The safety of nitrous oxide: glass half-full or half-empty?

A systematic review of clinical trials confirms that including nitrous oxide in the gas mixture for general anaesthesia has minor short-term benefits and does not impact most patient safety outcomes. However, no risk-benefit analysis of nitrous oxide should ignore its known environmental effects. If continued nitrous oxide use is supported, strategies to minimise and monitor the contribution of medical nitrous oxide to global warming are vital.

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.

A modal definition of ideal alveolar oxygen.

In the three-compartment model of lung ventilation-perfusion heterogeneity (VA/Q scatter), both Bohr dead space and shunt equations require values for central "ideal" compartment O2 and CO2 partial pressures. However, the ideal alveolar gas equation most accurately calculates mixed (ideal and alveolar dead space) PAO2 . A novel "modal" definition has been validated for ideal alveolar CO2 partial pressure, at the VA/Q ratio in a lung distribution where CO2 elimination is maximal. A multicompartment computer model of physiological, lognormal distributions of VA and Q was used to identify modal "ideal" PAO2 , and find a modification of the alveolar gas equation to estimate it across a wide range of severity of VA/Q heterogeneity and FIO2 . This was then validated in vivo using data from a study of 36 anesthetized, ventilated patients with FIO2 0.35-80. Substitution in the alveolar gas equation of respiratory exchange ratio R with modalR = R - 1 - PEtC O 2 / P aCO 2 $$ \kern0.5em \mathrm{modalR}=\mathrm{R}\hbox{--} \left(1\hbox{--} \mathrm{PEtC}{\mathrm{O}}_2/\mathrm{P}{\mathrm{aCO}}_2\right) $$ achieved excellent agreement (r2 = 0.999) between the calculated ideal PAO2 and the alveolar-capillary Pc'O2 at the modal VO2 point ("modal" Pc'O2 ), across a range of log standard deviation of VA 0.25-1.75, true shunt 0%-20%, overall VA/Q 0.4-1.6, and FIO2 0.18-1.0, where the modeled PaO2 was over 50 mm Hg. Modal ideal PAO2 can be reliably estimated using routine blood gas measurements.

The relationship between study findings and publication outcome in anesthesia research following implementation of mandatory trial registration: A systematic review of publication bias.

Previously, we reviewed 1052 randomized-controlled trial abstracts presented at the American Society of Anesthesiologists annual meetings from 2001-2004. We found significant positive publication bias in the period examined, with the odds ratio for abstracts with positive results proceeding to journal publication over those with null results being 2.01 [95% confidence interval: 1.52, 2.66; P < 0.001]. Mandatory trial registration was introduced in 2005 as a required standard for publication. We sought to examine whether mandatory trial registration has decreased publication bias in the anesthesia and perioperative medicine literature. We reviewed all abstracts from the 2010-2016 American Society of Anesthesiologists meetings that reported on randomized-controlled trials in humans. We scored the result of each abstract as positive or null according to a priori definitions. We systematically searched for any subsequent publication of the studies and calculated the odds ratio for journal publication, comparing positive vs null studies. We compared the odds ratio from the 2010-2016 abstracts (post-mandatory trial registration) with the odds ratio from the 2001-2004 abstracts (pre-mandatory trial registration) as a ratio of odds ratios. We defined a 33% decrease in the odds ratio as significant, corresponding to a new odds ratio of 1.33. We reviewed 9789 abstracts; 1049 met inclusion criteria as randomized-controlled trials, with 542 (51.7%) of the abstracts going on to publication. The odds ratio for abstracts with positive results proceeding to journal publication was 1.28 [95% CI: 0.97, 1.67; P = 0.076]. With adjustment for sample size and abstract quality, the difference in publication rate between positive and null abstracts was statistically significant (odds ratio 1.34; 95% CI: 1.02, 1.76; P = 0.037). The ratio of odds ratios, comparing the odds ratio from the 2010-2016 abstracts (post-mandatory trial registration) to the odds ratio from the 2001-2004 abstracts (pre-mandatory trial registration), was 0.63 (95% CI: 0.43, 0.93); P = 0.021). We present the first study in the anesthesia and perioperative medicine literature that examines and compares publication bias over two discrete periods of time, prior to and after the implementation of mandatory trial registration. Our results suggest that the amount of publication bias has decreased markedly following implementation of mandatory trial registration. However, some positive publication bias in the anesthesia and perioperative medicine literature remains.

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.

Trial registration of abstracts from the American Society of Anesthesiologists Meetings 2010-2016: A review of prospective trial registration and selective outcome reporting.

Mandatory prospective trial registration was introduced in 2005 to reduce publication bias and selective outcome reporting. In this study, we measured the proportion of prospective trial registration in randomized controlled trials in the anesthesia literature after this introduction, discrepancies between these trial protocols and subsequent publications, the association between being prospectively registered and reporting positive or negative results, and between being prospectively registered and achieving publication. We reviewed all abstracts from the American Society of Anesthesiologists annual meetings between 2010-2016 and included randomized controlled trials in humans. The abstract conclusions were scored as positive or negative according to predetermined definitions. We conducted a systematic search for trial registration and subsequent publication. Of the 9789 abstracts reviewed, 1070 abstracts were included. 222 (21%) of these abstracts had undergone prospective trial registration. 168/222 (76%) had a corresponding journal publication. 81(48%) had a major discrepancy between registration and publication. 149 (67%) of the abstracts with registration had positive outcomes compared with 616 (73%) of those without (Odds Ratio 0.77; 95% CI: 0.56 to 1.06; P = 0.105). Abstracts that had been registered were more likely to proceed to publication than those that had not (Odds Ratio 3.82; 95% CI 2.73 to 5.35; P < 0.001). The proportion of randomized controlled trials being prospectively registered in anesthesia remains low. Discrepancies between registry entries and corresponding journal publications are common. There was no association between prospective trial registration and subsequent positive outcomes. There was a strong association between prospective trial registration and the likelihood of progression to journal publication.

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.

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.