Candidate Kidney Protective Strategies for Patients Undergoing Major Abdominal Surgery: A Secondary Analysis of the RELIEF Trial Cohort.

BACKGROUND: Acute kidney injury (AKI) is common after major abdominal surgery. Selection of candidate kidney protective strategies for testing in large trials should be based on robust preliminary evidence. METHODS: A secondary analysis of the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial was conducted in adult patients undergoing major abdominal surgery and randomly assigned to a restrictive or liberal perioperative fluid regimen. The primary outcome was maximum AKI stage before hospital discharge. Two multivariable ordinal regression models were developed to test the primary hypothesis that modifiable risk factors associated with increased maximum stage of postoperative AKI could be identified. Each model used a separate approach to variable selection to assess the sensitivity of the findings to modeling approach. For model 1, variable selection was informed by investigator opinion; for model 2, the Least Absolute Shrinkage and Selection Operator (LASSO) technique was used to develop a data-driven model from available variables. RESULTS: Of 2,444 patients analyzed, stage 1, 2, and 3 AKI occurred in 223 (9.1%), 59 (2.4%), and 36 (1.5%) patients, respectively. In multivariable modeling by model 1, administration of a nonsteroidal anti-inflammatory drug or cyclooxygenase-2 inhibitor, intraoperatively only (odds ratio, 1.77 [99% CI, 1.11 to 2.82]), and preoperative day-of-surgery administration of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker compared to no regular use (odds ratio, 1.84 [99% CI, 1.15 to 2.94]) were associated with increased odds for greater maximum stage AKI. These results were unchanged in model 2, with the additional finding of an inverse association between nadir hemoglobin concentration on postoperative day 1 and greater maximum stage AKI. CONCLUSIONS: Avoiding intraoperative nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors is a potential strategy to mitigate the risk for postoperative AKI. The findings strengthen the rationale for a clinical trial comprehensively testing the risk-benefit ratio of these drugs in the perioperative period.

Intraoperative dexamethasone and chronic postsurgical pain: a propensity score-matched analysis of a large trial.

BACKGROUND: Dexamethasone has been shown to reduce acute pain after surgery, but there is uncertainty as to its effects on chronic postsurgical pain (CPSP). We hypothesised that in patients undergoing major noncardiac surgery, a single intraoperative dose of dexamethasone increases the incidence of CPSP. METHODS: We devised a propensity score-matched analysis of the ENIGMA-II trial CPSP dataset, aiming to compare the incidence of CPSP in patients who had received dexamethasone or not 12 months after major noncardiac surgery. The primary outcome was the incidence of CPSP. We used propensity score matching and inverse probability weighting to balance baseline variables to estimate the average marginal effect of dexamethasone on patient outcomes, accounting for confounding to estimate the average treatment effect on those treated with dexamethasone. RESULTS: We analysed 2999 patients, of whom 116 of 973 (11.9%) receiving dexamethasone reported CPSP, and 380 of 2026 (18.8%) not receiving dexamethasone reported CPSP, unadjusted odds ratio 0.76 (95% confidence interval 0.78-1.00), P=0.052. After propensity score matching, CPSP occurred in 116 of 973 patients (12.2%) receiving dexamethasone and 380 of 2026 patients (13.8%) not receiving dexamethasone, adjusted risk ratio 0.88 (95% confidence interval 0.61-1.27), P=0.493. There was no difference between groups in quality of life or pain interference with daily activities, but 'least pain' (P=0.033) and 'pain right now' (P=0.034) were higher in the dexamethasone group. CONCLUSIONS: Dexamethasone does not increase the risk of chronic postsurgical pain after major noncardiac surgery. CLINICAL TRIAL REGISTRATION: Open Science Framework Registration DOI https://doi.org/10.17605/OSF.IO/ZDVB5.

Effects of N2 O elimination on the elimination of second gases in a two-step mathematical model of heterogeneous gas exchange.

We have investigated the elimination of inert gases in the lung during the elimination of nitrous oxide (N2 O) using a two-step mathematical model that allows the contribution from net gas volume expansion, which occurs in Step 2, to be separated from other factors. When a second inert gas is used in addition to N2 O, the effect on that gas appears as an extra volume of the gas eliminated in association with the dilution produced by N2 O washout in Step 2. We first considered the effect of elimination in a single gas-exchanging unit under steady-state conditions and then extended our analysis to a lung having a log-normal distribution of ventilation and perfusion. A further increase in inert gas elimination was demonstrated with gases of low solubility in the presence of the increased ventilation-perfusion mismatch that is known to occur during anesthesia. These effects are transient because N2 O elimination depletes the input of that gas from mixed venous blood to the lung, thereby rapidly reducing the magnitude of the diluting action.

Low tidal volume ventilation for patients undergoing laparoscopic surgery: a secondary analysis of a randomised clinical trial.

BACKGROUND: We recently reported the results for a large randomized controlled trial of low tidal volume ventilation (LTVV) versus conventional tidal volume (CTVV) during major surgery when positive end expiratory pressure (PEEP) was equal between groups. We found no difference in postoperative pulmonary complications (PPCs) in patients who received LTVV. However, in the subgroup of patients undergoing laparoscopic surgery, LTVV was associated with a numerically lower rate of PPCs after surgery. We aimed to further assess the relationship between LTVV versus CTVV during laparoscopic surgery. METHODS: We conducted a post-hoc analysis of this pre-specified subgroup. All patients received volume-controlled ventilation with an applied PEEP of 5 cmH2O and either LTVV (6 mL/kg predicted body weight [PBW]) or CTVV (10 mL/kg PBW). The primary outcome was the incidence of a composite of PPCs within seven days. RESULTS: Three hundred twenty-eight patients (27.2%) underwent laparoscopic surgeries, with 158 (48.2%) randomised to LTVV. Fifty two of 157 patients (33.1%) assigned to LTVV and 72 of 169 (42.6%) assigned to conventional tidal volume developed PPCs within 7 days (unadjusted absolute difference, - 9.48 [95% CI, - 19.86 to 1.05]; p = 0.076). After adjusting for pre-specified confounders, the LTVV group had a lower incidence of the primary outcome than patients receiving CTVV (adjusted absolute difference, - 10.36 [95% CI, - 20.52 to - 0.20]; p = 0.046). CONCLUSION: In this post-hoc analysis of a large, randomised trial of LTVV we found that during laparoscopic surgeries, LTVV was associated with a significantly reduced PPCs compared to CTVV when PEEP was applied equally between both groups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry no: 12614000790640.

Postoperative Pulmonary Complications in the ENIGMA II Trial: A Post Hoc Analysis.

BACKGROUND: Nitrous oxide promotes absorption atelectasis in poorly ventilated lung segments at high inspired concentrations. The Evaluation of Nitrous oxide In the Gas Mixture for Anesthesia (ENIGMA) trial found a higher incidence of postoperative pulmonary complications and wound sepsis with nitrous oxide anesthesia in major surgery compared to a fraction of inspired oxygen of 0.8 without nitrous oxide. The larger ENIGMA II trial randomized patients to nitrous oxide or air at a fraction of inspired oxygen of 0.3 but found no effect on wound infection or sepsis. However, postoperative pulmonary complications were not measured. In the current study, post hoc data were collected to determine whether atelectasis and pneumonia incidences were higher with nitrous oxide in patients who were recruited to the Australian cohort of ENIGMA II. METHODS: Digital health records of patients who participated in the trial at 10 Australian hospitals were examined blinded to trial treatment allocation. The primary endpoint was the incidence of atelectasis, defined as lung atelectasis or collapse reported on chest radiology. Pneumonia, as a secondary endpoint, required a diagnostic chest radiology report with fever, leukocytosis, or positive sputum culture. Comparison of the nitrous oxide and nitrous oxide-free groups was done according to intention to treat using chi-square tests. RESULTS: Data from 2,328 randomized patients were included in the final data set. The two treatment groups were similar in surgical type and duration, risk factors, and perioperative management recorded for ENIGMA II. There was a 19.3% lower incidence of atelectasis with nitrous oxide (171 of 1,169 [14.6%] vs. 210 of 1,159 [18.1%]; odds ratio, 0.77; 95% CI, 0.62 to 0.97; P = 0.023). There was no difference in pneumonia incidence (60 of 1,169 [5.1%] vs. 52 of 1159 [4.5%]; odds ratio, 1.15; 95% CI, 0.77 to 1.72; P = 0.467) or combined pulmonary complications (odds ratio, 0.84; 95% CI, 0.69 to 1.03; P = 0.093). CONCLUSIONS: In contrast to the earlier ENIGMA trial, nitrous oxide anesthesia in the ENIGMA II trial was associated with a lower incidence of lung atelectasis, but not pneumonia, after major surgery.

Postoperative anaemia and patient-centred outcomes after major abdominal surgery: a retrospective cohort study.

BACKGROUND: Compared with anaemia before surgery, the underlying pathogenesis and implications of postoperative anaemia are largely unknown. METHODS: This retrospective cohort study analysed prospective data obtained from 2983 adult patients across 47 centres enrolled in a clinical trial evaluating restrictive and liberal intravenous fluids. The primary endpoint was persistent disability or death up to 90 days after surgery. Secondary endpoints included major septic complications, hospital stay, and patient quality of recovery using a 15-item quality of recovery (QoR-15) score, hospital re-admissions, and disability-free survival up to 12 months after surgery. Anaemia and disability were defined according to the WHO definitions. Multivariable regression was used to adjust for baseline risk and surgery. RESULTS: A total of 2983 patients met inclusion criteria for this study, of which 78.5% (95% confidence interval [CI], 76.7-80.1%) had postoperative anaemia. Patients with postoperative anaemia had a higher adjusted risk of death or disability up to 90 days after surgery when compared with those without anaemia: 18.2% vs 9.2% (risk ratio [RR]=1.51; 95% CI, 1.10-2.07, P=0.011); lower QoR-15 scores on Day 3 and Day 30, 105 (95% CI, 87-119) vs 114 (95% CI, 99-128; P<0.001), and 130 (95% CI, 112-140) vs 139 (95% CI, 121-144; P<0.011), respectively; higher adjusted risk of a composite of mortality/septic complications, 2.01 (95% CI, 1.55-42.67; P<0.001); unplanned admission to ICU (RR=2.65; 95% CI, 1.65-4.23; P<0.001); and longer median (inter-quartile range [IQR]) hospital stays, 6.6 (4.4-12.4) vs 3.7 (2.5-6.5) days (P<0.001). CONCLUSIONS: Postoperative anaemia is common and is independently associated with poor outcomes after surgery. Optimal prevention and treatment strategies need to be investigated. CLINICAL TRIAL REGISTRATION: NCT04978285 (ClinicalTrials.gov).

Inclusion, characteristics, and outcomes of male and female participants in large international perioperative studies.

BACKGROUND: We compared baseline characteristics and outcomes and evaluated the subgroup effects of randomised interventions by sex in males and females in large international perioperative trials. METHODS: Nine randomised trials and two cohort studies recruiting adult patients, conducted between 1995 and 2020, were included. Baseline characteristics and outcomes common to six or more studies were evaluated. Regression models included terms for sex, study, and an interaction between the two. Comparing outcomes without adjustment for baseline characteristics represents the 'total effect' of sex on the outcome. RESULTS: Of 54 626 participants, 58% were male and 42% were female. Females were less likely to have ASA physical status ≥3 (56% vs 64%), to smoke (15% vs 23%), have coronary artery disease (21% vs 32%), or undergo vascular surgery (10% vs 23%). The pooled incidence of death was 1.6% in females and 1.8% in males (risk ratio [RR] 0.92; 95% confidence interval [CI]: 0.81-1.05; P=0.20), of myocardial infarction was 4.2% vs 4.5% (RR 0.92; 95% CI: 0.81-1.03; P=0.10), of stroke was 0.5% vs 0.6% (RR 1.03; 95% CI: 0.79-1.35; P=0.81), and of surgical site infection was 8.6% vs 8.3% (RR 1.03; 95% CI: 0.79-1.35; P=0.70). Treatment effects of three interventions demonstrated statistically significant effect modification by sex. CONCLUSIONS: Females were in the minority in all included studies. They were healthier than males, but outcomes were comparable. Further research is needed to understand the reasons for this discrepancy. CLINICAL TRIAL REGISTRATION: International Registry of Meta-Research (UID: IRMR_000011; 5 January 2021).

Intraoperative low tidal volume ventilation and the risk of ICD-10 coded delirium and the use for antipsychotic medications.

BACKGROUND: Low tidal volume (VT) ventilation and its associated increase in arterial carbon dioxide (PaCO2) may affect postoperative neurologic function. We aimed to test the hypothesis that intraoperative low VT ventilation affect the incidence of postoperative ICD-10 coded delirium and/or the need for antipsychotic medications. METHODS: This is a post-hoc analysis of a large randomized controlled trial evaluating low vs. conventional VT ventilation during major non-cardiothoracic, non-intracranial surgery. The primary outcome was the incidence of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay, and the absolute difference with its 95% confidence interval (CI) was calculated. RESULTS: We studied 1206 patients (median age of 64 [55-72] years, 59.0% males, median ARISCAT of 26 [19-37], and 47.6% of ASA 3). ICD-10 coded delirium and /or antipsychotic medication use was diagnosed in 11.2% with similar incidence between low and conventional VT ventilation (11.1% vs. 11.3%; absolute difference, -0.24 [95%CI, -3.82 to 3.32]; p = 0.894). There was no interaction between allocation group and type of surgery. CONCLUSION: In adult patients undergoing major surgery, low VT ventilation was not associated with increased risk of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12614000790640 .

Gas Phase Diffusion Does Not Limit Lung Volatile Anesthetic Uptake Rate.

BACKGROUND: Inefficiency of lung gas exchange during general anesthesia is reflected in alveolar (end-tidal) to arterial (end-tidal-arterial) partial pressure gradients for inhaled gases, resulting in an increase in alveolar deadspace. Ventilation-perfusion mismatch is the main contributor to this, but it is unclear what contribution arises from diffusion limitation in the gas phase down the respiratory tree (longitudinal stratification) or at the alveolar-capillary barrier, especially for gases of high molecular weight such as volatile anesthetics. METHODS: The contribution of longitudinal stratification was examined by comparison of end-tidal-arterial partial pressure gradients for two inhaled gases with similar blood solubility but different molecular weights: desflurane and nitrous oxide, administered together at 2 to 3% and 10 to 15% inspired concentration (FiG), respectively, in 17 anesthetized ventilated patients undergoing cardiac surgery before cardiopulmonary bypass. Simultaneous measurements were done of tidal gas concentrations, of arterial and mixed venous blood partial pressures by headspace equilibration, and of gas uptake rate calculated using the direct Fick method using thermodilution cardiac output measurement. Adjustment for differences between the two gases in FiG and in lung uptake rate (VG) was made on mass balance principles. A 20% larger end-tidal-arterial partial pressure gradient relative to inspired concentration (PetG - PaG)/FiG for desflurane than for N2O was hypothesized as physiologically significant. RESULTS: Mean (SD) measured (PetG - PaG)/FiG for desflurane was significantly smaller than that for N2O (0.86 [0.37] vs. 1.65 [0.58] mmHg; P < 0.0001), as was alveolar deadspace for desflurane. After adjustment for the different VG of the two gases, the adjusted (PetG - PaG)/FiG for desflurane remained less than the 20% threshold above that for N2O (1.62 [0.61] vs. 1.98 [0.69] mmHg; P = 0.028). CONCLUSIONS: No evidence was found in measured end-tidal to arterial partial pressure gradients and alveolar deadspace to support a clinically significant additional diffusion limitation to lung uptake of desflurane relative to nitrous oxide.

Methylomic and transcriptomic characterization of postoperative systemic inflammatory dysregulation.

In this study, we define and validate a state of postoperative systemic inflammatory dysregulation (PSID) based on postoperative phenotypic extremes of plasma C-reactive protein concentration following major abdominal surgery. PSID manifested clinically with significantly higher rates of sepsis, complications, longer hospital stays and poorer short, and long-term outcomes. We hypothesized that PSID will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression suggests that dysregulation is mediated at multiple levels within specific gene sets and hence, nonspecific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy.

Intra-operative ventilator mechanical power as a predictor of postoperative pulmonary complications in surgical patients: A secondary analysis of a randomised clinical trial.

BACKGROUND: Studies in critically ill patients suggest a relationship between mechanical power (an index of the energy delivered by the ventilator, which includes driving pressure, respiratory rate, tidal volume and inspiratory pressure) and complications. OBJECTIVE: We aimed to assess the association between intra-operative mechanical power and postoperative pulmonary complications (PPCs). DESIGN: Post hoc analysis of a large randomised clinical trial. SETTING: University-affiliated academic tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. PATIENTS: Adult patients undergoing major noncardiothoracic, nonintracranial surgery. INTERVENTION: Dynamic mechanical power was calculated using the power equation adjusted by the respiratory system compliance (CRS). Multivariable models were used to assess the independent association between mechanical power and outcomes. MAIN OUTCOME MEASURES: The primary outcome was the incidence of PPCs within the first seven postoperative days. The secondary outcome was the incidence of acute respiratory failure. RESULTS: We studied 1156 patients (median age [IQR]: 64 [55 to 72] years, 59.5% men). Median mechanical power adjusted by CRS was 0.32 [0.22 to 0.51] (J min-1)/(ml cmH2O-1). A higher mechanical power was also independently associated with increased risk of PPCs [odds ratio (OR 1.34, 95% CI, 1.17 to 1.52); P < 0.001) and acute respiratory failure (OR 1.40, 95% CI, 1.21 to 1.61; P < 0.001). CONCLUSION: In patients receiving ventilation during major noncardiothoracic, nonintracranial surgery, exposure to a higher mechanical power was independently associated with an increased risk of PPCs and acute respiratory failure. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry no: 12614000790640.

Effects of an open lung ventilatory strategy on lung gas exchange during laparoscopic surgery.

In general anaesthesia, early collapse of poorly ventilated lung segments with low alveolar ventilation-perfusion ratios occurs and may lead to postoperative pulmonary complications after abdominal surgery. An 'open lung' ventilation strategy involves lung recruitment followed by 'individualised' positive end-expiratory pressure titrated to maintain recruitment of low alveolar ventilation-perfusion ratio lung segments. There are limited data in laparoscopic surgery on the effects of this on pulmonary gas exchange. Forty laparoscopic bowel surgery patients were randomly assigned to standard ventilation or an 'open lung' ventilation intervention, with end-tidal target sevoflurane of 1% supplemented by propofol infusion. After peritoneal insufflation, stepped lung recruitment was performed in the intervention group followed by maintenance positive end-expiratory pressure of 12-15 cmH2O adjusted to maintain dynamic lung compliance at post-recruitment levels. Baseline gas and blood samples were taken and repeated after a minimum of 30 minutes for oxygen and carbon dioxide and for sevoflurane partial pressures using headspace equilibration. The sevoflurane arterial/alveolar partial pressure ratio and alveolar deadspace fraction were unchanged from baseline and remained similar between groups (mean (standard deviation) control group = 0.754 (0.086) versus intervention group = 0.785 (0.099), P = 0.319), while the arterial oxygen partial pressure/fractional inspired oxygen concentration ratio was significantly higher in the intervention group at the second timepoint (control group median (interquartile range) 288 (234-372) versus 376 (297-470) mmHg in the intervention group, P = 0.011). There was no difference between groups in the sevoflurane consumption rate. The efficiency of sevoflurane uptake is not improved by open lung ventilation in laparoscopy, despite improved arterial oxygenation associated with effective and sustained recruitment of low alveolar ventilation-perfusion ratio lung segments.

Sugammadex, neostigmine and postoperative pulmonary complications: an international randomised feasibility and pilot trial.

BACKGROUND: Sugammadex reduces residual neuromuscular blockade after anaesthesia, potentially preventing postoperative pulmonary complications. However, definitive evidence is lacking. We therefore conducted a feasibility and pilot trial for a large randomised controlled trial of sugammadex, neostigmine, and postoperative pulmonary complications. METHODS: Patients aged ≥40 years having elective or expedited abdominal or intrathoracic surgery were recruited in Australia and Hong Kong. Perioperative care was at the discretion of clinicians, except for the use of rocuronium and/or vecuronium for neuromuscular blockade and the randomised intervention (sugammadex or neostigmine) for reversal. Feasibility measurements included recruitment, crossover, acceptability, completeness, and workload. Trial coordinator feedback was systematically sought. Patient-reported quality of life was measured using the EQ-5D-5L score. The primary pilot outcome was the incidence of new pulmonary complications up to hospital discharge (or postoperative day 7 if still in hospital). RESULTS: Among 150 eligible patients, 120 consented to participate (recruitment rate 80%, 95% confidence interval [CI] 73 to 86%). The randomised intervention was administered without crossover to 115 of 117 patients who received reversal (98%, 95% CI 94 to 100%). The protocol was acceptable or highly acceptable to the anaesthetist in 108 of 116 cases (93%, 95% CI 87 to 97%; missing = 4). Four patients of the 120 patients were lost to follow-up at 3 months (3.3%, 95% CI 0.9 to 8.3%). Case report forms were complete at 3 months for all remaining patients. The median time to complete trial processes was 3.5 h (range 2.5-4.5 h). Trial coordinators reported no barriers to trial processes. Patients were aged 64 (standard deviation 11) years, 70 (58%) were male and 50 (42%) were female, and planned surgeries were thoracic (23 [19%]), upper abdominal (41 [34%]), and lower abdominal (56 [47%]). The primary outcome was observed in 5 (8.5%) of the 59 sugammadex patients and 5 (8.2%) of the 61 neostigmine patients (odds ratio 1.02, 95% CI 0.28 to 3.67). CONCLUSIONS: A large international randomised controlled trial of sugammadex, neostigmine and postoperative pulmonary complications in adult patients having abdominal and intrathoracic surgery, including collection of cost-effectiveness evidence for Health Technology Appraisal, is feasible. TRIAL REGISTRATION: Prospectively registered at the Australian and New Zealand Clinical Trials Registry ( ACTRN12620001313921 ) on December 7, 2020. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380645&isReview=true .

Ideal alveolar gas defined by modal gas exchange in ventilation-perfusion distributions.

Under the three-compartment model of ventilation-perfusion ([Formula: see text]) scatter, Bohr-Enghoff calculation of alveolar deadspace fraction (VDA/VA) uses arterial CO2 partial pressure measurement as an approximation of "ideal" alveolar CO2 (ideal [Formula: see text]). However, this simplistic model suffers from several inconsistencies. Modeling of realistic physiological distributions of [Formula: see text] and [Formula: see text] instead suggests an alternative concept of "ideal" alveolar gas at the [Formula: see text] ratio where uptake or elimination rate of a gas is maximal. For alveolar-capillary partial pressure, this "modal" point equals the mean of expired alveolar and arterial partial pressures, regardless of [Formula: see text] scatter severity or overall [Formula: see text]. For example, modal ideal [Formula: see text] can be estimated from the following equation: [Formula: see text]Using a multicompartment computer model of log-normal distributions of [Formula: see text] and [Formula: see text], agreement of this estimate with the modal ideal [Formula: see text] located at the [Formula: see text] ratio of maximal compartmental [Formula: see text] was assessed across a wide range of severity of [Formula: see text] scatter and overall [Formula: see text] ratio. Agreement of VDA/VA for CO2 from the Bohr equation using modal ideal PCO2, with that using the estimated value was also assessed. Estimated modal ideal [Formula: see text] agreed closely with modal ideal [Formula: see text], intraclass correlation (ICC) > 99.9%. There was no significant difference between VDA/VA using either value for ideal [Formula: see text]. Modal ideal [Formula: see text] reflects a physiologically realistic concept of ideal alveolar gas where there is maximal gas exchange effectiveness in a physiological distribution of [Formula: see text], which is generalizable to any inert gas and is practical to estimate from arterial and end-expired CO2 partial pressures.NEW & NOTEWORTHY The three-compartment model of lung ventilation-perfusion mismatch postulates definitive alveolar deadspace and "ideal gas" lung compartments, but these are, in fact, widely different for gases of different blood solubility. Physiologically realistic distributions of ventilation, perfusion, and gas exchange instead suggest an individual "ideal" ventilation-perfusion ratio for every gas, where its alveolar-capillary uptake or elimination rate is maximal (modal). For carbon dioxide, this "ideal" partial pressure is the mean of the arterial and end-tidal partial pressures.

Effect of fluid strategy on stroke volume, cardiac output, and fluid responsiveness in adult patients undergoing major abdominal surgery: a sub-study of the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial.

BACKGROUND: We designed a prospective sub-study of the larger Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial to measure differences in stroke volume and other haemodynamic parameters at the end of the intraoperative fluid protocols. The haemodynamic effects of the two fluid regimens may increase our understanding of the observed perioperative outcomes. METHODS: Stroke volume and cardiac output were measured with both an oesophageal Doppler ultrasound monitor and arterial pressure waveform analysis. Stroke volume variation, pulse pressure variation, and plethysmographic variability index were also obtained. A passive leg raise manoeuvre was performed to identify fluid responsiveness. RESULTS: Analysis of 105 patients showed that the primary outcome, Doppler monitor-derived stroke volume index, was higher in the liberal group: restrictive 38.5 (28.6-48.8) vs liberal 44.0 (34.9-61.9) ml m-2; P=0.043. Similarly, there was a higher cardiac index in the liberal group: 2.96 (2.32-4.05) vs 2.42 (1.94-3.26) L min-1 m-2; P=0.015. Arterial-pressure-based stroke volume and cardiac index did not differ, nor was there a significant difference in stroke volume variation, pulse pressure variation, or plethysmographic variability index. The passive leg raise manoeuvre showed fluid responsiveness in 40% of restrictive and 30% of liberal protocol patients (not significant). CONCLUSIONS: The liberal fluid group from the RELIEF trial had significantly higher Doppler ultrasound monitor-derived stroke volume and cardiac output compared with the restrictive fluid group at the end of the intraoperative period. Measures of fluid responsiveness did not differ significantly between groups. CLINICAL TRIAL REGISTRATION: ACTRN12615000125527.

Effect of Intraoperative Low Tidal Volume vs Conventional Tidal Volume on Postoperative Pulmonary Complications in Patients Undergoing Major Surgery: A Randomized Clinical Trial.

Importance: In patients who undergo mechanical ventilation during surgery, the ideal tidal volume is unclear. Objective: To determine whether low-tidal-volume ventilation compared with conventional ventilation during major surgery decreases postoperative pulmonary complications. Design, Setting, and Participants: Single-center, assessor-blinded, randomized clinical trial of 1236 patients older than 40 years undergoing major noncardiothoracic, nonintracranial surgery under general anesthesia lasting more than 2 hours in a tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. The last date of follow-up was February 17, 2019. Interventions: Patients were randomized to receive a tidal volume of 6 mL/kg predicted body weight (n = 614; low tidal volume group) or a tidal volume of 10 mL/kg predicted body weight (n = 592; conventional tidal volume group). All patients received positive end-expiratory pressure (PEEP) at 5 cm H2O. Main Outcomes and Measures: The primary outcome was a composite of postoperative pulmonary complications within the first 7 postoperative days, including pneumonia, bronchospasm, atelectasis, pulmonary congestion, respiratory failure, pleural effusion, pneumothorax, or unplanned requirement for postoperative invasive or noninvasive ventilation. Secondary outcomes were postoperative pulmonary complications including development of pulmonary embolism, acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis, acute kidney injury, wound infection (superficial and deep), rate of intraoperative need for vasopressor, incidence of unplanned intensive care unit admission, rate of need for rapid response team call, intensive care unit length of stay, hospital length of stay, and in-hospital mortality. Results: Among 1236 patients who were randomized, 1206 (98.9%) completed the trial (mean age, 63.5 years; 494 [40.9%] women; 681 [56.4%] undergoing abdominal surgery). The primary outcome occurred in 231 of 608 patients (38%) in the low tidal volume group compared with 232 of 590 patients (39%) in the conventional tidal volume group (difference, -1.3% [95% CI, -6.8% to 4.2%]; risk ratio, 0.97 [95% CI, 0.84-1.11]; P = .64). There were no significant differences in any of the secondary outcomes. Conclusions and Relevance: Among adult patients undergoing major surgery, intraoperative ventilation with low tidal volume compared with conventional tidal volume, with PEEP applied equally between groups, did not significantly reduce pulmonary complications within the first 7 postoperative days. Trial Registration: ANZCTR Identifier: ACTRN12614000790640.

End-tidal to Arterial Gradients and Alveolar Deadspace for Anesthetic Agents.

BACKGROUND: According to the "three-compartment" model of ventilation-perfusion ((Equation is included in full-text article.)) inequality, increased (Equation is included in full-text article.)scatter in the lung under general anesthesia is reflected in increased alveolar deadspace fraction (VDA/VA) customarily measured using end-tidal to arterial (A-a) partial pressure gradients for carbon dioxide. A-a gradients for anesthetic agents such as isoflurane are also significant but have been shown to be inconsistent with those for carbon dioxide under the three-compartment theory. The authors hypothesized that three-compartment VDA/VA calculated using partial pressures of four inhalational agents (VDA/VAG) is different from that calculated using carbon dioxide (VDA/VACO2) measurements, but similar to predictions from multicompartment models of physiologically realistic "log-normal" (Equation is included in full-text article.)distributions. METHODS: In an observational study, inspired, end-tidal, arterial, and mixed venous partial pressures of halothane, isoflurane, sevoflurane, or desflurane were measured simultaneously with carbon dioxide in 52 cardiac surgery patients at two centers. VDA/VA was calculated from three-compartment model theory and compared for all gases. Ideal alveolar (PAG) and end-capillary partial pressure (Pc'G) of each agent, theoretically identical, were also calculated from end-tidal and arterial partial pressures adjusted for deadspace and venous admixture. RESULTS: Calculated VDA/VAG was larger (mean ± SD) for halothane (0.47 ± 0.08), isoflurane (0.55 ± 0.09), sevoflurane (0.61 ± 0.10), and desflurane (0.65 ± 0.07) than VDA/VACO2 (0.23 ± 0.07 overall), increasing with lower blood solubility (slope [Cis], -0.096 [-0.133 to -0.059], P < 0.001). There was a significant difference between calculated ideal PAG and Pc'G median [interquartile range], PAG 5.1 [3.7, 8.9] versus Pc'G 4.0[2.5, 6.2], P = 0.011, for all agents combined. The slope of the relationship to solubility was predicted by the log-normal lung model, but with a lower magnitude relative to calculated VDA/VAG. CONCLUSIONS: Alveolar deadspace for anesthetic agents is much larger than for carbon dioxide and related to blood solubility. Unlike the three-compartment model, multicompartment (Equation is included in full-text article.)scatter models explain this from physiologically realistic gas uptake distributions, but suggest a residual factor other than solubility, potentially diffusion limitation, contributes to deadspace.

Frequency of hyperoxaemia during and after major surgery.

The oxygen concentration (FiO2) and arterial oxygen tension (PaO2) delivered in patients undergoing major surgery is poorly understood. We aimed to assess current practice with regard to the delivered FiO2 and the resulting PaO2 in patients undergoing major surgery. We performed a retrospective cohort study in a tertiary hospital. Data were collected prospectively as part of a larger randomised controlled trial but were analysed retrospectively. Patients were included if receiving controlled mandatory ventilation and arterial line monitoring. Anaesthetists determined the FiO2 and the oxygenation saturation (SpO2) targets. An arterial blood gas (ABG) was obtained 15-20 minutes after induction of anaesthesia, immediately before the emergence phase of anaesthesia and 15 minutes after arrival in the post-anaesthesia care unit (PACU). We defined hyperoxaemia as a PaO2 of >150 mmHg and included a further threshold of PaO2 >200 mmHg. We studied 373 patients. The median (interquartile range (IQR)) lowest intraoperative FiO2 and SpO2 values were 0.45 (IQR 0.4-0.5) and 97% (IQR 96-98%), respectively, with a median PaO2 on the first and second ABG of 237 mmHg (IQR 171-291 mmHg) and 189 mmHg (IQR 145-239 mmHg), respectively. In the PACU, the median lowest oxygen flow rate was 6 L/min (IQR 3-6 L/min), and the PaO2 was 158 mmHg (IQR 120-192 mmHg). Hyperoxaemia occurred in 82%, 73% and 54% of participants on the first and second intraoperative and postoperative ABGs respectively. A PaO2 of >200 mmHg occurred in 64%, 41% and 21% of these blood gases, respectively. In an Australian tertiary hospital, a liberal approach to FiO2 and PaO2 was most common and resulted in a high incidence of perioperative hyperoxaemia.

Elucidating the roles of solubility and ventilation-perfusion mismatch in the second gas effect using a two-step model of gas exchange.

The second gas effect occurs when high inspired concentrations of a first gas, usually nitrous oxide, enhance the uptake of other gases administered simultaneously. The second gas effect is greater in blood than in the gas phase, persists well into the period of nitrous oxide maintenance anesthesia, increases as the degree of ventilation-perfusion mismatch increases, and is most pronounced with the low soluble agents in current use. Yet, how low gas solubility and increased ventilation-perfusion mismatch can combine to improve gas transfer remains unclear, which is the focus of the present study. Specifically, we have used a two-step model of gas exchange to separate the effect of gas volume contraction, which accompanies the first gas uptake, from other factors. Step 1 involves the uptake of the second gas at constant volume. Contraction of gas volume takes place in step 2 and is most effective in transferring further amounts of gas to blood if the volume of second gas exposed to the contraction is maximized, i.e., if the loss of second gas in step 1 is minimized. Minimization depends on having a gas with a low solubility in blood and increases as the degree of ventilation-perfusion mismatch increases. The effectiveness of the contraction also requires a favorable alignment with the retained second gas. Alignment depends on the solubility of both gases and the degree of ventilation-perfusion mismatch. The model is fully consistent with classical concepts of gas exchange.NEW & NOTEWORTHY Gas exchange in the lung can always be represented as the sum of two components: gas exchange at constant volume followed by gas exchange on volume correction. Using this sequence to study the second gas effect, low gas solubility and increased ventilation-perfusion mismatch are shown to act together to enhance second gas uptake. While appearing to contravene classical concepts of gas exchange, a detailed theoretical analysis shows it is fully consistent with these concepts.