BACKGROUND:Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection, in which neuroimmune dysfunction plays a central role. The medial prefrontal cortex (mPFC) is involved in autonomic and immune regulation. However, its role in modulating peripheral immune responses during sepsis remains unclear. This study investigated whether glutamatergic neurons in the mPFC regulate systemic inflammation and organ injury during sepsis via autonomic pathways and adrenergic signaling. METHODS:Glutamatergic neurons in the mPFC were selectively manipulated using optogenetic activation or chemogenetic inhibition. Mice were assigned to four main groups: ChR2 (optogenetic activation), mCherry (optogenetic control), hM4Di (chemogenetic inhibition), and EGFP (chemogenetic control). Sepsis was then induced by intraperitoneal injection of Escherichia coli or by cecal ligation and puncture. Serum and splenic cytokines were quantified by enzyme-linked immunosorbent assay (ELISA), organ injury was assessed histologically, and splenic immune cell populations and macrophage polarization were analyzed by flow cytometry. Left cervical vagotomy (LcVGX), β2-adrenergic receptor (ADRB2) antagonism (ICI-118,551), and splenic denervation via 6-hydroxydopamine (6-OHDA) were applied to explore underlying mechanisms. RESULTS:Sepsis significantly activated mPFC neurons. Optogenetic activation of mPFC glutamatergic neurons reduced proinflammatory cytokine levels and attenuated liver, kidney, and lung injury, whereas chemogenetic inhibition exacerbated systemic inflammation and organ damage. Mechanistically, activation of mPFC neurons promoted macrophage polarization toward the M2 phenotype, whereas inhibition shifted polarization toward the M1 phenotype. LcVGX abolished the anti-inflammatory effects of mPFC activation (percentage of M2 macrophages: ChR2-sham vs mCherry-sham, mean ± SEM 19.4 ± 0.87% vs 14.4 ± 1.15%, P = .023; ChR2-LcVGX vs mCherry-LcVGX, mean ± SEM 14.0 ± 0.89% vs 14.2 ± 1.33%, P > .999; n = 5/group), indicating vagal dependence. Additionally, chemogenetic inhibition increased ADRB2 expression in the spleen, and ADRB2 blockade or splenic denervation reversed the proinflammatory macrophage polarization (percentage of M1 macrophages: hM4Di-saline vs EGFP-saline, mean ± SEM 30.8 ± 1.71% vs 23.0 ± 1.06%, P = .030; hM4Di-ICI-118,551 vs EGFP-ICI-118,551, mean ± SEM 20.9 ± 2.04% vs 21.6 ± 2.14%, P = .992; hM4Di-6-OHDA vs EGFP-6-OHDA, mean ± SEM 26.3 ± 3.00% vs 26.2 ± 2.34%, P > .999; n = 4/group). CONCLUSIONS:Glutamatergic neurons in the mPFC play a critical role in regulating peripheral immune responses during sepsis. The mPFC influences macrophage polarization, systemic inflammation, and organ injury via autonomic pathways involving the vagus and splenic nerves and ADRB2-dependent signaling. Targeting mPFC-mediated neuroimmune pathways may represent a potential therapeutic strategy for sepsis.
BACKGROUND:Remote ischemic preconditioning (RIPC) demonstrated potential benefits in terms of organ protection in preclinical and several clinical settings. This systematic review of randomized controlled trials (RCTs) evaluates the association of RIPC with mortality and other relevant clinical outcomes in patients undergoing noncardiac surgery. METHODS:We conducted a systematic review and meta-analysis of RCTs assessing the effects of RIPC in adult patients undergoing noncardiac surgery. A comprehensive search was performed in PubMed, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and in proceedings from major congresses up to June 2025. Eligible studies compared RIPC with either standard care or a sham intervention. The primary outcome was all-cause mortality, assessed at the longest follow-up available. Exploratory outcomes included stroke, length of hospital stay, kidney and cardiac function. The risk of bias for each included RCT was assessed using the Cochrane risk-of-bias tool for randomized trials version 2. Rare binary outcomes were analyzed using odds ratios (ORs) with 95% confidence intervals (CIs) estimated via random-effects generalized linear mixed models (GLMMs). Non-rare binary outcomes were analyzed using risk ratios (RRs) with 95% CIs via Mantel-Haenszel random-effects models. RESULTS:We included 79 RCTs involving 9340 patients, predominantly single-center in design, with abdominal surgery (25 studies) being the most prevalent clinical setting. RIPC was primarily obtained by inflating a blood pressure cuff on upper limbs. RIPC was not associated with a statistically significant reduction in mortality compared to control in the overall population (OR = 0.79; 95% CI, 0.51-1.24; P = .30), but was associated with a significant reduction in mortality in the subgroup of patients receiving it before anesthesia induction (OR = 0.37; 95% CI, 0.17-0.81; P = .013). Exploratory findings suggested a reduction in stroke rate (OR = 0.41; 95% CI, 0.22-0.78; P = .006), length of hospital stay (mean difference = -0.84 days; P < .001), and peak postoperative serum neutrophil gelatinase-associated lipocalin (NGAL; mean difference = -10.27; P = .008) in RIPC patients. The strength of the data reported in the included studies may have been partially limited by the presence of different clinical conditions that could have either diminished or enhanced the effects of RIPC. CONCLUSIONS:RIPC was not associated with a significant reduction in mortality in the noncardiac surgical population, except for the subgroup of patients who received RIPC before anesthesia induction. However, RIPC showed beneficial effects on biomarkers of renal damage, stroke rate, and length of hospital stay. Our results support further investigation of RIPC specifically when applied before the induction of anesthesia.
BACKGROUND:Postoperative delirium (POD) is a serious complication in older surgical patients. Although both body mass index (BMI) and comorbidity burden influence perioperative outcomes, it is unclear whether an "obesity paradox" applies to POD and, crucially, whether comorbidity burden modifies that relationship. We therefore examined the independent association of BMI with POD and formally tested whether comorbidity burden, measured by the Charlson Comorbidity Index (CCI), modifies this association in older adults. METHODS:This retrospective cohort study included 4320 patients aged ≥65 years who underwent noncardiac, non-neurological surgery under general anesthesia (2015-2024). Patients with BMI <18.5 kg/m2 or missing key data were excluded. BMI was categorized as normal (18.5-24.9), overweight (25.0-29.9), class 1 obesity (30.0-34.9), and class ≥2 obesity (≥35.0). The CCI was dichotomized as low (0-2) or high (≥3). The primary outcome was POD within 7 postoperative days, assessed daily with the Korean-validated Confusion Assessment Method (CAM) or CAM for the intensive care unit (CAM-ICU). The prespecified primary analysis was a single multivariable logistic regression model including a BMI × CCI interaction term. Propensity score matching and a restricted cubic spline for BMI were predefined supportive analyses. RESULTS:POD occurred in 625 of 4320 patients (14.5%). Compared with normal weight, adjusted odds ratios (aORs) were 0.81 (95% confidence interval [CI], 0.68-0.96) for overweight, 0.76 (0.60-0.97) for class 1 obesity, and 1.02 (0.78-1.33) for class ≥2 obesity. The BMI × CCI interaction was significant (P = .040), and this was the central finding: in patients with low CCI, overweight and class 1 obesity were protective (aOR 0.69 [0.53-0.90] and 0.65 [0.46-0.92]), whereas in patients with high CCI no BMI category differed from normal weight. Propensity score-matched estimates were consistent (overweight OR 0.74 [0.60-0.90]; class 1 obesity OR 0.72 [0.53-0.98]). CONCLUSIONS:The relationship between BMI and POD is not uniform; it is conditional on comorbidity burden. Overweight and class 1 obesity are associated with reduced POD risk only in older adults with low comorbidity burden. BMI should therefore be interpreted together with comorbidity burden when assessing delirium risk in elderly surgical patients.
BACKGROUND:Myocardial injury after noncardiac surgery (MINS) is common and often clinically silent. Older adults with diabetes mellitus (DM) and/or hypertension (HTN) may have autonomic dysfunction that impairs hemodynamic compensation during surgical stress. We hypothesized that a preoperatively identifiable autonomic vulnerability phenotype would be associated with adjudicated ischemic MINS after major noncardiac surgery and that this association would be amplified at higher intraoperative hypotension (IOH) burden. METHODS:In this single-center retrospective cohort study, patients aged ≥65 years undergoing major noncardiac surgery with perioperative high-sensitivity cardiac troponin T (hs-cTnT) surveillance were analyzed. Autonomic vulnerability was defined as DM and/or HTN plus documented neuropathy, orthostatic hypotension or syncope/presyncope, or unexplained resting bradycardia/chronotropic incompetence. Propensity score matching (1:1) balanced measured confounders. The primary outcome was adjudicated ischemic MINS. Secondary outcomes included postoperative hs-cTnT elevation, 30-day major adverse cardiac events (MACE), 1-year all-cause mortality, and IOH effect modification. RESULTS:Among 2184 eligible patients, 612 matched pairs were analyzed. MINS occurred in 87 of 612 patients (14.2%) in the autonomic vulnerability group and 53 of 612 (8.7%) in the control group (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.23-2.49; P = .002). Postoperative hs-cTnT elevation was also more frequent (27.1% vs 18.5%; OR, 1.63; 95% CI, 1.28-2.07; P < .001). Thirty-day MACE (hazard ratio [HR], 1.68; 95% CI, 1.12-2.51; P = .012) and 1-year mortality (HR, 1.54; 95% CI, 1.07-2.22; P = .020) were increased. IOH burden modified the autonomic vulnerability-MINS association (P for interaction = .018), with the highest excess risk in the highest IOH quartile (OR, 2.84; 95% CI, 1.62-4.97; P < .001). CONCLUSIONS:In older adults undergoing major noncardiac surgery, a preoperative electronic health record-based autonomic vulnerability phenotype was associated with higher risk of adjudicated ischemic MINS, and this association was stronger at higher IOH burden. These hypothesis-generating findings require external validation with formal autonomic testing.
BACKGROUND:Precise control of propofol anesthesia depth is critical for perioperative safety; however, the dynamic reorganization of large-scale cortical functional networks throughout propofol anesthesia and recovery remains incompletely understood. This study employs wide-field imaging to record neuronal activity and functional connectivity across the entire cortex to investigate these cortical network dynamics during propofol anesthesia and emergence. METHODS:By synchronously recording behavioral videos and electroencephalogram-electromyogram signals, we characterized the anesthesia depth in head-fixed mice. We performed retro-orbital sinus injections of AAV2/PHP.eB-hSyn-jGCaMP8s in 8-week-old C57BL/6J mice and recorded Ca2+ signals from the dorsal cortex under a wide-field microscope. Through functional connectivity analyses in different anesthesia stages, we elucidated the dynamic changes in functional connectivity between different cortical regions during propofol anesthesia. RESULTS:Wide-field Ca2+ imaging revealed a progressive, global suppression of cortical activity as propofol anesthesia deepened, followed by partial recovery upon emergence. During the burst-suppression stage, brief high-amplitude slow waves transiently synchronized activity across all recorded cortical regions, resulting in maximal functional connectivity. In contrast, the persistent desynchronization following emergence exhibited region-specific patterns, with a greater reduction in intra-area coherence observed in motor and somatosensory cortices (Wake_pre vs Recovery: secondary motor cortex (MOs)-primary motor cortex (MOp), somatosensory, barrel field cortex (SSb)-somatosensory, upper limb cortex (SSu), SSb-somatosensory, lower limb cortex (SSl), SSu-SSl; P < 0.05) compared with visual and retrosplenial cortices. After emergence, the inter-regional correlation coefficient declined and remained below pre-anesthesia baseline for at least 1.5 hours, despite recovery of local cortical Ca2+ activity (Wake_pre vs Recovery (mean ± SEM): 0.82 ± 0.02 vs 0.67 ± 0.03 for motor cortex (MO)-somatosensory cortex (SS), 0.61 ± 0.06 vs 0.46 ± 0.06 for MO-visual cortex (VIS), 0.69 ± 0.03 vs 0.54 ± 0.06 for MO-retrosplenial cortex (RSP), 0.72 ± 0.03 vs 0.50 ± 0.10 for SS-RSP; P < 0.05). CONCLUSIONS:These findings demonstrate a dissociation between recovery of local cortical activity and restoration of large-scale network coordination during emergence from propofol anesthesia. The persistence of impaired inter-regional synchrony after behavioral recovery suggests that normalization of cortical network integration lags behind the return of consciousness. This multimodal framework provides network-level insights into anesthesia-induced brain state transitions and has implications for improving perioperative monitoring and management.
BACKGROUND:Clinical studies indicate that sedation with propofol is associated with loss of rapid eye movement (REM) sleep, whereas animal experiments suggest that propofol anesthesia may be functionally equivalent to naturally occurring sleep. However, most preclinical studies of propofol's effects on sleep have used sedative doses in young animals, despite the frequent use of high doses in the operating room and the increased susceptibility of older individuals to sleep disturbances. Here, we investigated how surgical levels of propofol anesthesia affect sleep in aged mice. We hypothesized that anesthetic-dose propofol would significantly alter both the quantity and architecture of sleep in geriatric mice compared to baseline and vehicle-treated controls. METHODS:Eighteen- to twenty-month-old mice (N = 20) were implanted with frontal and parietal epidural electroencephalographic (EEG) electrodes and allowed a minimum recovery of 10 days. EEG recordings were obtained in three animal groups. After baseline EEG recordings (control group), mice were randomized to receive either intubation via a 22-gauge intravenous cannula and a propofol infusion titrated to EEG delta waves through a central catheter (propofol group) or an equivalent infused volume of intralipid (intralipid group). Non-rapid eye movement (NREM), REM sleep, wakefulness, and NREM stage III quantity; number and duration of sleep-wake bouts; burst suppression ratio and delta power were measured during continuous 24-hour EEG recordings and analyzed using one- and two-way repeated-measures analysis of variance. RESULTS:Propofol mice exhibited increased wakefulness (820 ± 93.3 vs 658 ± 71.1 min; P < .001) and decreased NREM sleep (539 ± 93.3 vs 699 ± 64.2 min; P < .001) compared to controls. Early after propofol emergence, NREM stage III (15.7 ± 10.9 vs 52.0 ± 19.0 min; P = .0050), REM sleep (4.31 ± 2.81 vs 23.1 ± 8.26 min; P < .001), the number of REM bouts (13.9 ± 8.28 vs 32.0 ± 11.4; P = .0491), and their mean duration (14.9 ± 8.59 vs 41.9 ± 7.52 min; P < .001) were markedly decreased relative to controls. CONCLUSIONS:Surgical-level propofol anesthesia differentially influenced NREM and REM sleep. Although propofol anesthesia satisfied NREM sleep homeostasis, delayed REM rebound during recovery was compatible with altered REM regulation.
BACKGROUND:Electrical muscle stimulation (EMS) is used in critically ill patients to prevent intensive care unit-acquired weakness. It promotes anabolic responses partly through interleukin-6 (IL-6) signaling under non-inflammatory conditions; however, its effects during systemic inflammation remain unclear. We hypothesized that EMS applied during lipopolysaccharide (LPS)-induced systemic inflammation exacerbates skeletal muscle atrophy through activation of IL-6-mediated catabolic signaling. METHODS:Male C57BL/6J mice were randomly assigned to control, EMS, LPS, or EMS/LPS groups. Intraperitoneal LPS (2 mg/kg) or phosphate-buffered saline was administered, followed by EMS applied to the left hindlimb 8 h later (80 Hz, 5 mA, 30 min). Gastrocnemius muscle fiber cross-sectional area (CSA) was measured as an index of muscle atrophy, with three mice analyzed per group. Gastrocnemius muscles and blood samples were collected after treatment, and muscle morphology and CSA were analyzed histologically. Protein expression of Atrogin-1, MuRF1, C/EBPδ, phosphorylated mTOR, p70S6K, and STAT3 was assessed by Western blot, and IL-6 expression by qRT-PCR and ELISA. Data are presented as mean ± standard deviation (SD). RESULTS:Compared with control, EMS alone increased CSA (mean ± SD,1610 ± 468 vs 1350 ± 437 μm2; P < .0001), and the phosphorylation of mTOR (1.72 ± 0.234-fold; P < .0001) and p70S6K (2.34 ± 0.559-fold; P < .0001). In contrast, compared with LPS alone, EMS applied under LPS did not enhance the phosphorylation of mTOR or p70S6K, but reduced muscle fiber CSA (680 ± 327 vs 991 ± 453 μm2; P < .0001), and upregulated Atrogin-1 (13.1 ± 3.72 vs 7.85 ± 2.26-fold; p = 0.0014) and MuRF1 (3.77 ± 1.45 vs 2.50 ± 0.998 -fold; p = 0.0094) expression. These catabolic changes were accompanied by increased STAT3 phosphorylation and C/EBPδ expression (8.28 ± 4.16 vs 4.56 ± 1.88 -fold; p = 0.0098, 39.2 ± 16.4 vs 22.8 ± 12.3-fold; p = 0.0107). Additionally, IL-6 expression was elevated in both stimulated muscle (335 ± 242 vs 140 ± 23.1-fold; p = 0.0095) and serum (28.5 ± 4.60 vs 9.35 ± 3.19 ng/mL; P < .0001) in the EMS/LPS group. Similar atrophic changes were observed in the contralateral, non-stimulated limb. CONCLUSIONS:EMS applied during LPS-induced systemic inflammation exacerbated skeletal muscle atrophy and was associated with activation of IL-6/STAT3-C/EBPδ signaling and proteolytic pathways. These findings provide mechanistic insight into the effects of EMS under inflammatory conditions and warrant further investigation.
BACKGROUND:Approximately 10% to 15% of all red blood cell (RBC) transfusions in the United States and United Kingdom occur during cardiac surgery. Despite efforts to standardize patient blood management, transfusion practices remain highly variable across providers and institutions. We launched the Transfusion Improvement to Minimizing Excess in Cardiac Surgery (TIMELESS) initiative to identify modifiable drivers of transfusion at our high-volume cardiac surgery center. METHODS:Our mixed-methods approach combined a retrospective data review and a survey to assess perioperative RBC and blood component (platelets, plasma, cryoprecipitate) transfusion through three key domains: (1) preoperative assessment/optimization (evaluation of modifiable risk factors for transfusion: preoperative anemia, malnutrition, anticoagulant/platelet inhibitor use); (2) perioperative blood conservation (modifiable risk factors: intraoperative antifibrinolytic use, hyperglycemia, perioperative hypothermia); (3) transfusion behaviors (laboratory guidance and transfusion triggers). These domains were investigated through (i) a retrospective database analysis that examined the association of risk factors with total intraoperative and early postoperative blood product transfusion in adult cardiac surgical patients between January 2018 and June 2024; and (ii) a structured front-line provider survey that examined opinions and behaviors that drive blood transfusion (including transfusion thresholds, triggers, and barriers to laboratory-guided practice) in anesthesia, surgical, and intensive care unit caregivers. RESULTS:Of 24,005 cardiac surgical patients in the database review, 13,420 (55.9%) received transfusions during surgery and/or early postoperatively. Of 258 front-line providers surveyed, 112 (43%) responded. Preoperative assessment/optimization (domain #1) and perioperative blood conservation (#2) found that five of six modifiable factors were associated with greater risk-adjusted transfusion: preoperative anemia (incidence rate ratio [IRR] 1.74, 95% confidence interval [CI], 1.67-1.83), malnutrition (IRR 1.44, 95% CI, 1.36-1.54), perioperative hypothermia (IRR 1.66, 95% CI, 1.59-1.73), and hyperglycemia (IRR 1.02 per 10 mg/dL, 95% CI, 1.02-1.02), whereas antifibrinolytic therapy was associated with reduced transfusion (IRR 0.90, 95% CI, 0.86-0.93). Transfusion triggers/laboratory guidance (#3) found that many transfusions were given empirically without laboratory-guidance (RBC 32.1%, platelets 44.9%, cryoprecipitate 55.0%, plasma 82.4%). Survey found that most providers (91/112, 81%) endorsed restrictive hemoglobin thresholds (<7.5 g/dL) for stable, non-bleeding patients; platelet and cryoprecipitate transfusion thresholds varied by specialty; laboratory-guidance was omitted for urgent bleeding/coagulopathy (99/112, 88%), prolonged surgical time (49/112, 44%), and long laboratory turnaround time (49/112, 44%). CONCLUSIONS:This large mixed-methods quality initiative identified modifiable risk factors, provider opinions, and transfusion behaviors to understand key drivers of transfusion in our cardiac surgery center. These results lay the groundwork to modify risk factors and transfusion behaviors and ultimately optimize perioperative blood transfusion therapy.
BACKGROUND:Intraoperative anesthesia handovers are common in academic practice due to shift-based staffing, duty-hour limits, and the demands of prolonged procedures, and occur among both attending anesthesiologists and supervised providers. Although handovers may serve as important safety checkpoints, they also represent vulnerable periods during which loss of critical information can occur. This study evaluated whether intraoperative handovers among attending anesthesiologists are associated with prolonged hospital length of stay (HLOS) and increased risk of unplanned 30-day readmission. METHODS:We conducted a retrospective multicenter cohort study of noncardiac, nonambulatory adult patients who underwent general anesthesia between 2007 and 2021 at two academic healthcare networks in the Bronx, New York, and Boston, Massachusetts. The exposure was intraoperative handover of anesthesia care among attending anesthesiologists. The primary outcome was HLOS. The secondary outcome was unplanned 30-day readmission. We used multivariate linear regression models (continuous outcomes) and modified Poisson regression with robust error variances (binary outcomes) to assess the association between exposure and outcomes. We conducted an interaction analysis to investigate the effect modification of the primary and secondary association by case complexity. Additionally, we evaluated handovers among certified registered nurse anesthetists (CRNAs) and/or residents in exploratory analyses, as well as the time of anesthesia handover. RESULTS:A total of 145,383 patients were included, of whom 16,984 of 145,383 (11.7%) underwent an intraoperative handover of anesthesia care. Handovers were associated with a prolonged HLOS (median [interquartile range {IQR}]: 4.0 [2.0-7.0] vs 3.0 [2.0-5.0] days; adjusted model estimate [MEadj], 1.02 [95% confidence interval {CI}, 1.02-1.03]; P < .001) and higher hospital readmission rate compared to of no-handover cases; (14.0% vs 12.3%, respectively, adjusted risk ratios [RRadj], 1.06 [95% CI, 1.02-1.11], P = .003). The association between handover and HLOS was more pronounced in patients undergoing major surgery (MEadj, 1.04 [95% CI, 1.03-1.05], P < .001) compared to nonmajor surgeries (MEadj, 1.01 [95% CI, 1.00-1.02], P = .023, P-for-interaction = .001), was significant among CRNAs and/or residents (MEadj, 1.03 [95% CI, 1.02-1.05], P < .001) and when the handover occurred late in the day or at night compared to earlier in the day (late versus early: MEadj, 1.08 [95% CI, 1.05-1.11], P < .001; night versus early: MEadj 1.12 [95% CI, 1.08-1.16]; P < .001). CONCLUSIONS:Intraoperative handover of anesthesia care is associated with a small but measurable increase in HLOS and increased 30-day unplanned readmission, particularly in major surgical cases. Handovers among supervised providers may contribute to prolonged hospitalization.
BACKGROUND:Effective postoperative pain management in gynecological surgery is challenging because of complex visceral-somatic pain interactions and the adverse effects of conventional analgesics. HSK21542, a novel peripherally restricted kappa-opioid receptor (KOR) agonist that selectively targets visceral pain pathways enriched with KORs, may provide adequate analgesia without systemic adverse events. METHODS:We conducted a pooled post-hoc analysis of data from two phase III, multicenter, triple-blinded, randomized controlled trials (Study 301, HSK21542 vs placebo; Study 303, HSK21542 vs tramadol vs placebo). Eligible patients undergoing elective gynecological surgery were included. The primary outcome was the summed pain-intensity difference over 12 and 24 hours (SPID 12h and SPID 24h ). Secondary outcomes were pain-relief quality (proportion of patients relieved from severe pain with a pain numerical rating score ≤ 3 between 0 and 24 hours) and rescue-analgesic requirements (number of doses and time to first rescue analgesic). Adverse events were also assessed. RESULTS:A total of 370 patients were analyzed: 150 received HSK21542, 139 received a placebo, and 81 received tramadol. After inverse probability of treatment weighting (IPTW) adjustment, baseline characteristics were well-balanced across treatment groups (all standardized mean differences [SMD] <0.1; see Table 1 for 95% CIs). HSK21542 produced greater reductions in pain intensity over 12 and 24 hours than placebo (least-squares mean differences -8.1 and -16.3 for SPID 12h and SPID 24h , respectively. Both P < .001) and no statistically significant difference was observed between HSK21542 and tramadol ( P > .05). Significantly more patients in the HSK21542 group were relieved from severe pain at 0 to 12 hours (92.7% vs 82.7%, P < .001) and required fewer rescue doses at 0 to 12 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) and 0 to 24 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) than those in the placebo group, whereas no significant differences with tramadol both in 0 to 12 and 0 to 24 hours. HSK21542 was also associated with significantly lower incidences of nausea (24.7% vs 66.7%) and vomiting (21.3% vs 60.5%) than tramadol. Only one case of dizziness occurred in the tramadol group. CONCLUSIONS:HSK21542 could provide adequate postoperative analgesia with few adverse events in patients undergoing gynecological surgery.
BACKGROUND:Median sternotomy for cardiac surgery is associated with significant postoperative pain. We evaluated whether repeated ropivacaine boluses via bilateral deep parasternal intercostal plane (DPIP) catheters improve analgesia after cardiac surgery. METHODS:In this randomized, placebo-controlled trial, 120 adult patients undergoing elective coronary artery bypass grafting or heart valve replacement were allocated to receive repeated boluses of either ropivacaine (R) or saline (P) via bilateral DPIP catheters for 72 hours postoperatively. Patients, researchers, and clinical staff were blinded to group allocation. The primary endpoint was postoperative pain intensity, assessed by the visual analog scale or, in sedated patients, the behavioral pain scale. Secondary endpoints included cumulative oxycodone consumption, adverse events, postoperative sedation, and mechanical ventilation. RESULTS:Pain trajectories over the 72-hour postoperative period did not differ between groups (group × time interaction P = .77 at rest; P = 1.00 with movement). No statistically significant differences were observed between groups in cumulative opioid consumption. For the first 12 hours, the median (95% confidence interval [CI] for median) oxycodone dose was 24 mg (18-27) (P = .55) and from 12 to 24 hours, 24 mg (21-30) in the placebo group and 30 mg (24-39) in the ropivacaine group (P = .32). Corresponding values from 24 to 48 hours were 39 mg (33-45) and 48 mg (39-66) (P = .23), and from 48 to 72 hours 18 mg (12-24) and 24 mg (12-33), respectively (P = .21). Postoperative nausea and vomiting was the most common adverse event, occurring in 38% overall: 18 of 60 (30%) in the placebo group and 28 of 60 (46.7%) in the ropivacaine group, with a higher incidence among ropivacaine-treated valve surgery patients (placebo 9/34 [26.5%] vs ropivacaine 20/33 [60.6%], P = .012). Five patients had symptoms suggestive of local anesthetic systemic toxicity; all cases were self-limiting. Four pneumothoraces occurred, one of which was clearly surgically related. The catheter became dislodged in nine patients. Also, among the dropouts, three patients reported pain during injection of the study drug indicating suboptimal catheter positioning. Postoperative sedation and mechanical ventilation times did not differ between groups. Median (interquartile range and 95% CI for median) time until extubation was 348 minutes (278-412 minutes; CI 337-446 minutes) in the placebo group and 340 minutes (289-539 minutes; CI 400-650 minutes) in the ropivacaine group. CONCLUSIONS:Repeated ropivacaine boluses via DPIP catheters did not improve postoperative pain control or reduce opioid consumption compared with placebo after median sternotomy. Routine use of DPIP catheters after cardiac surgery should therefore be avoided. Further research is warranted to determine whether continuous infusion techniques or selective use in high-risk patients may yield greater benefit.
