Background
There are approximately 390 million dengue virus (DENV) infections worldwide, resulting in 500,000 hospitalizations and 20,000 deaths annually [
1]. The mosquito-borne DENV, of which there are four serotypes, causes substantial morbidity and mortality in tropical and sub-tropical regions of the world [
2]. The clinical manifestations of DENV infection range from a self-limited febrile illness comprising fever, rash, headache and myalgias known as dengue fever (DF) to a potentially life-threatening plasma leakage syndrome, dengue hemorrhagic fever (DHF). In the evaluation of DHF patients, plasma leakage may manifest as pleural effusion, ascites, or hemoconcentration [
2]. Pleural effusions are a common sign of plasma leakage in patients with DHF and have been positively correlated with disease severity [
2‐
4]. If detected early, the effects of plasma leakage are manageable with judicious use of intravenous fluids; case-fatality rates at experienced medical facilities ranges between 0.5% - 1%. However, progression to DHF often relies on serial history and physical examinations and clinical laboratory evaluations to detect hemoconcentration (rising hematocrit) and thrombocytopenia. Chest x-ray and ultrasound have also been shown to be effective in identification of pleural effusions and/or ascites in DHF patients [
3]. While non-invasive, these measurements are not practical for prediction of plasma leakage in resource poor settings. Due to the relatively rapid nature of the onset of shock, these crude measures may not be done at the appropriate time to support preventive fluid administration.
Near infrared spectroscopy (NIRS) is a non-invasive technique which can be used to continuously assess tissue oxygenation in cerebral as well as in muscle tissue. It has been widely used on children [
5] and has been shown to have important uses in trauma and critical care settings [
6]. Muscle oxygen saturation (SmO
2) is distinct from tissue oxygen saturation (StO
2) in that the determination of oxygenated and deoxygenated hemoglobin is performed on spectra which have been corrected for spectral interferences from skin pigment and fat [
7]. SmO
2 has been shown to be sensitive for the early detection of hypovolemia by tracking increased oxygen extraction resulting from peripheral vasoconstriction to shunt blood to the heart and brain [
8‐
10]. Since decreased peripheral perfusion is a clinical observation in patients with DHF [
2], we hypothesized that NIRS-determined SmO
2 would be effective in identifying DHF patients with significant plasma leakage. An easy, non-invasive method which would permit early (i.e. prior to more tradition clinical tools) identification of plasma leakage would be an invaluable tool for early identification of progression to DHF and support fluid management to prevent shock in children with severe dengue.
Discussion
To our knowledge, this is the first study to use NIRS to evaluate dengue patients for markers of plasma leakage that may result in shock. Our data show that SmO2 values less than 48% have a high sensitivity and specificity for being associated with pleural effusions in the study patients. A tool which permits real time detection of plasma leakage via SmO2 monitoring may help to determine which individuals will require earlier fluid intervention, thereby reducing the number of dengue patients who proceed to shock.
Earlier studies using strain gauge plethysmography demonstrated that pleural effusion in dengue patients was accompanied by microvascular fluid leakage into the extravascular space [
15]. Recent studies confirm that pleural effusions were the most common sign of plasma leakage in DHF patients [
3,
4]. Plasma leakage may result in reduced intravascular volume, a higher risk for shock and thereby reduced SmO
2. It has been previously demonstrated that SmO
2 is a very early indicator of central hypovolemia using a human laboratory model of pre-shock hemorrhage: lower body negative pressure (LBNP). Significant decreases in SmO
2 occurred well before decreases in blood pressure and arterial oxygen saturation by pulse oximetry (SpO
2) and increases in heart rate [
8,
9]. In the LBNP model, decreases in SmO
2 were highly correlated with increases in total peripheral resistance, indicating that this observed increase in oxygen extraction results from vasoconstriction that is shunting blood away from the skeletal muscle toward the heart in an effort to maintain normal blood pressure [
8,
10]. In a similar fashion, the decreases in SmO
2 observed in these DHF patients likely result from intravascular volume depletion and subsequent compensatory vasoconstriction.
In a study by Libraty et al., the ratio of extracellular to intracellular water (ECW/ICW) was determined by bioelectrical impedance spectroscopy for patients with DF, DHF and other febrile illnesses [
16]. Around the time of defervescence, the ECW/ICW ratio increased in proportion to disease severity. The authors suggested that the positive fluid balance that accompanied the increase in extracellular water was due to a reduction in renal water clearance [
16]. An increase in extravascular water could reduce tissue blood flow and increase oxygen extraction, thereby lowering SmO
2. During the time surrounding defervescence and fluid administration, it is not known if the decrease in SmO
2 is a result of hypovolemia or excess interstitial water reducing blood flow. Gaining a better understanding of this may help in developing tools to guide fluid resuscitation for dengue patients in a manner which will avoid fluid overload.
One limitation of this study may be the use of daily minimum SmO2 for statistical analysis. Patients without pleural effusion had fewer NIRS readings per day than patients with pleural effusion, likely because these patients were less sick and therefore more ambulatory.
This pilot study investigated the noninvasive monitoring of SmO2 in patients with dengue infection. Low levels of SmO2 were shown to be associated with pleural effusions detected with ultrasound and chest x-ray. This technology provides continuous SmO2 readout to track of the progression and treatment of patients with diseases which cause plasma leakage and heightened risk of shock. This initial study determined a SmO2 cutoff of 48%, but this value would need to be confirmed in additional dengue cohorts of both adults and children. Once validated, at risk patients could be routinely monitored because the display provides immediate feedback to the clinician. The SmO2 monitor is significantly lower in cost than ultrasound equipment, but it is recognized that to be widely adopted in countries with limited resources the cost to use it must be modest.
Acknowledgements
The authors thank the staff of the Department of Virology, Armed Forces Research Institute of Medical Sciences for sample collection, diagnostic testing, and research support; Dr. Suchitra Nimmannitya for reviewing the clinical diagnoses; doctors and nurses of the Queen Sirikit National Institute of Child Health for patient care; and the subjects and families who participated in this study. This work was supported by National Institutes of Health Grant NIH-P01AI34533 (AS ALR SG SK), the Military Infectious Disease Research Program (RVG IY SJT SK) and the Telemedicine & Advanced Technology Research Center (BS FZ).
The views expressed in this article are those of the authors and do not represent the official policy or position of the U.S. Department of the Army, Department of Defense, or U.S. Government.
Competing interests
BS and FZ are employees of Reflectance Medical Inc. and hold stock or stock options in the company. BS is an officer of Reflectance Medical. The remaining authors have no conflicts to declare.
Authors’ contributions
Conceived and designed the experiments: ALR BS IY SJT SG. Performed the experiments: RVG AS SJT SK. Analyzed the data: BS FZ ALR AS SJT SG. Enrolled patients: AS SK. Wrote the paper: BS AS ALR IY RVG SK SJT SG. All authors read and approved the final manuscript.