Abstract
Background
Serum osmolality is a potential prognostic biomarker in critical illnesses. However, its predictive value for mortality in patients with acute respiratory failure (ARF) remains unclear. This study aimed to evaluate the association between serum osmolality and 28-day mortality in critically ill patients with ARF.
Methods
Patients with ARF were identified from the Medical Information Mart for Intensive Care IV database and grouped into quintiles based on their serum osmolality. Serum osmolality was derived from the first laboratory values obtained during the period from 6 hours before to 24 hours after intensive care unit (ICU) admission. The association between serum osmolality and 28-day mortality was assessed using Cox proportional hazards regression and restricted cubic splines (RCS).
Results
Among the 9,748 patients enrolled, the median age was 68.0 years, 55.0% were male, and the 28-day mortality rate was 25.6%. After multivariable adjustment, patients in the lowest (Q1) and highest (Q5) serum osmolality quintiles had an increased mortality risk compared to Q2: [hazard ratio (HR) =1.17; 95% confidence interval (CI): 1.02–1.35] and (HR =1.30; 95% CI: 1.14–1.49). RCS analysis demonstrated a U-shaped association between serum osmolality and 28-day mortality, and a two-piecewise Cox model identified a threshold at 287.79 mmol/L. Below this threshold, each unit increase in osmolality was associated with lower mortality (HR =0.99; 95% CI: 0.98–0.99), while above it, each unit increase was associated with higher mortality (HR =1.01; 95% CI: 1.01–1.01).
Conclusions
Serum osmolality demonstrated a U-shaped association with 28-day mortality in patients with ARF, suggesting its potential as a biomarker for risk stratification.
Keywords: Medical Information Mart for Intensive Care IV (MIMIC-IV), serum osmolality, acute respiratory failure (ARF), mortality
Highlight box.
Key findings
• Serum osmolality exhibits a U-shaped association with 28-day mortality in acute respiratory failure (ARF), with both low and high levels elevating risk.
What is known and what is new?
• Established evidence reveals a nonlinear relationship between serum osmolality and mortality in critically ill populations. For instance, one study identified a U-shaped association in patients with sepsis.
• While serum osmolality shows prognostic value in critical illness, its specific role in ARF remains unclear. To address this gap, this retrospective study aims to investigate the association between serum osmolality and mortality risk in patients with ARF.
What is the implication, and what should change now?
• The primary aim of this study is to aid clinicians in identifying patients with ARF who are at high risk of mortality. Ultimately, this may facilitate earlier personalized interventions to improve outcomes. As our work is a retrospective cohort study, future prospective longitudinal research is warranted to validate these findings.
Introduction
Acute respiratory failure (ARF) is defined as a sudden failure to maintain adequate gas exchange, presenting as type I (hypoxemia without hypercapnia), type II (hypercapnia), or a mixed form (1). This dysfunction serves as a key driver for life-threatening acid-base disorders through the impairment of blood oxygenation, carbon dioxide elimination, or the fulfillment of metabolic demands (2). ARF presents a major challenge to public health worldwide (3). As a leading cause of intensive care unit (ICU) admission, ARF is associated with a mortality rate of approximately 35% (4). The early identification and intervention of ARF are imperative in the management of at-risk patients (5). Therefore, the discovery of easily monitored biomarkers for prognostication in ARF is crucial, as it would enable clinicians to identify high-risk patients earlier and implement precise management strategies to improve outcomes.
Serum osmolality, the sum of the osmotic pressures contributed by all dissolved particles in the blood such as sodium, glucose, and blood urea nitrogen (BUN), serves as a critical indicator for assessing the body’s water and electrolyte balance (6). Serum osmolality is crucial for maintaining transcellular water balance and ensuring the preservation of normal cell volume and morphology as a fundamental prerequisite for proper physiological function (7). Studies have demonstrated a U-shaped correlation between serum osmolality and increased mortality among critically ill ICU patients (8). Moreover, a nonlinear association between serum osmolality and mortality has also been established in populations with sepsis, myocardial infarction, and heart failure (9-11). However, the prognostic value of serum osmolality for critically ill patients with respiratory diseases remains controversial (8,12). Therefore, this study was designed to specifically evaluate the association between serum osmolality and 28-day mortality in patients with ARF. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2531/rc) (13).
Methods
Database
This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV; version 3.1). The database contains critical care records of patients admitted to the ICU at Beth Israel Deaconess Medical Center (Boston, MA, USA) between 2008 and 2022 (14). Data extraction was conducted by Y.Z., who is an authorized user of the MIMIC-IV database and has completed the required Collaborative Institutional Training Initiative (CITI) program training (ID: 65870736). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Study population
A total of 94,458 patients were initially identified from the database. For those with multiple admissions, only the first hospital and ICU admissions were included. The final analytic cohort comprised 9,748 adult patients with ARF, who met all the following criteria: a hospital stay of at least 24 hours and an ICU stay of at least 24 hours, no receipt of renal replacement therapy (RRT), and complete data for serum sodium, glucose, and BUN. ARF was identified by the presence of ICD‑9/10 codes 51851, 51881, J95821, J960, J9600, J9601, and J9602.
Data extraction
The following data were extracted to characterize the study population and their clinical status. Patient demographics included age, gender, and race. Disease severity was assessed using the Charlson comorbidity index (CCI), Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology Score III (APS III). Physiological and laboratory parameters included weight, mean blood pressure (MBP), heart rate, respiratory rate, peripheral oxygen saturation (SpO2), arterial partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2), pH, lactate, bicarbonate, white blood cell count (WBC), hemoglobin, platelet count, red blood cell distribution width (RDW), sodium, potassium, glucose, BUN, creatinine, prothrombin time (PT), and partial thromboplastin time (PTT). Documented comorbidities included hypertension, diabetes, malignant cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, myocardial infarction, liver disease, renal disease, and sepsis. The administration of invasive mechanical ventilation, vasoactive drugs, and loop diuretics was recorded. Physiological and laboratory parameters were collected from the first available records within a specified time window relative to ICU admission, encompassing data from the preceding 6 hours to the subsequent 24 hours. Serum osmolality was calculated using the following formula: serum osmolality (mmol/L) = 2 × sodium (mmol/L) + glucose (mg/dL)/18 + BUN (mg/dL)/2.8 (9). Data extraction was performed using Structured Query Language (SQL) with pgAdmin (version 4) and Navicat Premium (version 17).
Study endpoints
The primary outcome was 28-day mortality, with 365-day mortality defined as a secondary outcome.
Statistical analysis
Continuous variables with non-normal distribution are presented as median with interquartile range (IQR) and compared using the Kruskal-Wallis H test. Categorical variables are summarized as frequency with percentage and compared with the Chi-squared test. Based on their serum osmolality values, patients were categorized into five quintiles: Q1 (serum osmolality <284.75 mmol/L), Q2 (284.75 mmol/L≤ serum osmolality <290.94 mmol/L), Q3 (290.94 mmol/L≤ serum osmolality <296.41 mmol/L), Q4 (296.41 mmol/L≤ serum osmolality <303.75 mmol/L), and Q5 (serum osmolality ≥303.75 mmol/L). We employ multiple interpolation methods to address missing values.
The association between serum osmolality and 28-day mortality was evaluated using multivariable Cox proportional hazards models, with serum osmolality included as a categorical variable. Covariates were selected based on clinical relevance and prior literature. Three progressively adjusted models were built: Model 1 included demographics; Model 2 additionally adjusted for disease severity, comorbidities, and treatments; Model 3 further incorporated physiological and laboratory parameters (excluding sodium, glucose, and BUN). In all models, the second serum osmolality quintile served as the reference. The same modeling approach was applied to the secondary outcomes. Based on the final multivariable Cox model (Model 3), we plotted covariate-adjusted Kaplan-Meier curves for 28- and 365-day mortality according to serum osmolality groups and compared groups using the log-rank test.
The association of serum osmolality with 28-day mortality in patients with ARF was analyzed using multivariable-adjusted restricted cubic splines (RCS). A threshold was first identified using a recursive algorithm. Subsequently, a piecewise Cox proportional hazards model was fitted to assess the association between serum osmolality and mortality on either side of this threshold. The same analytical approach was applied to the secondary outcomes.
Subgroup analysis was conducted by stratifying participants according to age (<65, ≥65 years), gender (male, female), SOFA score (<6/≥6), renal disease (yes/no), diabetes (yes/no), chronic pulmonary disease (yes/no), congestive heart failure (yes/no), and sepsis (yes/no). Interactions between serum osmolality and these variables were evaluated through likelihood ratio tests.
A sensitivity analysis was conducted to assess the robustness of the findings. Specifically, patients were categorized into seven groups based on serum osmolality percentiles to ensure approximately equal group sizes. The association with 28-day mortality was then re-analyzed by repeating the Cox regressions across all aforementioned models.
Statistical analyses were performed using Free Statistics (version 2.1.1) and R (version 4.5.1, R Foundation for Statistical Computing, Vienna, Austria) software. A two-sided P<0.05 was considered statistically significant.
Results
Population and baseline characteristics
Data from 9,748 eligible participants were analyzed (Figure 1). The baseline characteristics of the cohort are summarized in Table 1. The median age was 68.0 years (IQR, 56.0 to 79.0 years), and the population comprised 55.0% males (5,366/9,748) and 61.0% White individuals (5,943/9,748). The overall mortality rates were 25.6% at 28 days and 41.2% at 365 days. Participants were categorized into quintiles based on a median serum osmolality of 293.6 mmol/L (IQR, 286.5 to 301.6 mmol/L). Participants in higher serum osmolality quintiles had a higher prevalence of diabetes, congestive heart failure, myocardial infarction, renal disease, and sepsis, but a lower prevalence of hypertension and malignant cancer. They also exhibited higher respiratory rates and levels of lactate, WBC, RDW, sodium, potassium, glucose, BUN, and creatinine, alongside lower values for SpO2, PaO2/FiO2, bicarbonate, hemoglobin, and platelet count. The Q5 group demonstrated higher rates of invasive ventilation use, vasoactive drugs use, and loop diuretics use. Moreover, higher serum osmolality levels were correlated with elevated SOFA, APS III, and CCI scores.
Figure 1.
Flowchart of patient selection from the MIMIC-IV database. ICU, intensive care unit; MIMIC-IV, Medical Information Mart for Intensive Care IV.
Table 1. Baseline characteristics of participants according to serum osmolality levels.
| Variables | Total (n=9,748) | Baseline serum osmolality levels | P value | ||||
|---|---|---|---|---|---|---|---|
| Q1 (n=1,949) | Q2 (n=1,946) | Q3 (n=1,952) | Q4 (n=1,949) | Q5 (n=1,952) | |||
| Baseline variables | |||||||
| Age (years) | 68.0 [56.0, 79.0] | 64.0 [52.0, 75.0] | 65.0 [54.0, 77.0] | 67.0 [56.0, 78.0] | 70.0 [59.0, 81.0] | 75.0 [63.0, 84.0] | <0.001 |
| Gender | 0.10 | ||||||
| Male | 5,366 (55.0) | 1,029 (52.8) | 1,058 (54.4) | 1,082 (55.4) | 1,085 (55.7) | 1,112 (57.0) | |
| Female | 4,382 (45.0) | 920 (47.2) | 888 (45.6) | 870 (44.6) | 864 (44.3) | 840 (43.0) | |
| Race | <0.001 | ||||||
| White | 5,943 (61.0) | 1,209 (62) | 1,197 (61.5) | 1,204 (61.7) | 1,183 (60.7) | 1,150 (58.9) | |
| Black | 868 (8.9) | 159 (8.2) | 171 (8.8) | 163 (8.4) | 164 (8.4) | 211 (10.8) | |
| Asian | 285 (2.9) | 89 (4.6) | 46 (2.4) | 42 (2.2) | 48 (2.5) | 60 (3.1) | |
| Unknown | 1,577 (16.2) | 286 (14.7) | 301 (15.5) | 308 (15.8) | 341 (17.5) | 341 (17.5) | |
| Others | 1,075 (11.0) | 206 (10.6) | 231 (11.9) | 235 (12) | 213 (10.9) | 190 (9.7) | |
| Weight (kg) | 78.7 [65.1, 95.0] | 75.6 [62.6, 90.3] | 79.6 [66.0, 95.6] | 80.0 [66.4, 96.8] | 80.0 [66.4, 97.0] | 78.3 [65.0, 94.2] | <0.001 |
| Vital signs | |||||||
| Heart rate (beats/min) | 90.0 [77.0, 106.0] | 93.0 [80.0, 109.0] | 90.0 [78.0, 105.0] | 89.0 [76.0, 103.0] | 89.0 [76.0, 107.0] | 90.0 [77.0, 105.0] | <0.001 |
| Respiratory rate (breaths/min) | 20.0 [16.0, 25.0] | 20.0 [16.0, 25.0] | 20.0 [16.0, 24.0] | 20.0 [16.0, 24.0] | 20.0 [17.0, 25.0] | 21.0 [17.0, 25.0] | <0.001 |
| MBP (mmHg) | 83.0 [71.0, 96.0] | 82.0 [71.0, 94.0] | 83.0 [72.0, 97.0] | 85.0 [73.0, 99.0] | 84.0 [72.0, 97.0] | 81.0 [70.0, 94.0] | <0.001 |
| SpO2 (%) | 98.0 [95.0, 100.0] | 98.0 [95.0, 100.0] | 98.0 [95.0, 100.0] | 98.0 [95.0, 100.0] | 98.0 [95.0, 100.0] | 97.0 [94.0, 100.0] | 0.009 |
| Laboratory parameters | |||||||
| Serum osmolality (mmol/L) | 293.6 [286.5, 301.6] | 279.7 [274.7, 282.5] | 288.0 [286.5, 289.5] | 293.6 [292.2, 295.1] | 299.6 [297.9, 301.5] | 311.1 [306.6, 319.4] | <0.001 |
| PaO2/FiO2 (mmHg) | 226.0 [140.0, 335.0] | 230.0 [141.0, 343.0] | 234.0 [138.0, 337.8] | 228.0 [146.8, 336.0] | 226.0 [138.0, 336.0] | 215.0 [138.0, 327.0] | 0.11 |
| pH | 7.4 [7.3, 7.4] | 7.4 [7.3, 7.4] | 7.4 [7.3, 7.4] | 7.4 [7.3, 7.4] | 7.4 [7.3, 7.4] | 7.3 [7.3, 7.4] | <0.001 |
| Lactate (mmol/L) | 1.6 [1.1, 2.5] | 1.6 [1.1, 2.5] | 1.5 [1.1, 2.2] | 1.6 [1.1, 2.4] | 1.7 [1.1, 2.6] | 1.8 [1.2, 3.0] | <0.001 |
| Bicarbonate (mmol/L) | 23.0 [20.0, 25.0] | 23.0 [20.0, 25.0] | 23.0 [20.0, 25.0] | 23.0 [20.0, 26.0] | 22.0 [20.0, 26.0] | 22.0 [18.0, 26.0] | <0.001 |
| WBC (K/μL) | 11.6 [8.2, 16.1] | 11.4 [7.8, 15.8] | 11.3 [8.2, 15.4] | 11.4 [8.2, 15.6] | 11.8 [8.5, 16.4] | 12.3 [8.6, 17.1] | <0.001 |
| Hemoglobin (g/dL) | 11.1 [9.4, 12.8] | 10.8 [9.2, 12.4] | 11.4 [9.8, 12.9] | 11.5 [9.9, 13.1] | 11.3 [9.5, 12.9] | 10.5 [8.9, 12.2] | <0.001 |
| Platelet (K/μL) | 199.0 [142.0, 270.0] | 199.0 [134.0, 285.0] | 199.0 [145.0, 265.0] | 200.0 [147.0, 265.0] | 202.0 [145.0, 268.0] | 194.0 [135.0, 267.0] | 0.11 |
| RDW (%) | 14.5 [13.5, 16.1] | 14.5 [13.4, 16.3] | 14.3 [13.3, 15.8] | 14.3 [13.4, 15.7] | 14.5 [13.5, 15.9] | 15.1 [14.0, 16.8] | <0.001 |
| Sodium (mmol/L) | 139.0 [135.0, 141.0] | 133.0 [130.0, 135.0] | 137.0 [136.0, 138.0] | 139.0 [138.0, 141.0] | 141.0 [139.0, 143.0] | 143.0 [140.0, 146.0] | <0.001 |
| Potassium (mmol/L) | 4.1 [3.7, 4.5] | 4.0 [3.7, 4.5] | 4.0 [3.7, 4.5] | 4.1 [3.7, 4.5] | 4.1 [3.7, 4.5] | 4.2 [3.7, 4.7] | <0.001 |
| Glucose (mg/dL) | 133.0 [108.0, 175.0] | 120.0 [100.0, 148.0] | 125.0 [103.0, 154.0] | 133.0 [109.0, 170.0] | 143.0 [114.0, 190.0] | 160.0 [121.0, 228.0] | <0.001 |
| BUN (mg/dL) | 20.0 [14.0, 32.0] | 14.0 [10.0, 21.0] | 16.0 [12.0, 23.0] | 19.0 [14.0, 26.0] | 23.0 [17.0, 34.0] | 42.0 [27.0, 63.0] | <0.001 |
| Creatinine (mg/dL) | 1.0 [0.7, 1.4] | 0.8 [0.6, 1.1] | 0.9 [0.7, 1.2] | 0.9 [0.7, 1.3] | 1.1 [0.8, 1.5] | 1.5 [1.0, 2.3] | <0.001 |
| PT (s) | 14.1 [12.5, 16.9] | 14.3 [12.6, 17.4] | 14.0 [12.5, 16.4] | 13.8 [12.3, 16.2] | 13.8 [12.4, 16.5] | 14.7 [12.7, 18.2] | <0.001 |
| PTT (s) | 30.6 [27.0, 37.1] | 31.2 [27.4, 38.0] | 30.3 [27.0, 36.0] | 30.2 [26.7, 36.2] | 30.2 [26.7, 36.9] | 31.1 [27.3, 38.2] | <0.001 |
| Score system | |||||||
| SOFA | 6.0 [4.0, 9.0] | 6.0 [4.0, 9.0] | 6.0 [4.0, 8.0] | 6.0 [4.0, 9.0] | 6.0 [4.0, 9.0] | 8.0 [5.0, 10.0] | <0.001 |
| APS III | 46.0 [34.0, 60.0] | 44.0 [32.0, 58.0] | 41.0 [31.0, 54.0] | 42.0 [31.0, 56.0] | 47.0 [35.0, 61.0] | 55.0 [44.0, 71.2] | <0.001 |
| CCI | 5.0 [3.0, 7.0] | 5.0 [3.0, 7.0] | 5.0 [3.0, 7.0] | 5.0 [3.0, 7.0] | 5.0 [3.0, 8.0] | 7.0 [5.0, 8.0] | <0.001 |
| Comorbidities | |||||||
| Hypertension | 3,888 (39.9) | 809 (41.5) | 821 (42.2) | 835 (42.8) | 781 (40.1) | 642 (32.9) | <0.001 |
| Diabetes | 2,845 (29.2) | 372 (19.1) | 426 (21.9) | 512 (26.2) | 668 (34.3) | 867 (44.4) | <0.001 |
| Malignant cancer | 1,609 (16.5) | 458 (23.5) | 308 (15.8) | 308 (15.8) | 253 (13.0) | 282 (14.4) | <0.001 |
| Cerebrovascular disease | 1,767 (18.1) | 279 (14.3) | 352 (18.1) | 372 (19.1) | 391 (20.1) | 373 (19.1) | <0.001 |
| Chronic pulmonary disease | 3,011 (30.9) | 562 (28.8) | 616 (31.7) | 608 (31.1) | 618 (31.7) | 607 (31.1) | 0.27 |
| Congestive heart failure | 3,271 (33.6) | 501 (25.7) | 547 (28.1) | 604 (30.9) | 751 (38.5) | 868 (44.5) | <0.001 |
| Myocardial infarct | 1,709 (17.5) | 249 (12.8) | 289 (14.9) | 336 (17.2) | 383 (19.7) | 452 (23.2) | <0.001 |
| Liver disease | 1,387 (14.2) | 388 (19.9) | 255 (13.1) | 226 (11.6) | 229 (11.7) | 289 (14.8) | <0.001 |
| Renal disease | 1,860 (19.1) | 189 (9.7) | 227 (11.7) | 287 (14.7) | 450 (23.1) | 707 (36.2) | <0.001 |
| Sepsis | 6,910 (70.9) | 1,340 (68.8) | 1,301 (66.9) | 1,331 (68.2) | 1,375 (70.5) | 1,563 (80.1) | <0.001 |
| Interventions | |||||||
| Invasive vent | 6,906 (70.8) | 1,362 (69.9) | 1,332 (68.4) | 1,400 (71.7) | 1,386 (71.1) | 1,426 (73.1) | 0.02 |
| Vasoactive drugs | 4,115 (42.2) | 814 (41.8) | 789 (40.5) | 807 (41.3) | 805 (41.3) | 900 (46.1) | 0.003 |
| Loop diuretics | 2,793 (28.7) | 492 (25.2) | 531 (27.3) | 544 (27.9) | 600 (30.8) | 626 (32.1) | <0.001 |
| Outcomes | |||||||
| Status28 | 2,497 (25.6) | 486 (24.9) | 361 (18.6) | 406 (20.8) | 504 (25.9) | 740 (37.9) | <0.001 |
| Status365 | 4,020 (41.2) | 803 (41.2) | 629 (32.3) | 671 (34.4) | 817 (41.9) | 1,100 (56.4) | <0.001 |
| In hospital mortality | 2,230 (22.9) | 467 (24.0) | 329 (16.9) | 359 (18.4) | 443 (22.7) | 632 (32.4) | <0.001 |
| In ICU mortality | 1,403 (14.4) | 266 (13.6) | 200 (10.3) | 234 (12.0) | 299 (15.3) | 404 (20.7) | <0.001 |
| Hospital length of stay (days) | 11.6 [6.7, 19.9] | 12.9 [7.5, 22.1] | 11.3 [6.8, 20.0] | 11.3 [6.6, 19.7] | 10.9 [6.4, 18.5] | 11.2 [6.2, 18.8] | <0.001 |
| ICU length of stay (days) | 4.2 [2.2, 8.6] | 4.5 [2.2, 9.0] | 4.0 [2.2, 8.2] | 4.3 [2.2, 9.2] | 4.2 [2.2, 8.4] | 4.2 [2.3, 8.2] | 0.38 |
Data are presented as median [interquartile range] or n (%). Q1: <284.75 mmol/L. Q2: 284.75–290.93 mmol/L. Q3: 290.94–296.40 mmol/L. Q4: 296.41–303.74 mmol/L. Q5: ≥303.75 mmol/L. Status28: number (%) of patients who died within 28 days. Status365: number (%) of patients who died within 365 days. APS III, Acute Physiology Score III; BUN, blood urea nitrogen; CCI, Charlson comorbidity index; FiO2, fraction of inspired oxygen; ICU, intensive care unit; MBP, mean blood pressure; PaO2, arterial partial pressure of oxygen; PT, prothrombin time; PTT, partial thromboplastin time; RDW, red blood cell distribution width; SOFA, Sequential Organ Failure Assessment; SpO2, saturation of peripheral oxygen; WBC, white blood cell count.
Association between serum osmolality and mortality
Table 2 shows the association between serum osmolality and 28-day mortality based on Cox regression models. In the crude model, the risk of mortality was higher in Q1 [hazard ratio (HR) =1.38; 95% confidence interval (CI): 1.21–1.59] and Q5 (HR =2.34; 95% CI: 2.06–2.66) compared with Q2. After full adjustment, using Q2 as the reference, the risk remained significantly elevated in Q1 (HR =1.17; 95% CI: 1.02–1.35) and Q5 (HR =1.30; 95% CI: 1.14–1.49). The risk distribution followed a significant trend, with higher risks at both extremes compared to the reference, suggesting a potential nonlinear relationship. A similar pattern was observed for 365-day mortality.
Table 2. Association of serum osmolality with 28- and 365-day mortality in ARF patients.
| Variables | Crude model | Model 1 | Model 2 | Model 3 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | ||||
| 28-day mortality | |||||||||||
| Q1 | 1.38 (1.21–1.59) | <0.001 | 1.44 (1.26–1.65) | <0.001 | 1.22 (1.06–1.40) | 0.005 | 1.17 (1.02–1.35) | 0.02 | |||
| Q2 | Reference | Reference | Reference | Reference | |||||||
| Q3 | 1.14 (0.99–1.31) | 0.07 | 1.09 (0.94–1.25) | 0.24 | 1.06 (0.92–1.22) | 0.41 | 1.04 (0.90–1.20) | 0.61 | |||
| Q4 | 1.46 (1.28–1.67) | <0.001 | 1.30 (1.14–1.49) | <0.001 | 1.22 (1.06–1.40) | 0.005 | 1.18 (1.03–1.36) | 0.01 | |||
| Q5 | 2.34 (2.06–2.66) | <0.001 | 1.90 (1.68–2.16) | <0.001 | 1.43 (1.25–1.63) | <0.001 | 1.30 (1.14–1.49) | <0.001 | |||
| P for trend | <0.001 | <0.001 | <0.001 | 0.01 | |||||||
| 365-day mortality | |||||||||||
| Q1 | 1.35 (1.22–1.50) | <0.001 | 1.41 (1.27–1.57) | <0.001 | 1.22 (1.09–1.35) | <0.001 | 1.16 (1.04–1.29) | 0.007 | |||
| Q2 | Reference | Reference | Reference | Reference | |||||||
| Q3 | 1.08 (0.97–1.21) | 0.15 | 1.03 (0.92–1.15) | 0.60 | 1.00 (0.90–1.12) | 0.97 | 0.99 (0.89–1.10) | 0.82 | |||
| Q4 | 1.39 (1.26–1.55) | <0.001 | 1.24 (1.12–1.38) | <0.001 | 1.17 (1.05–1.30) | 0.003 | 1.14 (1.03–1.27) | 0.01 | |||
| Q5 | 2.16 (1.96–2.38) | <0.001 | 1.76 (1.59–1.94) | <0.001 | 1.37 (1.24–1.52) | <0.001 | 1.25 (1.12–1.39) | <0.001 | |||
| P for trend | <0.001 | <0.001 | <0.001 | 0.01 | |||||||
Crude model (no adjustment). Model 1 adjusted for age, gender, race. Model 2 adjusted for SOFA, APS III, CCI, hypertension, diabetes, malignant cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, myocardial infarct, liver disease, renal disease, sepsis, invasive vent, vasoactive drugs, loop diuretics, based on Model 1. Model 3 adjusted for weight, heart rate, respiratory rate, MBP, SpO2, PaO2/FiO2, pH, lactate, bicarbonate, WBC, hemoglobin, platelet, RDW, potassium, creatinine, PT, PTT, based on Model 2. Q1: <284.75 mmol/L. Q2: 284.75–290.93 mmol/L. Q3: 290.94–296.40 mmol/L. Q4: 296.41–303.74 mmol/L. Q5: ≥303.75 mmol/L. APS III, Acute Physiology Score III; ARF, acute respiratory failure; CCI, Charlson comorbidity index; CI, confidence interval; FiO2, fraction of inspired oxygen; HR, hazard ratio; MBP, mean blood pressure; PaO2, arterial partial pressure of oxygen; PT, prothrombin time; PTT, partial thromboplastin time; RDW, red blood cell distribution width; SOFA, Sequential Organ Failure Assessment; SpO2, saturation of peripheral oxygen; WBC, white blood cell count.
Since the mortality risks associated with Q2 and Q3 of serum osmolality were similarly low, these two quintiles were combined to form a new, robust reference group (new Q2). The remaining groups were subsequently renamed accordingly, with the original Q4 and Q5 designated as the new Q3 and Q4, respectively. As shown in Table 3, we repeated the Cox regression analysis with the previously described model. After full adjustment for covariates, the risks of mortality were significantly elevated in both the new Q1 (HR =1.15; 95% CI: 1.02–1.29) and the new Q4 (HR =1.28; 95% CI: 1.14–1.43) compared to the new reference group. The covariate-adjusted Kaplan-Meier curves for 28-day survival demonstrated a significant difference among the serum osmolality groups (log-rank P≤0.001). Patients in the new reference group (new Q2) had the highest survival probability, while those in both the lower (new Q1) and higher (new Q3, new Q4) serum osmolality groups showed lower probabilities (Figure 2). These findings confirm that both lower and higher levels of serum osmolality are associated with an increased risk of mortality. Similar associations were observed for the secondary outcome.
Table 3. Association of serum osmolality with 28- and 365-day mortality in ARF patients [reference group: combined Q2 (original Q2 + Q3)].
| Variables | Crude model | Model 1 | Model 2 | Model 3 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | ||||
| 28-day mortality | |||||||||||
| Q1 | 1.29 (1.16–1.45) | <0.001 | 1.38 (1.23–1.55) | <0.001 | 1.18 (1.05–1.33) | 0.004 | 1.15 (1.02–1.29) | 0.01 | |||
| Q2 (original Q2 + Q3) | Reference | Reference | Reference | Reference | |||||||
| Q3 | 1.37 (1.22–1.53) | <0.001 | 1.25 (1.12–1.40) | <0.001 | 1.18 (1.05–1.32) | 0.004 | 1.16 (1.03–1.30) | 0.01 | |||
| Q4 | 2.19 (1.98–2.42) | <0.001 | 1.82 (1.65–2.02) | <0.001 | 1.39 (1.25–1.54) | <0.001 | 1.28 (1.14–1.43) | <0.001 | |||
| P for trend | <0.001 | <0.001 | <0.001 | 0.006 | |||||||
| 365-day mortality | |||||||||||
| Q1 | 1.30 (1.19–1.42) | <0.001 | 1.39 (1.28–1.52) | <0.001 | 1.22 (1.11–1.33) | <0.001 | 1.16 (1.06–1.27) | 0.001 | |||
| Q2 (original Q2 + Q3) | Reference | Reference | Reference | Reference | |||||||
| Q3 | 1.34 (1.23–1.46) | <0.001 | 1.22 (1.12–1.34) | <0.001 | 1.17 (1.07–1.28) | 0.001 | 1.15 (1.05–1.26) | 0.002 | |||
| Q4 | 2.08 (1.92–2.25) | <0.001 | 1.73 (1.60–1.88) | <0.001 | 1.37 (1.26–1.50) | <0.001 | 1.26 (1.15–1.37) | <0.001 | |||
| P for trend | <0.001 | <0.001 | <0.001 | 0.005 | |||||||
Crude model (no adjustment). Model 1 adjusted for age, gender, race. Model 2 adjusted for SOFA, APS III, CCI, hypertension, diabetes, malignant cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, myocardial infarct, liver disease, renal disease, sepsis, invasive vent, vasoactive drugs, loop diuretics, based on Model 1. Model 3 adjusted for weight, heart rate, respiratory rate, MBP, SpO2, PaO2/FiO2, pH, lactate, bicarbonate, WBC, hemoglobin, platelet, RDW, potassium, creatinine, PT, PTT, based on Model 2. Q1: <284.75 mmol/L. Q2: 284.75–296.40 mmol/L. Q3: 296.41–303.74 mmol/L. Q4: ≥303.75 mmol/L. APS III, Acute Physiology Score III; ARF, acute respiratory failure; CCI, Charlson comorbidity index; CI, confidence interval; FiO2, fraction of inspired oxygen; HR, hazard ratio; MBP, mean blood pressure; PaO2, arterial partial pressure of oxygen; PT, prothrombin time; PTT, partial thromboplastin time; RDW, red blood cell distribution width; SOFA, Sequential Organ Failure Assessment; SpO2, saturation of peripheral oxygen; WBC, white blood cell count.
Figure 2.
Adjusted Kaplan-Meier curves for (A) 28-day mortality and (B) 365-day mortality according to serum osmolality groups. New Q1 (<284.75 mmol/L), new Q2 (284.75–296.40 mmol/L), new Q3 (296.41–303.74 mmol/L), new Q4 (≥303.75 mmol/L). Fully adjusted model: adjusted for age, gender, race, SOFA, APS III, CCI, hypertension, diabetes, malignant cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, myocardial infarct, liver disease, renal disease, sepsis, invasive vent, vasoactive drugs, loop diuretics, weight, heart rate, respiratory rate, MBP, SpO2, PaO2/FiO2, pH, lactate, bicarbonate, WBC, hemoglobin, platelet, RDW, potassium, creatinine, PT, PTT. APS III, Acute Physiology Score III; CCI, Charlson comorbidity index; FiO2, fraction of inspired oxygen; MBP, mean blood pressure; PaO2, arterial partial pressure of oxygen; PT, prothrombin time; PTT, partial thromboplastin time; RDW, red blood cell distribution width; SOFA, Sequential Organ Failure Assessment; SpO2, saturation of peripheral oxygen; WBC, white blood cell count.
Nonlinear association between serum osmolality and mortality
A significant non-linear relationship between serum osmolality and 28-day mortality was revealed by the fully adjusted RCS model (non-linearity P=0.001, Figure 3). Using a two-piecewise Cox model, we identified a significant threshold of 287.79 mmol/L for serum osmolality in predicting 28-day mortality (Table 4). On the left side of the threshold, higher serum osmolality levels were inversely associated with mortality risk (HR =0.99; 95% CI: 0.98–0.99; P<0.001). Conversely, on the right side, each unit increase in osmolality significantly increased the risk (HR =1.01; 95% CI: 1.01–1.01; P<0.001). This U-shaped association was also evident for 365-day mortality.
Figure 3.
The nonlinear relationship of serum osmolality with (A) 28-day and (B) 365-day mortality. The reference point was set at the median (293.6 mmol/L). Fully adjusted model: adjusted for age, gender, race, SOFA, APS III, CCI, hypertension, diabetes, malignant cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, myocardial infarct, liver disease, renal disease, sepsis, invasive vent, vasoactive drugs, loop diuretics, weight, heart rate, respiratory rate, MBP, SpO2, PaO2/FiO2, pH, lactate, bicarbonate, WBC, hemoglobin, platelet, RDW, potassium, creatinine, PT, PTT. APS III, Acute Physiology Score III; CCI, Charlson comorbidity index; FiO2, fraction of inspired oxygen; MBP, mean blood pressure; PaO2, arterial partial pressure of oxygen; PT, prothrombin time; PTT, partial thromboplastin time; RDW, red blood cell distribution width; SOFA, Sequential Organ Failure Assessment; SpO2, saturation of peripheral oxygen; WBC, white blood cell count.
Table 4. Threshold effect of serum osmolality on 28- and 365-day mortality.
| Threshold and serum osmolality range | HR (95% CI) | P value |
|---|---|---|
| 28-day mortality | ||
| Inflection point (mmol/L) | 287.79 | |
| Serum osmolality <287.79 mmol/L | 0.99 (0.98, 0.99) | <0.001 |
| Serum osmolality ≥287.79 mmol/L | 1.01 (1.01, 1.01) | <0.001 |
| P for log likelihood ratio test | <0.001 | |
| 365-day mortality | ||
| Inflection point (mmol/L) | 288.36 | |
| Serum osmolality <288.36 mmol/L | 0.99 (0.98, 0.99) | <0.001 |
| Serum osmolality ≥288.36 mmol/L | 1.01 (1.01, 1.01) | <0.001 |
| P for log likelihood ratio test | <0.001 |
Fully adjusted model: adjusted for age, gender, race, SOFA, APS III, CCI, hypertension, diabetes, malignant cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, myocardial infarct, liver disease, renal disease, sepsis, invasive vent, vasoactive drugs, loop diuretics, weight, heart rate, respiratory rate, MBP, SpO2, PaO2/FiO2, pH, lactate, bicarbonate, WBC, hemoglobin, platelet, RDW, potassium, creatinine, PT, PTT. APS III, Acute Physiology Score III; CCI, Charlson comorbidity index; CI, confidence interval; FiO2, fraction of inspired oxygen; HR, hazard ratio; MBP, mean blood pressure; PaO2, arterial partial pressure of oxygen; PT, prothrombin time; PTT, partial thromboplastin time; RDW, red blood cell distribution width; SOFA, Sequential Organ Failure Assessment; SpO2, saturation of peripheral oxygen; WBC, white blood cell count.
Subgroup analysis
Table 5 presents the results of subgroup analyses. Higher and lower serum osmolality was consistently associated with an increased risk of 28-day mortality across all subgroups, including those based on age, gender, SOFA score, renal disease, diabetes, chronic pulmonary disease, congestive heart failure, and sepsis. No significant interaction was observed between serum osmolality and any of these variables (all P for interaction >0.05). Similar results were observed for the secondary outcomes.
Table 5. Subgroup analyses of the association between serum osmolality and 28- and 365-day mortality.
| Variables | Q1, HR (95% CI) | Q2, HR (95% CI) | Q3, HR (95% CI) | Q4, HR (95% CI) | P for interaction |
|---|---|---|---|---|---|
| 28-day mortality | |||||
| Age | 0.42 | ||||
| <65 years | 1.05 (0.85–1.28) | Reference | 1.10 (0.87–1.38) | 1.48 (1.17–1.86) | |
| ≥65 years | 1.14 (0.99–1.32) | Reference | 1.17 (1.03–1.34) | 1.27 (1.12–1.44) | |
| Gender | 0.81 | ||||
| Male | 1.02 (0.86–1.20) | Reference | 1.11 (0.95–1.29) | 1.27 (1.09–1.47) | |
| Female | 1.27 (1.07–1.50) | Reference | 1.23 (1.04–1.46) | 1.27 (1.07–1.50) | |
| SOFA score | 0.11 | ||||
| <6 | 1.07 (0.86–1.33) | Reference | 0.94 (0.75–1.17) | 1.45 (1.16–1.82) | |
| ≥6 | 1.21 (1.05–1.39) | Reference | 1.23 (1.08–1.41) | 1.28 (1.12–1.45) | |
| Renal disease | 0.74 | ||||
| Yes | 0.86 (0.60–1.23) | Reference | 1.09 (0.85–1.40) | 1.24 (0.99–1.55) | |
| No | 1.19 (1.05–1.35) | Reference | 1.17 (1.03–1.33) | 1.25 (1.10–1.43) | |
| Diabetes | 0.70 | ||||
| Yes | 1.11 (0.86–1.45) | Reference | 1.22 (0.99–1.51) | 1.27 (1.04–1.56) | |
| No | 1.16 (1.01–1.32) | Reference | 1.13 (0.99–1.30) | 1.27 (1.11–1.45) | |
| Chronic pulmonary disease | 0.96 | ||||
| Yes | 1.09 (0.88–1.36) | Reference | 1.13 (0.92–1.39) | 1.23 (1.00–1.51) | |
| No | 1.19 (1.03–1.36) | Reference | 1.17 (1.02–1.34) | 1.32 (1.16–1.51) | |
| Congestive heart failure | 0.80 | ||||
| Yes | 1.02 (0.81–1.29) | Reference | 0.94 (0.77–1.15) | 1.19 (0.99–1.44) | |
| No | 1.21 (1.06–1.39) | Reference | 1.28 (1.11–1.47) | 1.30 (1.13–1.50) | |
| Sepsis | 0.07 | ||||
| Yes | 1.20 (1.05–1.37) | Reference | 1.18 (1.03–1.34) | 1.26 (1.11–1.42) | |
| No | 1.03 (0.81–1.32) | Reference | 1.09 (0.86–1.39) | 1.52 (1.19–1.94) | |
| 365-day mortality | |||||
| Age | 0.99 | ||||
| <65 years | 1.04 (0.89–1.21) | Reference | 1.10 (0.92–1.31) | 1.40 (1.17–1.69) | |
| ≥65 years | 1.17 (1.05–1.31) | Reference | 1.17 (1.06–1.30) | 1.26 (1.14–1.40) | |
| Gender | 0.46 | ||||
| Male | 1.08 (0.95–1.23) | Reference | 1.15 (1.01–1.29) | 1.28 (1.13–1.44) | |
| Female | 1.23 (1.08–1.40) | Reference | 1.17 (1.02–1.33) | 1.23 (1.08–1.40) | |
| SOFA score | 0.47 | ||||
| <6 | 1.11 (0.95–1.30) | Reference | 1.04 (0.89–1.22) | 1.29 (1.09–1.53) | |
| ≥6 | 1.20 (1.07–1.34) | Reference | 1.19 (1.07–1.33) | 1.26 (1.14–1.40) | |
| Renal disease | 0.83 | ||||
| Yes | 1.06 (0.82–1.36) | Reference | 1.11 (0.92–1.34) | 1.22 (1.03–1.45) | |
| No | 1.17 (1.07–1.29) | Reference | 1.15 (1.04–1.28) | 1.25 (1.13–1.39) | |
| Diabetes | 0.31 | ||||
| Yes | 1.12 (0.91–1.36) | Reference | 1.13 (0.96–1.32) | 1.20 (1.03–1.40) | |
| No | 1.18 (1.07–1.31) | Reference | 1.15 (1.03–1.28) | 1.27 (1.14–1.41) | |
| Chronic pulmonary disease | 0.32 | ||||
| Yes | 1.12 (0.95–1.32) | Reference | 1.11 (0.95–1.29) | 1.13 (0.96–1.32) | |
| No | 1.19 (1.07–1.32) | Reference | 1.16 (1.04–1.30) | 1.32 (1.19–1.47) | |
| Congestive heart failure | 0.61 | ||||
| Yes | 1.19 (1.00–1.41) | Reference | 1.11 (0.96–1.29) | 1.27 (1.10–1.47) | |
| No | 1.15 (1.04–1.28) | Reference | 1.16 (1.04–1.3) | 1.25 (1.11–1.40) | |
| Sepsis | 0.31 | ||||
| Yes | 1.19 (1.07–1.33) | Reference | 1.16 (1.04–1.28) | 1.26 (1.14–1.39) | |
| No | 1.14 (0.95–1.36) | Reference | 1.13 (0.95–1.35) | 1.34 (1.10–1.62) |
Fully adjusted model: adjusted for age, gender, race, SOFA, APS III, CCI, hypertension, diabetes, malignant cancer, cerebrovascular disease, chronic pulmonary disease, congestive heart failure, myocardial infarct, liver disease, renal disease, sepsis, invasive vent, vasoactive drugs, loop diuretics, weight, heart rate, respiratory rate, MBP, SpO2, PaO2/FiO2, pH, lactate, bicarbonate, WBC, hemoglobin, platelet, RDW, potassium, creatinine, PT, PTT. Q1: <284.75 mmol/L. Q2: 284.75–296.40 mmol/L. Q3: 296.41–303.74 mmol/L. Q4: ≥303.75 mmol/L. APS III, Acute Physiology Score III; CCI, Charlson comorbidity index; CI, confidence interval; FiO2, fraction of inspired oxygen; HR, hazard ratio; MBP, mean blood pressure; PaO2, arterial partial pressure of oxygen; PT, prothrombin time; PTT, partial thromboplastin time; RDW, red blood cell distribution width; SOFA, Sequential Organ Failure Assessment; SpO2, saturation of peripheral oxygen; WBC, white blood cell count.
Sensitivity analysis
To evaluate the robustness of our findings, we conducted a sensitivity analysis by re-categorizing eligible patients into seven groups based on percentiles of serum osmolality. After full adjustment for covariates and using Q3 as the reference, the risk of 28-day mortality was significantly elevated at both extremes: in Q1 (HR =1.29; 95% CI: 1.09–1.51) and Q7 (HR =1.38; 95% CI: 1.18–1.62). The mortality risk exhibited a U-shaped relationship, declining from Q1 to Q3 and then increasing from Q4 to Q7. This analysis confirmed the robustness of this U-shaped association, which was consistently observed for 365-day mortality (Table S1).
Discussion
This study revealed a U-shaped relationship between serum osmolality and 28-day mortality risk in patients with ARF. Specifically, mortality risk was inversely associated with serum osmolality below the threshold of 287.79 mmol/L and positively associated above it. The lowest mortality risk was observed within the range of 284.75 to 296.41 mmol/L. These findings indicate that both lower and higher serum osmolality levels are independent risk factors for mortality, suggesting that serum osmolality assessment could improve risk stratification for ARF patients.
Accumulating evidence suggests that serum osmolality has prognostic value, as recently demonstrated by He et al. in heart failure patients with normal serum sodium (15). In ARF, however, previous findings were inconsistent, with Çelik et al. reporting no association between serum osmolality and outcomes (12). The U-shaped relationship observed in our study may explain this discrepancy, as RCS enabled us to characterize this nonlinear pattern. Our results also align with studies reporting nonlinear associations in sepsis, myocardial infarction, and heart failure (9-11). The mechanisms underlying this association warrant further investigation.
In patients with ARF, elevations in sodium, glucose, or BUN are common, often resulting from fluid imbalance, stress-induced metabolic changes, and renal dysfunction (16-18). These alterations, whether occurring singly or in combination, may contribute to increased serum osmolality. Hyperosmolality may contribute to multi-organ dysfunction through disruption of pulmonary fluid equilibrium, small airway dysfunction, neurological injury, cardiac autonomic dysregulation, and renal tubular injury (19-22). These effects may collectively explain the increased mortality associated with elevated serum osmolality in our ARF cohort, corresponding to the right arm of the U-shaped curve. Conversely, a proportion of patients with ARF present with low serum osmolality, likely due to abnormal antidiuretic hormone secretion or inappropriate fluid therapy (23,24). This low osmolality state may lead to worse outcomes by exacerbating pulmonary edema and promoting arrhythmias, consistent with the left arm of the U-shaped curve in our ARF cohort (25,26). Given the physiological importance of fluid balance, both high serum osmolality and low serum osmolality may contribute to adverse outcomes (27). Our findings highlight an intermediate osmolality range associated with lower mortality, suggesting a potential clinical target.
Strengths and limitations
This study has several strengths. To our knowledge, it is the first to investigate the association between serum osmolality and mortality in patients with ARF. Second, we identified robust associations that were consistent for both short- and long-term mortality and stable across multiple sensitivity and subgroup analyses. Third, the clinical indicators used for calculating serum osmolality are routinely available, enhancing the potential clinical applicability of our findings.
Several limitations must also be acknowledged. Despite extensive adjustment for covariates, residual confounding from unmeasured factors remains possible. Furthermore, the retrospective design precludes causal inference, necessitating validation in future interventional studies. Additionally, due to the structure of the MIMIC-IV database, ARF subtype classification was not performed in this study. Our findings therefore reflect ARF as a whole, and future studies should explore potential differences across subtypes. The precise underlying cause of ARF for each patient was also not available in the database. However, subgroup analyses for comorbidities commonly observed in patients with ARF yielded consistent results, supporting the robustness of our findings. Moreover, because patients receiving RRT were excluded from this study, our findings may not be generalizable to those with severe renal failure requiring dialysis. Finally, as a single-center study, the generalizability of our findings requires verification in multicenter, prospective cohorts. Despite these limitations, the identified U-shaped association supports the potential value of integrating serum osmolality into prognostic assessment and clinical management for ARF patients.
Conclusions
In patients with ARF, serum osmolality demonstrates a U-shaped relationship with mortality, supporting its potential as a prognostic biomarker. Both higher and lower levels are associated with increased mortality risk, with the lowest risk observed within the range of 284.75 to 296.41 mmol/L. The assessment of serum osmolality could therefore facilitate early risk stratification, potentially guiding timely interventions to improve outcomes.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2531/rc
Funding: This work was supported by the Department of Education of Jilin Province (No. JGJX2023D25) and the Jilin University (No. 24AI098Z).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2531/coif). The authors have no conflicts of interest to declare.
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