Abstract
Background
Fluid therapy is commonly used for patients with severe stroke, for whom fluid balance is a safety endpoint for evaluating the therapy. We aimed to investigate the association of fluid balance with 3-month outcomes in patients with severe ischaemic stroke.
Methods
We enrolled patients with severe ischaemic stroke (National Institutes of Health Stroke Scale score ≥15) admitted to the department of neurology within 24 hours after the onset of stroke symptoms. Daily fluid balance volume in millilitres was defined as 24-hour fluid input minus fluid output. We calculated the mean value of daily fluid balance for the first 3 days after admission, and categorised patients as having positive fluid balance (daily fluid balance>+500 mL), even fluid balance (between −500 and +500 mL) and negative fluid balance (<−500 mL). The primary outcome was all-cause death at 3 months. We conducted multivariable logistic regression to investigate the association of fluid balance with 3-month death, with even fluid balance as the reference group.
Results
Of the 354 patients (mean age 73.1±12.9 years, 48.6% males) with severe ischaemic stroke, 94 patients (26.6%) had positive fluid balance, 194 patients (54.8%) had even fluid balance and 66 patients (18.6%) had negative fluid balance. Patients with positive fluid balance had a higher risk of 3-month death (adjusted OR 2.18, 95% CI 1.24 to 3.85, p=0.007), while patients with negative fluid balance did not show a significant difference (adjusted OR 1.68, 95% CI 0.88 to 3.20, p=0.115). The restricted cubic spline analysis illustrated a U-shaped trend of dose response relationship for mean daily fluid balance in relation to the adjusted OR of 3-month death (p for non-linearity=0.02).
Conclusion
In patients with severe ischaemic stroke, the positive fluid balance in the first 3 days was associated with a higher risk of death at 3 months.
Keywords: Stroke, Malignant, Mortality
WHAT IS ALREADY KNOWN ON THIS TOPIC
Fluid balance is a fundamental strategy of neurocritical care for patients with brain injury, by maintaining circulation and cerebral perfusion as well as modulating brain oedema. However, there is insufficient evidence to guide fluid management for patients with ischaemic stroke.
WHAT THIS STUDY ADDS
Compared with even fluid balance, positive fluid balance in the first 3 days was associated with a higher risk of death at 3 months in patients with severe ischaemic stroke.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Future studies are expected to investigate whether interventions to avoid positive fluid balance could improve outcomes after severe ischaemic stroke, and to explore optimal fluid management strategies for these patients.
Introduction
Stroke is a leading cause of death and disability in the world.1 Severe stroke is often assessed clinically by the severity of neurological deficits or radiologically by the extent of brain infarction.2 Patients with severe stroke are more prone to clinical deterioration and subsequently have a higher risk of death and disability.3 Clinical worsening after stroke primarily occurred in the first 3 days after the onset of stroke.4 Intensive monitoring and management during the acute phase is crucial for patients with severe ischaemic stroke.5 6
To maintain adequate systemic blood flow and cerebral perfusion, fluid therapy is part of routine care for patients with critical brain injuries, including severe ischaemic stroke.7 Cardiac dysfunction and renal dysfunction are common complications of severe stroke, which require restrictive fluid intake and even dehydration therapy.8 Thus, fluid balance is an important safety endpoint for neurocritical care of severe patients.9 On the one hand, positive fluid balance is associated with poor prognosis in patients with intracerebral haemorrhage, subarachnoid haemorrhage or those with traumatic brain injury.10,12 On the other hand, negative fluid balance should be avoided after brain injury to maintain adequate cerebral perfusion pressure.13 In addition, plasma osmolality is associated with long-term prognosis in patients with severe ischaemic stroke.14 However, little evidence is available to guide fluid management for patients with severe ischaemic stroke.15
Therefore, this study aimed to explore the association between fluid balance in the first 3 days after stroke and 3-month outcomes in patients with severe ischaemic stroke.
Methods
Study design and participants
Patients with ischaemic stroke, who had been admitted to the Neurology Department, West China Hospital from January 2017 to December 2022, were screened for eligibility. The diagnosis of ischaemic stroke was based on clinical symptoms and signs and confirmed by brain imaging. Inclusion criteria were: (a) age ≥18 years; (b) admitted <24 hours after stroke onset; (c) patients presenting with severe ischaemic stroke, defined as a National Institutes of Health Stroke Scale (NIHSS) score ≥15 on admission;16 and (d) had fluid balance chart recorded for the first 3 days of hospitalisation. We excluded patients who had been discharged within 3 days after admission or patients who had been lost to follow-up at 3 months. This study was part of a cohort study for severe ischaemic stroke (ClinicalTrials.gov NCT03222024).
We collected demographic information (age and sex) and vascular risk factors (smoking, alcohol consumption, hypertension, diabetes and hyperlipidaemia) from the medical record. Stroke severity on admission was evaluated by the treating neurologist according to the NIHSS score. Large middle cerebral artery (MCA) infarction was defined as an infarction involving at least 50% of the MCA territory on brain CT or MRI. The aetiological subtypes of stroke were assessed according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification.17 We recorded reperfusion therapy (ie, intravenous thrombolysis and/or endovascular thrombectomy) as well as decompressive hemicraniectomy. We collected the use of osmotic agents (mannitol or glycerol fructose), loop diuretics (furosemide) and vasopressors (dopamine, norepinephrine or metaraminol) during the first 3 days after admission. We recorded in-hospital complications including pneumonia (defined as the presence of auscultatory respiratory crackles, with fever ≥38°C, purulent sputum or positive signs on chest radiograph),18 gastrointestinal bleeding (defined as the presence of haematemesis, melena or gastric drainage of dark red fluid with positive occult blood test),19 renal dysfunction (defined as pre-existing chronic kidney disease with estimated glomerular filtration rate <60 mL/min/1.73 m2,20 or newly onset acute kidney injury based on the change of serum creatinine21 during the first 3 days after admission) and cardiac dysfunction (defined as pre-existing chronic heart failure or acute heart failure attack during the first 3 days after admission, diagnosed based on symptoms and signs of heart failure, with reduced left ventricular ejection fraction of less than 40% on echocardiogram).22
Data collection
Assessment and classification of fluid balance
We recorded fluid input and output for each patient in a 24-hour interval (from 07:00 to 07:00 on the next morning). The fluid balance for each patient was recorded on a paper-based chart at the bedside, and the total fluid volumes of 24-hour input and 24-hour output were recorded in the web-based medical system every morning at 07:00. Fluid input included intravenous fluid infusion, oral fluid intake, enteral fluid feeding and fluid given with medicine. Fluid output included urine output, fluid drainage from the gastric tube and ultrafiltration fluid (if applicable). Daily fluid balance volume in millilitres was defined as 24-hour fluid input volume minus fluid output volume. For patients admitted after 19:00, we added the fluid balance between admission and 07:00 the next day to the next 24-hour interval as the fluid balance for the first day.23 We recorded daily fluid balance and calculated the mean value for the first 3 days after admission and categorised patients into three groups: positive fluid balance (the patient’s fluid input was higher than their output for more than 500 mL, ie, +500 mL), even fluid balance (the volume of fluid input minus the volume of fluid output ranged from −500 mL up to +500 mL) and negative fluid balance (the patient’s fluid input was lower than their output for more than 500 mL, ie, −500 mL).24
Outcomes
Trained researchers, blinded to clinical and imaging information of the patient, conducted the follow-up interview by telephone. The primary outcome was all-cause death at 3 months, and the secondary outcome was unfavourable functional outcome (defined as a score of modified Rankin Scale ≥3)25 at 3 months after stroke onset.
Statistical analysis
We presented continuous variables as mean±SD or median with IQR as appropriate, and categorical variables as proportions (%). Baseline characteristics between the three groups were compared using one-way analysis of variance or Kruskal-Wallis H test for continuous variables, and χ2 or Fisher’s exact test for categorical variables. Multivariable logistic regression was conducted to investigate the associations of the mean volume of daily fluid balance for the first 3 days (as a categorical variable with the even fluid balance of ±500 mL as the reference) with 3-month death and 3-month unfavourable outcome, respectively. We performed post-hoc sensitivity analyses to further explore the association of alternative fluid balance thresholds (±250 mL and ±750 mL, respectively) with the primary outcome. We also performed multivariable logistic regression for the association of the mean volume of fluid input in the first 3 days (as the ordinal variable with per 100 mL increase) with outcomes at 3 months. Since renal dysfunction and cardiac dysfunciton are well-established risk factors of fluid overload and both conditions interact with each other, we integrated an indicator variable for the presence of either renal dysfunction or cardiac dysfunction for multivariable logistic regression analysis.26 Considering clinical relevance and statistical significance, the following variables were adjusted in the multivariable logistic regression: age, male sex, NIHSS score, large MCA infarction, reperfusion therapy, pneumonia, and either renal dysfunction or cardiac dysfunction. For logistic regression analysis, we calculated variance inflation factors (VIF) for independent variables to assess collinearity, which showed no significant collinearity between variables, with all VIF values <2.
We performed subgroup analyses by stratifying patients according to the presence of either renal dysfunction or cardiac dysfunction, the use of loop diuretics or the use of vasopressors. The potential non-linear association of the mean volume of daily fluid balance for the first 3 days and death at 3 months was illustrated on a continuous scale with a restricted cubic spline function with four knots (at the 5th, 35th, 65th and 95th percentiles). All statistical analyses were conducted with SPSS V.26.0 and R V.4.1.1 (R Foundation, Vienna, Austria). All statistical tests were two-tailed with a significance level of p value at 0.05.
Results
Of 2283 patients with ischaemic stroke admitted within 24 hours after stroke onset, 783 adult patients had severe stroke. We excluded 96 patients who were discharged within 3 days after admission (online supplemental table S1). Among the remaining 687 patients, 370 patients had complete records of fluid input volume and output volume for the first 3 days after admission, of whom 16 patients were lost to follow-up. Finally, 354 patients were included for analysis (figure 1). Compared with 317 patients who did not have the complete record of fluid input and output, 354 patients who had the complete record had older age, more frequent reperfusion therapy, less frequent decompressive hemicraniectomy, more frequent use of osmotic agents and loop diuretics, and higher incidence of pneumonia, gastrointestinal bleeding, renal dysfunction and cardiac dysfunction (all p<0.05; online supplemental table S2).
Figure 1. Flow chart of patients’ screening and selection during the study. NIHSS, National Institutes of Health Stroke Scale.
Of 354 patients included (mean age 73.1±12.9 years, 48.6% males), 194 (54.8%) patients had even fluid balance, 94 (26.6%) patients had positive fluid balance and 66 (18.6%) patients had negative fluid balance. Compared with the other two groups, patients with positive fluid balance had a higher proportion of men (61.7% for positive vs 45.9% for even vs 37.9% for negative) and a higher proportion of renal dysfunction (35.1% for positive vs 21.6% for even vs 12.1% for negative). Patients with positive fluid balance (17.0%) and negative fluid balance (22.7%) had a higher proportion of cardiac dysfunction than patients with even fluid balance (10.8%; table 1).
Table 1. Clinical characteristics and outcomes of patients who had a severe stroke with positive, even and negative fluid balance.
| Positive fluid balance (n=94) |
Even fluid balance (n=194) |
Negative fluid balance (n=66) |
P value | |
|---|---|---|---|---|
| Demographics | ||||
| Age, years | 74.7±12.3 | 73.0±13.1 | 71.0±13.0 | 0.202 |
| Male sex | 58 (61.7) | 89 (45.9) | 25 (37.9) | 0.006 |
| Stroke characteristics | ||||
| Onset to admission time, hours | 4.0 (3.0–5.0) | 4.0 (3.0–6.0) | 4.0 (3.0–5.0) | 0.579 |
| Admission NIHSS | 19 (16–23) | 18 (16–22) | 19 (16–22) | 0.642 |
| Large MCA infarct | 36 (38.3) | 88 (45.4) | 34 (51.5) | 0.243 |
| Vascular risk factors | ||||
| Hypertension | 59 (62.8) | 120 (61.9) | 40 (60.6) | 0.962 |
| Diabetes mellitus | 24 (25.5) | 37 (19.1) | 19 (28.8) | 0.193 |
| Hyperlipidaemia | 4 (4.3) | 16 (8.2) | 6 (9.1) | 0.361 |
| Atrial fibrillation | 56 (59.6) | 113 (58.2) | 37 (56.1) | 0.906 |
| Smoking | 28 (29.8) | 48 (24.7) | 13 (19.7) | 0.344 |
| Alcohol consumption | 18 (19.1) | 28 (14.4) | 8 (12.1) | 0.426 |
| TOAST | 0.903 | |||
| Large artery atherosclerosis | 30 (31.9) | 54 (27.8) | 17 (25.8) | |
| Cardioembolic | 58 (61.7) | 124 (63.9) | 45 (68.2) | |
| Other aetiology | 3 (3.2) | 11 (5.7) | 3 (4.5) | |
| Undetermined aetiology | 3 (3.2) | 5 (2.6) | 1 (1.5) | |
| Management | ||||
| Reperfusion therapy | 73 (77.7) | 143 (73.7) | 49 (74.2) | 0.763 |
| Decompressive craniectomy | 0 (0.0) | 1 (0.5) | 0 (0.0) | 0.547 |
| Osmotic agents | 84 (89.4) | 164 (84.5) | 60 (90.9) | 0.302 |
| Loop diuretics | 49 (52.1) | 96 (49.5) | 37 (56.1) | 0.644 |
| Vasopressors | 7 (7.4) | 11 (5.7) | 6 (9.1) | 0.616 |
| In-hospital complications | ||||
| Pneumonia | 86 (91.5) | 163 (84.0) | 56 (84.8) | 0.215 |
| Gastrointestinal bleeding | 34 (36.2) | 65 (33.5) | 18 (27.3) | 0.49 |
| Fluid overload risk factors | ||||
| Renal dysfunction | 33 (35.1) | 42 (21.6) | 8 (12.1) | 0.002 |
| Cardiac dysfunction | 16 (17.0) | 21 (10.8) | 15 (22.7) | 0.047 |
| Outcomes at 3 months | ||||
| mRS scored 3–6 | 83 (88.3) | 155 (79.9) | 57 (86.4) | 0.153 |
| Death | 42 (44.7) | 50 (25.8) | 24 (36.4) | 0.005 |
| Mean daily fluid balance, mL | 850 (669 to 1118) | −8 (−202 to 245) | −757 (−965 to −594) | <0.01 |
| Mean daily fluid input, mL | 3032 (2585 to 3525) | 2548 (2052 to 3066) | 2670 (2106 to 3111) | <0.01 |
MCA, middle cerebral artery; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; TOAST, Trial of Org 10172 in Acute Stroke Treatment classification.
At 3-month follow-up, 116 (32.8% of 354) patients died, who had higher NIHSS scores, more frequent use of osmotic agents, loop diuretics and vasopressors, higher incidence of pneumonia, gastrointestinal bleeding, renal dysfunction and cardiac dysfunction, and less reperfusion therapy, than those who had survived by 3 months(table 2). In multivariable logistic regression with the even fluid balance group as the reference (figure 2), patients with positive fluid balance had higher risk of 3-month death (adjusted OR 2.18, 95% CI 1.24 to 3.85, p=0.007), while patients with negative fluid balance showed no significant difference (adjusted OR 1.68, 95% CI 0.88 to 3.20, p=0.115). The restricted cubic spline curve analysis implied a U-shape association of the mean daily fluid balance with 3-month death, with the intersection at 0 mL (p for non-linearity=0.02; figure 3). The increased fluid input was associated with an increased risk of 3-month death (adjusted OR 1.05, 95% CI 1.02 to 1.09 per 100 mL, p=0.004, figure 4).
Table 2. Comparison of characteristics in patients with 3-month death versus 3-month survival.
| 3-month death (n=116) |
3-month survival (n=238) |
P value | |
|---|---|---|---|
| Demographics | |||
| Age, years | 74.7±11.0 | 72.3±13.7 | 0.098 |
| Male sex | 60 (51.7) | 112 (47.1) | 0.41 |
| Stroke characteristics | |||
| Onset to admission time, hours | 4.0 (3.0–5.0) | 4.0 (3.0–5.0) | 0.2 |
| Admission NIHSS | 20 (16–25) | 18 (16–22) | 0.035 |
| Large MCA infarct | 60 (51.7) | 98 (41.2) | 0.061 |
| Vascular risk factors | |||
| Hypertension | 69 (59.5) | 150 (63.0) | 0.52 |
| Diabetes mellitus | 32 (27.6) | 48 (20.2) | 0.117 |
| Hyperlipidaemia | 5 (4.3) | 21 (8.8) | 0.127 |
| Atrial fibrillation | 69 (59.5) | 137 (57.6) | 0.731 |
| Smoking | 28 (24.1) | 61 (25.6) | 0.761 |
| Alcohol consumption | 14 (12.1) | 40 (16.8) | 0.245 |
| TOAST | 0.290 | ||
| Large artery atherosclerosis | 29 (25.0) | 72 (30.3) | |
| Cardioembolic | 80 (69.0) | 147 (61.8) | |
| Other aetiology | 6 (5.2) | 11 (4.6) | |
| Undetermined aetiology | 1 (0.9) | 8 (3.4) | |
| Management | |||
| Reperfusion therapy | 78 (67.2) | 187 (78.6) | 0.021 |
| Decompressive craniectomy | 1 (0.9) | 0 (0.0) | 0.151 |
| Osmotic agents | 109 (94.0) | 199 (83.6) | 0.007 |
| Loop diuretics | 79 (68.1) | 103 (43.3) | <0.001 |
| Vasopressors | 15 (12.9) | 9 (3.8) | 0.001 |
| In-hospital complications | |||
| Pneumonia | 107 (92.2) | 198 (83.2) | 0.021 |
| Gastrointestinal bleeding | 55 (47.4) | 62 (26.1) | <0.001 |
| Fluid overload risk factors | |||
| Renal dysfunction | 46 (39.7) | 37 (15.5) | <0.001 |
| Cardiac dysfunction | 29 (25.0) | 23 (9.7) | <0.001 |
MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; TOAST, Trial of Org 10172 in Acute Stroke Treatment classification.
Figure 2. Forest plot of multivariable logistic regression for the association of mean daily fluid balance for the first 3 days with death at 3 months. Association of the mean volume of daily fluid balance for the first 3 days (as a categorical variable, with the even fluid balance of ±500 mL as the reference) with 3-month death was presented as adjusted ORs and relevant 95% CIs. Covariables included in the regression analysis were age, male sex, NIHSS score, large MCA infarction, reperfusion therapy, pneumonia, and either renal dysfunction or cardiac dysfunction. MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale.
Figure 3. Restricted cubic splines of adjusted OR and 95% CI for the association between mean daily fluid balance for the first 3 days (as a continuous variable) and death at 3 months. Relationship of mean daily fluid balance with 3-month death in patients with severe ischaemic stroke. Adjusted ORs and 95% CIs derived from restricted cubic spline regression, with knots placed at the 5th, 35th, 65th and 95th percentiles of the distribution of mean daily fluid balance levels. The value of 0 mL was set as the reference point (corresponding OR=1, shown as the dotted horizontal line). Adjusted factors included age, male sex, NIHSS score, large MCA infarction, reperfusion therapy, pneumonia and either renal dysfunction or cardiac dysfunction. Solid curve lines represent the OR of 3 month death, dotted curve lines represent the corresponding 95% CI. MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale.
Figure 4. Forest plot of multivariable logistic regression for the association of mean daily fluid input for the first 3 days with death at 3 months. Association of the mean volume of fluid input in the first 3 days (as an ordinal variable, with per 100 mL increase) with 3-month death was presented as adjusted ORs and relevant 95% CIs. Covariables included in regression analysis were age, male sex, NIHSS score, large MCA infarction, reperfusion therapy, pneumonia, and either renal dysfunction or cardiac dysfunction. MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale.
Sensitivity analyses showed consistent results in the primary outcome for the threshold of ±250 mL for fluid balance, but not for the threshold of ±750 mL (online supplemental table S3). In subgroup analyses, the association of positive fluid balance with 3-month death was evident in patients who did not have renal dysfunction or cardiac dysfunction, patients who did not use loop diuretics or patients who did not use vasopressors (online supplemental table S4).
Compared with patients with even fluid balance, patients with positive fluid balance (adjusted OR 1.95, 95% CI 0.95 to 4.27, p=0.079) or those with negative fluid balance (adjusted OR 1.63, 95% CI 0.75 to 3.86, p=0.239) showed no significant difference in the risk of unfavourable functional outcome at 3 months (online supplemental table S5). Patients with increased fluid input had a higher risk of a 3-month unfavourable outcome (adjusted OR 1.10, 95% CI 1.05 to 1.15 per 100 mL, p<0.001; online supplemental table S6).
Discussion
In the current cohort of patients with severe ischaemic stroke, 45.2% of patients had fluid imbalance during the first 3 days after admission (26.6% had positive fluid balance and 18.6% had negative fluid balance). Compared with patients with even fluid balance, patients who had positive fluid balance in the first 3 days after stroke had a higher risk of death at 3 months.
Fluid therapy is a fundamental strategy of neurocritical care for patients who had a stroke. We focused on fluid balance, which is an important safety endpoint for fluid therapy.27 Renal dysfunction and cardiac function are common complications of severe stroke. Both conditions would influence fluid balance, predisposing patients who had a stroke to fluid overload status.28 29 The current study demonstrated that, compared with those with the even fluid balance, patients with the positive fluid balance (ie, +500 mL or more input fluid volume than output fluid volume) for the first 3 days had a higher risk of death at 3 months after stroke. This is consistent with previous studies where the positive fluid balance increased the risk of unfavourable outcomes in patients who had received endovascular thrombectomy30 and in patients who had received decompressive hemicraniectomy due to large hemispheric infarction.31 The current study extended the findings to a relatively non-selected patient cohort. In addition, the sensitivity analysis implied a more sensitive threshold of even fluid balance (by +250 mL or more input fluid volume than output fluid volume) for the first 3 days, which was associated with a higher risk of death at 3 months.
Positive fluid balance reflects a hypervolaemia status with excessive capillary hydrostatic pressure.32 As a consequence, excessive fluid retention would develop interstitial oedema and progressive organ dysfunction, including the involvement of the central nervous system.33 In addition, pre-existing congestive heart failure,28 chronic renal disease29 and ischaemic stroke mediated kidney dysfunction34 could impede redundant water excretion, which predisposes positive fluid balance after stroke. Furthermore, heart and kidneys are bidirectionally interconnected; injury to one organ would lead to dysfunction of the other.35 Both cardiac dysfunction and renal dysfunction would contribute to fluid overload. Moreover, persistent positive fluid balance could in turn exert adverse effects on kidney.36 This is consistent with our findings that patients with positive fluid balance had a higher proportion of renal dysfunction. However, it is unknown if positive fluid balance causes renal dysfunction, or vice versa; nevertheless, either approach could have adverse effects on functional outcomes of patients. We identified a U-shaped association between the mean daily fluid balance in the first 3 days and the risk of death at 3 months, where the risk of death increased at both extremes of fluid imbalance as shown on the restricted cubic spline curve. This may be explained by the positive fluid balance increases cardiac and renal burdens, while negative fluid balance compromises cerebral perfusion, both associated with adverse outcomes. These findings imply the importance of maintaining an even fluid balance.
Fluid imbalance is a modifiable factor in clinical practice. A randomised trial of patients with invasive mechanical ventilation reported that the diuretic therapy was safe to reduce positive fluid balance, although it did not improve functional outcome.37 Another trial of critically ill patients showed that restrictive fluid management did not reduce 60-day mortality.38 Maintenance fluids therapy is important for neurocritical patients. An expert consensus of the European Society of Intensive Care Medicine suggests against the use of restrictive fluid strategies for patients with neurointensive care,9 as hypovolaemia would contribute to secondary brain injury and tissue hypoperfusion. Our study suggested that an even fluid balance was optimal for patients with severe stroke. The endpoint of fluid management is aiming for a neutral fluid balance. Given the association revealed in the current study between positive fluid balance and death after stroke, future trials are expected to investigate interventions targeting an even fluid balance for patients with severe stroke.
The current study has some limitations. First, we included patients with severe stroke with a baseline NIHSS score ≥15. Some patients with an incomplete record of fluid balance had been excluded from analysis, while the included patients with a complete record of fluid balance had more severe stroke and more complications such as renal dysfunction and cardiac dysfunction. Thus, findings from the current study are representative of a group of patients with severe ischaemic stroke. Second, due to the small sample size and observational nature of the current study, we could not infer any causality between fluid balance and 3-month outcomes. However, based on the events per variable principle,39 our study provided sufficient sample size to conduct multivariable regression (ie, nine variables in the regression model for 116 outcome events of 3-month death). Future trials are needed to verify the association between fluid balance and 3-month death as revealed in the current study.
Conclusions
In patients with severe ischaemic stroke, the positive fluid balance in the first 3 days was associated with a higher risk of death at 3 months. Whether treatment strategies to maintain fluid balance could improve functional outcome and what is the optimal fluid volume for balance is worth further investigation in future trials.
Supplementary material
Footnotes
Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 82171285), the Science and Technology Department of Sichuan Province (2024YFHZ0330), the 1·3·5 project for disciplines of excellence - Clinical Research Fund, West China Hospital, Sichuan University (2024HXFH022).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants and was approved by Biomedical Research Ethics Committee of West China Hospital, Sichuan University (reference No. 2017[130]). All participants (or their legal proxies) had provided written informed consent prior to participation.
Data availability statement
Data are available upon reasonable request.
References
- 1.Wu S, Liu M. Global burden of stroke: dynamic estimates to inform action. Lancet Neurol. 2024;23:952–3. doi: 10.1016/S1474-4422(24)00363-6. [DOI] [PubMed] [Google Scholar]
- 2.Hua X, Liu M, Wu S. Definition, prediction, prevention and management of patients with severe ischemic stroke and large infarction. Chin Med J. 2023;136:2912–22. doi: 10.1097/CM9.0000000000002885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Mazya MV, Lees KR, Collas D, et al. IV thrombolysis in very severe and severe ischemic stroke: Results from the SITS-ISTR Registry. Neurology (ECronicon) 2015;85:2098–106. doi: 10.1212/WNL.0000000000002199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wu S, Wang Y, Yuan R, et al. Clinical course, causes of worsening, and outcomes of severe ischemic stroke: A prospective multicenter cohort study. Chin Med J (Engl) 2025;138:1578–86. doi: 10.1097/CM9.0000000000003556. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kirkman MA, Citerio G, Smith M. The intensive care management of acute ischemic stroke: an overview. Intensive Care Med. 2014;40:640–53. doi: 10.1007/s00134-014-3266-z. [DOI] [PubMed] [Google Scholar]
- 6.Wijdicks EFM, Sheth KN, Carter BS, et al. Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:1222–38. doi: 10.1161/01.str.0000441965.15164.d6. [DOI] [PubMed] [Google Scholar]
- 7.van der Jagt M. Fluid management of the neurological patient: a concise review. Crit Care. 2016;20:126. doi: 10.1186/s13054-016-1309-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kumar S, Selim MH, Caplan LR. Medical complications after stroke. Lancet Neurol. 2010;9:105–18. doi: 10.1016/S1474-4422(09)70266-2. [DOI] [PubMed] [Google Scholar]
- 9.Oddo M, Poole D, Helbok R, et al. Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations. Intensive Care Med. 2018;44:449–63. doi: 10.1007/s00134-018-5086-z. [DOI] [PubMed] [Google Scholar]
- 10.Shen Y, Huang X, Hu Y, et al. Positive fluid balance is associated with increased in-hospital mortality in patients with intracerebral hemorrhage. Brain Inj. 2019;33:212–7. doi: 10.1080/02699052.2018.1539870. [DOI] [PubMed] [Google Scholar]
- 11.Kissoon NR, Mandrekar JN, Fugate JE, et al. Positive Fluid Balance Is Associated With Poor Outcomes in Subarachnoid Hemorrhage. J Stroke Cerebrovasc Dis. 2015;24:2245–51. doi: 10.1016/j.jstrokecerebrovasdis.2015.05.027. [DOI] [PubMed] [Google Scholar]
- 12.Wiegers EJA, Lingsma HF, Huijben JA, et al. Fluid balance and outcome in critically ill patients with traumatic brain injury (CENTER-TBI and OzENTER-TBI): a prospective, multicentre, comparative effectiveness study. Lancet Neurol. 2021;20:627–38. doi: 10.1016/S1474-4422(21)00162-9. [DOI] [PubMed] [Google Scholar]
- 13.Wright WL. Sodium and fluid management in acute brain injury. Curr Neurol Neurosci Rep. 2012;12:466–73. doi: 10.1007/s11910-012-0284-5. [DOI] [PubMed] [Google Scholar]
- 14.Liu M, Deng Y, Cheng Y, et al. Association between Plasma Osmolality and Case Fatality within 1 Year after Severe Acute Ischemic Stroke. Yonsei Med J. 2021;62:600–7. doi: 10.3349/ymj.2021.62.7.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50:e344–418. doi: 10.1161/STR.0000000000000211. [DOI] [PubMed] [Google Scholar]
- 16.Brott T, Adams HP, Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–70. doi: 10.1161/01.str.20.7.864. [DOI] [PubMed] [Google Scholar]
- 17.Adams HP, Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41. doi: 10.1161/01.str.24.1.35. [DOI] [PubMed] [Google Scholar]
- 18.Smith CJ, Kishore AK, Vail A, et al. Diagnosis of Stroke-Associated Pneumonia: Recommendations From the Pneumonia in Stroke Consensus Group. Stroke. 2015;46:2335–40. doi: 10.1161/STROKEAHA.115.009617. [DOI] [PubMed] [Google Scholar]
- 19.Lanas A, Dumonceau J-M, Hunt RH, et al. Non-variceal upper gastrointestinal bleeding. Nat Rev Dis Primers. 2018;4:18020. doi: 10.1038/nrdp.2018.20. [DOI] [PubMed] [Google Scholar]
- 20.Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158:825–30. doi: 10.7326/0003-4819-158-11-201306040-00007. [DOI] [PubMed] [Google Scholar]
- 21.Khwaja A. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Nephron Clin Pract. 2012;120:c179–84. doi: 10.1159/000339789. [DOI] [PubMed] [Google Scholar]
- 22.Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895–1032. doi: 10.1161/CIR.0000000000001063. [DOI] [PubMed] [Google Scholar]
- 23.Fletcher JJ, Bergman K, Blostein PA, et al. Fluid balance, complications, and brain tissue oxygen tension monitoring following severe traumatic brain injury. Neurocrit Care. 2010;13:47–56. doi: 10.1007/s12028-010-9345-2. [DOI] [PubMed] [Google Scholar]
- 24.Rass V, Gaasch M, Kofler M, et al. Fluid Intake But Not Fluid Balance Is Associated With Poor Outcome in Nontraumatic Subarachnoid Hemorrhage Patients. Crit Care Med. 2019;47:e555–62. doi: 10.1097/CCM.0000000000003775. [DOI] [PubMed] [Google Scholar]
- 25.van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604–7. doi: 10.1161/01.str.19.5.604. [DOI] [PubMed] [Google Scholar]
- 26.Lee J, de Louw E, Niemi M, et al. Association between fluid balance and survival in critically ill patients. J Intern Med. 2015;277:468–77. doi: 10.1111/joim.12274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hoste EA, Maitland K, Brudney CS, et al. Four phases of intravenous fluid therapy: a conceptual model. Br J Anaesth. 2014;113:740–7. doi: 10.1093/bja/aeu300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Cosentino N, Marenzi G, Muratori M, et al. Fluid balance in heart failure. Eur J Prev Cardiol. 2023;30:ii9–15. doi: 10.1093/eurjpc/zwad166. [DOI] [PubMed] [Google Scholar]
- 29.Deabes AA, Essa A. Fluid and electrolyte imbalance in renal dysfunction. Anaesth Intensive Care Med. 2024;25:316–9. doi: 10.1016/j.mpaic.2024.03.006. [DOI] [Google Scholar]
- 30.Schell M, Mayer C, Woo MS, et al. Fluid excess on intensive care unit after mechanical thrombectomy after acute ischemic stroke is associated with unfavorable neurological and functional outcomes: An observational cohort study. Eur Stroke J. 2025;10:74–83. doi: 10.1177/23969873241271642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Pelz JO, Fischer MM, Bungert-Kahl P, et al. Fluid Balance Variations During the Early Phase of Large Hemispheric Stroke Are Associated With Patients’ Functional Outcome. Front Neurol. 2019;10:720. doi: 10.3389/fneur.2019.00720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Mythen M, Vercueil A. Fluid balance. Vox Sang. 2004;87 Suppl1:77–81. doi: 10.1111/j.1741-6892.2004.00436.x. [DOI] [PubMed] [Google Scholar]
- 33.O’Connor ME, Prowle JR. Fluid Overload. Crit Care Clin. 2015;31:803–21. doi: 10.1016/j.ccc.2015.06.013. [DOI] [PubMed] [Google Scholar]
- 34.Zhao Q, Yan T, Chopp M, et al. Brain-kidney interaction: Renal dysfunction following ischemic stroke. J Cereb Blood Flow Metab. 2020;40:246–62. doi: 10.1177/0271678X19890931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Buryskova Salajova K, Malik J, Valerianova A. Cardiorenal Syndromes and Their Role in Water and Sodium Homeostasis. Physiol Res. 2024;73:173–87. doi: 10.33549/physiolres.935110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Hofer DM, Ruzzante L, Waskowski J, et al. Influence of fluid accumulation on major adverse kidney events in critically ill patients - an observational cohort study. Ann Intensive Care. 2024;14:52. doi: 10.1186/s13613-024-01281-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Cinotti R, Lascarrou J-B, Azais M-A, et al. Diuretics decrease fluid balance in patients on invasive mechanical ventilation: the randomized-controlled single blind, IRIHS study. Crit Care. 2021;25:98. doi: 10.1186/s13054-021-03509-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Bollaert P-E, Monnier A, Schneider F, et al. Fluid balance control in critically ill patients: results from POINCARE-2 stepped wedge cluster-randomized trial. Crit Care. 2023;27:66. doi: 10.1186/s13054-023-04357-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49:1373–9. doi: 10.1016/s0895-4356(96)00236-3. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available upon reasonable request.