Pediatric zinc

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Pediatric zinc

  1. 1. FROM DISCOVERY TO DELIVERY Zinc in the management of diarrhoea Dr. B. K. Iyer 3 Mar 2011
  2. 2. The important question for today <ul><li>Is there any major new evidence in diarrhoea to improve child survival that: </li></ul>3 Mar 2011 <ul><ul><li>adds to or changes our current thinking in childhood diarrhoeas? </li></ul></ul><ul><ul><li>significantly changes the potential of the new interventions? </li></ul></ul><ul><ul><ul><li>For new intervention(s) to be added? </li></ul></ul></ul><ul><ul><ul><li>For more effective delivery strategies? </li></ul></ul></ul><ul><ul><li>If so, what is this new revised strategy? </li></ul></ul>
  3. 3. Global Revised Diarrhoea Treatment Strategy <ul><li>Prevention of dehydration [ORT] – early replacement of fluids with appropriate home fluids, Sugar-salt solution, or any  fluid and feeding / Low osmolarity ORS. </li></ul><ul><li>Recognition of signs of dehydration or other symptoms (blood in stools) </li></ul><ul><li>Continued feeding (or increase breastfeeding) </li></ul><ul><li>Antibiotic use only when appropriate (bloody diarrhea or shigellosis) </li></ul><ul><li>Abstain from using antidiarrhoeal drugs </li></ul><ul><li>Provide Zinc in doses of 20 mg per day for 10-14 days (for children 6 months or older) </li></ul>3 Mar 2011 Source: WHO/UNICEF. Joint statement on the clinical management of acute diarrhea. 2004.
  4. 4. Why changes in ORS formulation? <ul><li>Improved efficacy of ORS </li></ul><ul><ul><li> stool output by 20%, </li></ul></ul><ul><ul><li> vomiting by 30%, and </li></ul></ul><ul><ul><li> need for unscheduled IV by 35%. </li></ul></ul>3 Mar 2011 Source: Kosek et al. Bulletin of the WHO 2003; 81:197-204 <ul><li>Reduction of levels of glucose / salt shortens duration of diarrhoea; </li></ul><ul><li>Reduced osmolarity decreases stool output; </li></ul><ul><li> effectiveness for children with acute, non-cholera diarrhoea </li></ul>Standard formulation of ORS New formulation of ORS Sodium 90 MEq/L Sodium 75 mEq/L Osmolarity of 311 mmol/L Osmolarity 245 mmol/L
  5. 5. Why the need to give zinc? <ul><li>Zinc deficiency is biochemically defined as a serum concentration of less than 9  mol/l. </li></ul><ul><li>Zinc deficiency is common in children of developing countries: </li></ul>3 Mar 2011 <ul><ul><li>Breast milk not sufficient source >6 mo </li></ul></ul><ul><ul><li>Intake of complementary foods low, </li></ul></ul><ul><ul><li>Low content in soil, of foods </li></ul></ul><ul><ul><li>Limited bioavailability;  phytates from cereals </li></ul></ul><ul><ul><li>High fecal losses during diarrhoeal illness </li></ul></ul>
  6. 6. Zinc deficiency regions 3 Mar 2011 Hotz & Brown. Food Nutr Bull 2004. < 14.9% < 15-24.9% > 25%
  7. 7. Zinc deficiency outcomes <ul><li>Zinc deficiency is evident as low immunity of the individual ; </li></ul>3 Mar 2011 <ul><ul><li>Reduction in the number B lymphocytes and  T-dependent lymphocyte antibody responses due to increased apoptosis that also reduces their functional capacity. </li></ul></ul><ul><ul><li>Compromise in functions of the macrophage; </li></ul></ul><ul><ul><li>Disturbance in the production and potency of several cytokines. </li></ul></ul>
  8. 8. Zinc in diarrhoea management <ul><li>Zinc supplementation </li></ul><ul><ul><li>New addition to the diarrhoea treatment strategy </li></ul></ul><ul><ul><li>Greatly impacts diarrhoea management. </li></ul></ul>3 Mar 2011 Source: Kosek et al. Bulletin of the WHO 2003; 81:197-204 <ul><ul><li>Now being recommended for the standard case management of both dysenteric and non-dysenteric acute diarrhoea by </li></ul></ul><ul><ul><ul><li>WHO, </li></ul></ul></ul><ul><ul><ul><li>UNICEF, & </li></ul></ul></ul><ul><ul><ul><li>countries around the world </li></ul></ul></ul>
  9. 9. Zinc in diarrhoea management - trials 3 Mar 2011 13 trials in acute diarrhoea 5 trials in persistent diarrhoea Age groups = 3 to 60 months Trials evaluating the therapeutic effect of zinc supplementation on acute diarrhoea have been subjected to a meta-analysis Hospital based studies Community based studies Studies in which Zinc was mixed with ORS Additional studies on zinc supplementation in acute diarrhoea have been divided in 3 groups
  10. 10. Zinc in diarrhoea management - role <ul><li>Multiple functions of zinc help to maintain the gut mucosal integrity to reduce or prevent fluid loss </li></ul><ul><li>Thus, in diarrhoea, zinc deficiency affects various mucosal functions: </li></ul>3 Mar 2011 <ul><ul><li>Disrupts intestinal mucosa </li></ul></ul><ul><ul><li>Reduces brush border enzymes </li></ul></ul><ul><ul><li>Increases mucosal permeability </li></ul></ul><ul><ul><li>Increases intestinal secretion </li></ul></ul><ul><li>Note: these responses can occur within 48 hours – </li></ul><ul><ul><li>much faster than the direct effects of zinc on cellular development. </li></ul></ul>
  11. 11. Zinc in diarrhoea management-outcome 3 Mar 2011 Recovery from diarrhoea Continuation of diarrhoea for >7 days Stool volume / frequency Morbidity / Mortality Outcomes of Zinc interventions in diarrhoea have been studies on the following parameters
  12. 12. Evidence-based interventions <ul><li>Probability of continuing diarrhea on zinc therapy </li></ul><ul><ul><li>20% reduction for duration of acute diarrhea </li></ul></ul><ul><ul><li>25% reduction in stool output in acute diarrhea </li></ul></ul><ul><ul><li>24% reduction for persistent diarrhea </li></ul></ul><ul><li>42% reduction in treatment failure or death in persistent diarrhea </li></ul>3 Mar 2011 The Zinc Investigators Collaborative Group: Therapeutic effects of oral Zinc in acute and persistent diarrhea in children in developing countries: Pooled analysis and randomized controlled trials. Am J Clin Nut 2000; 72:1516-22
  13. 13. Zinc in acute diarrhoea 3 Mar 2011 Effect on recovery Study No. of subjects Relative Hazards (95% CI) Sazawal, 1995 931 0.79 (0.69, 0.90)* Hidayat, 1998 1368 0.92 (0.83, 1.02) Roy, 1997 101 0.85 (0.57, 1.28) Strand, 2002 891 0.79 (0.68, 0.93)* Bahl, 2002 805 0.89 (0.80, 0.99)* Baqui, 2002 1252 0.75 (0.65, 0.90)* Bhatnagar, 2004 266 0.76 (0.59, 0.97)* Combined estimate (Meta-analysis) 0.84 (0.78 to 0.89)*
  14. 14. Zinc in acute diarrhoea 3 Mar 2011 Effect on continuation > 7 days Study No. of subjects Odds ratio (95% CI) Sazawal, 1995 931 0.85 (0.60, 1.19) Hidayat, 1998 1368 0.72 (0.48, 1.07) Roy, 1997 101 0.77 (0.33, 1.79) Strand, 2002 891 0.57 (0.38, 0.86)* Bahl, 2002 805 0.61 (0.33, 1.12) Bhatnagar, 2004 266 0.09 (0.01, 0.73)* Combined estimate (Meta-analysis) 0.66 (0.52 to 0.83)*
  15. 15. Zinc in acute diarrhoea 3 Mar 2011 Effect on stool frequency Study No. of subjects Difference in means/ Rate ratio(95% CI) Sazawal, 1995 931 -2.0 (-3.6, -0.4)* Sachadev, 1988 50 -1.7 (-4.1, 0.7)* Cuevas, 2001 74 -5.9 (-9.5, -2.3)* Strand, 2002 891 0.91 (0.85, 0.97)* Bahl, 2002 805 0.73 (0.63, 0.84)*
  16. 16. Zinc in acute diarrhoea 3 Mar 2011 Effect on stool volume Study No. of subjects Difference in means/ Ratio of GM(95% CI) Roy, 1997 101 -91g Dutta, 2000 80 -900 (-1200, -590)* Bhatnagar, 2004 266 0.69 (0.48, 0.99)*
  17. 17. Zinc in acute diarrhoea [for 14 days] 3 Mar 2011 Effect on mortality and hospitalization Study Intervention Controls Rate Ratio (95% CI) Child-years of follow up 5866 6015 0.49 (0.25 to 0.94)* Diarrhoea hospitalizations 8.15 10.34 0.76 (0.59 to 0.98)* ALRI hospitalizations 5.05 5.99 0.81 (0.53 to 1.23) Baqui et al, 2002
  18. 18. Zinc in acute diarrhoea [community based trial] <ul><li>Rural Bangladesh, 30 clusters randomized for health workers and volunteers to treat diarrhea with </li></ul><ul><ul><li>ORS alone or ORS + zinc (20mg/d for 14 days) </li></ul></ul><ul><li>2-year study, 12,000 child-years of observation </li></ul><ul><li>24% decrease in duration of all diarrhea episodes in zinc treatment compared to control clusters (RH 0.76, 95% CI 0.65-0.90) </li></ul>3 Mar 2011
  19. 19. Zinc in diarrhoea [community based efficacy studies] <ul><li>In the management of diarrhoea, zinc treatment led to significant reduction : </li></ul><ul><ul><li>Overall diarrhoea prevalence by 25% </li></ul></ul><ul><ul><li>Hospitalization from diarrhoea by 30% </li></ul></ul><ul><ul><li>Antibiotic use rate by more than 70% </li></ul></ul><ul><li>And to significant increase : </li></ul><ul><ul><li>ORS use rate from 10% to 70%. </li></ul></ul>3 Mar 2011
  20. 20. Zinc add-vantages <ul><li>Zinc supplements [given during an episode of diarrhoea and for 14 days after] </li></ul><ul><ul><li> duration & severity of the episode </li></ul></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 Indicated for diarrhea, regardless of duration or type (acute or persistent; bloody or watery) Reduces mortality in children Reduces admissions to hospitals for diarrhoea
  21. 21. Zinc bonus advantages <ul><li>Zinc supplements given during an episode of diarrhoea and for 14 days after </li></ul><ul><ul><li>has longer term effects on childhood illnesses in the 2-3 months after treatment </li></ul></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 34% reduction in incidence of diarrhoea 26% reduction the incidence of pneumonia
  22. 22. Zinc – specifications for use in diarrhoea <ul><li>Dosage : </li></ul><ul><ul><li>each individual dose of zinc should contain 20mg of elemental zinc </li></ul></ul><ul><li>Type of zinc salt : </li></ul><ul><ul><li>the zinc salt should be soluble in water (zinc sulfate, acetate or gluconate) </li></ul></ul><ul><li>Formulation: </li></ul><ul><ul><li>acceptable for use in very young infants. </li></ul></ul>3 Mar 2011
  23. 23. Zinc – specifications for use in diarrhoea <ul><li>Taste masking : </li></ul><ul><ul><li>the metallic after-taste of zinc should be totally masked </li></ul></ul><ul><li>Shelf-life : </li></ul><ul><ul><li>the zinc product should have a shelf-life of at least 2 years. </li></ul></ul><ul><li>Costing : </li></ul><ul><ul><li>the cost of a dose should not exceed US$0.02 </li></ul></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002
  24. 24. Zinc in diarrhoea- questions that need answers <ul><li>Does zinc supplementation during treatment of acute diarrhoea have an effect on: </li></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 <ul><ul><li>Duration of the episode </li></ul></ul><ul><ul><li>Stool volume </li></ul></ul><ul><ul><li>Stool frequency, </li></ul></ul><ul><ul><li>Need for unscheduled IV therapy, and </li></ul></ul><ul><ul><li>Death? </li></ul></ul>Yes Yes Yes Yes
  25. 25. Zinc in diarrhoea- questions that need answers <ul><li>Is the effect of zinc supplementation on acute diarrhoea dependent on: </li></ul><ul><ul><li>Age; or </li></ul></ul><ul><ul><li>Nutritional status? </li></ul></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 <ul><li>No conclusive evidence of difference in efficacy in sub-groups based on - age , nutritional status, serum zinc levels or aetiology of diarrhoea noted to date. </li></ul><ul><li>Zinc has been used in children 3-6 months of age too without any complaints </li></ul>
  26. 26. Zinc in diarrhoea- questions that need answers <ul><li>Is there an impact of zinc supplementation on vomiting? </li></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 <ul><li>No. </li></ul><ul><li>In fact, vomiting is the only reported adverse effect of zinc supplementation with 2/7 trials report higher vomiting rates in zinc group while 5/7 trials report no difference between zinc and placebo </li></ul>
  27. 27. Zinc in diarrhoea- questions that need answers <ul><li>Is there an impact of zinc supplementation when given together with other micronutrients? </li></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 <ul><li>Yes, zinc interferes with the absorption of iron and copper. </li></ul><ul><li>Copper deficiency can occur with immunosuppression and other subtle and apparent adverse effects. </li></ul><ul><li>For this reason, zinc doses > 2 times RDA are not recommended. </li></ul>
  28. 28. Zinc in diarrhoea- questions that need answers <ul><li>Is it feasible to add zinc to ORS and would it have the same efficacy? </li></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 Yes, but studies have revealed that efficacy does not remain the same and hence there is no combination of the 2.
  29. 29. Zinc in diarrhoea- questions that need answers <ul><li>What is the ideal daily dose and form of zinc? </li></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 <ul><li>WHO and UNICEF recommend daily - </li></ul><ul><li>20 mg zinc supplements for 10–14 days for children with acute diarrhoea, in a single dose or 2-3 divided doses, and </li></ul><ul><li>10 mg per day for infants < 6 months old. </li></ul>Source: WHO/UNICEF JOINT STATEMENT - CLINICAL MANAGEMENT OF ACUTE DIARRHOEA, MAY 2004
  30. 30. Zinc in diarrhoea- questions that need answers <ul><li>Why is the ideal daily dose and duration of zinc to be followed? </li></ul>3 Mar 2011 Source: BMJ VOLUME 325 9 NOVEMBER 2002 Studies show that - To enable the &quot;protective&quot; benefit of Zinc on preventing future episodes for 2 to 3 months. it is important to insist on compliance for 10 to 14 days therapy. Source: WHO/UNICEF JOINT STATEMENT - CLINICAL MANAGEMENT OF ACUTE DIARRHOEA, MAY 2004
  31. 31. Probiotics and zinc in infantile diarrhoea <ul><li>Evaluation of a diet containing probiotics and zinc [10 mg/ day] for the treatment of mild diarrheal illness in children younger than one year of age showed that diarrhoeal resolution occurred earlier as compared to controls; </li></ul><ul><li>However, whether this combination is better than either the addition of probiotics or zinc alone is yet to be determined. </li></ul>3 Mar 2011 Source: Journal of the American College of Nutrition, Vol. 24, No. 5, 370-375 (2005)
  32. 32. Conclusions <ul><li>12 years have been necessary to demonstrate the benefits of zinc in the management of diarrhoea and to develop an adequate product that </li></ul><ul><ul><li>suggests cost-effectiveness and decreases need for expensive hospitalization and inappropriate use of antibiotics and other drugs </li></ul></ul><ul><li>It is never too late to invest in developing sustainable health systems that provide evidence based, cost effective and high impact interventions with high coverage and quality . </li></ul>3 Mar 2011 Source: Robberstad, Strand, Sommerfelt, and Black. Bull WHO 2004. Baqui, Black, Arifeen. J Health Pop Nutr (In Press).
  33. 33. Conclusions <ul><li>Need in developing countries in Africa: </li></ul><ul><ul><li>To produce zinc preparations locally and to develop delivery mechanisms. </li></ul></ul><ul><ul><li>To create standards for zinc supplies and test (quality control) </li></ul></ul><ul><ul><li>To establish capacity to produce / procure the zinc supplements & newly recommended ORS. </li></ul></ul><ul><li>The biggest challenge </li></ul><ul><ul><li>Scaling up production and ensure that the therapy reaches the poorest of the poor. </li></ul></ul>3 Mar 2011
  34. 34. References <ul><li>Reduced osmolarity oral rehydration salts (ORS) formulation. Consensus statement of WHO and UNICEF. Geneva: World Health Organization; 2001. Document WHO/FCH/CAH/01.22 </li></ul><ul><li>Jones G, Steketee RW, Black RE. How many child deaths can we prevent this year. Lancet 2003;5(362):65-71. </li></ul><ul><li>Black RE, Morris SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003;28(361):2226-34. </li></ul><ul><li>Baqui AH, Black RE, El Arifeen S. Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ 2002; 325(7372):1059-65. </li></ul><ul><li>Hotz C and Brown KH. Estimated risk of zinc deficiency by country. Food Nutr Bull 2004;25(4):S189-S195. </li></ul>3 Mar 2011
  35. 35. References <ul><li>Zinc Investigators’ Collaborative Group. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. AJCN 2000;72:1516-22. </li></ul><ul><li>Robberstad B, Strand T, Black RE, and Sommerfelt H. Cost-effectiveness of zinc as adjunct therapy for acute childhood diarrhoea in developing countries. Bull WHO 2004; 82(7):523-31. </li></ul><ul><li>WHO/UNICEF. Joint statement on the clinical management of acute diarrhoea. 2004. </li></ul><ul><li>Zinc Investigators’ Collaborative Group. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. J Pediatr 1999;135(6):689-97. </li></ul>3 Mar 2011
  36. 36. References <ul><li>Black RE. Zinc deficiency, infectious disease, and mortality in the developing world. J Nutr 2003;133:1485S-1489S. </li></ul><ul><li>Zinc Investigators’ Collaborative Group. Effect of zinc supplementation on clinical course of acute diarrhoea. J Health Popul Nutr 2001;19(4):338-46. </li></ul><ul><li>International Zinc Nutrition Consultative Group (IZiNCG) Technical Document #1. Food Nutr Bull March 2004;25 Supplement 2. </li></ul>3 Mar 2011

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