Digestive Diseases and Sciences | 2019
Development and Pathophysiology of Oral Rehydration Therapy for the Treatment for Diarrhea
Abstract
Acute diarrhea is a major health problem primarily in the developing world and especially in the young. Multiple infectious organisms frequently transmitted via contaminated water and food are responsible for enteric diseases [1]. Profuse watery diarrhea may frequently lead to substantial fluid losses, dehydration, and death if adequate rehydration is not provided. During the past decade, emphasis has focused on the effects of repeated episodes of infectious diarrhea that often lead to altered intestinal function—environmental enteropathy (EE)—frequently resulting in physical and/or mental stunting [2]. This latter phenomenon is beyond the scope of this present discussion that will focus on the development of and rationale for oral rehydration solutions (ORSs) in the treatment for acute diarrhea. Acute diarrhea is often self-limiting, but morbidity is frequently related to the effects of severe dehydration, especially in very young children. Prior to the development of ORS over the past 50 years, the traditional approach to the treatment for acute diarrhea was either fasting (i.e., nil per os or NPO) or fluid replacement with the administration of water. These approaches were not satisfactory as acute diarrhea and especially that seen in cholera were associated with extremely high mortality and morbidity. In western countries, volume depletion associated with severe diarrhea is treated with intravenous fluid replacement. Nevertheless, the ability to provide intravenous fluids to provide rehydration in such patients is markedly limited in most developing countries, especially during epidemics due to cost and lack of practitioners. Studies of the mechanism by which cholera induces such substantial losses of fluid and electrolytes were initiated in the 1960s [3]. These studies that were performed primarily in laboratory animals demonstrated the Vibrio cholera produced an exotoxin (a protein elaborated by bacteria and that has activity in cell-free filtrates) which when introduced into an isolated loop of small intestine (either in vivo or in vitro) produced substantial amounts of isotonic fluid secretion [4]. Subsequent studies established that the cholera enterotoxin induced water and HCO3-rich secretion via the production of cyclic AMP (cAMP) as the administration of cAMP (independent of the bacteria) also induced active Cl−and HCO3 secretion [5]. Oral fluid replacement with the administration of water prior to the development of ORS (see below) was not effective to restore adequate hydration. In the mid-1960s, laboratory studies of intestinal carbohydrate and protein absorption demonstrated that both carbohydrates and protein required hydrolysis to monosaccharides (i.e., glucose and galactose) and individual amino acids, respectively, for their absorption by the small intestine [6]. Furthermore, these laboratory experiments that were performed both in vivo and in vitro established that glucose absorption was sodium-dependent; that is, glucose absorption was markedly reduced in the absence of sodium; and conversely sodium absorption was substantially enhanced by the presence of glucose. These observations led to the concept of glucose-sodium co-transport and the subsequent identification of SGLT1 protein in the brush border of the mammalian small (but not large) intestine [7, 8]. These laboratory-based investigations led to the study in East Pakistan (now Bangladesh) and in India of a glucoseelectrolyte isotonic oral solution for the treatment for acute * Henry J. Binder [email protected]