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. Each hospital included in our study was nationally accredited by the Indonesia Ministry of Health standard that ensures the quality of care and standard facilities for the patients. The list of hospitals included provide internal medicine specialty service and standardized laboratory examination. In addition, this research performed routine laboratories such as complete peripheral blood, urea, creatinine, lactate, and albumin that already frequently performed in this 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. All recruited patients are observed and managed according to medical standards, namely, hemodynamic examination, physical examination, and laboratory tests.
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 fever within 5 days 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, anemia, and malnutrition, and patients who declined to participate. List of definition are such as follows:
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Metabolic syndrome: as per the National Cholesterol Education Program Adult Treatment Panel III (NCEP AT) III guidelines that becomes the worldwide most used criteria in which metabolic syndrome is diagnosed when at least three of the following five criteria are met: waist circumference exceeding 40 inches for men or 35 inches for women, blood pressure above 130/85 mmHg, fasting triglyceride (TG) level over 150 mg/dl, fasting high-density lipoprotein (HDL) cholesterol level below 40 mg/dl for men or 50 mg/dl for women, and fasting blood sugar greater than 100 mg/dl [15].
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Hypertension: following the International Society of Hypertension (ISH) guidelines for Hypertension in 2020 similar with other major guidelines in which hypertension should be diagnosed when a person’s systolic blood pressure (SBP) in a clinical setting is 140 mm Hg or higher and/or their diastolic blood pressure (DBP) is 90 mm Hg or higher after repeated measurements to all adults over 18 years old [16].
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Coronary Heart Disease (CHD): according to American Heart Association (AHA), CHD, also known as coronary artery disease (CAD), is characterized by the buildup of plaque within the coronary arteries, which supply blood to the heart muscle. This plaque buildup, known as atherosclerosis, can lead to reduced blood flow and oxygen to the heart, resulting in chest pain (angina), heart attacks (myocardial infarction), or other serious heart conditions. The diagnostic criteria encompasses clinical evaluation, stress testing, and imaging tests such as echocardiography, coronary angiography, and blood tests [17].
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Cirrhosis: The American Association for the Study of Liver Diseases (AASLD) defines cirrhosis as a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue, and regenerative nodules leading to progressive loss of liver function. Diagnosis is often based on a combination of clinical, laboratory, imaging, and histological findings [18].
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Sepsis: according to The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), sepsis is defined as a life-threatening condition resulting from organ dysfunction caused by an abnormal response of the body to an infection. Clinically, this can be identified by an increase of 2 points or more in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, which correlates with an in-hospital mortality rate exceeding 10% [19].
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Kidney Failure: according to Kidney Disease: Improving Global Outcomes (KDIGO), kidney failure can be divided into Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD). CKD is a condition characterized by a gradual loss of kidney function over time. Kidney failure in CKD is defined as a glomerular filtration rate (GFR) of less than 15 mL/min/1.73 m2 or the need for initiation of kidney replacement therapy (dialysis or transplantation) irrespective of GFR. Meanwhile, Acute Kidney Injury (AKI) is defined as a sudden decrease in kidney function, often reversible. AKI stages range from mild to severe, with severe AKI [20].
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Anemia: is defined by WHO as a hemoglobin concentration below 110 g/L for children under 5 years old and pregnant women at sea level, and below 120 g/L for non-pregnant women. Anemia is characterized by a hemoglobin concentration that falls below a certain threshold, which varies based on factors such as age, gender, physiological status, smoking habits, and the altitude of the population being assessed [21].
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Malnutrition: the WHO defines malnutrition broadly and provides specific criteria for different forms including undernutrition (wasting, stunting, underweight) micronutrient deficiencies, overweight, and obesity. Wasting is defined as low weight-for-height, indicating recent and severe weight loss while stunting is defined as low height-for-age, indicating chronic malnutrition. In addition, underweight refers to low weight-for-age, a composite measure reflecting both acute and chronic malnutrition. Micronutrient Deficiencies are defined as deficiencies in essential vitamins and minerals, such as iron, iodine, vitamin A, and zinc. Lastly, overweight and obesity are defined as excess weight-for-height (overweight) or high body mass index (BMI) for age (obesity) [22].
Randomization
Random allocation using the block randomization method was generated by utilizing WINPEPI software, with an equal number of subjects in each block. The type of block that was chosen was a block of two in which each block was represented with at least one treatment and one control patient to ensure every block was represented proportionally.
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. This study used grade classification by WHO in 2011. Based on WHO, the criteria for diagnosing dengue fever include (1) acute or continuous fever for 2 to 7 days; (2) manifestation of thrombocytopenia (100,000 cells/mm3); (3) hemoconcentration (increased hematocrit > 20% of the basic hematocrit value), as well as a picture of plasma leakage. Further, dengue fever is divided into two main categories which are Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF). Dengue Fever (DF) is characterized by the following symptoms such as the sudden onset of high fever, severe headache, pain behind the eyes (retro-orbital pain), severe muscle and joint pains (often referred to as “breakbone fever”), nausea and vomiting, and rash. Meanwhile, DHF is a more severe form of the disease and is divided into four grades (I to IV) based on severity. Grade I is characterized by a fever accompanied by nonspecific symptoms with the only hemorrhagic manifestation being a positive tourniquet test. Grade II showed spontaneous bleeding in addition to the manifestations of Grade I. Grade III manifests several signs of circulatory failure, such as a rapid and weak pulse, narrowing of pulse pressure, or hypotension. Grade IV is signaled by a profound shock with undetectable blood pressure and pulse. Therefore, through serial multiple laboratory examinations for hematocrit level in a day, the researcher was able to group patients with grade I and II DHF and give early albumin intervention to prevent exacerbation of plasma leakage.
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 h intravenously for the intervention group. Further intravenous fluid therapy was administered according to the WHO guidelines. During treatment with 5% albumin, the patient’s albumin level was continuously monitored by the research team through serial laboratory measurements that were conducted twice or thrice a day and reviewed by the internist in charge who also checked the patients ‘condition regularly. No significant side effects were reported during treatment. 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 h 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 h 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 h. 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 6 ml of venous blood was drawn in the ER 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 complete blood count test and another 3 mL was used for the blood chemistry test. A urine sample for quantitative protein analysis was stored in a urine container filled with toluene for 24 h. 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.
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