Edith Fleischmann

Aspirin in patients undergoing noncardiac surgery

BACKGROUND There is substantial variability in the perioperative administration of aspirin in patients undergoing noncardiac surgery, both among patients who are already on an aspirin regimen and among those who are not. METHODS Using a 2-by-2 factorial trial design, we randomly assigned 10,010 patients who were preparing to undergo noncardiac surgery and were at risk for vascular complications to receive aspirin or placebo and clonidine or placebo. The results of the aspirin trial are reported here. The patients were stratified according to whether they had not been taking aspirin before the study (initiation stratum, with 5628 patients) or they were already on an aspirin regimen (continuation stratum, with 4382 patients). Patients started taking aspirin (at a dose of 200 mg) or placebo just before surgery and continued it daily (at a dose of 100 mg) for 30 days in the initiation stratum and for 7 days in the continuation stratum, after which patients resumed their regular aspirin regimen. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days. RESULTS The primary outcome occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P=0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P=0.04). The primary and secondary outcome results were similar in the two aspirin strata. CONCLUSIONS Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).

Does Gastric Dilatation Limit the Success of Sleeve Gastrectomy as a Sole Operation for Morbid Obesity

Background: Sleeve gastrectomy as the sole bariatric operation has been reported for high-risk super-obese patients or as first-step followed by Roux-en-Y gastric bypass (RYGBP) or duodenal switch (DS) in super-super obese patients. The efficacy of laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients with a BMI of <50 kg/m2 and the incidence of gastric dilatation following LSG have not yet been investigated. Methods: 23 patients (15 morbidly obese, 8 super-obese) were studied prospectively for weight loss following LSG. The incidence of sleeve dilatation was assessed by upper GI contrast studies in patients with a follow-up of >12 months. Results: Patients who underwent LSG achieved a mean excess weight loss (EWL) at 6 and 12 months postoperatively of 46% and 56%, respectively. No significant differences were observed in %EWL comparing obese and super-obese patients. At a mean follow-up of 20 months, dilatation of the gastric sleeve was found in 1 patient and weight regain after initial successful weight loss in 3 of the 23 patients. Conclusion: LSG has been highly effective for weight reduction for morbid obesity even as the sole bariatric operation. Gastric dilatation was found in only 1 patient in this short-term follow-up. Weight regain following LSG may require conversion to RYGBP or DS. Follow-up will be necessary to evaluate long-term results.

Clonidine in Patients Undergoing Noncardiac Surgery

BACKGROUND Marked activation of the sympathetic nervous system occurs during and after noncardiac surgery. Low-dose clonidine, which blunts central sympathetic outflow, may prevent perioperative myocardial infarction and death without inducing hemodynamic instability. METHODS We performed a blinded, randomized trial with a 2-by-2 factorial design to allow separate evaluation of low-dose clonidine versus placebo and low-dose aspirin versus placebo in patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. A total of 10,010 patients at 135 centers in 23 countries were enrolled. For the comparison of clonidine with placebo, patients were randomly assigned to receive clonidine (0.2 mg per day) or placebo just before surgery, with the study drug continued until 72 hours after surgery. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days. RESULTS Clonidine, as compared with placebo, did not reduce the number of primary-outcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P=0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P=0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P<0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02). CONCLUSIONS Administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).

Thoracic epidural anesthesia increases tissue oxygenation during major abdominal surgery.

Intraoperative surgical stress may markedly increase adrenergic nerve activity and plasma catecholamine concentrations, which causes peripheral vasoconstriction and decreased tissue oxygen partial pressure possibly leading to tissue hypoxia. Tissue hypoxia is associated with an increased incidence of surgical wound infections. Thoracic epidural anesthesia blocks afferent neural stimuli and inhibits efferent sympathetic outflow in response to painful stimuli. Consequently, we tested the hypothesis that supplemental thoracic epidural anesthesia during major abdominal surgery improves tissue perfusion and subcutaneous oxygen tension. Thirty patients were randomly assigned to two groups: general (n = 15) or combined general and epidural anesthesia (n = 15). Anesthesia technique and fluid management were standardized. Subcutaneous tissue oxygen tension was measured continuously in the upper arm with a Clark type electrode. Data were compared with unpaired, two-tailed t-tests, Wilcoxon’s ranked sum test, or repeated-measures analysis of variance and Scheffé F tests as appropriate; P < 0.05 was considered statistically significant. After 60 min, intraoperative tissue oxygen tension was significantly larger during combined anesthesia than during general anesthesia (54.3 ± 7.4 mm Hg versus 42.1 ± 8.6 mm Hg; P = 0.0002). Subcutaneous tissue oxygen tension remained significantly higher in the combined general/epidural anesthesia group throughout the observation period. Hemodynamic responses and global oxygen variables were similar in the groups. Thoracic epidural anesthesia improved intraoperative tissue oxygen tension outside the area of the epidural block. Thus, our results give evidence that supplemental neural nociceptive block blunts generalized vasoconstriction caused by surgical stress and adrenergic responses.

Tissue oxygenation in obese and non-obese patients during laparoscopy

Background: Wound infection risk is inversely related to subcutaneous tissue oxygenation, which is reduced in obese patients and may be reduced even more during laparoscopic procedures. Methods: We evaluated subcutaneous tissue oxygenation (PsqO2) in 20 patients with a body mass index (BMI) ≥40 kg/m2 (obese group) and 15 patients with BMI <30 kg/m2 (non-obese group) undergoing laparoscopic surgery with standardized anaesthesia technique and fluid administration. Arterial oxygen tension was maintained near 150 mmHg. PsqO2 was measured from a surrogate wound on the upper arm. Results: A mean FIO2 of 51% (13%) was required in obese patients to reach an arterial oxygen tension of 150 mmHg; however, a mean FIO2 of only 40% (7%) was required to reach the same oxygen tension in non-obese patients (P=0.007). PsqO2 was significantly less in obese patients: 41 (10) vs 57 (15) mmHg (P<0.001). Conclusion: Obese patients having laparoscopic surgery require a significantly greater FIO2 to reach an arterial oxygen tension of about 150 mmHg than non-obese patients; they also have significantly lower subcutaneous oxygen tensions. Both factors probably contribute to an increased infection risk in obese patients.

Nitrous oxide and risk of surgical wound infection: A randomised trial

BACKGROUND Nitrous oxide inactivates vitamin B12 and methionine synthase, thereby impairing DNA formation and, consequently, new cell formation. The gas also inhibits methionine production, which can reduce scar formation and depresses chemotactic migration by monocytes. Therefore, we assessed whether nitrous oxide increases the incidence of surgical wound infection. METHODS We recruited 418 patients aged 18-80 years, scheduled for colon resection that was expected to last more than 2 h, at three hospitals in Austria and Hungary. Patients were randomly assigned 65% intraoperative nitrous oxide (n=208) or nitrogen (n=206), with remifentanil and isoflurane. The primary outcome was the incidence of clinical postoperative wound infection, analysed by intention to treat. FINDINGS 206 patients in the nitrous oxide group and 202 in the nitrogen group were included in the final analysis. Duration of surgery was longer in the nitrogen group (3.4 h [1.5]) than in the nitrous oxide group (3.0 h [SD 1.3]) and arterial pressure (84 mm Hg [10] vs 81 mm Hg [9]), bispectral index values (53 [9] vs 44 [8]), and end-tidal isoflurane concentration (0.64% [0.14] vs 0.56% [0.13]) were greater in patients given nitrogen than in those given nitrous oxide. Infection rate was 15% (31/206) in patients given nitrous oxide and 20% (40/202) in those given nitrogen (p=0.205). Additionally, the ASEPSIS wound healing score, wound collagen deposition, number of patients admitted to critical care unit, time to first food ingestion, duration of hospital stay, and mortality did not differ between treatment groups. INTERPRETATION Nitrous oxide does not increase the incidence of surgical wound infection.

Evaluation of stroke volume variation obtained by arterial pulse contour analysis to predict fluid responsiveness intraoperatively

BACKGROUND Fluid management guided by oesophageal Doppler monitor has been reported to improve perioperative outcome. Stroke volume variation (SVV) is considered a reliable clinical predictor of fluid responsiveness. Consequently, the aim of the present trial was to evaluate the accuracy of SVV determined by arterial pulse contour (APCO) analysis, using the FloTrac/Vigileo system, to predict fluid responsiveness as measured by the oesophageal Doppler. METHODS Patients undergoing major abdominal surgery received intraoperative fluid management guided by oesophageal Doppler monitoring. Fluid boluses of 250 ml each were administered in case of a decrease in corrected flow time (FTc) to <350 ms. Patients were connected to a monitoring device, obtaining SVV by APCO. Haemodynamic variables were recorded before and after fluid bolus application. Fluid responsiveness was defined as an increase in stroke volume index >10%. The ability of SVV to predict fluid responsiveness was assessed by calculation of the area under the receiver operating characteristic (ROC) curve. RESULTS Twenty patients received 67 fluid boluses. Fifty-two of the 67 fluid boluses administered resulted in fluid responsiveness. SVV achieved an area under the ROC curve of 0.512 [confidence interval (CI) 0.32-0.70]. A cut-off point for fluid responsiveness was found for SVV > or =8.5% (sensitivity: 77%; specificity: 43%; positive predictive value: 84%; and negative predictive value: 33%). CONCLUSIONS This prospective, interventional observer-blinded study demonstrates that SVV obtained by APCO, using the FloTrac/Vigileo system, is not a reliable predictor of fluid responsiveness in the setting of major abdominal surgery.

Mild Hypercapnia Increases Subcutaneous and Colonic Oxygen Tension in Patients Given 80% Inspired Oxygen during Abdominal Surgery

Background:Supplemental perioperative oxygen increases tissue oxygen tension and decreases incidence of wound infection in colorectal surgery patients. Mild intraoperative hypercapnia also increases subcutaneous tissue oxygen tension. However, the effect of hypercapnia in patients already receiving supplemental oxygen is unknown, as is the effect of mild hypercapnia on intestinal oxygenation in humans—although the intestines are presumably the tissue of interest for colon surgeries. The authors tested the hypothesis that mild intraoperative hypercapnia increases both subcutaneous tissue and intramural intestinal oxygen tension in patients given supplemental oxygen. Methods:Patients undergoing elective colon resection were randomly assigned to normocapnia (n = 15, end-tidal carbon dioxide tension 35 mmHg) or mild hypercapnia (n = 15, end-tidal carbon dioxide tension 50 mmHg). Intraoperative inspired oxygen concentration was 80%. The authors measured subcutaneous tissue oxygen tension in the right upper arm and intramural oxygen tension in the left colon. Measurements were averaged over time within each patient and, subsequently, among patients. Data were compared with chi-square, unpaired t, or Mann–Whitney rank sum tests; P < 0.05 was significant. Results:Morphometric characteristics and other possible confounding factors were similar in the groups. Intraoperative tissue oxygen tension in hypercapnic patients was significantly greater in the arm (mean ± SD: 116 ± 29 mmHg vs. 84 ± 25 mmHg; P = 0.006) and colon (median [interquartile range]: 107 [81–129] vs. 53 [41–104] mmHg; P = 0.020). Conclusions:During supplemental oxygen administration, mild intraoperative hypercapnia increased tissue oxygen tension in the arm and colon. Previous work suggests that improved tissue oxygenation will reduce infection risk via the proposed pathomechanism, although only an outcome study can confirm this.

Evidence for serotonin as a relevant inducer of liver regeneration after liver resection in humans

Liver regeneration (LR) involves a complex interplay of growth factors and antagonists. In this context, platelet‐derived serotonin (5‐HT) has been identified as a critical inducer of LR in mice. Clinical evidence for a role of 5‐HT in LR in humans is lacking. Accordingly, serum and plasma 5‐HT was monitored perioperatively in 60 patients undergoing liver resection, of which 35 served as exploration and 25 as validation sets. Intraplatelet (IP) levels of 5‐HT were calculated by subtraction of plasma 5‐HT from serum values. Serum markers of liver function were used to evaluate LR and liver dysfunction (LD). In the exploration setting, IP 5‐HT levels significantly decreased after liver resection (P < 0.001) and gradually recovered during the first week. IP 5‐HT measured before surgery specifically predicted LD in the subsequent 7 days (area under the curve: 0.721; P = 0.029). Patients suffering from postoperative LD and morbidity were found to have reduced IP 5‐HT levels during the entire perioperative period. Furthermore, we validated that reduced preoperative IP 5‐HT (<73 ng/mL) was associated with an increased incidence of postoperative LD and morbidity (P =0.045 and P = 0.021) and were able to demonstrate that IP 5‐HT levels were an independent predictor of poor clinical outcome. Conclusions: These findings provide evidence that IP 5‐HT correlates with LR in humans: Patients with low IP 5‐HT before liver resection suffered from delayed hepatic regeneration. Therefore, IP 5‐HT levels may prove a helpful clinical marker to predict postoperative LD and clinical outcome before hepatic resection and initiate suitable interventions. (Hepatology 2014;60:257‐266)

Perioperative Aspirin and Clonidine and Risk of Acute Kidney Injury A Randomized Clinical Trial

IMPORTANCE Acute kidney injury, a common complication of surgery, is associated with poor outcomes and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however, these effects are uncertain and each intervention has the potential for harm. OBJECTIVE To determine whether aspirin compared with placebo, and clonidine compared with placebo, alters the risk of perioperative acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS A 2 × 2 factorial randomized, blinded, clinical trial of 6905 patients undergoing noncardiac surgery from 88 centers in 22 countries with consecutive patients enrolled between January 2011 and December 2013. INTERVENTIONS Patients were assigned to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery, and were assigned to take oral clonidine (0.2 mg) or placebo 2 to 4 hours before surgery, and then a transdermal clonidine patch (which provided clonidine at 0.2 mg/d) or placebo patch that remained until 72 hours after surgery. MAIN OUTCOMES AND MEASURES Acute kidney injury was primarily defined as an increase in serum creatinine concentration from the preoperative concentration by either an increase of 0.3 mg/dL or greater (≥26.5 μmol/L) within 48 hours of surgery or an increase of 50% or greater within 7 days of surgery. RESULTS Aspirin (n = 3443) vs placebo (n = 3462) did not alter the risk of acute kidney injury (13.4% vs 12.3%, respectively; adjusted relative risk, 1.10; 95% CI, 0.96-1.25). Clonidine (n = 3453) vs placebo (n = 3452) did not alter the risk of acute kidney injury (13.0% vs 12.7%, respectively; adjusted relative risk, 1.03; 95% CI, 0.90-1.18). Aspirin increased the risk of major bleeding. In a post hoc analysis, major bleeding was associated with a greater risk of subsequent acute kidney injury (23.3% when bleeding was present vs 12.3% when bleeding was absent; adjusted hazard ratio, 2.20; 95% CI, 1.72-2.83). Similarly, clonidine increased the risk of clinically important hypotension. In a post hoc analysis, clinically important hypotension was associated with a greater risk of subsequent acute kidney injury (14.3% when hypotension was present vs 11.8% when hypotension was absent; adjusted hazard ratio, 1.34; 95% CI, 1.14-1.58). CONCLUSIONS AND RELEVANCE Among patients undergoing major noncardiac surgery, neither aspirin nor clonidine administered perioperatively reduced the risk of acute kidney injury. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01082874.