E-DRUG: JAMA on composition of ORS
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Dear e-druggers,
This is to alert you on this week's (second June) JAMA (Journal of the
American Medical Association) theme issue on global health. Contrary to
usual JAMA's policy, this special is free for all. [see
http://jama.ama-assn.org/cgi/content/full/291/21/2519, WB]
I have also copied below two papers which may be of particular relevance
both because of the importance of the problem and because of an e-drug
debate a long time ago when the reduced osmolarity ORS was endorsed by the
WHO.
The second paper has a table and a figure which obviously don't appear in
this message.
Valeria
-
Dr Valeria Frighi
Oxford Centre for Diabetes, Endocrinology and Metabolism
Churchill Hospital
Oxford
OX3 7LJ
UK
Tel # 44 1865 857300
Fax # 44 1865 857311
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[Full text at: http://jama.ama-assn.org/cgi/content/full/291/21/2628 WB]
Scientific Rationale for a Change in the Composition of Oral Rehydration
Solution
Christopher Duggan, MD, MPH; Olivier Fontaine, MD; Nathaniel F. Pierce, MD;
Roger I. Glass, MD, PhD; Dilip Mahalanabis, MD; Nur Haque Alam, MD; Maharaj
K. Bhan, MD; Mathuram Santosham, MD, MPH
JAMA. 2004;291:2628-2631.
Diarrheal diseases remain important causes of death and morbidity in
developing countries, with an estimated 1.5 billion episodes and 1.5 million
to 2.5 million deaths each year among children younger than 5 years.1-4
Although the number of children currently dying from diarrhea continues to
be unacceptably high, it is substantially lower than the 5 million deaths
per year estimated 20 years ago.5
A critical factor in this reduction in diarrhea deaths has been the
widespread adoption of oral rehydration solution (ORS) programs for the
treatment and prevention of diarrhea-associated dehydration.6-7 Indeed, ORS
has been hailed as one of the most important medical advances of the past
century,8 at least in part because of its simplicity, low cost, and
remarkable ease of use.
Oral rehydation solution works on the elegantly simple physiologic principle
of solute cotransport across the gastrointestinal epithelium (Figure 1).
Briefly, landmark studies published in 19689-10 among patients with Vibrio
cholera infections demonstrated that although the secretory nature of the
diarrhea causes massive stool losses of water and electrolytes,
sodium-coupled glucose cotransport remains largely intact and continues to
stimulate resorption of salt and water.11 Clinical trials documenting the
efficacy of ORS soon followed in the 1970s and 1980s.12-14
[Figure. Coupled Transport of Sodium and Glucose in Intestinal Epithelial
Cells
Although nutrient-independent sodium absorption across the brush border
membrane of intestinal epithelial cells is impaired in patients with
diarrhea, coupled transport of sodium and glucose is preserved, allowing
absorption of salt and water provided by oral rehydration solutions (ORSs).
Sodium-glucose transporter type 1 (SGLT1) mediates the transport of glucose
against its concentration gradient by coupling it to sodium transport.
Sodium that enters the cell is pumped into the blood by the Na+K+ATPase
(adenosine triphosphatase) pump in the basolateral membrane, maintaining the
sodium electrochemical gradient that drives the sodium-glucose cotransport
mechanism. Transport of glucose into the blood is facilitated by glucose
transporter type 2 (GLUT2). ]
For nearly 3 decades, the World Health Organization (WHO) and the United
Nations Children's Fund (UNICEF) have recommended a single formulation of
glucose-based ORS to treat or prevent dehydration from diarrhea of any
etiology and in individuals of any age.15-16 The composition of the
solution, which has proven both safe and effective in worldwide use, was
based on its efficacy in replacing water and electrolytes in individuals
with cholera infection, since these infections were in part the impetus
behind the development of ORS. Concern that the sodium concentration of 90
mEq/L was too high for the lower salt losses of viral and other causes of
childhood diarrhea17 was invoked to explain its low acceptance among
pediatricians in industrialized countries who were concerned about the
possible occurrence of hypernatremia.18 Some authors also noted that the
standard WHO ORS was occasionally associated with hypernatremia in children
in developing countries.19
In the hopes of actually reducing stool output, efforts to improve the
efficacy of ORS were made in the 1970s through 1990s. These included the
addition of other substrates for sodium cotransport (eg, the amino acids
glycine,20 alanine, and glutamine21) or substitution of complex
carbohydrates for glucose (eg, cooked rice powder and other cereal
powders).22 With the exception of rice-based ORS, which significantly
reduces stool output in cholera patients,23 these new ORS preparations were
not more effective than standard ORS and are more expensive.24 Solutions
with higher concentrations of cotransporters and higher osmolarity decrease
rather than increase intestinal sodium and water absorption, and
hypernatremia has been reported with their use.25
Recent efforts to improve the efficacy of ORS have focused on solutions of
reduced osmolarity (eg, sodium ranges of 60-75 mEq/L and glucose ranges of
75-90 mmol/L), although some cereal-based ORSs may also be lower in
osmolarity.26 These solutions generally preserve the 1:1 M ratio of sodium
to glucose that is critical for efficient cotransport of sodium but present
a lower osmolar load to the intestinal tract than does the original WHO ORS.
Animal27 and human studies have indicated that such solutions may be better
designed for optimal water and electrolyte transport into the bloodstream.
In intestinal perfusion studies, solutions of reduced osmolarity have shown
improved net water absorption and equivalent net sodium absorption compared
with the standard WHO ORS.28 In clinical trials, children treated with
reduced-osmolarity ORS experience less vomiting, less stool output, shorter
duration of illness, and less need for supplemental intravenous fluids than
do those treated with the standard WHO ORS.29-31
Advantages of Reduced-Osmolarity ORS
A number of randomized controlled trials have been conducted comparing the
standard (1975 WHO) and reduced-osmolarity (2002 WHO) solutions (Table 1).
In a trial of 300 adult patients with cholera,32 those who received
reduced-osmolarity ORS had no differences in stool output, duration of
diarrhea, or need for unscheduled intravenous therapy compared with those
treated with the standard WHO ORS. Patients who received reduced-osmolarity
ORS had an increased incidence of hyponatremia (serum sodium level <130
mmol/L) (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.1-4.1). The
mean difference in serum sodium at 24 hours of treatment between the 2
groups was 1.2 mEq/L, and none of the patients with hyponatremia in either
group was symptomatic.
[Table omitted]
In a large multicenter trial of children with acute diarrhea not due to
cholera,33 675 children aged 1 to 24 months from 5 countries were randomized
to receive standard or reduced-osmolarity ORS. Although stool output and
vomiting were not statistically different between the groups, the use of
unscheduled intravenous fluids following initial rehydration was reduced in
the group receiving reduced-osmolarity ORS (10% vs 15%) (OR, 0.6; 95% CI,
0.4-1.0). The occurrence of hyponatremia was not statistically different
between the groups (11% in the reduced-osmolarity group vs 9% in the
standard group) (OR, 1.3; 95% CI, 0.2-2.2).
In a meta-analysis that evaluated the effects of reduced-osmolarity ORS in
15 randomized trials of nearly 2400 children,31 use of a reduced-osmolarity
ORS was associated with less frequent use of unscheduled intravenous fluids
(combined OR, 0.61; 95% CI, 0.47-0.81) and less vomiting (combined OR, 0.71;
95% CI, 0.55-0.92). In addition, a statistically significant reduction in
stool output was noted (standardized mean difference, �0.21; 95% CI, �0.31
to �0.12). The incidence of hyponatremia was not significantly elevated
among children who received reduced-osmolarity ORS in these trials (OR,
1.45; 95% CI, 0.93-2.26).
Based on these and other relevant data, WHO and UNICEF convened a meeting in
2001 to review all published studies comparing standard and
reduced-osmolarity ORS.34 The conclusions were as follows:
1. Reduced osmolarity ORS was more effective than standard ORS for acute
noncholera diarrhea in children, as measured by clinically important
outcomes such as reduced stool output, reduced vomiting, and reduced need
for supplemental intravenous therapy. Although data were more limited,
reduced-osmolarity ORS also appeared safe and effective for children with
cholera;
2. Among adults with cholera, clinical outcomes were not different among
those treated with reduced-osmolarity ORS compared with standard ORS,
although the risk of transient asymptomatic hyponatremia was noted;
3. Given the programmatic and logistical advantages of using a single ORS
composition globally, it was recommended that this be a reduced-osmolarity
ORS (Table 1); and
4. Further monitoring, including postmarketing surveillance studies, were
strongly encouraged to better assess any risk of symptomatic hyponatremia in
cholera-endemic parts of the world.34
Concerns About Use of Reduced-Osmolarity ORS
Some concerns have been raised regarding the revised formulation of
ORS.35-37 We believe, however, that the published literature does not
support these concerns.
For example, concern has been raised that any reduction in the sodium
concentration of ORS will increase the risk of hyponatremia, especially
among cholera patients.35 Cholera stool sodium losses can be as high as 120
to 150 mEq/L, and in fact the composition of the original WHO ORS (90 mEq/L)
was a compromise between those who favored a solution with 120 mEq/L of
sodium and those who proposed a lower concentration better suited for
children with diarrhea due to causes other than cholera. Thus, even the
former formulation of standard WHO ORS contains less sodium than some
thought necessary for adequate sodium repletion in cholera.
Among subsets of children with cholera in 3 published clinical trials of
ORS,33, 38-39 the mean serum sodium concentration at 24 hours was 136 mEq/L
in those treated with standard ORS and only 0.8 mEq/L (95% CI, 0.2-1.4
mEq/L) lower in those treated with reduced-osmolarity ORS.34 Although, as
noted above, the incidence of hyponatremia was higher in adult cholera
patients treated with a lower sodium solution, the clinical significance of
this finding is unclear because all hyponatremic episodes in adults were
transient and asymptomatic.32
Preliminary data concerning the incidence of hyponatremia in cholera-endemic
areas of the world have been reassuring. A safety evaluation of
reduced-osmolarity ORS was recently completed in Bangladesh among nearly 50
000 adults and children treated for diarrhea. Preliminary data analysis
reveals that none of the adults had symptoms of hyponatremia during the
1-year study. Among close to 7000 children treated with reduced-osmolarity
ORS, symptomatic hyponatremia was detected in only a small percentage of
cases (0.2%), the majority of whom had another possible reason for
hyponatremia (eg, severe pneumonia, dysentery)(N.H.A., unpublished data).
Other electrolyte abnormalities, including chronic sodium deficit and
hypokalemia, have been hypothesized to occur with reduced-osmolarity ORS.35
It is likely that cholera patients, especially adults, treated with either
reduced-osmolarity or standard ORS are transiently sodium depleted, and that
the deficit would be somewhat greater with the reduced-osmolarity solution.
There is, however, no evidence that the deficit is clinically significant
with either solution. It is also likely that sodium stores would be restored
in the days following resumption of a normal salt-containing diet. It has
been suggested that balance studies be performed in which patients are
provided only standard or reduced-osmolarity ORS for 24 to 48 hours. The
practice of withholding food (and therefore additional sodium) from patients
with diarrhea is not in keeping with the past 15 years of standard diarrhea
management, which recommends immediate nutrition after successful
rehydration.40-43 These balance studies would therefore be unethical to
carry out and would have no relevance to current clinical care.
Likewise, hypokalemia has not been observed among patients treated with
reduced-osmolarity ORS. In the CHOICE study,33 mean (SEM) serum potassium at
24 hours was 4.0 (0.7) mEq/L in children treated with reduced-osmolarity ORS
vs 3.9 (0.8) mEq/L in those treated with the WHO ORS (O.F. unpublished data,
2001).
Concern has also been raised that reduced-osmolarity ORS may complicate the
management of patients with severe protein-energy malnutrition. Children
with severe protein-energy malnutrition are known to have significant
alterations in fluid and electrolyte homeostasis, with an excess of
extracellular fluid and resultant hyponatremia.44 However, total body sodium
is increased, and indeed sodium restriction is an important aspect of
clinical management. Clinical trials using reduced-osmolarity ORS among
malnourished children have actually shown improved clinical outcomes. Among
64 children younger than 4 years with weight for age less than 60% of the
standard, a reduced-osmolarity ORS (224 mOsm/L) was compared in a
double-blind fashion with the standard WHO ORS.45 Stool output, duration of
diarrhea, and intake of ORS were all significantly lower in the group
receiving the reduced-osmolarity ORS compared with those given standard ORS,
and mean serum sodium concentrations were normal in both groups at the end
of therapy. No patient had symptoms of hyponatremia. In another trial of 180
infants with diarrhea (35 of whom had cholera infection), treatment with
reduced-osmolarity ORS was associated with a significant reduction in stool
frequency, an effect that was greatest in children with severe
protein-energy malnutrition. Serum sodium levels in the 2 groups were not
significantly different.39
Among infants with persistent diarrhea (duration >14 days), who are at risk
of developing protein-energy malnutrition and early death,
reduced-osmolarity ORS has also been shown to be more effective than
standard ORS. In a study of 95 infants in Bangladesh hospitalized with
persistent diarrhea, receipt of reduced-osmolarity ORS was associated with
an approximate 40% reduction in stool output, a more prompt resolution of
diarrhea, and no evidence of hyponatremia.46
Conclusions
A number of randomized controlled trials have established the superiority of
reduced-osmolarity ORS over standard ORS in the management of diarrheal
diseases in children. Concerns about the safety of reduced-osmolarity ORS
center on its use in patients with cholera, especially adults. While the
provision of 17% less sodium to patients with cholera may lead to a slightly
greater negative sodium balance at the end of treatment, this deficit should
be rapidly corrected when a normal diet is resumed. Experience to date
provides no evidence that transient hyponatremia, which may also occur with
standard ORS, has significant adverse clinical consequences for cholera
patients.
The benefits of promoting the use of a single ORS solution for all patients
with diarrhea, including cholera, are enormous, as has been clearly
established with standard ORS. It is recognized, however, that any single
ORS formulation, including standard ORS, that is promoted for use in
patients of all ages and with diarrhea of any etiology must be a compromise
that takes into consideration both the substantial differences in stool
sodium losses that occur across the spectrum of diarrheal disease as well as
substantial differences in the global burden of cholera vs noncholera
diarrhea. It is estimated that acute noncholera diarrhea in children causes
1.5 million to 2.5 million deaths per year, whereas cholera causes
significantly fewer deaths in all age groups (approximately 120 000 per
year) (O.F., unpublished data). Reduced-osmolarity ORS has the potential to
substantially reduce childhood deaths from noncholera diarrhea due to the
reduced requirement for supplementary intravenous fluids. Although
reduced-osmolarity ORS may not have the same benefit for cholera patients,
clinical trials show it to be as effective as standard ORS. It is our view
that the current evidence demonstrates the benefits of reduced-osmolarity
ORS for the world's children, and that use of the revised formulation is
fully justified.
[References omitted; see full text at
http://jama.ama-assn.org/cgi/content/full/291/21/2628\]
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[Full text at: http://jama.ama-assn.org/cgi/content/full/291/21/2632 WB]
Clinical Concerns About Reduced-Osmolarity Oral Rehydration Solution
David R. Nalin, MD; Norbert Hirschhorn, MD; William Greenough III, MD;
George J. Fuchs, MD; Richard A. Cash, MD
JAMA. 2004;291:2632-2635.
Demonstration of the benefits of oral therapy for cholera in 19681 soon led
to application of the method to all forms of infectious diarrheal diseases.2
The original oral rehydration solution (ORS) formulation developed by the
World Health Organization (WHO) (Table 1) struck a compromise between the
ideal solutions for these diverse disorders to meet the programmatic goal of
a single formulation and packaging for global use in cholera and noncholera
diarrheas, in both adults and children. Recently, WHO recommended a new oral
solution (Table 1) for all acute diarrheas, including cholera. This new
formula would replace the original ORS, which saved millions of lives, with
a new formulation containing less sodium and glucose.3 This change was
ostensibly to reduce gross stool volume and use of unscheduled intravenous
therapy by lowering solution osmolarity. However, the reduced-osmolarity
formulation is particularly unsuitable for universal use because it contains
an amount of sodium insufficient to maintain sodium balance in cholera
patients, in whom its use induces negative sodium balance and may lead to
hyponatremia,4-5 polyuria,4 and a small but clinically significant risk of
neurologic complications. The new reduced-osmolarity formulation stretches
the original compromise to the breaking point. It may be time to promote use
of different solutions for patients with cholera, beginning in controlled
settings such as cholera treatment centers and hospitals.
[Table omitted]
Therapy of acute watery diarrhea requires replenishing water and electrolyte
losses (rehydration phase) and maintaining water and electrolyte balance
after rehydration until diarrhea ceases (maintenance phase). Oral
rehydration is successful when hourly oral intake matches or modestly
exceeds fluid losses (regardless of gross stool rate). When the solution
contains appropriate amounts of sodium, potassium, and bicarbonate or
base-precursor, electrolyte balance is also restored and maintained.
Dehydrated patients in shock need rapid intravenous rehydration followed by
oral maintenance. If intravenous fluids or skilled personnel are
unavailable, oral rehydration and maintenance can be effective even in
hypotensive patients.6 With lesser degrees of dehydration, most patients
respond without intravenous fluids, and dehydration can be prevented by
early oral maintenance therapy.
Cholera patients have the highest purging rates, stool sodium
concentrations, and loss of body sodium; adult losses exceed those of
children, who have lower stool sodium concentrations, the latter linked to
greater stool potassium losses.7 Patients with noncholera diarrhea generally
have lower purging rates.8 In early studies of adults with cholera, use of
oral maintenance solutions with glucose and 100 mEq/L of sodium resulted in
an average negative sodium balance of 50 mEq, ranging as low as �200
mEq.9-10 The original WHO formulation containing 90 mEq/L of sodium could
not offset sodium losses in adult cholera patients (120-140 mEq/L of cholera
stool). The reduced sodium formulation (75 mEq/L) would further aggravate
these sodium losses. In a randomized double-blind trial of 300 adults with
cholera, more patients given the new solution developed hyponatremia (sodium
<130 mEq/L) than those given the standard WHO ORS (odds ratio, 2.1; 95%
confidence interval [CI], 1.1-4.1]).5 There were no differences in diarrheal
duration or volume, vomiting, or use of unscheduled intravenous fluids
between patients receiving standard or reduced-sodium ORS.
The concern that hyponatremia may result from use of the reduced-osmolarity
formulation is not restricted to adults with cholera. In the multicenter
CHOICE study of 675 children with acute watery diarrhea,11 which helped
inform the decision to change the sodium content of the WHO ORS, more
children given the reduced sodium solution had hyponatremia than those given
the standard solution (serum sodium levels <130 were 11% vs 9% and <125
mEq/L were 4% vs 2%, respectively), but these differences were not
statistically significant. However, 1 of the 373 children (0.3%) with
hyponatremia who received the reduced-osmolarity solution had a generalized
seizure. Such seizures are not benign.12
One rationale for the new ORS was to reduce stool output by lowering
solution osmolarity because families and physicians were believed to be
reluctant to use the solution if gross stool output increased. The CHOICE
study11 showed no significant difference in stool output or duration of
illness among children who received reduced-osmolarity solution vs those who
received standard ORS. A difference in use of unscheduled intravenous fluids
was reported (10% vs 15%; odds ratio, 0.6; 95% CI, 0.4-1.0.) However, in
both groups, patients given unscheduled intravenous fluids had twice the
volume of stool output of those who did not receive intravenous fluids. This
suggests that transient glucose malabsorption may have played a role in this
outcome, and chance overallocation of several patients with glucose
malabsorption to the group that received the standard ORS could explain the
difference. (There is no evidence that oral solution sodium concentration
affects glucose tolerance.)
In a meta-analysis of 15 trials comparing use of the 2 solutions in children
hospitalized with dehydration associated with diarrhea,13 use of unscheduled
intravenous fluids was reported to be lower in those children who received
the lower-osmolarity solution. However, only 9 of 15 trials reviewed were
included in the analysis of unscheduled intravenous fluid needs, and in 5 of
these 9, including the largest trial, the odds ratios hovered near 1.0. The
meta-analysis also reported a reduction in stool output among those
receiving the reduced-osmolarity solution, but its magnitude could hardly be
noticed except by measuring stool volume.14 Stool output comparisons showed
close to zero difference in 8 of 12 trials analyzed. In addition, only 3
trials in the meta-analysis included children with cholera. Moreover, the
largest trials included showed the smallest differences.5, 11 Finally, none
of the 15 studies prestratified patients by diarrhea rates before randomized
allocation,13 which may explain the high interstudy variability in outcomes,
since the initial rate of stool loss determines overall diarrhea rate and
volume.15
No studies comparing outcomes of the standard WHO ORS to the new
reduced-osmolarity formulation have measured net sodium and potassium
losses. The impact of the reduced-osmolarity solution on sodium and
potassium balance is therefore unknown. Previous studies have shown that
standard WHO ORS inadequately replaces stool potassium losses,16 and
hyponatremia aggravates urine potassium losses.17 The new formulation
aggravates sodium deficits in cholera more than the original formulation.4-5
In some studies the 2 solutions performed similarly because both induce
negative sodium balance. Earlier oral solutions for cholera contained 100 to
120 mEq/L of sodium, matched stool electrolyte levels more closely, and
promoted modest positive sodium balance without hyponatremia or
hypernatremia.1, 18
Pediatric and adult cholera patients typically lose 100 to 135 mEq of sodium
per liter of diarrhea, respectively.19 The reduced-osmolarity solution with
75 mEq/L of sodium would therefore induce a negative sodium balance of �25
to �60 mEq/L ingested when matching intake to output. Adult diarrhea rates
in severe cholera approach 1 L/h, so losses of up to 300 mEq of sodium can
accrue within 5 hours of such treatment, enough to sharply lower blood
sodium levels. Even with antibiotics, oral maintenance usually lasts 24 to
44 hours in adult cholera patients,18, 20-21 enough to induce massive sodium
deficits using the low-sodium solution. Moreover, to expand intravascular
volume rapidly, patients must drink more of a low-sodium solution, which may
lead to fatigue and treatment failure.17
In malnourished patients with chronic hyponatremia and multiple diarrhea
episodes, very low-sodium oral solutions (45 mEq/L) also aggravate
hyponatremia (1 of 65 patients had seizure).22 Use of reduced-osmolarity
solution in these patients should be relatively contraindicated, but the new
recommendations do not address this point.3
Another difficulty is that all studies of the new formulation involved
single-incident diarrheal episodes. Where effective oral therapy programs
exist, children may receive therapy for multiple diarrhea episodes. Surveys
in several countries have shown more than 7 episodes of varied etiologies
per child annually.23-24 The risk of aggravated hyponatremia might exist
when such patients, already sodium depleted, present for treatment of
incident episodes. This deserves study to determine the safety of low-sodium
solutions in such patients. When programs are not yet developed, the fluids
given at home are also often associated with hyponatremia (and other
electrolyte disorders), which remain undetected until hospitalization.25
The studies that led to modification of the WHO ORS formulation have several
key limitations. First, resumption of intravenous fluids was based on
clinical criteria, with objective confirmation by measuring plasma specific
gravity in only 1 study.11 The methods of measuring intake and output, and
quality control procedures, were omitted or incompletely reported in all but
1 study.11 In another study,4 instead of matching oral intake to fluid
losses, patients who received low-sodium ORS drank twice their volume of
stool loss, and those who received standard ORS drank 3 times their stool
volume losses. In the 1 higher-quality study,11 125 of 676 children (18%)
discontinued or were excluded, which might partly explain why groups with
generally similar diarrhea duration and volume differed in the
administration of unscheduled intravenous fluids. In studies of adult
patients with cholera, those who received the new ORS had increased risk of
hyponatremia and polyuria but no significant reduction in rates of
unscheduled intravenous fluids. Lower diarrhea rates were reported among
those who received the new formulation in a small study,4 but this outcome
was not confirmed in a large randomized trial.5 Published data on pediatric
cholera patients are sparse. No difference in 24-hour stool volume was seen
in 1 study (n = 26); in 2 others (n = 19 each) stool output was reduced by
30% in those who received the new formulation, but there was also an
increase in rates of hyponatremia.11, 26-27
Consequence of a Lower-Sodium Solution
The normal small bowel adjusts luminal tonicity by both secretion and
absorption. Sodium enters the lumen according to its plasma-to-lumen
chemical gradient, regardless of luminal fluid tonicity. Water enters the
lumen when the luminal fluid is hypertonic and is absorbed from the lumen
when the luminal fluid is hypotonic. Cholera toxin causes high-output
diarrhea by interfering with the absorption of sodium and water, leading to
a defect in small intestinal osmoregulation, demonstrated in the canine
cholera model.28 Osmoregulation is then achieved only by changing the rate
of net secretion of salt or water into the lumen. Hypotonic luminal contents
are then adjusted by increased secretion of sodium into the lumen and
reduced secretion of water; hypertonic solutions are adjusted by increased
movement of water and sodium entering the lumen (Figure 1 A, B). Thus, in
experimental models, after application of cholera toxin, luminal plain water
can slow water secretion but causes a drastic increase in sodium loss into
the lumen.28 Two cholera patients treated with 0 to 50 mEq/L sodium
solutions with substrate rapidly lost more than 300 mEq of sodium and
developed hyponatremia.29 Similarly, 34 adult cholera patients4 randomly
allocated to low-sodium solution had 29% less stool output but 44% higher
urine output (19.9 vs 13.8 L of urine/48 h). Hyponatremia causes polyuria by
suppressing antidiuretic hormone. Three of these patients had serum sodium
levels lower than 125 mEq/L at 24 hours.4 Urine volumes in studies of an
earlier formulation with osmolarity of 380 mOsm/L were typically 1.6 L
during 30 hours' mean therapy.21 Among the 34 adult recipients of
reduced-sodium ORS, 12% needed unscheduled intravenous fluid vs 24% among 29
standard ORS recipients; this difference was not significant (P = .19). The
standard ORS recipients had a higher diarrhea rate in the preoral period,
probably accounting for the observed difference.4 In a much larger study,5
no difference in diarrhea rate was seen.
[Figure. Net Water and Ion Movement During Intestinal Osmoregulation in the
Presence of Cholera Toxin
Intestinal absorption of sodium, chloride, and water is severely impeded in
cholera. Osmoregulation of luminal fluids occurs chiefly by net sodium and
chloride movement into hypotonic saline solutions (A) and by net water
movement into hypertonic solutions (B). In A, water losses are slowed but
sodium losses are heightened; in B, water losses are massively increased and
diarrhea worsens. In C and D, addition of substrates, which enhance active
sodium transport, increases net sodium, chloride, and water absorption and
promotes rehydration. In C, however, net sodium deficits occur because
sodium enters luminal fluids when its concentration is below plasma
levels.18, 28-29 ]
The absorptive component of osmoregulation in cholera is restored by
substrates promoting sodium absorption. Indeed, the most hypertonic solution
yet tested, 510 mOsm/L, containing electrolytes and glucose plus glycine,
was also the most effective in reducing both diarrhea rate and duration in
adult and pediatric cholera patients18, 30 (Table 1). Likewise, oral
solutions containing rice-based substrate, which has a high glycine content,
reduce cholera diarrhea output.31 Thus, in cholera, osmolarity per se does
not determine changes in diarrhea rates or in net absorption associated with
different oral formulations; absorbability of the components contributing to
osmolarity, and their effects on sodium and water transport, are key (Figure
1 C, D).
However, glucose with glycine or rice-based solutions do not have the same
enhanced efficacy in noncholera diarrheas (except those sharing the cAMP
[cyclic adenosine monophosphate] diarrheagenic mechanism). A possible
explanation is that substrate-induced active transport, previously believed
to be intact in cholera, may actually be enhanced by the increased cAMP
induced by cholera toxin. This was demonstrated in intestinal cells and
oocytes of rabbits expressing mammalian sodium-glucose transporters.32
Experience With the Original WHO ORS
The original WHO formulation with 90 mEq/L of sodium and 111 mmol/L of
glucose (Table 1) proved a safe, effective formulation for all age groups
and cholera or noncholera diarrhea.2, 7, 9, 16, 25 However, failure to
communicate the information needed to ensure correct solution preparation,
concentration, and appropriate drinking volumes can lead to electrolyte
imbalance, whatever the formulation. Thus, inaccuracies in home-mixing of
solutions led to hypernatremia in Egypt, a situation that was reversed with
detailed instructions broadcast via television and taught in rehydration
clinics.33
Practical clinical recommendations using the original formulation offered
safe and effective variations on the basic regimen in noncholera areas,
including early feeding and allowing extra oral water, for example, the 2:1
regimen.16, 25 Mild, transient elevations of serum sodium levels occurred in
a minority of patients without cholera who were receiving the original
formulation (without extra water), without any adverse events.16 In fact,
the original formulation was found safe and effective for treating
hypernatremic dehydration34 but was less successful in correcting
hyponatremic dehydration.16
Conclusions
In conclusion, studies leading to the recommendation for the
reduced-osmolarity ORS for noncholera diarrhea therapy had variable
outcomes. Reduction in diarrhea rate, if real, is minimal; diarrhea duration
is unaffected. The need for unscheduled intravenous fluids was not
laboratory confirmed, and in the largest study11 it was not paralleled by
reduced stool losses. For these reasons, and the risk of induction of
hyponatremia, it remains unclear whether the new solution favorably alters
the benefit-to-risk ratio for pediatric and adult diarrhea patients without
cholera. Additional, more rigorous studies are needed to determine the
optimal solution for such patients. What is clear is that the
reduced-osmolarity ORS increases the risk for hyponatremia during therapy in
adults with cholera but offers them no clinical advantages. Moreover,
clinical findings in small numbers of pediatric patients with cholera were
contradictory.
The goal of reducing rates of unscheduled intravenous fluids and diarrhea
rate and duration in patients with cholera and nonvibrio cholera8 is best
met in controlled settings with a separate oral solution, such as that
containing glucose plus glycine or rice-based substrate, with electrolyte
concentrations that maintain electrolyte balance and avoid hyponatremia.
Such solutions are clearly more effective in cholera patients than either of
the WHO solutions.
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