Dextran Fractional Clearance Studies in Acute Dengue Infection

Abstract

Although increased capillary permeability is the major clinical feature associated with severe dengue infections the mechanisms underlying this phenomenon remain unclear. Dextran clearance methodology has been used to investigate the molecular sieving properties of the microvasculature in clinical situations associated with altered permeability, including during pregnancy and in various renal disorders. In order to better understand the characteristics of the vascular leak associated with dengue we undertook formal dextran clearance studies in Vietnamese dengue patients and healthy volunteers. We carried out serial clearance studies in 15 young adult males with acute dengue and evidence of vascular leakage a) during the phase of maximal leakage and b) one and three months later, as well as in 16 healthy control subjects. Interestingly we found no difference in the clearance profiles of neutral dextran solutions among the dengue patients at any time-point or in comparison to the healthy volunteers. The surface glycocalyx layer, a fibre-matrix of proteoglycans, glycosaminoglycans, and plasma proteins, forms a complex with the underlying endothelial cells to regulate plasma volume within circumscribed limits. It is likely that during dengue infections loss of plasma proteins from this layer alters the permeability characteristics of the complex; physical and/or electrostatic interactions between the dextran molecules and the glycocalyx structure may temporarily restore normal function, rendering the technique unsuitable for assessing permeability in these patients. The implications for resuscitation of patients with dengue shock syndrome (DSS) are potentially important. It is possible that continuous low-dose infusions of dextran may help to stabilize the permeability barrier in patients with profound or refractory shock, reducing the need for repeated boluses, limiting the total colloid volume required. Formal clinical studies should help to assess this strategy as an alternative to conventional fluid resuscitation for severe DSS. Dengue is a potentially serious common viral infection with no specific treatment. Plasma leakage from small blood vessels is the major severe problem, but we do not understand how this occurs. Techniques using controlled infusions of carbohydrate solutions, combined with careful measurement of the rate that the different-sized molecules clear from the circulation, have been successfully used to investigate leakage in other situations. We performed carbohydrate clearance studies in 15 Vietnamese adult males with dengue and plasma leakage, comparing results obtained during the acute illness with recovery values, and results from a group of healthy volunteers. However, we found no differences between any of the clearance profiles measured. One possible explanation may be that the carbohydrate molecules interact with blood vessels, temporarily restoring their normal barrier function. Although this means that the technique is unsuitable for investigating leakage in dengue patients, the implications for management of patients with severe leakage resulting in shock are potentially important. Patients with profound shock are usually managed with intermittent large boluses of carbohydrate or similar solutions, sometimes causing severe side-effects; however if continuous low-dose infusions actually stabilized the permeability barrier, this might reduce the need for repeated boluses, thereby minimizing these adverse effects.