Early Intervention of 5% Albumin shown Superior Control of Vascular Integrity and Function Compared to Ringer’s Lactate in Hospitalized Adult with Grade I &amp; II Dengue Hemorrhagic Fever: A Multicenter Randomized Controlled Trial in Indonesia

doi:10.21203/rs.3.rs-4324185/v1

Download PDF

Research Article

Early Intervention of 5% Albumin shown Superior Control of Vascular Integrity and Function Compared to Ringer’s Lactate in Hospitalized Adult with Grade I & II Dengue Hemorrhagic Fever: A Multicenter Randomized Controlled Trial in Indonesia

https://doi.org/10.21203/rs.3.rs-4324185/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 01 Oct, 2024

Read the published version in Tropical Diseases, Travel Medicine and Vaccines →

You are reading this latest preprint version

Background

Dengue virus remains a major public health problem with one of the hallmark pathologies is the vascular leakage caused by endothelial dysfunction which can lead to Dengue Hemorrhagic Fever (DHF) manifestation. In the status quo, no specific therapy has been discovered but rather heavily relies on judicious and frequent monitoring of intravenous fluids administration. The current guideline has discussed the roles of fluid therapy during the Dengue Shock Syndrome (DSS) stage, however, administration of early fluid intervention for DHF grade I and II remains uncharted territory. In addition, the choice and timing of colloid administration remains underexplored. As one of the widely available colloids, 5% albumin has known physiological properties that potentially minimize plasma leakage. Therefore, this study aimed to evaluate the benefit of early intervention of 5% albumin in adults with DHF in the hope of preventing the lethal progression to DSS and further, shorten the length of stay (LOS) for patients.

Methods

We conducted a multicenter, open-labeled, randomized controlled trial in Jakarta and Banten to compare the effect of early intervention with 5% albumin in adult patients with DHF compared to Ringer’s Lactate (RL). Statistical analyses were conducted using unpaired t-test and Mann-Whitney for normally and abnormally distributed data respectively.

Results

Adult patients with a diagnosis of DHF grade I and II that being hospitalized to receive the early intervention of 5% albumin had significantly lower levels of hemoconcentration 4, 12, and 24 hours (p = 0.002, 0.001, 0.003, respectively), higher platelet counts 4 hours (p = 0.036), higher serum albumin levels 48 hours (p = 0.036), lower proteinuria 24 and 48 hours post-albumin administration (p < 0.001, < 0.001, respectively), and shorter LOS (p < 0.001) when compared to the RL group.

Conclusion

Early intervention of 5% albumin showed better control on vascular integrity and function compared to ringer lactate in hospitalized adults with grade I & II DHF, thus halting the progression of DHF into DSS and other related complications which leads to faster recovery and shorter length of stay.

Trial Registration:

The study was registered to www.clinicaltrial.gov with trial registration number NCT04076254, and registration date October 31st 2016.

Dengue hemorrhagic fever

albumin

plasma leakage

ringer lactate

hemoconcentration

colloid

Dengue fever, a devastating disease caused by the dengue virus (DENV) remains a serious worldwide problem and a major burden in Indonesia.¹ Based on a global study, it was recorded that 400 million cases of dengue fever with over 22.000 deaths occurred annually, and further dengue infection becomes established both as epidemic and endemic transmission cycles.² The dramatic climate changes, high humidity especially in the equatorial region, and widespread urbanization all over the nation made the environment more suitable for Aedes aegypti, the host for DENV.³ DENV is classified into the genus Flavivirus, and belongs to the Flaviviridae family, with its main characteristic being a positive-stranded ribonucleic acid (RNA) genetic material. Four strains of DENV have been discovered (DENV-1,2,3,4) and currently a new serotype, DENV-5 reported from Malaysia back in 2007.⁴

According to the worldwide epidemiology study, Indonesia has the second-highest prevalence of dengue fever among 30 dengue-endemic countries.⁵ In addition, although the case fatality rate of DHF has changed significantly the number of incidences has been varying if not the trend tends to increase as a result of climate change and urbanization in Indonesia.⁶ Dengue fever has a spectrum of clinical manifestations, that includes from asymptomatic, unspecified mild fever to severe DHF and DSS.⁷ Although, the human immunity system can provide long-lasting protection after dengue fever infection specified into one serotype, it only gives partial and temporary effects toward other serotypes which can cause recurrence and multitude complications.⁸

To date, there is no specific treatment for dengue, and it mostly relies on judicious and frequent monitoring of fluid administration with no available practical guideline changes since the release of the 1997 World Health Organization (WHO) guidelines. It was suggested that colloids can be administered if the patient remains unresponsive to crystalloid administration that is being given to manage the increase of hemoconcentration above 20% as the primary hallmark of vascular leakage.^6,7 Patients with DHF and DSS can be treated with a variety of colloids, including 5% albumin. Albumin is a non-synthetic colloid that, due to its oncotic properties, is potent as a volume replacement. It has multiple physiological capabilities including an antioxidant, an anticoagulant, an anti-inflammatory agent, along a potent maintainer of vascular integrity.⁹ Furthermore, non-synthetic colloids are known to have fewer side effects than synthetic colloids.¹⁰

Despite years of advancements, the timing and indication for using colloid over another fluid therapy in DHF patients have not been fully elucidated. Currently, only four randomized clinical trials have explored different options of fluid therapies in DHF and DSS, but none of these trials have compared colloids such as 5% albumin specifically to crystalloids in exploring their full potency in improving vascular integrity and function in DHF patients. In addition, most trials focused on administering fluid therapy in severe DHF or DSS patients only in which widespread plasma leakage has occurred, thus limiting the benefit of fluid therapy to some extent. ^9–14 This highlights that no research has tried different approaches by administering fluid therapy such as 5% albumin as an early intervention despite its various physiological potency. Thus, we conducted a first, open-labeled, multi-centered, randomized controlled trial in Jakarta and Banten, Indonesia that sought to investigate the effectiveness of early intervention of 5% albumin compared with ringer lactate as standard treatment in dengue patients’ vascular integrity and function, in an attempt to prevent further progression of the hospitalized DHF grade I and grade II patients that would subsequently lead to shortening the length of stay and optimal treatment.

Aims

This study aims to evaluate the effect of early intervention of 5% albumin in comparison with RL as standard fluid therapy in dengue patients to prevent plasma leakage and its complications. This study assesses several outcomes relating to vascular integrity and function including hemoconcentration, thrombocyte level, albumin level, and proteinuria of patients that signify the progression of DHF. Further, this study also assesses the difference in length of stay (LOS) between intervention and control populations.

Study Design

This study was conducted as an open-labeled, multicenter, randomized controlled trial (RCT) using the concealment procedure. The study protocol has obtained ethical clearance from the ethics committee of Fakultas Kedokteran Universitas Indonesia-Rumah Sakit Ciptomangunkusumo (No.211/UN2.F1/ETIK/2016) and the study was registered to www.clinicaltrial.gov (NCT04076254).

Location, Setting, and Period of the Study

This multicenter study was conducted in several Indonesian governments and private hospitals located in Jakarta and Banten provinces. The hospitals were as follows: Tangerang Selatan District Hospital, Hermina Ciputat Hospital, Cengkareng District Hospital, Taman Sari District Hospital, Kembangan District Hospital, and Royal Taruma Hospital. Recruitment of patients started from January 2018 to February 2019. Grade I and II DHF patients were recruited from the emergency room or the ward by internists who were enrolled in the study team.

The Population of the Study

The target population of this study is hospitalized adult grade I and II DHF patients according WHO Classification of Dengue Infections and Grading of Severity of DHF 2011.

Eligibility Criteria

This study included hospitalized grade I and II DHF patients between the ages of 18 and 60 who had a 3-day history of fever and were diagnosed with dengue infection based on positive non-structural protein-1 (NS1) and/or serological tests, and the evidence of early plasma leakage by an increased more than 10% hematocrit from baseline, with or without hypoalbuminemia.

The exclusion criteria were pregnancy confirmed by the presence of β-Human chorionic gonadotropin (β-HCG) in urine, patients in their menstrual period, patients with any of the following conditions: metabolic syndrome, hypertension, coronary heart disease, cirrhosis, sepsis, kidney failure, hematological abnormalities, and malnutrition, and patients who declined to participate.

Randomization

Random allocation using the block randomization method was generated by utilizing WINPEPI software, with an equal number of subjects in each block.

Concealment Procedure

The randomization results were encased in a non-transparent envelope. The recruitment number was written on the outside of the envelope. In the envelope was inserted a piece of paper with the coded information of which fluid therapy was administered to the subject. The envelope was opened by the investigator when the patient was about to receive the fluid therapy. The investigator, the pharmacist, and the patient were all unblinded.

Recruitment Procedure

The study used a consecutive sampling of patients who met the eligibility criteria. The attending physicians recruited the potential patients. The physicians then requested the patient’s informed consent to participate in this study. If the patient agreed, they were asked to sign an informed consent form.

Interventions

All recruited subjects were observed and treated according to the standard of care of DHF management. This standard of care includes routine laboratory tests such as complete blood count, alanine transaminase, aspartate aminotransferase, and albumin. Additional laboratory examinations performed for this study include creatinine, urine, blood glucose, and urine β-HCG. All these laboratory examinations were performed at the respective hospital that was chosen as the site of a clinical trial.

The fluid therapy was administered to the recruited subjects according to the randomization that had been initially performed. The intervention group received 5% albumin while the control group received ringer’s lactate (RL). Other than the fluid therapy from the trial, both groups receive fluid therapy and other interventions in line with the WHO 1997 guidelines. The researcher, study subject, and the attending physician were not blinded in giving a fluid therapy regimen.

After the patient was enrolled in the study, RL was administered at a rate of 3–5 mL per kilogram body weight (BW) (1500–2000 mL/day) for the control group, and 5% albumin 250 mL was administered 4 hours intravenously for the intervention group. Further intravenous fluid therapy was administered according to the WHO guidelines. The participants of the study were observed for signs of hypovolemic shock and bleeding. Hypovolemic shock and bleeding in the study subjects were treated according to WHO guidelines.

All the study subjects were observed for their clinical conditions as well as serial laboratory examinations that included complete blood count 4,12-, and 24-hours post-intervention. The levels of serum albumin level and quantitative urine protein were measured 24- and 48-hours post-intervention. An experienced clinical pathologist supervised all these laboratory tests. A radiologist performed an abdominal ultrasonography (USG) four to five days after the patient's fever began to look for signs of further plasma leakage in the form of pleural effusion or ascites. The USG operator printed and/or wrote the abdominal USG results in the medical record.

Outcomes

The primary outcome of this study was the mean of delta hemoconcentration. This value was obtained by subtracting the highest hematocrit value and the lowest hematocrit value and then multiplied by 100% at 4,12, and 24 hours post-intervention using automatic hematologic analysis Sysmex XN-1000

The secondary outcomes of this study were delta platelets, serum albumin, proteinuria, and the length of stay. Delta platelets were defined as the thrombocyte count 4,12, and 24 hours post-intervention subtracted by the baseline thrombocyte value. Serum albumin was defined as the total amount of albumin (in grams) in 100mL of serum, analyzed by using bromocresol green via Architect Plus C 8000, Abbot, or Cobas C111. Proteinuria was defined as urine protein of more than 150 mg in 24 hours. Length of stay (LOS) was defined as the total number of days the patient was hospitalized, starting with the admission to the hospital until the patient was discharged by the attending physician.

The investigators entered the data into a case report form and monitored for adverse events (AE) and severe adverse events (SAE). All AE and SAE were reported to the ethics committee of each respective site. Bleeding was an expected AE, due to the pathophysiology of DHF and shock was a possible SAE as there is the possibility of disease progression from DHF to DSS.

Management of Samples

As many as 10.5 mL of venous blood was drawn in the emergency room or the ward (according to the location of the study subject). As many as 3 mL of venous blood from each subject was used for the laboratory test. A urine sample for quantitative protein analysis was stored in a urine container filled with toluene for 24 hours. Each site's laboratory received a complete blood count, albumin, biochemistry, and urine sample.

Variables

The independent variable was the fluid therapy, which was either 5% albumin for the intervention group or RL for the control group. The dependent variables were hematocrit, platelet count, serum albumin, urine protein, and length of stay.

Statistical Analysis

The data collected in this study were recorded in a case record form, clarified, and analyzed descriptively to show the baseline characteristics of the subjects. The Kolmogorov-Smirnov test was used to assess whether the data were normally distributed. The mean differences between groups were analyzed using an unpaired t-test for normally distributed data, and Mann–Whitney test for abnormally distributed data. Additional, adjusted, and subgroup analyses were not performed in this study.

In total, 126 subjects were recruited in the study from January 2018 until February 2019. Out of 126 patients, only 84 patients underwent randomization due to the exclusion criteria and insurance issues. After randomization, 42 patients were assigned to the RL group and 42 patients were assigned to the 5% albumin group. There was no significant difference in patient characteristics or baseline values between the RL and the 5% albumin groups.

Table 1 shows serial platelet counts and hematocrit values were measured every 4, 12, and 24 hours post-intervention. Early intervention with 5% albumin significantly decreased the elevation of hematocrit compared to the RL group.

Table 1

Baseline Characteristics of Subjects Receiving Early Intervention with 5% Albumin compared with Standard Care (RL)
Variable	Group
Variable	RL (n = 42)	Albumin 5% (n = 42)
Sex, n (%)
Males	27 (64.3)	20 (47.6)
Females	15 (35.7)	22 (52.4)
Age (years), median (IQR)	32 (23–39)	31 (21–36)
Fever (days), median (IQR)	3 (3–4)	3 (3–4)
DHF Grade
I	36 (85.7)	38 (90.5)
II	6 (14.3)	4 (9.5)
Infection
Primary	13 (31.0)	6 (14.3)
Secondary	29 (69.0)	36 (85.7)
Ureum (mg/dL), median (IQR)	22 (18.5–27.25)	23.5 (18.25–29.25)
Creatinine (mg/dL), median (IQR)	0.84 (0.6–1.07)	0.90 (0.70‒1.17)
Baseline serum Albumin (g/dL), median (IQR)	3.72 (3.4–4.10)	3.93 (3.67–4.12)
Baseline platelet (10³/µL), mean (SD)	113166.6 (17266.6)	110642 (18834)
Baseline hemoglobin (g/dL), mean (SD)	14.33 (SD 1.46)	13.94 (SD 1.52)
Baseline hematocrit (%), mean (SD)	40.50 (SD 4.38)	40.52 (SD 4.53)

Serial platelet counts and hematocrit values were measured every 4, 12, and 24 hour post-intervention. At all-time intervals after the intervention, Early intervention with 5% albumin significantly decreased the elevation of hematocrit compared to the RL group. (Table 2).

Table 2

Mean Difference in Hematocrit Values Between the 5% Albumin and the RL Groups
Mean Differences of Hematocrit (%)	Group		p*
Mean Differences of Hematocrit (%)	RL (n = 42)	Albumin (n = 42)	p*
4th hour, mean (SD)	-0.34 (2.29)	-2.26 (3.19)	0.002
12th hour, mean (SD)	-0.23 (2.72)	-2.38 (2.94)	0.001
24th hour, mean (SD)	-0.71 (3.04)	-2.67 (2.79)	0.003

*Unpaired T-test

Table 3 shows the 5 percent- albumin group has a significant reduction in thrombocytopenia 24 hours after the intervention. Intriguingly, there was no significant difference in thrombocytopenia between the two groups at the 4th and 12th-hour post-intervention.

Table 3

Mean Differences in Platelet Count Between the 5% Albumin and the RL Groups
Mean Differences of Platelet Count (10³/µl)	Groups		p*
Mean Differences of Platelet Count (10³/µl)	RL (n = 42)	Albumin 5% (n = 42)	p*
4th hour, mean (SD)	-34976 (20689.92)	-30350 (23846.84)	0.345
12th hour, mean (SD)	-41833 (28952.37)	-33109.52 (32377.29)	0.197
24th hour, mean (SD)	-45430 (36779.43)	-27095.23 (41931.30)	0.036

*Unpaired T-test

Table 4 shows at the 24th and 48th-hour post-intervention, serial serum albumin and quantitative urine protein levels were measured. We found no significant difference in mean differences of albumin levels at the 24th-hour post-intervention, but a significant decrease was obtained in the 5 percent albumin group at the 48th-hour post-intervention

Table 4

Mean Differences in Serum Albumin Level Between the 5% Albumin and the RL Groups
Mean Differences of Albumin Serum (g/dL)	Groups		p*
Mean Differences of Albumin Serum (g/dL)	RL (n = 41)	Albumin 5% (n = 42)	p*
24th hour, mean (SD)	-0.27 (0.32)	-0.15 (0.38)	0.121
48th hour, mean (SD)	-0.25 ( 0.37)	-0.086 (0.32)	0.036

*Unpaired T-test

Table 5 shows, the 5 percent albumin group had a significant decrease in proteinuria at all-time points. In addition, a significant decrease in the median length of stay (median: 4, IQR: 3–5) compared to the RL group (median: 5, IQR: 4–6) with a p-value less than 0.001

Table 5

Median and Inter Quartile Range of in Proteinuria Between the 5% Albumin and the RL Groups
Quantitative Urine Protein (mg/dL)	Groups		p**
Quantitative Urine Protein (mg/dL)	RL (n = 42)	Albumin 5% (n = 40)	p**
24th hour, median (IQR)	230.00 (27.00–1459.00)	93.00 (6.00–768.00)	<0.001
48th hour, median (IQR)	212.00 (0.00–1625.00)	68.00 (0.00–579.00)	<0.001

**Mann Whitney

Adults with grade I and II DHF are at risk of developing grade III and IV DHF if there is a continuation of plasma leakage. The mechanism under this phenomenon is explained by the transient progression of vascular permeability which is caused by endothelial dysfunction that occurs in the severe stage such as in grade III and IV DHF.¹⁵ Although the vascular leakage and its pathogenesis were not yet fully elucidated, it was known that the vascular permeability was associated with vascular leakage, further creating an accumulation of fluid both in peritoneal and pleural cavities, that subsequently led to a systematic decrease of blood and pulse pressure, ultimately lead to poor organ perfusion and mortality.¹⁶ Deeper analysis investigating the molecular process finds that complex interaction between host endothelial cells, immune response, and virus along with serotype-cross antibodies and its mediators, contribute to disruption in the barrier integrity leading to non-functional endothelial cells that produce plasma leakage.¹⁷ Hemoconcentration becomes one of the main processes that indicates the presence of plasma leakage, and this occurred almost always in the case of classic DHF and becomes even more prominent in patients with severe DHF and shock.¹⁸

In adults with grade I and II DHF, early intervention with albumin at 5% significantly reduces hemoconcentration at 4,12, and 24 hours post-intervention compared to the RL group. This indicates that the administration of 5% albumin may prevent additional plasma leakage and show superior results compared to crystalloid in this case RL. This observation can be explained by the oncotic features of colloid, which is its capacity to generate plasma expansion by maintaining intravascular volume for an extended period while retracting previously extravasated fluid through exerting an increase of oncotic pressure.⁹ In addition, the anti-inflammatory and antioxidant properties of albumin may mitigate the damage to the surface of vascular endothelial cells induced by cytokines, NS1-DENV, and the activation of complement factors.⁸ This suggests that, while other colloids may be able to normalize hematocrit values rapidly,^9–12 the physiological function of albumin may provide advantages in DHF patients when compared to other commonly used colloids which also warrant further molecular investigation and clinical trial.

This study also found that early intervention with 5% albumin significantly reduced thrombocytopenia 24 hours after intervention compared to the RL group. A prior study found no significant differences in mean platelet count during admission and after hospitalization.¹¹ While, other fluid resuscitation trials on DHF and DSS patients did not measure thrombocytopenia as an outcome.^10–14 The reduced platelet count can be explained by the effect of albumin on platelets. Albumin has anticoagulant and anti-aggregation properties. Albumin binds anti-thrombin, which increases the neutralization of coagulation factor Xa. Albumin also binds with platelet-aggregating molecules such as arachidonic acid, thromboxane A2, platelet-activating factor (PAF), and prostacyclin.¹⁹ While thrombocytopenia may not be associated with bleeding events during the disease,²⁰ sequential platelet count was found as a significant predictor of progression to DSS in children.²¹ This suggests that early intervention with 5% albumin may prevent DHF from progressing to DSS.

Early intervention with 5% albumin in DHF patients was also found to significantly decrease hypoalbuminemia compared to the RL group in 48 hours post-albumin administration. Most dengue fluid therapy trials did not measure serum albumin post-intervention. In addition, only one study¹⁰, found that serum albumin levels were not significantly different between groups on trial that used four different IV therapies which includes colloids (protein digest gelafundin 35,000 or dextran 70) or crystalloids (0.9%-weight/volume saline or Ringer’s lactate). It should be remarked that in another study, instead of 5% albumin, hyperosmolar sodium lactate (HSL) was used in the intervention group.¹² Hyperosmolar sodium lactate and most colloids are not known to affect endothelial integrity, whereas albumin does. Albumin is one of the hallmarks of plasma leakage. It is well known that the transcapillary escape rate of albumin significantly increased 48 hours after inflammation.²² Interestingly, early intervention with 5% albumin significantly decreased hypoalbuminemia, implying that 5% albumin has a repairing effect on the endothelium through plasma expansion and decreasing the rate of transcapillary escape.²³

Based on the observation, it shows that early intervention with 5% albumin significantly reduced proteinuria at 24- and 48 hours post-intervention in Grade I and II DHF adult patients compared to the RL group. Current research has proposed that proteinuria can be used as a prognosticating adult dengue patient with a high level of sensitivity and specificity.²⁴ Proteinuria should be highlighted since it can predict the severity and likely development of DHF to DSS, as well as identify patients with DHF who require close monitoring.^25–26 Despite this finding, proteinuria was not measured in the majority of DHF resuscitation fluid studies.^10–13 Proteinuria in DHF can be explained by the vascular endothelial glycocalyx dysfunction in the glomerulus and proximal tubules, as well as microvascular hypoxia caused by plasma leakage.⁸ This suggests that early intervention with 5% albumin could possibly repair and maintain vascular integrity, thereby reducing plasma leakage. Therefore, early intervention with 5% albumin may prevent the progression of DHF to DSS, which is characterized by a decrease in proteinuria.

Up until now, 5% albumin has not been investigated in many RCT.^10–13 According to a large-scale trial, five percent albumin and saline were both equally effective for intravascular volume resuscitation. However, it should be noted that this was a large-scale trial conducted in a heterogeneous population of Intensive Care Unit (ICU) patients, not specifically for DHF or DSS patients, and its effect to prevent further plasma leakage cannot be generalized from its outcome.²⁷ In addition, not only judicious reasoning between the usage of crystalloid or colloid is needed, but another conundrum arises in choosing between natural or synthetic colloid. Albumin is a natural colloid with various advantages over synthetic colloids like dextran, gelatin, and starch. Non-synthetic colloids have fewer side effects of pruritus, anaphylactoid responses, and coagulopathy.²⁸ Albumin also has anti-inflammatory, ligand-binding, and antioxidant properties. Therefore, albumin has potential advantages over other commonly used synthetic colloids due to its innate physiological properties. Albumin's function may allow it to be used not only as a symptomatic volume replacement but also as a preventive and curative approach to DHF patients.

Early intervention with 5% albumin significantly decreased the LOS in patients following early intervention with 5% albumin. Another problem relating to this scope of outcome is that most fluid resuscitation trials in dengue infection did not include the LOS as a study outcome.^10–13 One of the research found that DHF as a relatively high cost of illness that includes both direct and indirect costs, also further concludes that the correlation between the LOS in the cost of hospitalization was significant in DHF patients.²⁹ Therefore, LOS should be more highlighted as it possibly generates more cost-effective treatment for patients and hospitals.

Although Ringer Lactate still offers benefits in managing grade I and grade II DHF adult patients, the superior benefit of 5% albumin shown by this RCT should have its spotlight and be further taken into consideration. Despite these promising findings, 5% albumin is still not widely available in many healthcare facilities due to its high cost. It is important to note that Indonesia has one of the world’s highest dengue infection economic burdens, with hospitalized care accounting for 90% of the cost.³⁰ This potential cost-effective treatment relies on the albumin’s function in maintaining vascular integrity along with its physiological properties that enhance the recovery progress, prevent the lethal progression of DHF to DSS, and further reduce the number of administrations to the ICU subsequently cutting the need for intensive treatment.¹⁹ Therefore, further research with a larger scale is warranted on how early intervention with 5% albumin can deliver cost-effective treatment to patients and hospitals, and be further implemented in guidelines.

To the best of our knowledge, this is the first RCT in Indonesia that uses 5% albumin as an early intervention in DHF. We conducted a multi-centered randomized controlled trial, in which the randomization was done using a computer, resulting in equal characteristics in both groups. The analysis was carried out using the Intention-to-Treat (ITT) technique, which is a pragmatic analysis technique used in clinical trials. The external assessment was also conducted objectively. Therefore, this study has good internal validity. However, it was not possible to conduct a double-blinded study. This was because the dosage form and the packaging of 5% albumin and ringer’s lactate were different and the researcher could not alter the packaging as both fluids were already in a sterile condition. Hence, we conducted an open-labeled study. We recommend that future trial to be conducted in pediatric populations since the mortality rate of DENV infection and the prevalence of DSS is higher in children.

Early intervention with 5% albumin significantly decreased hemoconcentration, thrombocytopenia, proteinuria, and increased serum albumin levels, as well as the shortened length of stay in adult with grade I and II DHF, compared to RL. The findings suggest that the early intervention with albumin may aid in maintaining vascular integrity during plasma leakage and potentially preventing DHF from progressing to DSS.

adverse events

β-HCG

β-Human chorionic gonadotropin

Body Weight

DENV

Dengue Virus

DHF

Dengue Hemorrhagic Fever

DSS

Dengue Shock Syndrome

HSL

Hyperosmolar Sodium Lctate

ICU

Intensive Care Unit

ITT

Intention-to-Treat

LOS

Length of Stay

NS-1

Dengue Non-Structural Protein-1

PAF

Platelet-Activating Factor

RCT

Randomized Controlled Trial

Ringer’s Lactate

RNA

Ribonucleic Acid

SAE

Severe Adverse Events

USG

Ultrasonography

WHO

World Health Organization

Ethics Approval and Consent to Participate.

Ethics was approved by the ethics committee and the authors made sure the study was conducted by the principles listed in the Declaration of Helsinki and the authors made sure the study was conducted following the ICH Guidelines for Good Clinical Practice. All participants enrolled in this study gave their written informed consent.

Consent for Publication.

Not applicable.

Availability of Data and Materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing Interests

The authors declare that they have no competing interests.

Funding

This study was not sponsored or funded by any institution or body.

Author’s Contribution

RB conveyed the whole trial and was involved in the protocol design, data collection, data interpretation, and the writing of this manuscript. SS was involved in the design of the study protocol and acted as the main advisor of the trial. HP was involved in the design and an acting supervisor of the trial. JP was involved in the data analysis of the trial. HAR was involved and the data collection and sample management of the trial. BED was involved in the design of the study protocol and acted as supervisor of the trial. MS was acting as supervisor of the trial. AR was an acting supervisor of the trial and was involved in the substantial revision of the manuscript. HY was an acting supervisor of the trial.

Acknowledgment

The author would like to greatly appreciate all the patients and their families who have consented to participate in this trial and provided essential biological samples and data and the author would like to thank the Faculty of Medicine, the University of Indonesia for providing the author with the facilities to conduct this trial.

Author Information

Name : Dr. dr. Rika Bur. SpPD-KPTI

Affiliation : Division of Tropical and Infectious Disease, Departement of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Harapan Kita Women and Children National Hospital, Jakarta, Indonesia

Email address : [email protected]

ID Orcid : https://orcid.org/0000-0002-2863-4115

Name : Prof.Dr. dr. Suhendro. SpPD-KPTI

Affiliation : Division of Tropical and Infectious Disease, Departement of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Email address : [email protected]

ID Orcid : https://orcid.org/0000-0001-6394-0591

Name : Dr. dr. Joedo Prihartono, MPH.

Affiliation : Community Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Email address : [email protected]

ID Orcid : https://orcid.org/0000-0001-5684-9693

Name : Dra. Beti Ernawati Dewi, PhD.

Affiliation : Microbiology Department, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Email address : [email protected]

ID Orcid : https://orcid.org/0000-0001-5671-1299

Name : Dr. dr. Andhika Rachman, SpPD-KHOM

Affiliation : Division of Hematology and Oncology, Departement of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Email address : [email protected]

ID Orcid : https://orcid.org/0000-0003-3246-3352

Name : dr. Alida Roswita Harahap, SpPK (K), PhD.

Affiliation : Eijkman Institute for Molecular Biology, Jakarta, Indonesia

Email address : [email protected]

ID Orcid : http://orcid.org/0000-0001-7879-8321

Name : Prof. dr. Herdiman T Pohan. SpPD-KPTI

Affiliation : Division of Tropical and Infectious Disease, Departement of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Email address : [email protected]

ID Orchid : http://orcid.org/0000-0003-4680-5712

Name : Prof. dr. Mohamad Sadikin, D.Sc.

Affiliation : Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Email address : [email protected]

ID Orchid : http://orcid.org/0000-0001-7511-0050

Utama IMS, Lukman N, Sukmawati DD, Alisjahbana B, Alam A, Murniati D et al. Dengue viral infection in Indonesia: Epidemiology, diagnostic challenges, and mutations from an observational cohort study. PLoS Negl Trop Dis. 2019;13(10).
Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. The global economic burden of dengue: a systematic analysis. Lancet Infect Dis. 2016;16(8):935–41.
Roy SK, Bhattacharjee S. Dengue virus: epidemiology, biology, and disease aetiology. Can J Microbiol. 2021;67(10):687–702.
Mustafa MS, Rasotgi V, Jain S, Gupta V. Discovery of fifth serotype of dengue virus (DENV-5): A new public health dilemma in dengue control. Med J Armed Forces India. 2015;71(1):67–70.
Harapan H, Michie A, Mudatsir M, Sasmono RT, Imrie A. Epidemiology of dengue hemorrhagic fever in Indonesia: Analysis of five decades data from the National Disease Surveillance. BMC Res Notes. 2019;12(1).
World Health Organization. Regional Office for South-East Asia. Comprehensive guidelines for prevention and control of dengue and dengue hemorrhagic fever. World Health Organization Regional Office for South-East Asia; 2011. p. 196.
World Health Organization. Dengue hemorrhagic fever: diagnosis, treatment, prevention, and control. World Health Organization; 1997. p. 84.
Collins SR, Blank RS, Deatherage LS, Dull RO. The endothelial glycocalyx: Emerging concepts in pulmonary edema and acute lung injury. Anesth Analg. 2013;117(3):664–74.
Nainggolan L, Wiguna C, Hasan I, Dewiasty E. Gallbladder Wall Thickening for Early Detection of Plasma Leakage in Dengue Infected Adult Patients. Acta Med Indones. 2018;50(3):193–9.
Dung NM, Day NPJ, Tam DTH, Loan HT, Chau HTT, Minh LN et al. Fluid Replacement in Dengue Shock Syndrome: A Randomized, Double-Blind Comparison of Four Intravenous Fluid Regimens [Internet]. 1999. https://academic.oup.com/cid/article/29/4/787/451550.
Somasetia DH, Setiati TE, Sjahrodji AM, Idjradinata PS, Setiabudi D, Roth H et al. Early resuscitation of dengue shock syndrome in children with hyperosmolar sodium-lactate: A randomized single-blind clinical trial of efficacy and safety. Crit Care. 2014;18(5).
Wills BA, Nguyen MD, Ha TL, Dong TH, Tran TN, Le TT, Tran VD, Nguyen TH, Nguyen VC, Stepniewska K, White NJ, Farrar JJ. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med. 2005;353(9):877–89.
Nhan NT, Xuan C, Phuong T, Kneen R, Wills B, van My N et al. Acute Management of Dengue Shock Syndrome: A Randomized Double-Blind Comparison of 4 Intravenous Fluid Regimens in the First Hour [Internet]. https://academic.oup.com/cid/article/32/2/204/319560.
Prasetyo R, Azis A, Soegijanto S. Comparison of the efficacy and safety of hydroxyethyl starch 130/0.4 and Ringer’s lactate in children with grade III dengue hemorrhagic fever. Paediatr Indones. 2009;49(2):97–103.
Lee TH, Lee LK, Lye DC, Leo YS. Current management of severe dengue infection. Expert Rev Anti Infect Ther. 2017;15:67–78.
Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. Microvascular and endothelial function for risk prediction in dengue: an observational study. Lancet. 2015;385(Suppl 1):S102.
Eram S, Setyabudi Y, Sadono TI, Sutrisno DS, Gubler DJ, Sulianti-Saroso J. Epidemic dengue hemorrhagic fever in rural Indonesia: clinical studies. Am J Trop Med Hyg. 1979;28:711–6.
Srikiatkhachorn A. Plasma leakage in dengue haemorrhagic fever. Thromb Haemost. 2009;102(6):1042–9.
Paar M, Rossmann C, Nusshold C, Wagner T, Schlagenhauf A, Leschnik B et al. Anticoagulant action of low, physiologic, and high albumin levels in whole blood. PLoS ONE. 2017;12(8).
John KJ, Gunasekaran K, Prasad JD, Mathew D, Das S, Sultan N, Abraham AM, Iyyadurai R. Predictors of Major Bleeding and Mortality in Dengue Infection: A Retrospective Observational Study in a Tertiary Care Centre in South India. Interdiscip Perspect Infect Dis. 2019;2019:4823791.
Lam PK, van Ngoc T, Thu Thuy TT, Hong Van NT, Nhu Thuy TT, Hoai Tam DT et al. The value of daily platelet counts for predicting dengue shock syndrome: Results from a prospective observational study of 2301 Vietnamese children with dengue. PLoS Negl Trop Dis. 2017;11(4).
Komáromi A, Estenberg U, Hammarqvist F, Rooyackers O, Wernerman J, Norberg Å. Simultaneous assessment of the synthesis rate and transcapillary escape rate of albumin in inflammation and surgery. Crit Care. 2016;20(1).
Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF. Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular permeability. Anesthesiology. 2006;104(6):1223–31.
Charisma AM, Farida EA, Anwari F. Detection Of Proteinuria By Colorimetric Method And Correlation With Disease Severity In Patients Dengue. Indones J Med Lab. 2021;27(3):244–8.
Vasanwala FF, Thein TL, Leo YS, Gan VC, Hao Y, Lee LK et al. Predictive Value of Proteinuria in Adult Dengue Severity. PLoS Negl Trop Dis. 2014;8(2).
Vasanwala FF, Puvanendran R, Fook-Chong S, Ng JM, Suhail SM, Lee KH. Could peak proteinuria determine whether patients with dengue fever develop dengue hemorrhagic/dengue shock syndrome? - A prospective cohort study. BMC Infect Dis. 2011;11.
Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247–56.
Mitra S, Khandelwal P. Are all colloids same? How to select the right colloid? Indian J Anaesth. 2009;53(5):592–607.
Supadmi W, Izzah QN, Suwantika AA, Perwitasari DA, Abdulah R. Cost of Illness Study of Patients with Dengue Hemorrhagic Fever at One of the Private Hospitals in Yogyakarta. J Pharm Bioallied Sci. 2019;11(Suppl 4):S587–93.
Nadjib M. The economic burden of dengue in Indonesia. Int Pest Control. 2019;61(2):90–1.

No competing interests reported.

Download PDF

Journal Publication

published 01 Oct, 2024

Read the published version in Tropical Diseases, Travel Medicine and Vaccines →

Editorial decision: Revision requested
26 Jun, 2024
Reviews received at journal
09 Jun, 2024
Reviews received at journal
04 Jun, 2024
Reviewers agreed at journal
28 May, 2024
Reviewers agreed at journal
23 May, 2024
Reviewers invited by journal
23 May, 2024
Submission checks completed at journal
06 May, 2024
Editor assigned by journal
06 May, 2024
First submitted to journal
25 Apr, 2024

You are reading this latest preprint version

Early Intervention of 5% Albumin shown Superior Control of Vascular Integrity and Function Compared to Ringer’s Lactate in Hospitalized Adult with Grade I & II Dengue Hemorrhagic Fever: A Multicenter Randomized Controlled Trial in Indonesia

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Methods

Aims

Study Design

Location, Setting, and Period of the Study

The Population of the Study

Eligibility Criteria

Randomization

Concealment Procedure

Recruitment Procedure

Interventions

Outcomes

Management of Samples

Variables

Statistical Analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1