Elevated pre-extubation osmolality linked to early reintubation in two ICU databases

Critically ill adults with calculated serum osmolality above 300 mOsm/kg shortly before removal of an endotracheal tube had a higher risk of invasive reintubation within 48 hours in a retrospective study of two independent critical care databases. The association was observed in 2,639 eligible extubations from MIMIC-IV, representing 2,639 unique patients, and independently replicated in 1,390 eligible extubations from 1,334 patients in the multicenter eICU Collaborative Research Database. After adjustment for eight prespecified clinical factors, the risk ratio for 48-hour reintubation was 1.31 (95% confidence interval, 1.05–1.62) in MIMIC-IV and 1.88 (1.27–2.77) in eICU-CRD. These observational results identify pre-extubation hyperosmolarity as a potential metabolic–renal risk signal, but they do not establish that it causes reintubation or that calculating osmolality should guide clinical decisions.

The absolute event rates differed between the databases, underscoring the importance of distinguishing a reproducible relative association from a universal risk estimate. In MIMIC-IV, invasive reintubation within 48 hours occurred in 13.6% of 1,124 extubations with calculated osmolality above 300 mOsm/kg and 10.8% of 1,515 extubations at or below that level, an absolute difference of 2.8 percentage points. In eICU-CRD, the respective rates were 10.5% of 486 extubations and 4.6% of 904, a difference of 5.8 percentage points. The association also persisted when the outcome window was extended to 72 hours, with adjusted risk ratios of 1.25 (1.02–1.52) in MIMIC-IV and 1.53 (1.19–1.97) in eICU-CRD. The replication therefore involved the same exposure definition, outcome definitions, adjustment variables, transformations and analytic plan, rather than a threshold or model selected from the replication dataset.

Calculated serum osmolality was derived from the most recent complete set of sodium, glucose and blood urea nitrogen measurements available within 24 hours before extubation, with no more than two hours separating component collection times. The formula was 2 × sodium + glucose/18 + blood urea nitrogen/2.8, with sodium in millimoles per liter and glucose and blood urea nitrogen in milligrams per deciliter. Median calculated osmolality was 297.5 mOsm/kg in MIMIC-IV and 295.2 mOsm/kg in eICU-CRD; 42.6% and 35.0% of the respective cohorts exceeded 300 mOsm/kg. The investigators emphasized that this calculated value is not interchangeable with directly measured serum osmolality or effective osmolality, which excludes urea. It functions instead as a practical summary combining water–solute balance, glycemic stress and renal or catabolic burden using routinely available laboratory data.

The retrospective cohort included the first eligible extubation in each hospital admission after adults had received invasive mechanical ventilation. Exclusions covered tracheostomy conversion, terminal or palliative extubation, death-related cessation of ventilation and boundaries that could not be classified reliably. Noninvasive ventilation, continuous or bilevel positive airway pressure, high-flow nasal oxygen and standby ventilator modes were not treated as invasive ventilation. Invasive reintubation was tracked throughout the same hospital admission, and noninvasive respiratory support alone did not count as reintubation. Sensitivity analyses addressed planned versus unplanned extubation, potentially procedure-related reintubation, repeated admissions, narrower exposure windows, respiratory severity, fluid balance, renal status and identifiable hypertonic treatment.

Adjustment covered age, sex, ventilation duration, pre-extubation respiratory rate, oxygen saturation, Glasgow Coma Scale score, serum creatinine and vasopressor use during the preceding 24 hours. Missing covariates were handled separately within each database with 30 multiply imputed datasets, and complete-case analyses served as sensitivity checks. Additional respiratory adjustment had little effect within the subsets where PaO2/FiO2 was recorded. For example, in 1,329 MIMIC-IV extubations with 169 reintubations, the risk ratio was 1.47 both before and after adjustment for the oxygenation ratio. In 771 eICU-CRD extubations with 52 events, the corresponding estimates were 1.21 and 1.23, although their confidence intervals included no association. Adjustment for recorded fluid balance, loop-diuretic exposure and creatinine-based acute kidney injury likewise produced little change in the main pattern, but several analyses contained few events and were imprecise.

Exposure shape and biochemical-component analyses suggested that the result was not explained by a single laboratory value. Neighboring thresholds of above 295, 300 and 305 mOsm/kg produced associations in the same direction, although precision varied. An exploratory MIMIC-IV-derived threshold of 301.964 mOsm/kg, applied unchanged to eICU-CRD, corresponded to a risk ratio of 2.04 (1.41–2.96), but bootstrap-derived thresholds had substantial dispersion. Continuous associations differed between databases: each 10-mOsm/kg increase had an adjusted risk ratio of 1.03 (0.96–1.11) in MIMIC-IV and 1.21 (1.06–1.39) in eICU-CRD. Neither restricted cubic spline analysis showed evidence of nonlinearity. Separately modeled sodium, glucose and blood urea nitrogen did not reproduce the categorical association across both databases, while effective osmolality, which excludes urea, showed weaker estimates. The authors consequently interpret 300 mOsm/kg as a pragmatic stratification point rather than a sharply defined biological threshold.

Competing-event analyses showed that hyperosmolarity was also associated with death before reintubation within 48 hours. Cause-specific hazard ratios were 1.29 (1.02–1.63) in MIMIC-IV and 1.96 (1.34–2.89) in eICU-CRD, while Fine–Gray subdistribution hazard ratios were 1.34 (1.06–1.69) and 2.03 (1.45–2.86), respectively. For a composite endpoint of reintubation or death, however, the adjusted risk ratios attenuated to 1.09 (0.97–1.23) and 1.42 (1.13–1.78). This pattern indicates that some of the association with reintubation overlaps with a broader association involving mortality. It also reinforces the need to interpret calculated hyperosmolarity as a marker of overall illness severity rather than as an isolated mechanism specific to airway failure.

Secondary prognostic analyses found that calculated hyperosmolarity added little to the transportable accuracy of existing clinical models. In external validation with MIMIC-IV coefficients fixed before transfer to eICU-CRD, the area under the receiver operating characteristic curve increased from 0.5875 for the base model to 0.6074 after adding calculated hyperosmolarity. The numerical difference was 0.0199, but its 95% confidence interval ranged from −0.0327 to 0.0434 and included no improvement. Differences in precision–recall area and Brier score were also small. Original external validation indicated overprediction of absolute risk in eICU-CRD, with observed-to-expected ratios of 0.45 for both the base and osmolality-augmented models. The results support the marker’s value as an adjunctive risk signal, not as a replacement for respiratory mechanics, airway protection, secretion management, neurologic function or other established elements of extubation assessment.

The study has important limitations inherent to retrospective electronic health record research. Residual confounding is possible because cough strength, secretion burden and the rapid shallow breathing index could not be harmonized across databases. The eICU-CRD lacked a comparably reliable field for distinguishing planned from unplanned extubation, while treatment documentation was incomplete, particularly for medication names and high-flow nasal oxygen. Oxygenation and fluid data were available only in selected subsets, acute kidney injury was defined from serum creatinine rather than complete urine-output and kidney-replacement-therapy criteria, and calculated osmolality was not a direct laboratory measurement. Explicit causes of reintubation were recorded for too few events, and post-extubation laboratory sampling was influenced by the opportunity to obtain measurements. With only 93 primary reintubation events in eICU-CRD, some subgroup estimates were especially unstable. Both databases also represent US critical care practice, so replication in contemporary non-US cohorts would be needed to assess broader generalizability. The findings support prospective evaluation of calculated osmolality as a complementary component of extubation assessment, rather than a validated treatment threshold.

Subject of Research: Association of pre-extubation calculated serum hyperosmolarity with early invasive reintubation in critically ill adults

Article Title: Pre-extubation calculated serum osmolality and early invasive reintubation in critically ill adults: a dual-database study with multicenter external replication

Article References: Huang, W., Bian, J., Chen, Y., Huang, B., Liu, C., & Chen, C. (2026). Pre-extubation calculated serum osmolality and early invasive reintubation in critically ill adults: a dual-database study with multicenter external replication. Frontiers in Medicine, 13, Article 1984164. https://doi.org/10.3389/fmed.2026.1984164

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1984164

Keywords: calculated serum osmolality, extubation, invasive reintubation, critical care, mechanical ventilation, hyperosmolarity, metabolic–renal status, retrospective cohort study, MIMIC-IV, eICU-CRD, Pre-extubation, calculated