Oral Rehydration Solution: Future Prospect

Dr. Md. Nur Haque AlamNur H. Alam, MBBS, MD

Senior ScientistClinical Sciences Division

ICDDR, B Presented at GHSI Workshop on October 18th, 2010

Ingredients Old-ORS (WHO-ORS)

New-ORS (Reduced osmolarity ORS)

Sodium (mmol/L) 90 75

Potassium (mmol/L) 20 20

Chloride (mmol/L) 80 65

Citrate (mmol/L) 10 10

Glucose (mmol/L) 111 75

Osmolarity (mosml/L) 311 245

Year of recommendation 1975 2004

WHO/UNICEF recommended ORS solution for the treatment of all causes of diarrhea in all

age groups

Pre-physiologic era

- Empirical use of oral fluid for cholera- advocated by Sushruta(Sushruta Samita, Volume III, BC 3000 yrs; Chatterjee, Lancet,1953; Harrison, 1954)

- In 1950, MRC, UK recommended glucose-electrolyte solution for treatment of diarrhea in children

- Meneghello, 1960, reported similar experience in children in

Chile

Development of ORT

• Glucose/aminoacid linked sodium absorption

• Glucose and sodium absorption in equimolar proportion

• glucose linked sodium absorption is unaffected incholera

Riklis, Quastel, Schultz, Curran and others (1950 – 1964)

Phillips et al, 1964)

Physiology of sodium-glucose transport through intestinal mucosa

Duggan, 2004

•

• Demonstration of fluid containing optimum glucose and salts could replace massive losses of diarrhea stool due to cholera (Pierce et al. 1968, 1969,Hirschorn N. et al 1968, Nalin DR, Sack RB, 1968. ( Dhaka and Calcutta)

Field trial in most adverse situation occurred during a cholera epidemic in West Bengal refugee camps during the Bangladesh war of independence.

• Case fatality rate reduced from 30% to 1% (Mahalanabis, 1973)

“Oral rehydration therapy (ORT), using a mixture of water, sugar and salt, potentially the most important medical advances of this century” (The Lancet, 1978)

CDD programme (1978) for promotion of ORSin the developing countries because itwas proved to be:

• Safe, effective• Simple• Less expensive• Effective in reducing diarrhoea morbidity and mortality and

hospital admission

Limitations

• WHO-ORS does not reduce the diarrhea stool

volume and duration

• Parents are concerned to stop the diarrhea but not

the dehydration due to diarrhea

In search of a super ORS

2 major approaches were tried to develop an improvedORS/Super ORS exploiting the knowledge:

1. Other than glucose, certain neutral amino acids (Glycine, L-alanine, glutamine and dipeptides ) enhance the absorption of sodium independently

- ORS solution with added glycine- ORS solution with L-alanine- ORS solution with glutamine- Rice ORS (salts without glucose)

2. Reducing sodium, glucose leads to low osmolarity

Reasons for replacing glucose with rice:

-Rice is digested slowly in small intestineproducing glucose and amino acids and stimulate sodium and water absorption

-Rice does not increase osmolality of ORS

- Rice contains antisecretory factor that

-Some unabsorbed starch are fermented-in the colon producing SCFAs

Limitations

-Unavailability of ready to use -It needs boiling -Once prepared can’t be kept for long time-Short shelf life-Cost is at least 3 times higher than standard glucose ORS

Adult cholera Acute non cholera diarrhoea in children

Stool output

Duration of diarrhoea

Stool output Duration of diarrhoea

Glucose vs. glucose+glycine

-50% -25, -30% (2 studies)

No impact No impact (7 studies)

Glucose vs.Glucose+alanine

-20, –40% -9, -15% (2 studies)

No impact No impact (3 studies)

Glucose vs.Glucose+glutamine

-30% -13% (1 study) No impact No impact (2 studies)

Glucose vs. Rice -30, -50% 0%, -30% (6 studies, mixed

less impact No impact (9 studies)

Summary of the results of clinical trials

Reduced osmolarity ORS (low sodium and low glucose ORS): is it a better alternative?

Disagreement persists about its ideal composition in the developed world because:

- Cholera is rare there

- Children mostly suffer from viral diarrhoea where sodium excretion is much less (40 mmol/L) than in the WHO-ORS

- Some animal and human perfusion studies have shown better water and sodium absorption with hypotonic ORS than WHO-ORS

- Some clinical studies already have shown positive results

Normal Stool

Cholera Stool

ETEC stool

Rotavirus stool

adult children adult children adult children

Na 31 46 133 88 97 53 37

K 75 91 20 30 30 37 38

CI 16 100 86 66 24 22

HCO3 40 41 32 37 18 6

Electrolyte composition of diarrhoeal stools (means expressed in mmol/L

Ingredients Old-ORS (WHO-ORS)

New-ORS (Reduced osmolarity ORS)

Sodium (mmol/L) 90 75

Potassium (mmol/L) 20 20

Chloride (mmol/L) 80 65

Citrate (mmol/L) 10 10

Glucose (mmol/L) 111 75

Osmolarity (mosml/L) 311 245

Year of recommendation 1975 2004

WHO/UNICEF recommended ORS solution for the treatment of all causes of diarrhoea in all

age groups

This formulation was selected because:

a) its osmolarity is within the range of reduced osmolarity ORS solution studied to date

b) this formulation has already been evaluated in two trials

c) its sodium content is only modestly less than in standard ORS which may be important for treatment of cholera

d) its glucose content at least balance that of sodium

WHO/UNICEF consultative meeting on ORS formulation in New York, July 2001

- To review results of all studies

- If possible new recommendation

Meta-analysis of all randomized clinical trials in children with acute watery diarrhea

Difference in mean Odds ratio for children stool output new ORS when compared

to those receiving Old ORS(95% CI))

Unscheduled IV therapy 0.61 (0.47-0.81)*

Stool output -0.214 (-0.305 to –0.123)* -

Vomiting - 0.71 (0.55-0.92)*

Hyponatraemia - 1.45 (0.93-2.26)

*P<0.05

BMJ, 2001

New ORS(n=147)

Old ORS(n=153)

Odds Ratio(95% CI)

<130 mmol/L

<125 mmol/L

<120 mmol/L

29 (20%)

7 (5%)

16 (12%)

4 (3)%

1 (<1%)

2.1 (1.1-4.1)*

1.9 (0.9-3.6)

*p<0.05

Hyponatraemia 24 h after admission

Old and new ORS in adult cholera patients

Alam NH et al.1999

Recommendations of WHO and UNICEF (2001)

• New ORS formulation (reduced osmolarity ORS) should be manufactured and used for all causes of diarrhoea in all age groups

• Further monitoring (post marketing surveillance) is required to better assess the risk if any, of symptomatic hyponatraemia, especially in adult patients with cholera

ICDDR,B introduced the new ORS for treatment of diarrhea and a surveillance study (post marketing monitoring) was undertaken in January 2003 for its safety

Objectives

To examine whether patients given the ‘new’ ORS formulationsfor their diarrhoea irrespective of etiology and age, experiencemajor adverse events (seizure) that might influence its routineclinical use

Significance

Data from this type of post marketing surveillance is crucial forreassuring the policy makers, manufacturers, social marketingcompanies, and users of ORS of the safety of the new ORS

Study design: Phase IV Clinical trial

Study site: Dhaka and Matlab hospital of ICDDR,B

Study Period: One year for surveillance and 3 months for data analysis

Sample size: about 50000 to 60000 patients in Dhaka hospital and 10000 to 15000 patients in Matlab hospital

Children <6 months received glucose ORS ( Low osmolarity)

Children above 6 months and adults received Rice ORS

Rehydration ongoing in Short Stay Ward

Identification of seizure/altered consciousness cases associated with new ORS

- Admission in special care unit

- Clinical history and detailed investigation (bloodbiochemistry, Culture and CSF studies, stool culture etc.)

- Treatment

- To identify the cause of seizure and control the seizure by anticonvulsant

Results

Frequency of symptomatic (seizure/altered consciousness) hyponatraemia (serum Na <130 mmol/L) in one year of observation was 21

Incidence rate of overall symptomatic hyponatraemia -(0.05%)/year

• The incidence of hyponatraemia associated with symptoms (seizure/altered consciousness) in patients with diarrhea when treated with new hypoosmolar oral rehydration solution recommended by WHO was infrequent

• The rate was not more than the rate when patients treated with old standard WHO-ORS

Summary of the results

Conclusion

The new hypoosmolar oral rehydration solution inthe treatment of all causes of diarrhea in all agegroups is safe and its recommendation by WHOand UNICEF for use in diarrhea universally isjustified

Further Development of ORS

Addition of Soluble Dietary fiber (SF) / Amylase resistant Starch (ARS)

Rationale:

- SF / ARS not digested in small intestine usually degraded in large bowel

by colonic bacteria producing short chain fatty (SCFAs)- SCFAs stimulates sodium & water absorption in colon resulting in reduction of the severity of diarrhea

Results of some studies using ARS or SF:Ramakrishna BS et. Al. 2000 Glucose ORS vs. Glucose ORS ARS in adult Cholera

Stool wt (g) 27% in ARS group (stat. sig)Duration of diarrhea 37% in ARS group (stat. sig)

Raghupathy P et. al. 2006Glucose ORS (old formula) vs. Glucose ORS+ARS in children with acute diarrhea

Stool wt (g) 30% (NS)Duration of diarrhea 15% (sig)

Ramakrishna BS et al. 2008Glucose ORS (New formula) vs. ARS ORS (without glucose) in Adult dehydrating

diarrheaStool wt (g) 65% (stat. sig)Duration of diarrhea (h) 55% (stat. sig)

Alam NH et al. 2000Glucose ORS (old formula) vs. Glucose ORS + PHGG 20 g/L in the treatment of

acute diarrhea in children

Stool wt (g) 16% (NS)Duration of diarrhea (h) 20% (stat. sig)

Prospective ORS Trial with addition of Lactoferrin andLysozyme with existing rice based or glucose based ORS

Objectves

In children with acute watery diarrhea, treatment with the new ORS containing Lactoferrin and Lysozyme will- Reduce 24 hours/total stool output by 25/30%- Reduce the duration of diarrhea by 20/25%when compared with treatment with standard WHO and UNICEF recommended reduced osmolarity ORS/ rice ORS

Objectves

-reduce requirement of unscheduled IV fluid therapy by 20/25%

Design: Randomized double blind controlled clinical trial

Subjects: Children 6 months to 36 months

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Diarrhoea Treatment Protolcol at ICDDRB Hospital

Triage areaNo sign of Dehydration

SCU

LSW

Short Stay Ward (Adult male)

Short Stay Ward (Adult female)

Short Stay Ward (Children)

Entrance

Reg, Desk

Initial assessment

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STW

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