visual analogue pain scores (0 to 10 cm) at rest and while coughing, and Prince-Henry pain scores (0 to 4 points) were used to assess postoperative analgesia at 2, 24 and 48 h after surgery. We assessed the noninferiority of SAPBs with TPVBs on all three primary pain outcomes using a delta of 1 cm or one point as appropriate. RESULTS The mean difference (95% confidence intervals) in visual analogue scores between the SAPBs and TPVBs was -0.04 (-0.10 to 0.03) cm at rest, -0.22 (-0.43 to -0.01) cm during coughing and -0.10 (-0.25 to 0.05) for Prince-Henry pain scores. As the upper limit of the confidence intervals were less than 1 (all P

To test the hypotheses that in adults having cardiac surgery with cardio-pulmonary bypass, perioperative hypotension increases the risk of delirium and atrial fibrillation during the initial five postoperative days.Sub-analysis of the DECADE multi-center randomized trial.Patients who had cardiac surgery with cardiopulmonary bypass at the Cleveland Clinic.In the underlying trial, patients were randomly assigned 1:1 to dexmedetomidine or normal saline placebo.Intraoperative mean arterial pressures were recorded at 1-min intervals from arterial catheters or at 1-5-min intervals oscillometrically. Postoperative blood pressures were recorded every half-hour or more often. The co-primary outcomes were atrial fibrillation and delirium occurring between intensive care unit admission and the earlier of postoperative day 5 or hospital discharge. Delirium was assessed twice daily during the initial 5 postoperative days while patients remained hospitalized with the Confusion Assessment Method for the intensive care unit. Assessments were made by trained research fellows who were blinded to the dexmedetomidine administration.There was no significant association between intraoperative hypotension and delirium, with an adjusted odds ratio of 0.94 (95% CI: 0.81, 1.09; P = 0.419) for a doubling in AUC of mean arterial pressure (MAP)60 mmHg. An increase in intraoperative AUC of MAP60 mmHg was not significantly associated with the odds of atrial fibrillation (adjusted odds ratio = 0.99; 95% CI: 0.87, 1.11; P = 0.819). Postoperative MAP70 mmHg per hour 1.14 (97.5% CI: 1.04,1.26; P = 0.002) and MAP80 mmHg per hour 1.05 (97.5%: 1.01, 1.10; P = 0.010) were significantly associated with atrial fibrillation.In patients having cardiac surgery with cardio-pulmonary bypass, neither intraoperative nor postoperative hypotension were associated with delirium. Postoperative hypotension was associated with atrial fibrillation, although intraoperative hypotension was not.

To test whether patients who experience hypotension in the post-anesthesia care unit or during surgery are most likely to experience hypotension on surgical wards.A prediction study using data from two randomized controlled trials.Operating room, post-anesthesia care unit, and surgical ward.550 adult patients having abdominal surgery with ASA physical status I-IV.Blood pressure measurement per routine intraoperatively, and with continuous non-invasive monitoring postoperatively.The primary predictors were minimum mean arterial pressure (60,65,70 and 80 mmHg) and minimum systolic blood pressure (70,75,80,85 mmHg) in the post-anesthesia care unit. The secondary predictors were intraoperative minimum blood pressures with the same thresholds as the primary ones. Our outcome was ward hypotension defined as mean pressure 70 mmHg or systolic pressure 85 mmHg. A threshold was considered clinically useful if both sensitivity and specificity exceeded 0.75.Minimum mean and systolic pressures in the post-anesthesia care unit similarly predicted ward mean or systolic hypotension, with the areas under the curves near 0.74. The best performing threshold was mean pressure 80 mmHg in the post-anesthesia care unit which had a sensitivity of 0.41 (95% confidence interval [CI], 0.35, 0.47) and specificity of 0.91 (95% CI, 0.87, 0.94) for ward mean pressure 70 mmHg and a sensitivity of 0.44 (95% CI, 0.37, 0.51) and specificity of 0.88 (95% CI, 0.84, 0.91) for ward systolic pressure 85 mmHg. The areas under the curves using intraoperative hypotension to predict ward hypotension were roughly similar at about 0.60, with correspondingly low sensitivity and specificity.Intraoperative hypotension poorly predicted ward hypotension. Pressures in the post-anesthesia care unit were more predictive, but the combination of sensitivity and specificity remained poor. Unless far better predictors are identified, all surgical inpatients should be considered at risk for postoperative hypotension.

Summary Terms such as prospective, interventional, and controlled are redundant in the context of randomised trials, and are therefore distracting. Pragmatic should probably be reserved for trials that intentionally control little except the exposure. The term pilot should be reserved for trials that were designated to a priori and registered as pilot trials, and have appropriate pilot outcomes. ‘Pragmatic' and ‘real-world' should not be inserted to excuse poor trial design; and similarly, ‘pilot' should not be appended to excuse inadequate power.

Background Whether supplemental oxygen worsens long-term mortality remains unclear, with contradictory trial results. The authors therefore tested the hypothesis that supplemental oxygen (80% vs. 30%) increases the hazard for long-term mortality. Methods The authors conducted a post hoc analysis of a large multiple crossover cluster trial in which more than 5,000 colorectal surgeries on 4,088 adults were allocated to receive either 30% or 80% inspired oxygen during general anesthesia. The authors assessed the effect of 80% versus 30% target-inspired oxygen on long-term mortality and calculated Kaplan–Meier survival estimates. Analysis was restricted to patients with a home address in Ohio because the authors could obtain reliable vital status information from the Ohio Department of Health (Columbus, Ohio) for them. Results A total of 3,471 qualifying colorectal surgeries performed in 2,801 patients were analyzed, including 1,753 (51%) surgeries in 1,577 patients given 80% oxygen and 1,718 surgeries in 1,551 patients given 30% oxygen. The observed incidence of death after a median of 3 yr was 13% (234 of 1,753) in the 80% oxygen group and 14% (245 of 1,718) in the 30% oxygen group. The estimated hazard ratio for mortality was 0.94 (95% CI, 0.78 to 1.13; P = 0.493). Conclusions In this post hoc analysis of a large, controlled trial, supplemental oxygen did not increase postoperative mortality. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Epidural block are often used for analgesia after open nephrectomy surgery. Subcostal anterior quadratus lumborum block may be an alternative. We therefore tested the hypothesis that the continuous subcostal anterior quadratus lumborum block is noninferior to epidural block for analgesia in patients having open partial nephrectomies. Methods Adults having open partial nephrectomies were randomly allocated to epidural or unilateral subcostal anterior quadratus lumborum block. The joint primary outcomes were opioid consumption measured in morphine equivalents and pain measured on a numeric rating scale (0-10) from postanesthesia care unit (PACU) until 72 hours after surgery. The noninferiority deltas were 30% for opioid consumption and 1 point on a 0-10 scale for pain. Secondary outcomes included patient global assessment of pain management on the third postoperative day, the number of antiemetic medication doses through the third postoperative day, duration of PACU stay, and postoperative duration of hospitalization. Results Twenty-six patients were randomized to anterior quadratus lumborum block and 29 to epidural analgesia. Neither pain scores nor opioid consumption in the quadratus lumborum patients were noninferior to epidural analgesia. At 72 hours, mean ± standard deviation pain scores in subcoastal anterior quadratus lumborum block and epidural group were 4.7 ± 1.8 and 4.1 ± 1.7, with an estimated difference in pain scores of 0.62 (95% confidence interval [CI], 0.74-1.99; noninferiority P = .21). The median [Q1, Q3] opioid consumption was more than doubled in quadratus lumborum patients at 70 mg [43, 125] versus 30 mg [18, 75] in the epidural group with an estimated ratio of geometric means of 1.69 (95% CI, 0.66-4.33; noninferiority P = .80). Patient global assessment and duration of PACU and hospital stays did not differ significantly in the 2 groups. Conclusions We were unable to show that subcostal anterior quadratus lumborum block are noninferior to epidural analgesia in terms of pain scores and opioid consumption for open partial nephrectomies. Effectiveness of novel blocks should be rigorously tested in specific surgical setting before widespread adoption.

BACKGROUND Inadvertent perioperative hypothermia is a common complication of surgery, and active body surface warming (ABSW) systems are used to prevent adverse clinical outcomes. Prior data on certain outcomes are equivocal (ie, blood loss) or limited (ie, pain and opioid consumption). The objective of this study was to provide an updated review on the effect of ABSW on clinical outcomes and temperature maintenance. METHODS We conducted a systematic review of randomized controlled trials evaluating ABSW systems compared to nonactive warming controls in noncardiac surgeries. Outcomes studied included postoperative pain scores and opioid consumption (primary outcomes) and other perioperative clinical variables such as temperature changes, blood loss, and wound infection (secondary outcomes). We searched Ovid MEDLINE daily, Ovid MEDLINE, EMBASE, CINHAL, Cochrane CENTRAL, and Web of Science from inception to June 2019. Quality of evidence (QoE) was rated according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Subgroup analysis sought to determine the effect of preoperative + intraoperative warming versus intraoperative warming alone. Metaregression evaluated the effect of year of publication, use of neuromuscular blockers, anesthesia, and surgery type on outcomes. RESULTS Fifty-four articles (3976 patients) were included. Pooled results demonstrated that ABSW maintained normothermia compared to controls, during surgery (30 minutes postinduction [mean difference {MD}: 0.3°C, 95% confidence interval {CI}, 0.2-0.4, moderate QoE]), end of surgery (MD: 1.1°C, 95% CI, 0.9-1.3, high QoE), and up to 4 hours postoperatively (MD: 0.3°C, 95% CI, 0.2-0.5, high QoE). ABSW was not associated with difference in pain scores (

Intensive care units (ICUs) are an appropriate focus of antibiotic stewardship program efforts because a large proportion of any hospital's use of parenteral antibiotics, especially broad-spectrum, occurs in the ICU. Given the importance of antibiotic stewardship for critically ill patients and the importance of critical care practitioners as the front line for antibiotic stewardship, a workshop was convened to specifically address barriers to antibiotic stewardship in the ICU and discuss tactics to overcome these. The working definition of antibiotic stewardship is "the right drug at the right time and the right dose for the right bug for the right duration." A major emphasis was that antibiotic stewardship should be a core competency of critical care clinicians. Fear of pathogens that are not covered by empirical antibiotics is a major driver of excessively broad-spectrum therapy in critically ill patients. Better diagnostics and outcome data can address this fear and expand efforts to narrow or shorten therapy. Greater awareness of the substantial adverse effects of antibiotics should be emphasized and is an important counterargument to broad-spectrum therapy in individual low-risk patients. Optimal antibiotic stewardship should not focus solely on reducing antibiotic use or ensuring compliance with guidelines. Instead, it should enhance care both for individual patients (by improving and individualizing their choice of antibiotic) and for the ICU population as a whole. Opportunities for antibiotic stewardship in common ICU infections, including community- and hospital-acquired pneumonia and sepsis, are discussed. Intensivists can partner with antibiotic stewardship programs to address barriers and improve patient care.

Background Hyperinsulinemic normoglycemia augments myocardial glucose uptake and utilization. We tested the hypothesis that hyperinsulinemic normoglycemia reduces 30-day mortality and morbidity after cardiac surgery. Methods This dual-center, parallel-group, superiority trial randomized cardiac surgical patients between August 2007 and March 2015 at the Cleveland Clinic, Cleveland, Ohio, and Royal Victoria Hospital, Montreal, Canada, to intraoperative glycemic management with (1) hyperinsulinemic normoglycemia, a fixed high-dose insulin and concomitant variable glucose infusion titrated to glucose concentrations of 80 to 110 mg · dl–1; or (2) standard glycemic management, low-dose insulin infusion targeting glucose greater than 150 mg · dl–1. The primary outcome was a composite of 30-day mortality, mechanical circulatory support, infection, renal or neurologic morbidity. Interim analyses were planned at each 12.5% enrollment of a maximum 2,790 patients. Results At the third interim analysis (n = 1,439; hyperinsulinemic normoglycemia, 709, standard glycemic management, 730; 52% of planned maximum), the efficacy boundary was crossed and study stopped per protocol. Time-weighted average glucose concentration (means ± SDs) with hyperinsulinemic normoglycemia was 108 ± 20 versus 150 ± 33 mg · dl–1 with standard glycemic management, P < 0.001. At least one component of the composite outcome occurred in 49 (6.9%) patients receiving hyperinsulinemic normoglycemia versus 82 (11.2%) receiving standard glucose management (P < efficacy boundary 0.0085); estimated relative risk (95% interim-adjusted CI) 0.62 (0.39 to 0.97), P = 0.0043. There was a treatment-by-site interaction (P = 0.063); relative risk for the composite outcome was 0.49 (0.26 to 0.91, P = 0.0007, n = 921) at Royal Victoria Hospital, but 0.96 (0.41 to 2.24, P = 0.89, n = 518) at the Cleveland Clinic. Severe hypoglycemia (less than 40 mg · dl–1) occurred in 6 (0.9%) patients. Conclusions Intraoperative hyperinsulinemic normoglycemia reduced mortality and morbidity after cardiac surgery. Providing exogenous glucose while targeting normoglycemia may be preferable to simply normalizing glucose concentrations.

Purpose Current guidelines recommend maintaining a mean arterial pressure (MAP) ≥ 65 mmHg in septic patients. However, the relationship between hypotension and major complications in septic patients remains unclear. We, therefore, evaluated associations of MAPs below various thresholds and in-hospital mortality, acute kidney injury (AKI), and myocardial injury. Methods We conducted a retrospective analysis using electronic health records from 110 US hospitals. We evaluated septic adults with intensive care unit (ICU) stays ≥ 24 h from 2010 to 2016. Patients were excluded with inadequate blood pressure recordings, poorly documented potential confounding factors, or renal or myocardial histories documented within 6 months of ICU admission. Hypotension exposure was defined by time-weighted average mean arterial pressure (TWA-MAP) and cumulative time below 55, 65, 75, and 85 mmHg thresholds. Multivariable logistic regressions determined the associations between hypotension exposure and in-hospital mortality, AKI, and myocardial injury. Results In total, 8,782 patients met study criteria. For every one unit increase in TWA-MAP

Background The effect of ambient temperature, with and without active warming, on intraoperative core temperature remains poorly characterized. The authors determined the effect of ambient temperature on core temperature changes with and without forced-air warming. Methods In this unblinded three-by-two factorial trial, 292 adults were randomized to ambient temperatures 19°, 21°, or 23°C, and to passive insulation or forced-air warming. The primary outcome was core temperature change between 1 and 3 h after induction. Linear mixed-effects models assessed the effects of ambient temperature, warming method, and their interaction. Results A 1°C increase in ambient temperature attenuated the negative slope of core temperature change 1 to 3 h after anesthesia induction by 0.03 (98.3% CI, 0.01 to 0.06) °Ccore/(h.°Cambient) (P < 0.001), for patients who received passive insulation, but not for those warmed with forced-air (–0.01 [98.3% CI, –0.03 to 0.01] °Ccore/[h.°Cambient]; P = 0.40). Final core temperature at the end of surgery increased 0.13°C (98.3% CI, 0.07 to 0.20; P < 0.01) per degree increase in ambient temperature with passive insulation, but was unaffected by ambient temperature during forced-air warming (0.02 [98.3% CI, –0.04 to 0.09] °Ccore/°Cambient; P = 0.40). After an average of 3.4 h of surgery, core temperature was 36.3° ± 0.5°C in each of the forced-air groups, and ranged from 35.6° to 36.1°C in passively insulated patients. Conclusions Ambient intraoperative temperature has a negligible effect on core temperature when patients are warmed with forced air. The effect is larger when patients are passively insulated, but the magnitude remains small. Ambient temperature can thus be set to comfortable levels for staff in patients who are actively warmed.

Background The relative contributions of intraoperative and postoperative hypotension to perioperative morbidity remain unclear. We determined the association between hypotension and a composite of 30-day myocardial infarction and death over three periods: (1) intraoperative, (2) remaining day of surgery, and (3) during the initial four postoperative days. Methods This was a substudy of POISE-2, a 10,010-patient factorial-randomized trial of aspirin and clonidine for prevention of myocardial infarction. Clinically important hypotension was defined as systolic blood pressure less than 90 mmHg requiring treatment. Minutes of hypotension was the exposure variable intraoperatively and for the remaining day of surgery, whereas hypotension status was treated as binary variable for postoperative days 1 to 4. We estimated the average relative effect of hypotension across components of the composite using a distinct effect generalized estimating model, adjusting for hypotension during earlier periods. Results Among 9,765 patients, 42% experienced hypotension, 590 (6.0%) had an infarction, and 116 (1.2%) died within 30 days of surgery. Intraoperatively, the estimated average relative effect across myocardial infarction and mortality was 1.08 (98.3% CI, 1.03, 1.12; P < 0.001) per 10-min increase in hypotension duration. For the remaining day of surgery, the odds ratio was 1.03 (98.3% CI, 1.01, 1.05; P < 0.001) per 10-min increase in hypotension duration. The average relative effect odds ratio was 2.83 (98.3% CI, 1.26, 6.35; P = 0.002) in patients with hypotension during the subsequent four days of hospitalization. Conclusions Clinically important hypotension—a potentially modifiable exposure—was significantly associated with a composite of myocardial infarction and death during each of three perioperative periods, even after adjustment for previous hypotension.

Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

Background: Uncertainty remains about the effects of aspirin in patients with prior percutaneous coronary intervention (PCI) having noncardiac surgery. Objective: To evaluate benefits and harms of perioperative aspirin in patients with prior PCI. Design: Nonprespecified subgroup analysis of a multicenter factorial trial. Computerized Internet randomization was done between 2010 and 2013. Patients, clinicians, data collectors, and outcome adjudicators were blinded to treatment assignment. (ClinicalTrials.gov: NCT01082874). Setting: 135 centers in 23 countries. Patients: Adults aged 45 years or older who had or were at risk for atherosclerotic disease and were having noncardiac surgery. Exclusions were placement of a bare-metal stent within 6 weeks, placement of a drug-eluting stent within 1 year, or receipt of nonstudy aspirin within 72 hours before surgery. Intervention: Aspirin therapy (overall trial, n = 4998; subgroup, n = 234) or placebo (overall trial, n = 5012; subgroup, n = 236) initiated within 4 hours before surgery and continued throughout the perioperative period. Of the 470 subgroup patients, 99.9% completed follow-up. Measurements: The 30-day primary outcome was death or nonfatal myocardial infarction; bleeding was a secondary outcome. Results: In patients with prior PCI, aspirin reduced the risk for the primary outcome (absolute risk reduction, 5.5% [95% CI, 0.4% to 10.5%]; hazard ratio [HR], 0.50 [CI, 0.26 to 0.95]; P for interaction = 0.036) and for myocardial infarction (absolute risk reduction, 5.9% [CI, 1.0% to 10.8%]; HR, 0.44 [CI, 0.22 to 0.87]; P for interaction = 0.021). The effect on the composite of major and life-threatening bleeding in patients with prior PCI was uncertain (absolute risk increase, 1.3% [CI, -2.6% to 5.2%]). In the overall population, aspirin increased the risk for major bleeding (absolute risk increase, 0.8% [CI, 0.1% to 1.6%]; HR, 1.22 [CI, 1.01 to 1.48]; P for interaction = 0.50). Limitation: Nonprespecified subgroup analysis with small sample. Conclusion: Perioperative aspirin may be more likely to benefit rather than harm patients with prior PCI.

Study objective Our goal was to determine when postoperative delirium first occurs, and to assess evaluation strategies that reliably detect delirium with lowest frequency of testing’. Design This was a retrospective study that used a database from a five-center randomized trial. Setting Postoperative cardiothoracic ICU and surgical wards. Participant Adults scheduled for elective coronary artery bypass and/or valve surgery. Intervention and measurements Postoperative delirium was assessed using CAM-ICU questionnaires twice daily for 5 days or until hospital discharge. Data were analyzed using frequency tables and Kaplan-Meier time-to-event estimators, the latter being used to summarize time to first positive CAM-ICU over POD1–5 for all patients for various evaluation strategies, including all assessments, only morning assessment, and only afternoon assessments. Sensitivity for various strategies were compared using McNemar's test for paired proportions. Main results A total of 95 of 788 patients (12% [95% CI, 10% to 15%]) had at least 1 episode of delirium within the first 5 postoperative days. Among all patients with delirium, 65% were identified by the end of the first postoperative day. Delirium was detected more often in the mornings (10% of patients) than evenings (7% of patients). Compared to delirium assessments twice daily for five days, we found that twice daily assessments for 4 days detected an estimated 97% (95% CI 91%, 99%) of delirium. Measurements twice daily for three days detected 90% (82%, 95%) of delirium. Conclusions Postoperative delirium is common, and CAM-ICU assessments twice daily for 4 days, versus 5 days, detects nearly all delirium with 20% fewer assessments. Four days of assessment may usually be sufficient for clinical and research purposes.

Summary Background No randomised trials have addressed whether exposure to red blood cells (RBCs) stored longer than 35 days is associated with harm in patients. We aimed to assess the risk of in-hospital mortality associated with transfusing blood stored longer than 35 days. Methods We did a secondary analysis of the INforming Fresh versus Old Red cell Management (INFORM) trial, a pragmatic, multicentre, randomised controlled trial of patients (≥18 years) admitted to one of six hospitals in Australia, Canada, Israel, and the USA and expected to need RBC transfusions. Patients were randomly assigned (2:1) to receive blood in inventory stored for the longest time (standard care) or the shortest time, using a random allocation schedule and stratified by centre and patient ABO blood group. The primary objective of the INFORM trial was to assess all-cause in-hospital mortality in patients with blood group A and O who were transfused. For our exploratory secondary analysis, we classified individuals into one of three mutually exclusive exposure categories on the basis of the maximum storage duration of any blood unit patients had received on each day in hospital: exclusively exposed to RBCs stored no longer than 7 days, exposed to at least one unit of RBCs stored 8–35 days, and exposed to least one unit of RBCs stored longer than 35 days. Our primary objective was to determine the effect on risk of in-hospital death of time-dependent exposure to RBCs stored longer than 35 days compared with exclusive exposure to RBCs stored no longer than 7 days, both in patients of blood groups A and O and all patients. The INFORM trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN08118744. Findings Between April 2, 2012, and Oct 21, 2015, 31 497 patients were recruited, and 24 736 patients were eligible for inclusion in this analysis. We excluded nine patients for whom information about the storage duration of transfused blood was missing and one patient whose sex was unknown. 4480 (18%) patients were exposed to RBCs with longest storage, 1392 (6%) patients were exposed exclusively to RBCs with shortest storage, and 18 854 (76%) patients were exposed to RBCs stored 8–35 days. Median follow-up was 11 days (IQR 6–20). Exposure to RBCs stored longer than 35 days was not associated with increased risk of in-hospital death compared with exclusive exposure to the freshest RBC units after adjusting for demographic variables, diagnosis category, and blood product use history (in patients with blood group A or O: hazard ratio 0·94, 95% CI 0·73–1·20, p=0·60; in all patients: 0·91, 0·72–1·14, p=0·40). The risk of in-hospital death also did not differ between patients exposed to blood stored 8–35 days and patients exposed to blood stored 7 days or less (in patients with blood group A or O: 0·92, 0·74–1·15, p=0·48; in all patients: 0·90, 0·73–1·10, p=0·29). Interpretation These data provide evidence that transfusion of blood stored for longer than 35 days has no effect on in-hospital mortality, which suggests that current approaches to blood storage and inventory management are reasonable. Funding Canadian Institutes for Health Research, Canadian Blood Services, and Health Canada.

Class I evidence supporting a threshold for transfusion in the cardiac surgical setting is scarce. We randomly allocated patients to a transfusion hematocrit trigger of 24% versus 28% to compare morbidity, mortality, and resource use.From March 2007 to August 2014, two centers randomly assigned 722 adults undergoing coronary artery bypass graft surgery or valve procedures to a 24% hematocrit trigger (n = 363, low group) or 28% trigger (n = 354, high group). One unit of red blood cells was transfused if the hematocrit fell below the designated threshold. The primary endpoint was a composite of postoperative morbidities and mortality. Treatment effect was primarily assessed using an average relative effect generalized estimating equation model.At the second planned interim analysis, the a priori futility boundary was crossed, and the study was stopped. There was no detected treatment effect on the composite outcome (average relative effect odds ratio, low versus high, 0.86, 95% confidence interval: 0.29 to 2.54, p = 0.71). However, the low group received fewer red blood cell transfusions than the high group (54% versus 75%, p0.001), mostly administered in the operating room (low group, 112 [31%]; high group, 208 [59%]), followed by intensive care unit (low, 105 [31%]; high, 115 [34%]) and floor (low, 41 [12%]; high, 42 [13%]). The low group was exposed to lower hematocrits: median before transfusion, 22% (Q1 = 21%, Q3 = 23%) versus 24% (Q1 = 22%, Q3 = 25%).Negative exposures differed between treatment groups, with lower hematocrit in the 24% trigger group and more red blood cells used in the 28% group, but adverse outcomes did not differ. Because red blood cell use was less with a 24% trigger without adverse effects, our randomized trial results support aggressive blood conservation efforts in cardiac surgery.

OBJECTIVE To determine the effects of IV acetaminophen on core body temperature, blood pressure, and heart rate in febrile critically ill patients. DESIGN Randomized, double-blind, placebo-controlled clinical trial. SETTING Three adult ICUs at a large, urban, academic medical center. PATIENTS Forty critically ill adults with fever (core temperature, ≥ 38.3°C). INTERVENTION An infusion of acetaminophen 1 g or saline placebo over 15 minutes. MEASUREMENT AND MAIN RESULTS Core temperature and vital signs were measured at baseline and at 5-15-minute intervals for 4 hours after infusion of study drug. The primary outcome was time-weighted average core temperature adjusted for baseline temperature. Secondary outcomes included adjusted time-weighted average heart rate, blood pressure, and respiratory rate, along with changes-over-time for each. Baseline patient characteristics were similar in those given acetaminophen and placebo. Patients given acetaminophen had an adjusted time-weighted average temperature that was 0.47°C less than those given placebo (95% CI, -0.76 to -0.18; p = 0.002). The acetaminophen group had significantly lower adjusted time-weighted average systolic blood pressure (-17 mm Hg; 95% CI, -25 to -8; p < 0.001), mean arterial pressure (-7 mm Hg; 95% CI, -12 to -1; p = 0.02), and heart rate (-6 beats/min; 95% CI, -10 to -1; p = 0.03). Changes-over-time temperature, blood pressure, and heart rate outcomes were also significantly lower at 2 hours, but not at 4 hours. CONCLUSIONS Among febrile critically ill adults, treatment with acetaminophen decreased temperature, blood pressure, and heart rate. IV acetaminophen thus produces modest fever reduction in critical care patients, along with clinically important reductions in blood pressure.

Background Optimal analgesia for total knee arthroplasty remains challenging. Many modalities have been used, including peripheral nerve block, periarticular infiltration, and epidural analgesia. However, the relative efficacy of various modalities remains unknown. The authors aimed to quantify and rank order the efficacy of available analgesic modalities for various clinically important outcomes. Methods The authors searched multiple databases, each from inception until July 15, 2016. The authors used random-effects network meta-analysis. For measurements repeated over time, such as pain, the authors considered all time points to enhance reliability of the overall effect estimate. Outcomes considered included pain scores, opioid consumption, rehabilitation profile, quality of recovery, and complications. The authors defined the optimal modality as the one that best balanced pain scores, opioid consumption, and range of motion in the initial 72 postoperative hours. Results The authors identified 170 trials (12,530 patients) assessing 17 treatment modalities. Overall inconsistency and heterogeneity were acceptable. Based on the surface under the cumulative ranking curve, the best five for pain at rest were femoral/obturator, femoral/sciatic/obturator, lumbar plexus/sciatic, femoral/sciatic, and fascia iliaca compartment blocks. For reducing opioid consumption, the best five were femoral/sciatic/obturator, femoral/obturator, lumbar plexus/sciatic, lumbar plexus, and femoral/sciatic blocks. The best modality for range of motion was femoral/sciatic blocks. Femoral/sciatic and femoral/obturator blocks best met our criteria for optimal performance. Considering only high-quality studies, femoral/sciatic seemed best. Conclusions Blocking multiple nerves was preferable to blocking any single nerve, periarticular infiltration, or epidural analgesia. The combination of femoral and sciatic nerve block appears to be the overall best approach. Rehabilitation parameters remain markedly understudied.

Background Among transfused patients, the effect of the duration of red blood cell storage on mortality remains unclear. This study aims to compare the mortality of patients who were transfused with fresher versus older red blood cells. Methods We performed an updated systematic search in the CENTRAL, MEDLINE, EMBASE and CINAHL databases, from January 2015 to October 2016. RCTs of hospitalized patients of any age comparing transfusion of fresher versus older red blood cells were eligible. We used a random-effects model to calculate pooled risk ratios (RRs) with corresponding 95% confidence interval (CI). Results We identified 14 randomized trials that enrolled 26 374 participants. All-cause mortality occurred in 1219 of 9531 (12·8%) patients who received a transfusion of fresher red blood cells and 1810 of 16 843 (10·7%) in those who received older red blood cells (RR: 1·04, 95% CI: 0·98–1·12, P = 0·90, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). In six studies, in-hospital death occurred in 691 of 7479 (9·2%) patients receiving fresher red cells and 1291 of 14 757 (8·8%) receiving older red cells (RR: 1·06, 95% CI: 0·97–1·15, P = 0·81, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). Conclusion Transfusion of fresher red blood cells does not reduce overall or in-hospital mortality when compared with older red blood cells. Our results support the practice of transfusing patients with the oldest red blood cells available in the blood bank.

Background Inflammation after cardiopulmonary bypass may contribute to postoperative delirium and cognitive dysfunction. The authors evaluated the effect of high-dose methylprednisolone to suppress inflammation on the incidence of delirium and postoperative quality of recovery after cardiac surgery. Methods Five hundred fifty-five adults from three hospitals enrolled in the randomized, double-blind Steroids in Cardiac Surgery trial were randomly allocated to placebo or 250 mg methylprednisolone at induction and 250 mg methylprednisolone before cardiopulmonary bypass. Each completed the Postoperative Quality of Recovery Scale before surgery and on days 1, 2, and 3 and 1 and 6 months after surgery and the Confusion Assessment Method scale for delirium on days 1, 2, and 3. Recovery was defined as returning to preoperative values or improvement at each time point. Results Four hundred eighty-two participants for recovery and 498 participants for delirium were available for analysis. The quality of recovery improved over time but without differences between groups in the primary endpoint of overall recovery (odds ratio range over individual time points for methylprednisolone, 0.39 to 1.45; 95% CI, 0.08–2.04 to 0.40–5.27; P = 0.943) or individual recovery domains (all P > 0.05). The incidence of delirium was 10% (control) versus 8% (methylprednisolone; P = 0.357), with no differences in delirium subdomains (all P > 0.05). In participants with normal (51%) and low baseline cognition (49%), there were no significant differences favoring methylprednisolone in any domain (all P > 0.05). Recovery was worse in patients with postoperative delirium in the cognitive (P = 0.004) and physiologic (P < 0.001) domains. Conclusions High-dose intraoperative methylprednisolone neither reduces delirium nor improves the quality of recovery in high-risk cardiac surgical patients.

Background An update of evidence-based guidelines concerning liberation from mechanical ventilation is needed as new evidence has become available. The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have collaborated to provide recommendations to clinicians concerning liberation from the ventilator. Methods Comprehensive evidence syntheses, including meta-analyses, were performed to summarize all available evidence relevant to the guideline panel's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, and the results were summarized in evidence profiles. The evidence syntheses were discussed and recommendations developed and approved by a multidisciplinary committee of experts in mechanical ventilation. Results Recommendations for three population, intervention, comparator, outcome (PICO) questions concerning ventilator liberation are presented in this document. The guideline panel considered the balance of desirable (benefits) and undesirable (burdens, adverse effects, costs) consequences, quality of evidence, feasibility, and acceptability of various interventions with respect to the selected questions. Conditional (weak) recommendations were made to use inspiratory pressure augmentation in the initial spontaneous breathing trial (SBT) and to use protocols to minimize sedation for patients ventilated for more than 24 h. A strong recommendation was made to use preventive noninvasive ventilation (NIV) for high-risk patients ventilated for more than 24 h immediately after extubation to improve selected outcomes. The recommendations were limited by the quality of the available evidence. Conclusions The guideline panel provided recommendations for inspiratory pressure augmentation during an initial SBT, protocols minimizing sedation, and preventative NIV, in relation to ventilator liberation.