Postoperative systemic inflammation after major abdominal surgery: patient-centred outcomes.

Postoperative systemic inflammation is strongly associated with surgical outcomes, but its relationship with patient-centred outcomes is largely unknown. Detection of excessive inflammation and patient and surgical factors associated with adverse patient-centred outcomes should inform preventative treatment options to be evaluated in clinical trials and current clinical care. This retrospective cohort study analysed prospectively collected data from 3000 high-risk, elective, major abdominal surgery patients in the restrictive vs. liberal fluid therapy for major abdominal surgery (RELIEF) trial from 47 centres in seven countries from May 2013 to September 2016. The co-primary endpoints were persistent disability or death up to 90 days after surgery, and quality of recovery using a 15-item quality of recovery score at days 3 and 30. Secondary endpoints included: 90-day and 1-year all-cause mortality; septic complications; acute kidney injury; unplanned admission to intensive care/high dependency unit; and total intensive care unit and hospital stays. Patients were assigned into quartiles of maximum postoperative C-reactive protein concentration up to day 3, after multiple imputations of missing values. The lowest (reference) group, quartile 1, C-reactive protein ≤ 85 mg.l-1 , was compared with three inflammation groups: quartile 2 > 85 mg.l-1 to 140 mg.l-1 ; quartile 3 > 140 mg.l-1 to 200 mg.l-1 ; and quartile 4 > 200 mg.l-1 to 587 mg.l-1 . Greater postoperative systemic inflammation had a higher adjusted risk ratio (95%CI) of persistent disability or death up to 90 days after surgery, quartile 4 vs. quartile 1 being 1.76 (1.31-2.36), p < 0.001. Increased inflammation was associated with increasing decline in risk-adjusted estimated medians (95%CI) for quality of recovery, the quartile 4 to quartile 1 difference being -14.4 (-17.38 to -10.71), p < 0.001 on day 3, and -5.94 (-8.92 to -2.95), p < 0.001 on day 30. Marked postoperative systemic inflammation was associated with increased risk of complications, poor quality of recovery and persistent disability or death up to 90 days after surgery.

Reliability of alternative devices for postoperative patient temperature measurement: two prospective, observational studies.

Peri-operative hypothermia is associated with significant morbidity, yet limitations exist regarding non-invasive temperature assessment in the post-anaesthesia care unit (PACU). In this prospective study of 100 patients, we aimed to determine the reliability of two commonly used temperature measurement devices, forehead temporal artery temperature and tympanic measurement, in addition to an indwelling urinary catheter with temperature probe, in comparison with the final nasopharyngeal core temperature at the end of surgery. Agreement of forehead measurement with nasopharyngeal temperature showed a mean bias (±95% limits of agreement) of 0.15 °C (±1.4 °C), with a steep slope of the relationship on the Bland-Altman plot of -0.8, indicating a tendency to normalise patient temperature readings to 36.4 °C. Only 54% of hypothermic cases were correctly detected by the forehead measurement device. Agreement of tympanic measurement with nasopharyngeal core temperature measurement was marginally improved with a mean bias of 0.13 °C (95% limits of agreement ±1.15 °C). In contrast, agreement of bladder temperature with nasopharyngeal temperature showed a mean (SD) bias of 0.19 (0.28) °C (95% limits of agreement ±0.54 °C), with a relatively flat line of best fit. We demonstrated that two commonly used temperature measurement devices, forehead temporal artery temperature and tympanic measurement, compared with nasopharyngeal core temperature, were imprecise and unreliable following major surgery. However, the indwelling catheter with temperature sensor was precise and acceptable for continuous core temperature measurement in the PACU.

Systematic review and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: patient comfort.

BACKGROUND: Maximising patient comfort during and after surgery is a primary concern of anaesthetists and other perioperative clinicians, but objective measures of what constitutes patient comfort in the perioperative period remain poorly defined. The Standardised Endpoints in Perioperative Medicine initiative was established to derive a set of standardised endpoints for use in perioperative clinical trials. METHODS: We undertook a systematic review to identify measures of patient comfort used in the anaesthetic, surgical, and other perioperative literature. A multi-round Delphi consensus process that included up to 89 clinician researchers was then used to refine a recommended list of outcome measures. RESULTS: We identified 122 studies in a literature search, which were the basis for a preliminary list of 24 outcome measures and their definitions. The response rates for Delphi Rounds 1, 2, and 3 were 100% (n=22), 90% (n=79), and 100% (n=13), respectively. A final list of six defined endpoints was identified: pain intensity (at rest and during movement) at 24 h postoperatively, nausea and vomiting (0-6 h, 6-24 h, and overall), one of two quality-of-recovery (QoR) scales (QoR score or QoR-15), time to gastrointestinal recovery, time to mobilisation, and sleep quality. CONCLUSIONS: As standardised outcomes will support benchmarking and pooling (meta-analysis) of trials, one or more of these recommended endpoints should be considered for inclusion in clinical trials assessing patient comfort and pain after surgery.

Safety of sedation for gastrointestinal endoscopy in a group of university-affiliated hospitals: a prospective cohort study.

BACKGROUND: Service models for gastrointestinal endoscopy sedation must be safe, as endoscopy is the most common procedure performed under sedation in many countries. The aim of this prospective cohort study was to determine the patient risk profile, and incidence of and risk factors for significant unplanned events, in adult patients presenting for gastrointestinal endoscopy in a group of university-affiliated hospitals where most sedation is managed by anaesthetists. METHODS: Patients aged ≥18 yr presenting for elective and emergency gastrointestinal endoscopy under anaesthetist-managed sedation at nine hospitals affiliated with the University of Melbourne, Australia, were included. Outcomes included significant airway obstruction, hypoxia, hypotension and bradycardia; unplanned tracheal intubation; abandoned procedure; advanced life support; prolonged post-procedure stay; unplanned over-night admission and 30-day mortality. RESULTS: 2,132 patients were included. Fifty percent of patients were aged >60 yr, 50% had a BMI >27 kg m -2, 42% were ASA physical status III-V and 17% were emergency patients. The incidence of significant unplanned events was 23.0% (including significant hypotension 11.8%). Significant unplanned intraoperative events were associated with increasing age, BMI <18.5 kg m -2, ASA physical status III-V, colonoscopy and planned tracheal intubation. Thirty-day mortality was 1.2% (0.2% in electives and 6.0% in emergencies) and was associated with ASA physical status IV-V and emergency status. CONCLUSIONS: Patients presenting for gastrointestinal endoscopy at a group of public university-affiliated hospitals where most sedation is managed by anaesthetists, had a high risk profile and a substantial incidence of significant unplanned intraoperative events and 30-day mortality.

Poor agreement in significant findings between meta-analyses and subsequent large randomized trials in perioperative medicine.

BACKGROUND: The reliability of meta-analysis (MA) in predicting the findings of subsequent large randomized controlled trials (RCTs) has not been assessed in perioperative medicine and anaesthesia. METHODS: Using Medline and PubMed, large RCTs (n≥1000) published since 2000 in the anaesthesia and perioperative medicine/critical care literature were identified. All previous MAs of RCTs investigating the same intervention and population were sourced. For all reported major morbid endpoints common to each, results (significant/non-significant P<0.05) were compared. RESULTS: 18 large RCTs and 44 prior MAs investigating the effects of 16 interventions were identified. Where endpoint results in the large RCTs were each compared with the single largest recent preceding MA, 35 of a total of 57 outcomes were predicted correctly by the MAs (61.4%). The odds ratio for a significant result from MA compared with the subsequent large RCT was 3.6, P=0.033 Bonferroni corrected. The positive predictive value of MAs was 22.7%; the negative predictive value was 85.7%, Kappa was 0.094 indicating slight agreement. The estimated power for each endpoint for large RCTs and MAs were similar, but the median study size for large RCTs was larger than that of the MAs, n=4,482 vs 1,389, P<0.0001. CONCLUSIONS: There was a strong tendency towards positive findings in MA not substantiated by subsequent large RCTs, which was not attributable to differences in study power. This finding suggests caution in clinical decision-making in anaesthesia and perioperative medicine based on findings of meta-analysis.

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial.

BACKGROUND: Previous animal and clinical studies showed that nitrous oxide may produce long-term analgesia. The aim of this study was to evaluate the effect of nitrous oxide in preventing chronic postsurgical pain. We also explored whether methylenetetrahydrofolate reductase gene polymorphisms (1298A>C, 667C>T) would enhance nitrous oxide analgesia. METHODS: We conducted a telephone interview at 12 months after surgery on 2924 (41.1%) patients enrolled in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia-II trial. Pain at the wound site was recorded using the modified brief pain inventory and the neuropathic pain questionnaire. General health status was measured using the EQ-5D questionnaire. Genotyping was performed in a subset of 674 Asian patients in Hong Kong. RESULTS: At 12 months after surgery, 356 (12.2%) patients reported chronic postsurgical pain at the wound site and 112 (3.8%) patients had severe pain and required regular analgesic interventions. Nitrous oxide did not affect the rate of chronic postsurgical pain (11.8% nitrous oxide group; 12.5% no nitrous oxide group), relative risk (95% confidence intervals): 0.94 (0.75-1.17), P=0.57. However, in a planned subgroup analysis, nitrous oxide reduced the risk of chronic postsurgical pain in Asian patients, relative risk (95% confidence intervals): 0.70 (0.50-0.98), P=0.031. Patients who were homozygous for either gene polymorphism and who received nitrous oxide during surgery were less likely to report chronic postsurgical pain. CONCLUSIONS: Nitrous oxide administration had no impact on chronic postsurgical pain, but benefits may still be possible in Asian patients and patients with variants in methylenetetrahydrofolate reductase gene. CLINICAL TRIAL REGISTRATION: NCT00430989.

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 ß-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.

A meta-analysis of the accuracy and precision of the ultrasonic cardiac output monitor (USCOM).

The ultrasonic cardiac output monitor is a non-invasive, continuous-wave Doppler monitor that can be used to measure cardiac output. Its accuracy and precision in peri-operative and critical care has been assessed with varied results. We conducted a meta-analysis to calculate a pooled mean bias, precision and percentage error for this device. Six studies were suitable for inclusion into a pooled parametric analysis consisting of 320 measurements. The mean weighted bias was -0.39 l.min(-1) (95% CI -0.25 to -0.53 l.min(-1) ), precision 1.27 l.min(-1) and percentage error 42.7% (95% CI 38.5-46.9%). The ultrasonic cardiac output monitor achieved similar agreement with bolus thermodilution to that of other minimally invasive methods of peri-operative cardiac output monitoring, and may have a useful role in cardiac output monitoring.

The epidemiology of Medical Emergency Team calls for orthopedic patients in a teaching hospital: A retrospective cohort study.

BACKGROUND: Patients undergoing orthopedic surgery are at risk of post-operative complications and needing Medical Emergency Team (MET) review. We assessed the frequency of, and associations with MET calls in orthopedic patients, and whether this was associated with increased in-hospital morbidity and mortality. METHODS: Retrospective cohort study of patients admitted over four years to a University teaching hospital using hospital administrative and MET call databases. RESULTS: Amongst 6344 orthopedic patients, 55.8% were female, the median (IQR) age and Charlson comorbidity index were 66 years (47-79) and 3 (1-5), respectively. Overall, 54.5% of admissions were emergency admissions, 1130 (17.8%) were non-operative, and 605 (9.5%) patients received a MET call. The strongest independent associations with receiving a MET call was the operative procedure, especially hip and knee arthroplasty. Common MET triggers were hypotension (37.5%), tachycardia (25.0%) and tachypnoea (9.1%). Patients receiving a MET call were at increased risk of anemia, delirium, pressure injury, renal failure and wound infection. The mortality of patients who received a MET call was 9.8% compared with 0.8% for those who did not. After adjusting for pre-defined co-variates, requirement for a MET call was associated with an adjusted odd-ratio of 9.57 (95%CI 3.1-29.7) for risk of in-hospital death. CONCLUSIONS: Approximately 10% of orthopedic patients received a MET call, which was most strongly associated with major hip and knee arthroplasty. Such patients are at increased risk of morbidity and in-hospital mortality. Further strategies are needed to more pro-actively manage at-risk orthopedic patients.

The design and manufacture of 3D-printed adjuncts for powered air-purifying respirators.

Spurred in part by literature published in the immediate aftermath of the severe acute respiratory syndrome epidemic in 2003, powered air-purifying respirators have seen increased use worldwide during the COVID-19 pandemic. Whereas these devices provide excellent protection of the user, there is an added element of risk during doffing and cleaning of the device. An additional layer of barrier protection, in the form of a polypropylene gown, to be worn over the hood and motor belt, can be used to minimise this risk. However, the device entrains air perpendicular to the lie of the gown, resulting in the impermeable material being sucked into the air intake, and partial occlusion of flow. In this report, we describe a clinical-academic partnership whereby a bespoke filter guard was designed to disrupt airflow and prevent gown entrainment, thereby enabling full barrier protection of both the device and user. This intervention was simple, cheap, scalable and able to be mass produced.

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.

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.

The rate of alveolar-capillary uptake of sevoflurane and nitrous oxide following anaesthetic induction.

The rate of anaesthetic gas uptake from the breathing system has been extensively measured, but this does not reflect the true rate of early gas uptake by pulmonary blood, which drives inhalational induction of anaesthesia. In eight patients undergoing coronary bypass surgery, we measured the rate of alveolar-capillary uptake of anaesthetic gases up to 30 min following introduction of 0.5% sevoflurane and 33% nitrous oxide using the reverse Fick method, in which blood partial pressures were measured using a headspace equilibration technique. Simultaneous measurements of gas uptake from the breathing system were made by indirect calorimetry. Measured rates of sevoflurane and nitrous oxide uptake from the breathing system agreed well with previously described formulae when adjusted for inspired concentration. The time course of alveolar-capillary gas uptake followed a characteristic rising curve peaking at 3-4 min and then exponentially declining, and for nitrous oxide was significantly higher than previously estimated.

Survey of research capability at Australian and New Zealand College of Anaesthetists accredited training sites.

The Australian and New Zealand College of Anaesthetists (ANZCA) has more than 200 accredited training sites in Australia, New Zealand, Hong Kong, Malaysia and Singapore, many of which participate in ANZCA Clinical Trials Network (CTN)-endorsed clinical trials. We undertook a survey of accredited sites to determine research capability, activity and potential. With ethics committee approval an electronic survey was distributed to accredited sites in July 2015. Of 207 accredited sites, 167 were sent the questionnaire (after eliminating ineligible sites) and 128 responded. Response rates for Australia, New Zealand, Hong Kong, Malaysia and Singapore were 100%, 100%, 35%, 25% and 75% respectively. Forty-four (34%) of 128 responding sites had a head of research; 101 (80%) of 126 responding sites were active in research; 42 (33%) of 126 responding sites had no publications since January 2011 and 15 (12%) had >50 publications; 95 (76%) of 125 responding sites had at least one specialist anaesthetist engaged in research (median = 4 [range 1-25]); and 45 (36%) of 125 responding sites had at least one research coordinator (median = 2 [range 1-15]). Fifty-eight (28%) of the 207 accredited sites were identified as participating in recent ANZCA CTN-endorsed clinical trials. Research capability and activity were higher in these sites. This survey has identified a strong base upon which to expand clinical trial activity, and regions, sectors, investigators and research coordinators who may benefit from additional support.

The effect of a perioperative ketamine infusion on the incidence of chronic postsurgical pain-a pilot study.

Chronic postsurgical pain (CPSP) is a common and debilitating complication of major surgery. We undertook a pilot study at three hospitals to assess the feasibility of a proposed large multicentre placebo-controlled randomised trial of intravenous perioperative ketamine to reduce the incidence of CPSP. Ketamine, 0.5 mg/kg pre-incision, 0.25 mg/kg/hour intraoperatively and 0.1 mg/kg/hour for 24 hours, or placebo, was administered to 80 patients, recruited over a 15-month period, undergoing abdominal or thoracic surgery under general anaesthesia. The primary endpoint was CPSP in the area of the surgery reported at six-month telephone follow-up using a structured questionnaire. Fourteen patients (17.5%) reported CPSP (relative risk [95% confidence interval] if received ketamine 1.18 [0.70 to 1.98], P=0.56). Four patients in the treatment group and three in the control group reported ongoing analgesic use to treat CPSP and two patients in each group reported their worst pain in the previous 24 hours at ≥3/10 at six months. There were no significant differences in adverse event rates, quality of recovery scores, or cumulative morphine equivalents consumption in the first 72 hours. Numeric Rating Scale pain scores (median [interquartile range, IQR]) for average pain in the previous 24 hours among those patients reporting CPSP were 17.5 [0 to 40] /100 with no difference between treatment groups. A large (n=4,000 to 5,000) adequately powered multicentre trial is feasible using this population and methodology.

Ventilation-perfusion inhomogeneity increases gas uptake: theoretical modeling of gas exchange.

Ventilation-perfusion (VA/Q) inhomogeneity was modeled to measure its effect on gas exchange in the presence of inspired mixtures of two soluble gases using a two-compartment computer model. Theoretical studies involving a mixture of hypothetical gases with equal solubility in blood showed that the effect of increasing inhomogeneity of distributions of either ventilation or blood flow is to paradoxically increase uptake of the gas with the lowest overall uptake in relation to its inspired concentration. This phenomenon is explained by the concentrating effects that uptake of soluble gases exert on each other in low VA/Q compartments. Repeating this analysis for inspired mixtures of 30% O(2) and 70% nitrous oxide (N(2)O) confirmed that, during "steady-state" N(2)O anesthesia, uptake of N(2)O is predicted to paradoxically increase in the presence of worsening VA/Q inhomogeneity.

Ventilation-perfusion inhomogeneity increases gas uptake in anesthesia: computer modeling of gas exchange.

Ventilation-perfusion (VA/Q) inhomogeneity was modeled to measure its effect on overall gas exchange during maintenance-phase N(2)O anesthesia with an inspired O(2) concentration of 30%. A multialveolar compartment computer model was used based on physiological log normal distributions of VA/Q inhomogeneity. Increasing the log standard deviation of the distribution of perfusion from 0 to 1.75 paradoxically increased O(2) uptake (VO(2)) where a low mixed venous partial pressure of N(2)O [high N(2)O uptake (VN(2)O)] was specified. With rising mixed venous partial pressure of N(2)O, a threshold was observed where VO(2) began to fall, whereas VN(2)O began to rise with increasing VA/Q inhomogeneity. This phenomenon is a magnification of the concentrating effects that VO(2) and VN(2)O have on each other in low VA/Q compartments. During "steady-state" N(2)O anesthesia, VN(2)O is predicted to paradoxically increase in the presence of worsening VA/Q inhomogeneity.

Effect of ventilation-perfusion inhomogeneity and N(2)O on oxygenation: physiological modeling of gas exchange.

Ventilation-perfusion (VA/Q) inhomogeneity was modeled to measure its effect on arterial oxygenation during maintenance-phase anesthesia involving an inspired mixture of 30% O(2) and either N(2)O or N(2). A multialveolar compartment computer model was constructed based on a log normal distribution of VA/Q inhomogeneity. Increasing the log SD of the distribution of blood flow from 0 to 1.75 produced a progressive fall in arterial PO(2) (Pa(O(2))). The fall was less steep in the presence of N(2)O than when N(2) was present instead. This was due mainly to the concentrating effect of N(2)O uptake on alveolar PO(2) in moderately low VA/Q compartments. The improvement in Pa(O(2)) when N(2)O was present instead of N(2) was greatest when the degree of VA/Q inhomogeneity was in the range typically seen in anesthetized patients. Models based on distributions of expired and inspired alveolar ventilation give quantitatively different results for Pa(O(2)). In the presence of VA/Q inhomogeneity, second-gas and concentrating effects may have clinically significant effects on arterial oxygenation even at "steady-state" levels of N(2)O uptake.