Oral Rehydration Solution:

Future Prospect

Dr. Md. Nur Haque Alam

Nur H. Alam, MBBS, MD Senior Scientist Clinical Sciences Division ICDDR, B
Presented at GHSI Workshop on October 18th, 2010

WHO/UNICEF recommended ORS solution for the treatment of all causes of diarrhea in all age groups
Ingredients Sodium (mmol/L) Potassium (mmol/L) Chloride (mmol/L) Citrate (mmol/L) Glucose (mmol/L) Osmolarity (mosml/L) Year of recommendation Old-ORS (WHOORS) 90 20 80 10 111 311 1975 New-ORS (Reduced osmolarity ORS) 75 20 65 10 75 245 2004

Development of ORT
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

Physiology of sodium-glucose transport through intestinal mucosa

Glucose/aminoacid linked sodium absorption Glucose and sodium absorption in equimolar proportion glucose linked sodium absorption is unaffected in
cholera
Riklis, Quastel, Schultz, Curran and others (1950 1964) Phillips et al, 1964)

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

cholera epidemic in West Bengal refugee camps during the Bangladesh war of independence.

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 ORS in the developing countries because it was 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 improved ORS/Super ORS exploiting the knowledge: 1. Other than glucose, certain neutral amino acids (Glycine, Lalanine, glutamine and dipeptides ) enhance the absorption of sodium independently 2. ORS solution with added glycine ORS solution with L-alanine ORS solution with glutamine Rice ORS (salts without glucose)

Reducing sodium, glucose leads to low osmolarity

Reasons for replacing glucose with rice: -Rice is digested slowly in small intestine producing 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 cant be kept for long time -Short shelf life -Cost is at least 3 times higher than standard glucose ORS

Summary of the results of clinical trials

Adult cholera Stool output Glucose vs. glucose+glycine Glucose vs. Glucose+alanine Glucose vs. Glucose +glutamine Glucose vs. Rice -50% -20, 40% -30% Duration of diarrhoea -25, -30% (2 studies) -9, -15% (2 studies) -13% (1 study) Acute non cholera diarrhoea in children Stool output No impact No impact No impact Duration of diarrhoea No impact (7 studies) No impact (3 studies) No impact (2 studies) No impact (9 studies)

-30, -50%

0%, -30% (6 studies, mixed

less impact

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

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

Normal Stool adult Na K CI HCO3 31 75 16 40 children 46 91 Cholera Stool adult 133 20 100 41 children 88 30 86 32 adult 97 30 66 37 ETEC stool children 53 37 24 18 37 38 22 6 Rota virus stool

WHO/UNICEF recommended ORS solution for the treatment of all causes of diarrhoea in all age groups
Ingredients Sodium (mmol/L) Potassium (mmol/L) Chloride (mmol/L) Citrate (mmol/L) Glucose (mmol/L) Osmolarity (mosml/L) Year of recommendation Old-ORS (WHOORS) 90 20 80 10 111 311 1975 New-ORS (Reduced osmolarity ORS) 75 20 65 10 75 245 2004

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 stool output Odds ratio for children new ORS when compared to those receiving Old ORS (95% CI)) 0.61 (0.47-0.81)* -0.214 (-0.305 to 0.123)* 0.71 (0.55-0.92)* 1.45 (0.93-2.26)

Unscheduled IV therapy Stool output Vomiting Hyponatraemia

*P<0.05 BMJ, 2001

Old and new ORS in adult cholera patients

Hyponatraemia 24 h after admission
New ORS (n=147) <130 mmol/L <125 mmol/L <120 mmol/L 29 (20%) 7 (5%) Old ORS (n=153) 16 (12%) 4 (3)% 1 (<1%) Odds Ratio (95% CI) 2.1 (1.1-4.1)* 1.9 (0.9-3.6)

*p<0.05

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 formulations for their diarrhoea irrespective of etiology and age, experience major adverse events (seizure) that might influence its routine clinical use Significance Data from this type of post marketing surveillance is crucial for reassuring the policy makers, manufacturers, social marketing companies, 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 (blood biochemistry, 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

Summary of the results

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

Conclusion
The new hypoosmolar oral rehydration solution in the treatment of all causes of diarrhea in all age groups is safe and its recommendation by WHO and UNICEF for use in diarrhea universally is justified

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. 2006 Glucose ORS (old formula) vs. Glucose ORS+ARS in children with acute diarrhea Stool wt (g) Duration of diarrhea 30% (NS) 15% (sig)

Ramakrishna BS et al. 2008 Glucose ORS (New formula) vs. ARS ORS (without glucose) in Adult dehydrating diarrhea Stool wt (g) Duration of diarrhea (h) 65% (stat. sig) 55% (stat. sig)

Alam NH et al. 2000 Glucose ORS (old formula) vs. Glucose ORS + PHGG 20 g/L in the treatment of acute diarrhea in children Stool wt (g) Duration of diarrhea (h) 16% (NS) 20% (stat. sig)

Prospective ORS Trial with addition of Lactoferrin and Lysozyme 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 -

Diarrhoea Treatment Protolcol at ICDDRB Hospital

Entrance Reg, Desk

Initial

Triage area No sign of Dehydration

assessment Short Stay Ward (Adult male) Short Stay Ward (Adult female)

SCU

LSW

Short Stay Ward (Children)

STW

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