Cardiopulmonary exercise variables and their association with postoperative morbidity and mortality after major oesophagogastric cancer surgery-a multicentre observational study.

Background: Outcomes after oesophagogastric cancer surgery remain poor. Cardiopulmonary exercise testing (CPET) used for risk stratification before oesophagogastric cancer surgery is based on conflicting evidence. This study explores the relationship between CPET and postoperative outcomes, specifically for patients undergoing neoadjuvant treatment. Methods: Patients undergoing oesophagogastric cancer resection and CPET (pre- or post-neoadjuvant treatment, or both) were retrospectively enrolled into a multicentre pooled cohort study. Oxygen uptake at peak exercise (VO2 peak) was compared with 1-yr postoperative survival. Secondary analyses explored relationships between patient characteristics, tumour pathology characteristics, CPET variables (absolute, relative to weight, ideal body weight, and body surface area), and postoperative outcomes (morbidity, 1-yr and 3-yr survival) were assessed using logistic regression analyses. Results: Seven UK centres recruited 611 patients completing a 3-yr postoperative follow-up period. Oesophagectomy was undertaken in 475 patients (78%). Major complications occurred in 25%, with 18% 1-yr and 43% 3-yr mortality. No association between VO2 peak or other selected CPET variables and 1-yr survival was observed in the overall cohort. In the overall cohort, the anaerobic threshold relative to ideal body weight was associated with 3-yr survival (P=0.013). Tumour characteristics (ypT/ypN/tumour regression/lymphovascular invasion/resection margin; P<0.001) and Clavien-Dindo ≥3a (P<0.001) were associated with 1-yr and 3-yr survival. On subgroup analyses, pre-neoadjuvant treatment CPET; anaerobic threshold (absolute; P=0.024, relative to ideal body weight; P=0.001, body surface area; P=0.009) and VE/VCO2 at anaerobic threshold (P=0.026) were associated with 3-yr survival. No other CPET variables (pre- or post-neoadjuvant treatment) were associated with survival. Conclusions: VO2 peak was not associated with 1-yr survival after oesophagogastric cancer resection. Tumour characteristics and major complications were associated with survival; however, only some selected pre-neoadjuvant treatment CPET variables were associated with 3-yr survival. CPET in this cohort of patients demonstrates limited outcome predictive precision. Clinical trial registration: NCT03637647.

The impact of universal cardiopulmonary exercise testing on perioperative pathways and short-term patient outcomes following elective pancreatic surgery: A retrospective cohort study.

Background: The utility of Cardiopulmonary Exercise Testing (CPET) to identify higher risk surgical patients remains controversial. There is limited research investigating the value of preoperative CPET to plan perioperative pathways for patients undergoing major pancreatic surgery. Methods: Retrospective cohort study, comprising two groups before and after a change in referral policy for High Risk preoperative anaesthetic clinic with CPET. Period 1 discretionary referral and Period 2: universal referral. The primary aim was to investigate the impact of this policy change on critical care use (planned vs unplanned) on the day of surgery and on delayed critical care admission. Secondary end points included a comparison of the total number of critical care bed days, days in hospital, complication rates and mortality data between the two cohorts. Results: 177 patients were included; 114 in Period 1 and 63 in Period 2. There was a reduction in unplanned day of surgery postoperative admissions to critical care (28.1% vs. 11.1%, p = 0.008). Seven (6.1%) of patients in Period 1 and 1 (1.6%) patient in Period 2 had delayed admission, though no p value was calculated due to the small numbers involved. Complication rates were similar in each group. The median critical care bed days was 1 (range 0-21) days in Period 1 and 1 (0-13) days in Period 2. Conclusions: A universal referral policy for preoperative CPET demonstrated a decrease in unplanned day of surgery critical care admissions and a trend towards reducing delayed (>24 h postop) critical care admission which could be investigated in a larger study. No measurable impact was seen on clinical outcomes.

Correction: Heart rate recovery and morbidity after noncardiac surgery: Planned secondary analysis of two prospective, multi-centre, blinded observational studies.

[This corrects the article DOI: 10.1371/journal.pone.0221277.].

Heart rate recovery and morbidity after noncardiac surgery: Planned secondary analysis of two prospective, multi-centre, blinded observational studies.

BACKGROUND: Impaired cardiac vagal function, quantified preoperatively as slower heart rate recovery (HRR) after exercise, is independently associated with perioperative myocardial injury. Parasympathetic (vagal) dysfunction may also promote (extra-cardiac) multi-organ dysfunction, although perioperative data are lacking. Assuming that cardiac vagal activity, and therefore heart rate recovery response, is a marker of brainstem parasympathetic dysfunction, we hypothesized that impaired HRR would be associated with a higher incidence of morbidity after noncardiac surgery. METHODS: In two prospective, blinded, observational cohort studies, we established the definition of impaired vagal function in terms of the HRR threshold that is associated with perioperative myocardial injury (HRR ≤ 12 beats min-1 (bpm), 60 seconds after cessation of cardiopulmonary exercise testing. The primary outcome of this secondary analysis was all-cause morbidity three and five days after surgery, defined using the Post-Operative Morbidity Survey. Secondary outcomes of this analysis were type of morbidity and time to become morbidity-free. Logistic regression and Cox regression tested for the association between HRR and morbidity. Results are presented as odds/hazard ratios [OR or HR; (95% confidence intervals). RESULTS: 882/1941 (45.4%) patients had HRR≤12bpm. All-cause morbidity within 5 days of surgery was more common in 585/822 (71.2%) patients with HRR≤12bpm, compared to 718/1119 (64.2%) patients with HRR>12bpm (OR:1.38 (1.14-1.67); p = 0.001). HRR≤12bpm was associated with more frequent episodes of pulmonary (OR:1.31 (1.05-1.62);p = 0.02)), infective (OR:1.38 (1.10-1.72); p = 0.006), renal (OR:1.91 (1.30-2.79); p = 0.02)), cardiovascular (OR:1.39 (1.15-1.69); p<0.001)), neurological (OR:1.73 (1.11-2.70); p = 0.02)) and pain morbidity (OR:1.38 (1.14-1.68); p = 0.001) within 5 days of surgery. CONCLUSIONS: Multi-organ dysfunction is more common in surgical patients with cardiac vagal dysfunction, defined as HRR ≤ 12 bpm after preoperative cardiopulmonary exercise testing. CLINICAL TRIAL REGISTRY: ISRCTN88456378.

Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery.

BACKGROUND: Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion. METHODS: In a pragmatic, international trial, we randomly assigned 3000 patients who had an increased risk of complications while undergoing major abdominal surgery to receive a restrictive or liberal intravenous-fluid regimen during and up to 24 hours after surgery. The primary outcome was disability-free survival at 1 year. Key secondary outcomes were acute kidney injury at 30 days, renal-replacement therapy at 90 days, and a composite of septic complications, surgical-site infection, or death. RESULTS: During and up to 24 hours after surgery, 1490 patients in the restrictive fluid group had a median intravenous-fluid intake of 3.7 liters (interquartile range, 2.9 to 4.9), as compared with 6.1 liters (interquartile range, 5.0 to 7.4) in 1493 patients in the liberal fluid group (P<0.001). The rate of disability-free survival at 1 year was 81.9% in the restrictive fluid group and 82.3% in the liberal fluid group (hazard ratio for death or disability, 1.05; 95% confidence interval, 0.88 to 1.24; P=0.61). The rate of acute kidney injury was 8.6% in the restrictive fluid group and 5.0% in the liberal fluid group (P<0.001). The rate of septic complications or death was 21.8% in the restrictive fluid group and 19.8% in the liberal fluid group (P=0.19); rates of surgical-site infection (16.5% vs. 13.6%, P=0.02) and renal-replacement therapy (0.9% vs. 0.3%, P=0.048) were higher in the restrictive fluid group, but the between-group difference was not significant after adjustment for multiple testing. CONCLUSIONS: Among patients at increased risk for complications during major abdominal surgery, a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen and was associated with a higher rate of acute kidney injury. (Funded by the Australian National Health and Medical Research Council and others; RELIEF ClinicalTrials.gov number, NCT01424150 .).

Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness.

OBJECTIVES: Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function. DESIGN: Laboratory/clinical investigations. SETTING: University laboratory/medical centers. SUBJECTS: Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients. INTERVENTIONS: Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of <6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006). CONCLUSIONS: Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.

Monitoring needs and goal-directed fluid therapy within an enhanced recovery program.

Patients having major abdominal surgery need perioperative fluid supplementation; however, enhanced recovery principles mitigate against many of the factors that traditionally led to relative hypovolemia in the perioperative period. An estimate of fluid requirements for abdominal surgery can be made but individualization of fluid prescription requires consideration of clinical signs and hemodynamic variables. The literature supports goal-directed fluid therapy. Application of this evidence to justify stroke volume optimization in the setting of major surgery within an enhanced recovery program is controversial. This article places the evidence in context, reviews controversies, and suggests implications for current practice and future research.

Cardiopulmonary exercise capacity and preoperative markers of inflammation.

Explanatory mechanisms for the association between poor exercise capacity and infections following surgery are underexplored. We hypothesized that aerobic fitness-assessed by cardiopulmonary exercise testing (CPET)-would be associated with circulating inflammatory markers, as quantified by the neutrophil-lymphocyte ratio (NLR) and monocyte subsets. The association between cardiopulmonary reserve and inflammation was tested by multivariable regression analysis with covariates including anaerobic threshold (AT) and malignancy. In a first cohort of 240 colorectal patients, AT was identified as the sole factor associated with higher NLR (P = 0.03) and absolute and relative lymphopenia (P = 0.01). Preoperative leukocyte subsets and monocyte CD14(+) expression (downregulated by endotoxin and indicative of chronic inflammation) were also assessed in two further cohorts of age-matched elective gastrointestinal and orthopaedic surgical patients. Monocyte CD14(+) expression was lower in gastrointestinal patients (n = 43) compared to age-matched orthopaedic patients (n = 31). The circulating CD14(+)CD16(-) monocyte subset was reduced in patients with low cardiopulmonary reserve. Poor exercise capacity in patients without a diagnosis of heart failure is independently associated with markers of inflammation. These observations suggest that preoperative inflammation associated with impaired cardiorespiratory performance may contribute to the pathophysiology of postoperative outcome.

Combined femoral and sciatic nerve block vs combined femoral and periarticular infiltration in total knee arthroplasty: a randomized controlled trial.

This study tests the null hypothesis that there is no difference between sciatic nerve block (SNB) and periarticular anesthetic infiltration (PI) as adjuncts to femoral nerve blockade (FNB) in total knee arthroplasty in terms of postoperative opioid requirements. Fifty-two patients undergoing total knee arthroplasty were randomized to receive either (a) combined FNB-SNB or (b) combined FNB-PI. Average morphine consumption in the first 24 (20 vs 23 mg) and 48 hours (26 vs 33 mg) showed no significant difference. Visual Analogue Scale scores, knee flexion (60° vs 67.5°) and extension lag (0° vs 5°) were comparable. Anesthetic time, surgical time, and length of hospital stay (5.5 vs 6 days) were similar. This study showed no significant difference between the 2 groups. The PI offers a practical and potentially safer alternative to SNB.