Philip J. Peyton

Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial.

Background: Nitrous oxide is widely used in anesthesia, often administered at an inspired concentration around 70%. Although nitrous oxide interferes with vitamin B12, folate metabolism, and deoxyribonucleic acid synthesis and prevents the use of high inspired oxygen concentrations, the consequences of these effects are unclear. Methods: Patients having major surgery expected to last at least 2 h were randomly assigned to nitrous oxide–free (80% oxygen, 20% nitrogen) or nitrous oxide–based (70% N2O, 30% oxygen) anesthesia. Patients and observers were blind to group identity. The primary endpoint was duration of hospital stay. Secondary endpoints included duration of intensive care stay and postoperative complications; the latter included severe nausea and vomiting, and the following major complications: pneumonia, pneumothorax, pulmonary embolism, wound infection, myocardial infarction, venous thromboembolism, stroke, awareness, and death within 30 days of surgery. Results: Of 3,187 eligible patients, 2,050 consenting patients were recruited. Patients in the nitrous oxide–free group had significantly lower rates of major complications (odds ratio, 0.71; 95% confidence interval, 0.56–0.89; P = 0.003) and severe nausea and vomiting (odds ratio, 0.40; 95% confidence interval, 0.31–0.51; P < 0.001), but median duration of hospital stay did not differ substantially between groups (7.0 vs. 7.1 days; P = 0.06). Among patients admitted to the intensive care unit postoperatively, those in the nitrous oxide–free group were more likely to be discharged from the unit on any given day than those in the nitrous oxide group (hazard ratio, 1.35; 95% confidence interval, 1.05–1.73; P = 0.02). Conclusions: Avoidance of nitrous oxide and the concomitant increase in inspired oxygen concentration decreases the incidence of complications after major surgery, but does not significantly affect the duration of hospital stay. The routine use of nitrous oxide in patients undergoing major surgery should be questioned.

Minimally invasive measurement of cardiac output during surgery and critical care: a meta-analysis of accuracy and precision.

When assessing the accuracy and precision of a new technique for cardiac output measurement, the commonly quoted criterion for acceptability of agreement with a reference standard is that the percentage error (95% limits of agreement/mean cardiac output) should be 30% or less. We reviewed published data on four different minimally invasive methods adapted for use during surgery and critical care: pulse contour techniques, esophageal Doppler, partial carbon dioxide rebreathing, and transthoracic bioimpedance, to assess their bias, precision, and percentage error in agreement with thermodilution. An English language literature search identified published papers since 2000 which examined the agreement in adult patients between bolus thermodilution and each method. For each method a meta-analysis was done using studies in which the first measurement point for each patient could be identified, to obtain a pooled mean bias, precision, and percentage error weighted according to the number of measurements in each study. Forty-seven studies were identified as suitable for inclusion: N studies, n measurements: mean weighted bias [precision, percentage error] were: pulse contour N = 24, n = 714: –0.00 l/min [1.22 l/min, 41.3%]; esophageal Doppler N = 2, n = 57: –0.77 l/min [1.07 l/min, 42.1%]; partial carbon dioxide rebreathing N = 8, n = 167: –0.05 l/min [1.12 l/min, 44.5%]; transthoracic bioimpedance N = 13, n = 435: –0.10 l/min [1.14 l/min, 42.9%]. None of the four methods has achieved agreement with bolus thermodilution which meets the expected 30% limits. The relevance in clinical practice of these arbitrary limits should be reassessed.

Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial.

Objective To compare long term recurrence of cancer and survival of patients having major abdominal surgery for cancer. Design Long term follow-up of prospective randomised controlled clinical trial in which patients were randomly assigned to receive general anaesthesia with or without epidural block for at least three postoperative days. Setting 23 hospitals in Australia, New Zealand, and Asia. Participants 503 adult patients who had potentially curative surgery for cancer. Main outcome measure Cancer-free survival (analysis was by intention to treat). Results Long term follow-up data were available for 94% (n=446) of eligible participants. The median time to recurrence of cancer or death was 2.8 (95% confidence interval 0.7 to 8.7) years in the control group and 2.6 (0.7 to 8.7) years in the epidural group (P=0.61). Recurrence-free survival was similar in both epidural and control groups (hazard ratio 0.95, 95% confidence interval 0.76 to 1.17; P=0.61). Conclusion Use of epidural block in abdominal surgery for cancer is not associated with improved cancer-free survival. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12607000637448

Perioperative Epidural Analgesia and Outcome After Major Abdominal Surgery in High-Risk Patients

In a primary analysis of a large recently completed randomized trial in 915 high-risk patients undergoing major abdominal surgery, we found no difference in outcome between patients receiving perioperative epidural analgesia and those receiving IV opioids, apart from the incidence of respiratory failure. Therefore, we performed a selected number of predetermined subgroup analyses to identify specific types of patients who may have derived benefit from epidural analgesia. We found no difference in outcome between epidural and control groups in subgroups at increased risk of respiratory or cardiac complications or undergoing aortic surgery, nor in a subgroup with failed epidural block (all P > 0.05). There was a small reduction in the duration of postoperative ventilation (geometric mean [SD]: control group, 0.3 [6.5] h, versus epidural group, 0.2 [4.8] h; P = 0.048). No differences were found in length of stay in intensive care or in the hospital. There was no relationship between frequency of use of epidural analgesia in routine practice outside the trial and benefit from epidural analgesia in the trial. We found no evidence that perioperative epidural analgesia significantly influences major morbidity or mortality after major abdominal surgery.

Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial

BACKGROUND:There is a plausible pathophysiologic rationale for increased long-term cardiovascular morbidity and mortality in patients receiving significant exposure to nitrous oxide. However, this relationship has not been established clinically. The ENIGMA trial randomized 2050 patients having noncardiac surgery lasting more than 2 hours to nitrous oxide–based or nitrous oxide–free anesthesia. We conducted a follow-up study of the ENIGMA patients to evaluate the risk of cardiovascular events in the longer term. METHODS:The trial case report forms and medical records of all study patients were reviewed. The date and cause of death and occurrence of myocardial infarction or stroke were recorded. A telephone interview was then conducted with all surviving patients. The primary endpoint of the study was survival. RESULTS:The median follow-up time was 3.5 (range: 0 to 5.7) years. Three hundred eighty patients (19%) had died since the index surgery, 91 (4.5%) were recorded as having myocardial infarction, and 44 (2.2%) had a stroke during the entire follow-up period. Nitrous oxide did not significantly increase the risk of death [hazard ratio = 0.98 (95% confidence interval, CI: 0.80 to 1.20; P = 0.82)]. The adjusted odds ratio for myocardial infarction in patients administered nitrous oxide was 1.59 (95% CI: 1.01 to 2.51; P = 0.04) and for stroke was 1.01 (95% CI: 0.55 to 1.87; P = 0.97). CONCLUSIONS:The administration of nitrous oxide was associated with increased long-term risk of myocardial infarction, but not of death or stroke in patients enrolled in the ENIGMA trial. The exact relationship between nitrous oxide administration and serious long-term adverse outcomes will require confirmation by an appropriately designed large randomized controlled trial.

Risk factors for severe postoperative nausea and vomiting in a randomized trial of nitrous oxide-based vs nitrous oxide-free anaesthesia

BACKGROUND Refractory postoperative nausea and vomiting (PONV) requiring repeated treatment with antiemetic drugs is a miserable experience for the patient that may substantially increase the cost of care. As risk stratification may aid in prophylaxis and treatment, we explored risk factors for severe PONV in patients enrolled in a large international, randomized controlled trial (the ENIGMA trial). METHODS Two thousand and fifty patients, aged > or =18 yr and undergoing surgery anticipated to exceed 2 h in duration, were recruited. Patients were randomized to nitrous oxide (N(2)O)-based or N(2)O-free anaesthesia. Choice of other anaesthetic, analgesic, and antiemetic drugs was left to the discretion of the anaesthetist. Anaesthetic depth was adjusted according to clinical judgement and, if available, bispectral index (BIS) monitoring. Severe PONV was defined as: (i) two or more episodes of expulsion of gastric contents at least 6 h apart; (ii) received at least three doses of antiemetic medication for treatment of PONV, within 24 h of surgery; or both. We used logistic regression, and classification and regression tree analysis, to define risk factors for severe PONV. RESULTS Three hundred and thirty-three (16.6%) patients experienced severe PONV. Age <55 yr, female sex, abdominal surgery, N(2)O administration, absence of BIS monitoring, and longer duration of anaesthesia were predictors of severe PONV [area under receiver operating characteristic curve=0.70 (95% confidence interval: 0.67-0.73)]. CONCLUSIONS Severe PONV was common and risk factors for it were similar to those reported in other studies that included all patients reporting nausea, vomiting, or both.

Effect of nitrous oxide on plasma homocysteine and folate in patients undergoing major surgery

BACKGROUND Nitrous oxide (N(2)O) inhibits methionine synthetase resulting in elevated plasma homocysteine (Hcy) concentration after surgery. In epidemiological studies, hyperhomocysteinaemia is associated with increased risk of cardiovascular disease and dementia. METHODS Blood samples were obtained to measure plasma folate and Hcy concentrations from two centres participating in a multicentre randomized trial investigating the effects of N(2)O on the outcome after major surgery. The effect of N(2)O and duration of anaesthesia on plasma Hcy, and the relationship between hyperhomocysteinaemia and outcomes were assessed. RESULTS We enrolled 394 patients. The N(2)O Group had an increase in plasma Hcy concentration after surgery when compared with the N(2)O-free Group: 11.1 (3.8) vs 8.5 (4.0) micromol litre(-1), P<0.0005. Postoperative hyperhomocysteinaemia was associated with an increased risk of major complications: risk ratio (RR) 2.8 (95% CI: 1.4-5.4), P=0.002 and cardiovascular events, RR 5.1 (95% CI: 3.1-8.5), P<0.0005. There was a significant association between duration of anaesthesia and the relative change in plasma Hcy concentration, particularly in the N(2)O Group: r=0.42, P<0.001. CONCLUSIONS N(2)O increases plasma Hcy concentration; this effect is greater with a longer duration of anaesthesia. Hyperhomocysteinaemia is a risk factor for major postoperative complications. N(2)O-induced increases in plasma Hcy concentration may be a cause of postoperative cardiovascular morbidity.

Agreement of an inert gas rebreathing device with thermodilution and the direct oxygen Fick method in measurement of pulmonary blood flow.

Objective. Inert gas rebreathing is a well established method for the non-invasive measurement of pulmonary blood flow. We tested the agreement in measurement of pulmonary blood flow (Qt rb) by a new inert soluble gas rebreathing device, the Innocor (Innovision, Copenhagen), with bolus thermodilution (Qt td) and the direct oxygen Fick (Qt Fick) method. Methods. 9 patients pre- and post-cardiac surgery were recruited resulting in 20 sets of measurements overall. Arterial and mixed venous blood samples were collected simultaneously with a thermodilution measurement and rebreathing manoeuvre to measure both VO2 and effective pulmonary capillary blood flow. Results. Mean bias (95% confidence limits) was: Qt rb − Qt td 0.01 (± 0.42) L/min; Qt rb − Qt Fick + 0.34 (± 0.59) L/min. The standard deviation of the difference between paired measurements was: Qt td − Qt rb ± 0.89 L/min; Qt Fick − Qt rb ± 1.26 L/min. Conclusions. Acceptable overall agreement between the Innocor and these reference standards was demonstrated.

A new method for measurement of gas exchange during anaesthesia using an extractable marker gas

A new method for the measurement of pulmonary gas exchange during inhalational anaesthesia is described which measures fresh gas and exhaust gas flows using carbon dioxide as an extractable marker gas. The theoretical precision of the method was compared by Monte Carlo modelling with other approaches which use marker gas dilution. A system was constructed for automated measurement of uptake of oxygen, nitrous oxide, volatile anaesthetic agent and elimination of carbon dioxide by an anaesthetized patient. The accuracy and precision of the method was tested in vitro on a lung gas exchange simulator, by comparison with simultaneous measurements made using nitrogen as marker gas and the Haldane transformation. Good agreement was obtained for measurement of simulated uptake or elimination of all gases studied over a physiologically realistic range of values. Mean bias for oxygen and nitrous oxide uptake was 0.003 l min(-1), for isoflurane 0.0001 l min(-1) and for carbon dioxide 0.001 l min(-1). Limits of agreement lay within 10% of the mean uptake rate for nitrous oxide, within 5% for oxygen and isoflurane and within 1% for carbon dioxide. The extractable marker gas method allows accurate and continuous measurement of gas exchange in an anaesthetic breathing system with any inspired gas mixture.

Neuraxial block, death and serious cardiovascular morbidity in the POISE trial

BACKGROUND This post hoc analysis aimed to determine whether neuraxial block was associated with a composite of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal cardiac arrest within 30 days of randomization in POISE trial patients. METHODS A total of 8351 non-cardiac surgical patients at high risk of cardiovascular complications were randomized to β-blocker or placebo. Neuraxial block was defined as spinal, lumbar or thoracic epidural anaesthesia. Logistic regression, with weighting using estimated propensity scores, was used to determine the association between neuraxial block and primary and secondary outcomes. RESULTS Neuraxial block was associated with an increased risk of the primary outcome [287 (7.3%) vs 229 (5.7%); odds ratio (OR), 1.24; 95% confidence interval (CI), 1.02-1.49; P=0.03] and MI [230 (5.9%) vs 177 (4.4%); OR, 1.32; 95% CI, 1.07-1.64; P=0.009] but not stroke [23 (0.6%) vs 32 (0.8%); OR, 0.76; 95% CI, 0.44-1.33; P=0.34], death [96 (2.5%) vs 111 (2.8%); OR, 0.87; 95% CI, 0.65-1.17; P=0.37] or clinically significant hypotension [522 (13.4%) vs 484 (12.1%); OR, 1.13; 95% CI, 0.99-1.30; P=0.08]. Thoracic epidural with general anaesthesia was associated with a worse primary outcome than general anaesthesia alone [86 (12.1%) vs 119 (5.4%); OR, 2.95; 95% CI, 2.00-4.35; P<0.001]. CONCLUSIONS In patients at high risk of cardiovascular morbidity, neuraxial block was associated with an increased risk of adverse cardiovascular outcomes, which could be causal or because of residual confounding.