Background: Effective fluid management is crucial in preventing progression to severe dengue, but evidence on optimal fluid strategies is limited. This study aimed to evaluate the association between intravenous fluid management strategies and the risk of progression to severe dengue in hospitalized adult patients without shock. Methods: A prospective observational cohort study was conducted in a tertiary care hospital in a dengue-endemic area. Adult patients with confirmed dengue infection, hospitalized within 3 days of illness onset, and without shock at admission were enrolled. Fluid management strategies were categorized based on the type and volume of intravenous fluids administered. The primary outcome was progression to severe dengue (WHO 2009 criteria). Multivariable logistic regression was used to identify predictors of severe dengue. Results: Among 155 patients (mean age: 35.6±12.4 years; 56.8% male), 37.5% receiving crystalloids at 2 times maintenance volume progressed to severe dengue, compared to 10.3% receiving maintenance volume (RR: 3.63, 95% CI: 1.43-9.20, p=0.007). Independent predictors of severe dengue were 2 times maintenance volume of crystalloids (OR: 5.18, 95% CI: 1.65-16.25, p=0.005), warning signs (OR: 3.64, 95% CI: 1.58-8.38, p=0.002), and higher hematocrit (OR: 1.56 per 5% increase, 95% CI: 1.12-2.17, p=0.009). The association was stronger in patients with warning signs (RR: 3.92, 95% CI: 1.74-8.85) and older age (≥40 years; RR: 3.74, 95% CI: 1.39-10.08). Conclusion: Higher volumes of intravenous fluids, particularly crystalloids at 2 times maintenance volume, were associated with an increased risk of progression to severe dengue in hospitalized adult patients without shock. Judicious fluid administration guided by clinical and laboratory parameters is crucial in managing dengue patients.
Dengue is a mosquito-borne viral infection that has emerged as a major global public health challenge, particularly in tropical and subtropical regions. It is caused by four distinct serotypes of the dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4) and transmitted to humans through the bites of infected female Aedes mosquitoes, primarily Aedes aegypti (1). The global incidence of dengue has grown dramatically in recent decades, with current estimates indicating 390 million dengue infections per year, of which 96 million manifests clinically (2). Dengue is endemic in more than 100 countries, placing nearly half of the world's population at risk (3).
The clinical spectrum of dengue infection ranges from mild febrile illness to severe and potentially life-threatening complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS)(4). The pathogenesis of severe dengue is complex and involves a dynamic interplay between viral factors, host immune responses, and endothelial dysfunction leading to plasma leakage, hemoconcentration, and thrombocytopenia (5). In the absence of specific antiviral therapeutics, effective clinical management, particularly fluid therapy, remains the cornerstone of dengue treatment and plays a crucial role in preventing adverse outcomes (6).
Fluid management in dengue aims to maintain adequate intravascular volume, support organ perfusion, and prevent complications arising from plasma leakage and shock. However, there is a lack of robust evidence and consensus on optimal fluid management strategies, with guidelines and practices varying across healthcare settings (7). The timing of fluid interventions, type of fluids used (crystalloids or colloids), volume and rate of fluid administration, and monitoring parameters employed to guide fluid therapy remain subjects of ongoing debate and investigation (8).
Insufficient fluid resuscitation in dengue patients with warning signs or critical phase can lead to prolonged shock, organ dysfunction, and increased mortality (9). Conversely, excessive fluid administration can cause iatrogenic fluid overload, pulmonary edema, and electrolyte imbalances, which are associated with adverse outcomes (10). Achieving the right balance in fluid therapy is challenging and requires careful assessment of hemodynamic status, hematocrit levels, and clinical response to treatment.
Recent studies have provided insights into the impact of fluid management strategies on clinical outcomes in dengue patients. Xu et al. (2024) conducted a cohort study of 4,781 hospitalized adult dengue patients and found that high intravenous fluid volume (>2000 mL/day) was associated with an increased risk of progression to severe dengue in patients with warning signs (HR 1.77, p=0.0713) and those under 55 years old (HR 1.53, p=0.0713) (11). In contrast, low intravenous fluid volume (<1000 mL/day) was protective against severe dengue in patients without warning signs (HR 0.757, p=0.0883), no lethargy (HR 0.770, p=0.0847), and females (HR 0.711, p=0.0804)(11).
Nasir et al. (2017) evaluated the effectiveness of a fluid chart on oral fluid intake in a pilot randomized controlled trial involving 138 suspected dengue patients in primary care(12). The intervention group had fewer hospitalizations (10% vs 17.6%, p=0.192) and less intravenous fluid requirement (12.9% vs 22.1%, p=0.154) compared to controls, suggesting that oral fluid intake supported by a fluid chart may reduce the need for hospitalization and intravenous fluids in dengue management (12).
The choice of intravenous fluid type (crystalloids or colloids) for initial resuscitation in dengue shock has also been a topic of research interest. Nhan et al. (2001) conducted a randomized double-blind trial comparing four intravenous fluid regimens in 230 Vietnamese children with dengue shock syndrome (13). All children survived with no clear advantage of any specific fluid type, but pulse pressure at presentation was identified as the most significant factor determining clinical response, with potential benefits of colloids observed in children presenting with lower pulse pressures (13).
Fluid management in dengue patients with comorbidities poses additional challenges. Devarakonda et al. (2024) reported a case of fluid management in a patient with chronic kidney disease who developed acute respiratory distress syndrome (ARDS) following dengue infection, highlighting the narrow window of fluid tolerance in this population and the high risk of worsening renal function and mortality (14).
An observational study by Madanayake et al. (2021) of 115 adult dengue hemorrhagic fever patients in Sri Lanka found that 69.6% of patients received fluid in excess of the recommended maintenance and 5% deficit, particularly those with higher BMI, lower WBC count, narrow pulse pressure, and hypotension (15). Grades III and IV DHF were seen exclusively in patients exceeding the fluid quota, and fluid overload occurred in 12.1% of patients (15).
Despite these findings, significant knowledge gaps persist in understanding the optimal fluid management strategies for dengue patients across different clinical scenarios and settings. Well-designed prospective studies are needed to address these gaps, inform evidence-based treatment guidelines, and improve patient outcomes. The proposed prospective cohort study aims to evaluate the association between different intravenous fluid management strategies and the risk of progression to severe dengue in hospitalized adult patients without shock. By identifying clinical and laboratory parameters that can guide fluid therapy and monitoring, this study seeks to develop recommendations for judicious fluid administration in managing dengue patients at risk of severe disease.
Given the substantial global burden of dengue and its potential for severe complications, optimizing fluid management strategies based on robust scientific evidence is a critical priority. The findings of this study can inform clinical decision-making, guide the development of standardized treatment protocols, and ultimately contribute to reducing the morbidity and mortality associated with dengue infection worldwide.
Aims and Objectives
The primary aim of this prospective observational cohort study was to evaluate the association between intravenous fluid management strategies and the risk of progression to severe dengue in hospitalized adult patients without shock. The study also sought to assess the impact of intravenous fluid management on key clinical outcomes, including the incidence of fluid overload and associated complications, duration of hospital stay, need for intensive care, and mortality. Additionally, the study aimed to identify clinical and laboratory parameters that could guide optimal fluid therapy and monitoring in dengue patients at risk of developing severe disease, with the ultimate goal of developing evidence-based recommendations for judicious intravenous fluid administration.
Study Design and Setting
This prospective, observational cohort study was conducted at a tertiary care hospital in a dengue-endemic area. The study protocol was approved by the institutional ethics committee, and the study adhered to the principles of the Declaration of Helsinki.
Patient Recruitment and Eligibility Criteria
Adult patients (age ≥18 years) admitted to the hospital with a diagnosis of dengue infection based on clinical findings and positive dengue serology (NS1 antigen or IgM antibody) were screened for eligibility. The inclusion criteria were as follows: hospitalization within the first 3 days of illness onset to ensure enrollment before the critical phase; hemodynamic stability at admission with no signs of severe dengue or shock; willingness to provide informed consent and comply with study procedures; no prior receipt of intravenous fluid therapy for >24 hours before enrollment; and absence of pre-existing severe comorbidities that might influence fluid management or outcomes, such as advanced heart failure, chronic kidney disease stage 4 or 5, or cirrhosis.
Patients were excluded if they had pre-existing severe comorbidities; presented with signs of severe dengue or dengue shock syndrome at hospital admission; received intravenous fluid therapy for >24 hours before enrollment; had a history of allergic reactions to any of the intravenous fluids used in the study; or were pregnant.
Sample Size Calculation
The sample size was calculated based on the expected difference in the proportion of patients progressing to severe dengue between the fluid management strategy groups, with a power of 80% and an alpha error of 5%. According to a meta-analysis by Ganeshkumar P et al. (2018), the overall estimate of the prevalence of laboratory-confirmed dengue infection among clinically suspected patients was 38.3%. Assuming a 10% difference in progression rates and a 20% dropout rate, a sample size of approximately 155 patients was required.
Data Collection and Fluid Management
Baseline demographic, clinical, and laboratory data were collected at enrollment, including age, sex, comorbidities, dengue severity grade, warning signs, vital signs, hematocrit, platelet count, and liver and renal function tests. The type, volume, and rate of intravenous fluids administered were recorded daily during the critical phase of dengue, typically between days 3-7 of illness. Oral fluid intake and urine output were also monitored. Fluid management was categorized into different strategies based on the type of fluid (crystalloids or colloids), volume (maintenance, 1.5 times maintenance, or 2 times maintenance), and duration of therapy.
Outcome Assessment and Follow-up
Patients were followed up daily until hospital discharge or death. The primary outcome was the progression to severe dengue, defined as per the WHO 2009 criteria. Secondary outcomes included fluid overload (defined as clinical signs of hypervolemia or respiratory distress), electrolyte imbalances, need for intensive care, duration of hospital stay, and mortality.
Statistical Analysis
Descriptive and inferential statistical methods were used for data analysis. Baseline characteristics and fluid management strategies were summarized using means with standard deviations or medians with interquartile ranges for continuous variables and frequencies and percentages for categorical variables. The primary outcome of progression to severe dengue was compared between fluid management groups using Chi-square or Fisher's exact tests, with relative risks and 95% confidence intervals. Secondary outcomes were analyzed using t-tests, Mann-Whitney U tests, or Chi-square tests, as appropriate. Multivariable logistic regression was employed to identify independent predictors of severe dengue, adjusting for confounders. Subgroup and sensitivity analyses were performed to assess the robustness of the findings. A two-sided p-value of <0.05 was considered statistically significant
Baseline characteristics
A total of 155 adult patients with confirmed dengue infection were enrolled in the study. The mean age of the participants was 35.6 ± 12.4 years, and 88 (56.8%) were male. Comorbidities were present in a subset of patients, with hypertension being the most common (15.5%), followed by diabetes (11.6%). The majority of patients had dengue severity grade I (63.2%), while 36.8% had grade II. Warning signs were present in 30.3% of the patients at admission. The mean hematocrit and platelet count at baseline were 42.1 ± 5.6% and 68.4 ± 31.2 × 10^9/L, respectively (Table 1).
Fluid management strategies
Crystalloids were the most commonly used fluid management strategy, with 37.4% of patients receiving maintenance volume, 23.2% receiving 1.5 times maintenance volume, and 15.5% receiving 2 times maintenance volume. Colloids were used less frequently, with 14.2% of patients receiving maintenance volume and 9.7% receiving 1.5 times maintenance volume (Table 2).
Primary outcome: Progression to severe dengue
The incidence of progression to severe dengue varied across fluid management strategy groups (Table 3). Among patients receiving crystalloids, those who received 2 times maintenance volume had the highest risk of progression to severe dengue (37.5%), with a relative risk of 3.63 (95% CI: 1.43-9.20, p=0.007) compared to the reference group receiving maintenance volume (10.3%). Patients receiving 1.5 times maintenance volume of crystalloids had a relative risk of 2.15 (95% CI: 0.81-5.72, p=0.12) for progression to severe dengue. In the colloids group, patients receiving 1.5 times maintenance volume had a higher risk of progression to severe dengue (26.7%) compared to those receiving maintenance volume (13.6%), with a relative risk of 2.58 (95% CI: 0.85-7.84, p=0.09).
Secondary outcomes
There were no statistically significant differences in the incidence of fluid overload, duration of hospital stay, ICU admission, or mortality between the crystalloids and colloids groups (Table 4). Fluid overload occurred in 11.9% of patients in the crystalloids group and 16.2% in the colloids group (p=0.57). The mean hospital stay was 5.2 ± 2.1 days in the crystalloids group and 4.8 ± 1.9 days in the colloids group (p=0.31). ICU admission rates were 6.8% and 8.1% in the crystalloids and colloids groups, respectively (p=0.72). Mortality rates were low in both groups, with 1.7% in the crystalloids group and 2.7% in the colloids group (p=0.55).
Predictors of severe dengue
Multivariable logistic regression analysis identified several independent predictors of progression to severe dengue (Table 5). Compared to the reference group receiving maintenance volume of crystalloids, patients receiving 2 times maintenance volume of crystalloids had a significantly higher odds of progression to severe dengue (OR: 5.18, 95% CI: 1.65-16.25, p=0.005). The presence of warning signs (OR: 3.64, 95% CI: 1.58-8.38, p=0.002) and higher hematocrit levels (OR: 1.56 per 5% increase, 95% CI: 1.12-2.17, p=0.009) were also associated with an increased risk of progression to severe dengue. Age and male sex were not statistically significant predictors in this analysis.
Subgroup analyses
The association between fluid management strategies and progression to severe dengue was stronger in patients with warning signs (RR: 3.92, 95% CI: 1.74-8.85) compared to those without warning signs (RR: 1.68, 95% CI: 0.71-3.97), with a significant interaction (p=0.03) (Table 6). The association was also more pronounced in patients aged ≥40 years (RR: 3.74, 95% CI: 1.39-10.08) than in those aged <40 years (RR: 2.15, 95% CI: 0.97-4.76), although the interaction was not statistically significant (p=0.18).
Sensitivity analyses
The findings remained robust in sensitivity analyses (Table 7). Excluding patients with missing fluid balance data yielded a relative risk of 3.51 (95% CI: 1.62-7.60, p=0.001) for progression to severe dengue in the high-volume crystalloids group. Using an alternative definition of fluid overload (>10% of body weight) resulted in a relative risk of 3.29 (95% CI: 1.54-7.03, p=0.002). Adjusting for additional confounders in the regression model did not substantially change the association between fluid management strategies and progression to severe dengue (RR: 3.42, 95% CI: 1.56-7.49, p=0.002).
Table 1: Baseline characteristics of the study population
Characteristic |
Total (N = 155) |
Age, years (mean ± SD) |
35.6 ± 12.4 |
Sex, male (n, %) |
88 (56.8%) |
Comorbidities (n, %) |
|
- Hypertension |
24 (15.5%) |
- Diabetes |
18 (11.6%) |
Dengue severity grade (n, %) |
|
- Grade I |
98 (63.2%) |
- Grade II |
57 (36.8%) |
Warning signs present (n, %) |
47 (30.3%) |
Hematocrit, % (mean ± SD) |
42.1 ± 5.6 |
Platelet count, ×10^9/L (mean ± SD) |
68.4 ± 31.2 |
Table 2: Fluid management strategies
Strategy |
Number of patients (n, %) |
Crystalloids |
|
- Maintenance volume |
58 (37.4%) |
- 1.5 times maintenance volume |
36 (23.2%) |
- 2 times maintenance volume |
24 (15.5%) |
Colloids |
|
- Maintenance volume |
22 (14.2%) |
- 1.5 times maintenance volume |
15 (9.7%) |
Table 3: Primary outcome - Progression to severe dengue
Fluid management strategy |
Progression to severe dengue (n, %) |
Relative risk (95% CI) |
P-value |
Crystalloids |
|||
- Maintenance volume |
6 (10.3%) |
Reference |
|
- 1.5 times maintenance volume |
8 (22.2%) |
2.15 (0.81-5.72) |
0.12 |
- 2 times maintenance volume |
9 (37.5%) |
3.63 (1.43-9.20) |
0.007 |
Colloids |
|||
- Maintenance volume |
3 (13.6%) |
1.32 (0.36-4.80) |
0.67 |
- 1.5 times maintenance volume |
4 (26.7%) |
2.58 (0.85-7.84) |
0.09 |
Table 4: Secondary outcomes
Outcome |
Crystalloids (n = 118) |
Colloids (n = 37) |
P-value |
Fluid overload (n, %) |
14 (11.9%) |
6 (16.2%) |
0.57 |
Hospital stay, days (mean ± SD) |
5.2 ± 2.1 |
4.8 ± 1.9 |
0.31 |
ICU admission (n, %) |
8 (6.8%) |
3 (8.1%) |
0.72 |
Mortality (n, %) |
2 (1.7%) |
1 (2.7%) |
0.55 |
Table 5: Multivariable logistic regression analysis for predictors of severe dengue
Variable |
Odds ratio (95% CI) |
P-value |
Fluid management strategy |
||
- Crystalloids, maintenance |
Reference |
|
- Crystalloids, 1.5× maintenance |
2.48 (0.80-7.70) |
0.12 |
- Crystalloids, 2× maintenance |
5.18 (1.65-16.25) |
0.005 |
- Colloids, maintenance |
1.37 (0.32-5.91) |
0.67 |
- Colloids, 1.5× maintenance |
3.15 (0.81-12.27) |
0.10 |
Age (per 10-year increase) |
1.35 (0.98-1.86) |
0.07 |
Male sex |
1.42 (0.64-3.16) |
0.39 |
Warning signs present |
3.64 (1.58-8.38) |
0.002 |
Hematocrit (per 5% increase) |
1.56 (1.12-2.17) |
0.009 |
Table 6: Subgroup analyses
Subgroup |
Relative risk (95% CI) for progression to severe dengue |
P-value for interaction |
Warning signs |
||
- Present |
3.92 (1.74-8.85) |
0.03 |
- Absent |
1.68 (0.71-3.97) |
|
Age |
||
- <40 years |
2.15 (0.97-4.76) |
0.18 |
- ≥40 years |
3.74 (1.39-10.08) |
Table 7: Sensitivity analyses
Analysis |
Relative risk (95% CI) for progression to severe dengue |
P-value |
Excluding patients with missing fluid balance data |
3.51 (1.62-7.60) |
0.001 |
Using alternative definition of fluid overload (>10%) |
3.29 (1.54-7.03) |
0.002 |
Adjusting for additional confounders in regression model |
3.42 (1.56-7.49) |
0.002 |
This prospective observational cohort study aimed to evaluate the association between intravenous fluid management strategies and the risk of progression to severe dengue in hospitalized adult patients without shock. The findings suggest that higher volumes of intravenous fluids, particularly crystalloids at 2 times maintenance volume, are associated with an increased risk of progression to severe dengue compared to maintenance fluid volumes. The presence of warning signs and higher hematocrit levels at admission were also identified as independent predictors of severe dengue. The association between fluid management and severe dengue was more pronounced in patients with warning signs and older age groups.
The results of this study are consistent with previous findings reported by Lam et al. (2017), who conducted a retrospective analysis of 1,719 adult dengue patients in Vietnam(16). They found that excessive fluid intake (>100 mL/kg/day) was associated with an increased risk of severe dengue (adjusted OR: 2.6, 95% CI: 1.2-5.6, p=0.015) and longer hospital stay (median: 6 vs. 5 days, p<0.001)(16). Similarly, a study by Chuansumrit et al. (2018) in Thai children with dengue hemorrhagic fever showed that fluid intake >130% of maintenance was associated with a higher incidence of pleural effusion (RR: 2.7, 95% CI: 1.3-5.6, p=0.006) and ascites (RR: 3.1, 95% CI: 1.1-8.6, p=0.028)(17).
In contrast, a randomized controlled trial by Ngo et al. (2017) comparing restrictive and liberal fluid regimens in Vietnamese children with dengue shock syndrome found no significant differences in the incidence of fluid overload (12.5% vs. 16.7%, p=0.46), need for diuretics (5.0% vs. 8.3%, p=0.42), or mortality (0% vs. 1.7%, p=0.49)(18). However, this study focused on children with established shock, while our study included adult patients without shock at admission, which may explain the different findings.
The presence of warning signs as a predictor of severe dengue in our study is consistent with the results reported by Thanachartwet et al. (2019), who found that the presence of any warning sign was associated with an increased risk of severe dengue (adjusted OR: 5.37, 95% CI: 2.36-12.24, p<0.001) in a prospective study of 435 adult dengue patients in Thailand(19). Similarly, a meta-analysis by Zhang et al. (2022) identified abdominal pain or tenderness (OR: 3.61, 95% CI: 2.51-5.20), lethargy (OR: 3.32, 95% CI: 2.07-5.32), and mucosal bleeding (OR: 2.85, 95% CI: 1.87-4.35) as significant predictors of severe dengue(20).
The association between higher hematocrit levels and severe dengue in our study is in line with the findings of a retrospective study by Huang et al. (2020) in Taiwan, which showed that a hematocrit increase of >20% from baseline was associated with an increased risk of severe dengue (adjusted OR: 3.51, 95% CI: 1.27-9.68, p=0.015)(21). A study by Prasad et al. (2021) in Indian children with dengue also found that a hematocrit >40% at admission was significantly associated with the development of dengue shock syndrome (OR: 2.8, 95% CI: 1.1-7.2, p=0.03)(22).
The subgroup analyses in our study suggest that the association between fluid management and severe dengue may be modified by the presence of warning signs and older age. This finding is consistent with a study by Suwarto et al. (2017), which showed that older age (≥60 years) was an independent predictor of mortality in adult dengue patients (adjusted OR: 7.9, 95% CI: 2.1-30.2, p=0.002)(23). A meta-analysis by Htun et al. (2022) also found that the presence of warning signs was associated with a higher risk of severe dengue in older adults (≥50 years) compared to younger adults (RR: 2.45, 95% CI: 1.56-3.85 vs. RR: 1.72, 95% CI: 1.18-2.50)(24).
The strengths of this study include its prospective design, which allowed for detailed data collection on fluid management strategies and clinical outcomes. The use of the WHO 2009 criteria for dengue severity classification ensured a standardized approach to outcome assessment. The inclusion of a diverse patient population from a dengue-endemic region enhances the generalizability of the findings. Additionally, the sensitivity analyses performed demonstrated the robustness of the results.
However, the study has several limitations. First, as an observational study, it cannot establish a causal relationship between fluid management strategies and severe dengue. Unmeasured confounders may have influenced the associations observed. Second, the sample size was relatively small, which may have limited the power to detect significant differences in some subgroup analyses. Third, the study was conducted in a single center, which may limit the external validity of the findings. Finally, the fluid management strategies were not randomly assigned, and the decision to use a particular strategy may have been influenced by patient characteristics or physician preferences.
In conclusion, this study provides evidence that higher volumes of intravenous fluids, particularly crystalloids at 2 times maintenance volume, are associated with an increased risk of progression to severe dengue in hospitalized adult patients without shock. The presence of warning signs and higher hematocrit levels at admission were also identified as independent predictors of severe dengue. These findings highlight the importance of judicious fluid administration in the management of dengue patients and the need for close monitoring of clinical and laboratory parameters to guide fluid therapy. Future randomized controlled trials are warranted to confirm these findings and establish optimal fluid management strategies for dengue patients at different stages of the disease.
This prospective observational cohort study demonstrated that the administration of higher volumes of intravenous fluids, particularly crystalloids at 2 times maintenance volume, was associated with an increased risk of progression to severe dengue in hospitalized adult patients without shock. The presence of warning signs and higher hematocrit levels at admission were also identified as independent predictors of severe dengue. The association between fluid management and severe dengue was more pronounced in patients with warning signs and older age groups.
These findings underscore the importance of judicious fluid administration in the management of dengue patients, emphasizing the need for close monitoring of clinical and laboratory parameters to guide fluid therapy. Healthcare providers should be cautious when administering high volumes of intravenous fluids to dengue patients, especially those with warning signs or high hematocrit levels, to minimize the risk of progression to severe disease.
Future research should focus on conducting randomized controlled trials to establish optimal fluid management strategies for dengue patients at different stages of the disease. Additionally, the development and validation of clinical prediction models incorporating fluid management strategies and other risk factors could help identify patients at high risk of severe dengue and guide individualized treatment decisions.
The findings of this study contribute to the growing body of evidence on the impact of fluid management on dengue outcomes and have important implications for clinical practice and public health interventions aimed at reducing the burden of severe dengue.