The primary outcome measure was hospital mortality. Secondary outcomes were ICU mortality, RRT initiation in the ICU, ICU length of stay, and hospital length of stay.
Incidence, prevalence, patient characteristics and the outcomes of patients with MA by the two criteria were summarised using descriptive statistics. Group comparisons were performed using 𝑥2 or Fisher exact test for categorical variables, Student t test for normally distributed data and Wilcoxon rank sum test otherwise, with results presented as number (percentage), mean (standard deviation) and median (interquartile range) respectively. Diagnostic accuracy of the two criteria for hospital mortality was determined by calculating sensitivity, specificity, positive predictive value, and negative predictive value.
To evaluate whether MA diagnosed by the two criteria was an independent predictor of mortality, hierarchical logistic regression models were fitted adjusting for key factors. These factors included APACHE III-j score without the acidosis component, sex, chronic conditions, planned ICU admission, limitations of treatment orders at the ICU admission, ICU diagnosis categories of APACHE III-j, medical or surgical, potassium and PaCO2, with patients nested within sites and sites treated as a random effect.
We further explored incidence and prevalence of patients with MA, as well as hospital mortality of patients with and without MA stratified by year. To investigate the change in hospital mortality over time by moderate MA, logistic regression models were fitted with main effects for year of admission, MA along with their two-way interaction and adjusting for APACHE III-j risk of death, with ICU site treated as a random effect.
We further explored patient characteristics and outcomes in patients with MA diagnosed by both criteria after excluding chronic renal failure, ketoacidosis, and possible exogenous acidosis (patients with overdose) so as to simulate the patient screening in the BICAR-ICU trial in Australian and New Zealand ICUs.
We did not impute any missing values and all available data were analysed. We performed all analyses using R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria.) or SAS software version 9.4 (SAS Institute, Cary, NC, USA). Given the magnitude of the dataset, in order to more closely align statistical and clinical significance, a two-sided P value of 0.01 was chosen to indicate statistical significance.
Among the 1 513 836 ICU admissions registered in the ANZICS-APD, 437 749 records met the pre-set exclusion criteria, leaving 1 076 087 patients for analysis (Figure 1
). Of these, 244 740 were admitted to the ICU from 2017 to 2018. In this period, patients with MA by the BICAR-ICU criteria accounted only for 1.5% (1350/87 110; 157 630 patients were excluded due to missing data) of the patients in the ICU, whereas 8.4% (20 679/244 740) of patients had at least moderate MA (P
shows the characteristics, the interventions provided in ICU, and the outcomes of all patients and of patients with MA according to the two sets of criteria. Hypercapnia of PaCO2
> 45 mmHg was observed in 25.3% (61 967/244 740) of all patients. In addition, the rates of the hypercapnia were 54.6% (24 859/45 538) and 56.2% (6754/12 024) of patients, with pH < 7.30 and < 7.20 respectively. According to protocol, such patients were excluded.
Patients with MA by either criterion had higher mortality than those without MA.Hospital mortality was higher in patients with MA diagnosed by the BICAR-ICU criteria than moderate MA criteria (P < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value for hospital mortality of the BICAR-ICU criteria and moderate MA criteria were 8.4%, 99.1%, 48.3%, 91.7% and 21.7%, 92.8%, 21.5%, 92.8% respectively. Logistic regression analyses revealed that early MA by both criteria was independently associated with hospital mortality (early severe MA: adjusted odds ratio [aOR], 2.431; 95% CI, 2.098–2.817; P < 0.001; early moderate MA: aOR, 1.542; 95% CI, 1.464–1.623; P < 0.001).
shows the characteristics and outcomes of patients who met the eligibility criteria of the BICAR-ICU trial, after excluding end stage renal failure, ketoacidosis, and possible exogenous toxin acidosis. These patients were compared with patients with moderate MA after excluding these conditions.
Changes in the annual incidence and prevalence of moderate MA are shown in Figure 2
. For moderate MA, the average incidence rates during the period from 2008 to 2016 and the period from 2017 to 2018 were 411.5 per million per year and 349.2 per million per year respectively. While for early severe MA, the incidence was 39.5 per million per year in 2018. Annual unadjusted hospital mortality of patients with and without moderate MA as well as adjusted annual odds ratio for the hospital mortality are shown in Figure 3
. The P
value for interaction effect between moderate MA and year of admission was 0.016 for the period 2008 to 2016; however, the P
value was 0.78 in the latter period from 2017 to 2018.
Using the ANZICS-APD, we found that the diagnostic criteria for MA used in the BICAR-ICU trial applied to only for 1.5% of critically ill patients, and that hospital mortality for such patients was 48.3%. In contrast, patients with moderate MA accounted for 8.4% of the Australian and New Zealand ICU population and still carried a significant hospital mortality of 21.5%. In the latest 2 years of the study period, using a different methodology for BGA inclusion, the mortality of moderate MA appeared to be increasing.