Annals of Tropical Paediatrics International Child Health
ISSN: 0272-4936 (Print) 1465-3281 (Online) Journal homepage: http://www.tandfonline.com/loi/ypch19
Oral zinc supplementation in persistent diarrhoea in infants H. P. S. Sachdev, N. K. Mittal & H. S. Yadav To cite this article: H. P. S. Sachdev, N. K. Mittal & H. S. Yadav (1990) Oral zinc supplementation in persistent diarrhoea in infants, Annals of Tropical Paediatrics, 10:1, 63-69, DOI: 10.1080/02724936.1990.11747411 To link to this article: http://dx.doi.org/10.1080/02724936.1990.11747411
Published online: 13 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 27 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ypch19 Download by: [Australian Catholic University]
Date: 25 August 2017, At: 16:51
Annals of Tropical Paediatrics (1990) 10, 63-69
Oral zinc supplementation in persistent diarrhoea in infants H.P. S. SACHDEV,N. K.MITTAL&H. S. YADAV*
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Department of Pediatrics, Maulana Azad Medical College, New Delhi and* Institute of Nuclear Medicine and Allied Sciences, Delhi (Received 13 September 1989)
Summary. A controlled randomized trial was conducted in 40 infants (6-18 months old) with persistent diarrhoea ( > 2 weeks' duration) to evaluate the effect of oral zinc supplementation. After completion of rehydration, 20 infants in group A received oral zinc sulphate (20 mg elemental zinc twice daily) and an equal number in group B were given a placebo (glucose). Each child was given oral nalidixic acid and a similar milk-free feeding schedule. Both the groups were comparable with respect to various initial characteristics including nutrition, diarrhoea! disease, serum alkaline phosphatase and serum and rectal mucosal zinc content. During therapy, all the assessed parameters of zinc status (serum alkaline phosphatase and serum and rectal zinc) recorded significant elevation and reduction in groups A and B, respectively. At recovery, the zinc status of group A was significantly higher than that of group B. The diarrhoea! duration and frequency in the zinc-supplemented group were lower but the differences were not statistically significant (p=0.078 and p=0.076, respectively). Weight gain in both groups was comparable. It is concluded that in persistent diarrhoea there is depletion of zinc with the progression of disease and oral zinc administration can improve the zinc status. The possible anti-diarrhoeal effect of zinc, however, merits further study.
Introduction The majority of children with acute gastroenteritis have a self-limiting illness, and the diarrhoea diminishes after a few days. However, it is estimated that in the developing world almost 5-20% of episodes of diarrhoea that begin acutely persist beyond the expected period of recovery . 1' 2 Diarrhoea lasting for longer than 2-3 weeks is usually considered 'persistent'. Many of these children have growth failure, but this is not an inherent part of the definition. Also, certain well defined prolonged diarrhoea! illnesses such as coeliac disease, inflammatory bowel disease, genetically-determined illnesses, familial lethal diarrhoeas, and blind loop
syndromes owing to known causes are excluded. 1 The factors responsible for the persistence of diarrhoea are probably many, some of which are not entirely clear. There is, presently, no uniformly effective therapy for persistent diarrhoea, except for patients with known aetiologies (persistent bacterial and parasitic enteric infection, carbohydrate malabsorption, and protein intolerance). Conflicting results have been reported with antimicrobials, cholestyramine, antimotility agents and diverse diets. 1 Termination of diarrhoea is crucial for reducing mortality and preventing the vicious cycle of diarrhoea and malnutrition. Children with prolonged diarrhoea may be zinc-deficient since they have a significantly
Reprint requests to: Dr H. P. S. Sachdev, Associate Professor in Pediatrics, DII/145, West Kidwai Nagar, New Delhi 110 023, India.
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
64
H. P. S. Sachdev et al.
reduced content of serum zinc, serum alkaline phosphatase (a zinc-dependent enzyme) and rectal mucosal zinc.3-5 It should, however, be acknowledged that a low serum zinc concentration could also arise as a result of the infection itself. A recent balance study provides conclusive evidence of zinc depletion in diarrhoea. 6 Zinc is a constituent of several important enzymes in the human body. It is essential for DNA, RNA and protein synthesis and, as such, is important for cell division. 7 A deficiency may thus limit regeneration of gut epithelium and consequently delay recovery from diarrhoea. It has also been shown that the absorption of water and electrolytes is significantly diminished in zinc-deficient animals, 8•9 and that the transport of water and electrolytes is restored to normal following zinc repletion. 9 An earlier trial we conducted in infants with acute diarrhoea suggested that oral zinc administration can replenish body 'zinc status' (as assessed by serum zinc, serum alkaline phosphatase and rectal mucosal zinc) and this may shorten the diarrhoeal duration and frequency in children with relatively lower rectal mucosal zinc content. 10 A controlled, randomized study was therefore designed to evaluate the effect of oral zinc supplementation in 'persistent' diarrhoea.
Materials and methods The study population comprised 40 infants aged 6-18 months hospitalized with the diagnosis of'persistent diarrhoea', i.e. an episode of diarrhoea ( > 4 loose watery stools/24 h) that began acutely but persisted for at least 2 weeks with no intervening period of remission. Children with the following features were not included in the study: (i) a history of another diarrhoeal episode 1 month prior to the onset of the present illness; (ii) critically sick infants, i.e. infants requiring a life-support system, blood transfusion or total parenteral nutrition; (iii) obvious parenteral infections, e.g. septicaemia, meningitis, pneumonia or urinary tract infection: if the initial bacteriological screening showed
a patient to have parenteral infection, the child was excluded from the study and the next infant to be studied was allocated to the treatment group from which the infant had been excluded; (iv) severe malnutrition (grades Ill and IV), in order to minimize the effect of malnutrition-a known zincdeficient stateu-on zinc status. At admission, the infants were clinically assessed for the degree of dehydration and randomized to either of the two treatment groups. Informed consent was obtained from the parents or guardians at the time of admission. Irrespective of the assigned treatment group, infants who were considered to be severely dehydrated on admission (estimated dehydration > 10%) were given intravenous normal saline (2~30 ml/kg/h) until the blood pressure and pulse returned to normal. Subsequently, they completed rehydration and maintenance therapy with the World Health Organization (WHO) recommended oral rehydration solution (ORS). Those who were mildly to moderately dehydrated on admission were initially rehydrated and maintained with the WHOORS. The initially calculated deficit was replaced over the 1st 6-8 h on the basis of clinical assessment of dehydration on admission. The ORS was administered by the attendants in a supervised ad libitum fashion. Once clinical assessment indicated that hydration had been achieved (usually within 8 h), this treatment regimen was discontinued and only continuing stool losses were replaced on 1:1 approximation with the WHO-ORS. At this juncture, the infants were started on syrup nalidixic acid (50 mg/ kg per day in three divided doses) and half strength rice-dal mixture (vide infra). For every infant, enteral feeding was instituted in a sequential manner, viz. intravenous fluids (if required) followed by WHO-ORS, followed by half strength rice-dal mixture (RDM) on rehydration. The half strength RDM was upgraded to full strength after 24--36 h; simultaneously, solid food in the form of khichri (cooked mixture of rice, mung lentils and vegetable oil in solid form)
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Oral zinc in persistent diarrhoea and mashed ripe banana was allowed. The feeding was given in a supervised ad libitum manner; guidelines, however, were given to the parents regarding the desirable food intake per 24 h. Cow's milk, breast-milk and wheat products were strictly avoided. If, during any phase of enteral feeding, the diarrhoea worsened the infant was switched back to the earlier feeding sequence and the same food was retried only after a further 12-24 h. The decision to use nalidixic acid in every child was prompted by reports of frequent abnormal overgrowth of micro-organisms in the small bowel of infants with persistent diarrhoea, 1•12 and the use of oral gentamicin in this condition. 13 Earlier experience had revealed a uniform in vitro susceptibility of a vast majority of bacterial enteropathogens (E. coli, Shigella, Salmonella) to nalidixic acid. The full strength RDM consisted of rice powder 50 g, mung lentils 33 g, sugar 20 g, vegetable oil30 g, and NaC11 gin 1litre of water. 2 RD M was used for feeding in every case as facilities for laboratory diagnosis of cow's milk protein intolerance were not available and, furthermore, local experience had documented its acceptability and use in chronic diarrhoea. 2 The infants were closely monitored at regular intervals for hydration status, weight, and frequency and consistency of stools. The serum and rectal tissue samples for assessing the zinc status (vide infra) were taken at a fixed time of day following admission (9-10 a.m.) in the rehydrated state. Subsequently, in a randomized, doubleblind manner, the patients received twice daily either oral powdered zinc (group A) or placebo, i.e. glucose (group B). Oral zinc was given as 55 mg zinc sulphate (equivalent to 20 mg of elemental zinc) twice daily. The zinc supplementation dose was calculated on the basis of the following considerations: (a) stool zinc losses can be exceedingly high in infants with diarrhoea; values up to 2-3 mg per day are reported. 14 •15 Intravenous zinc supplementation in a dose of 300-500 f.lg/kg per day was required to reverse the clinical features of zinc deficiency
65
in these infants. The absorption of zinc in healthy individuals is reported to range from 5 to 25%,. 7 •16 In diarrhoea, the absorption is expected to be lower. Assuming an absorption of 50% and a parenteral requirement of 300 f.Ig/kg, the oral dose requirement would be 6 mg/kg. Similarly, for values of 10% and 500 f.Ig/kg, the oral dose works out at 5 mg/kg; (b) an oral zinc supplementation study in adults with non-responsive coeliac syndrome utilized 4-5.2 mg/kg elemental zinc; 17 (c) prior to the initiation of the study, it was estimated that the average rehydration weight would range between 7 and 8 kg. A supplementation dose of 5-6 mg/kg was therefore given as 20 mg elemental zinc twice daily. The pertinent investigations performed included haemogram; serum protein, albumin, zinc and alkaline phosphatase; stool sampling for pH, reducing substances, microscopic examination and bacteriological culture; urine sampling for microscopy and culture; blood culture; chest X-ray; and rectal biopsy for histopathology and rectal mucosal zinc content. Zinc estimations were performed on an atomic absorption spectroscope, taking adequate precautions to prevent contamination. The rectal biopsy samples were also collected in plastic tubes (pretested to be zinc-free). They were gently shaken with de-ionized water (pre-tested to be zinc-free) until they were blood- and stool-free. These were then stored in a deep freeze until analysis. The rectal tissue was dried to a constant weight (hot air oven for 30 min at 100°C) and acid digested (1 ml zinc-free concentrated nitric acid) before zinc estimation. For reasons outlined subsequently, 'zinc status' was assessed by concurrent measurement of three laboratory parameters, namely, serum zinc, rectal mucosal zinc and serum alkaline phosphatase. Similarly, the term 'nutritional status' refers to weight-for-age, length, mid-arm circumference, and serum protein and serum albumin levels. Statistical analyses were performed using the Student's t-test, paired t-test, chi-square test and Mann-Whitney U test.
66
H. P. S. Sachdev et al.
TABLE I. Initial characteristics of the treatment groups' Group A (zinc supplement)
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Feature No. Males/females Age (months) Duration of diarrhoea (days) Frequency (per 24 h) of diarrhoea before admission Range Weight for ageb Length (cm) Mid-arm circumference (cm) Degree of hydration Mild(10%) Weight gain during rehydration(%) Stool examination a. PMN leucocytes (per HPF) 10-20 >20 b. Red blood cells c. pH :,;;;; 5 and reducing substances Organisms isolated in stool: Shigella Salmonella EPEC E. coli' Klebsiella Rectal histology: moderate to severe colitis Heamoglobin (g/dl) Time (h) from hospitalization to zinc sampling No. requiring earlier sequence of feeding after starting therapy"
13/7
20 13 (65~ 0 ) 9.3 (2.2) 18.2 (2.4) 9.5 (6.0) (6-14) 73.4 (9.1) 66.2 (3.7) 11.1 (1. 7)
GroupB (placebo)
12/8
20 12 (60%) 9.5 (2.8) 19.0 (3.02) 10.1 (5.0) (7-13) 71.9 (10.0) 67.5 (4.1) 11.5 (1.9)
13 (65° 0 ) 6 (30°, 0 ) 1 (5%) 4.1 (3.8)
11 (55%) 8(40%) 1 (5%) 4.4 (3.3)
4 (20° 0 ) 8 (40° 0 ) 6(30%) 5 (25%)
5 (25%) 9(45%) 5 (25%) 6(30%)
6 (30° 0 ) 2 (10° 0 ) 3 (15%) 8 (40%) 4 (16~'0 )
4(20%) 3(15%) 2 (10%) 10 (50%) 3 (15%)
10 (50° 0 ) 9.1 (1.1) 15.7 (2.4)
8 (40° 0 ) 9.3 (1.2) 14.8 (2.0)
2 (10° 0 )
1 (5%)
'Values denote mean (SD). None of the differences between the groups was significant (p > 0.05). bExpressed as percentage of 50th centile ofNCHS standards. 'Non-enteropathogenic E. coli. •For details see 'Materials and methods'.
Results There were 20 cases each in groups A and B. The initial characteristics of the two treatment groups were comparable (Tables I and 11). The various characteristics of the treatment groups during the course of therapy are summarized in Table 11. The oral zinc supplements were well tolerated and none of the infants developed emesis secondary to zinc ingestion. Serum protein, serum albumin
and body weight were comparable within and between the treatment groups. During therapy all the assessed parameters of zinc status (serum alkaline phosphatase, serum zinc and rectal zinc) recorded a statistically significant elevation in the zinc-supplemented group, and a statistically significant reduction in the placebo group. Also, at recovery these parameters were significantly greater in the zinc-supplemented group. The diarrhoea! duration and average frequency in
Oral zinc in persistent diarrhoea
67
TABLE 11. Features of the treatment groups during therapy (mean (SD))
Feature
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Serum protein (g/dl) Initial Recovery Serum albumin (g/dl) Initial Recovery Serum alkaline phosphatase (KAU) Initial (Cl, 95° 0 ) Recovery (Cl, 95° 0 ) Serum zinc (mg/1)' Initial (Cl, 95° 0 ) Recovery (Cl, 95° 0 ) Rectal mucosal zinc (Jig/g dry weight)' Initial (Cl, 95° 0 ) Recovery (Cl, 95° 0 ) Weight(kg) Rehydration Recovery Diarrhoea! duration (h) (Cl, 95'Yu) Average diarrhoea! frequency/24 h (Cl, 95° 0 )
Group A (zinc supplement)
GroupB (placebo)
5.3 (0.4) 5.3 (0.4)
5.1 (0.5) 5.1 (0.5)
3.4 (0.3) 3.4 (0.3)
3.3 (0.4) 3.3 (0.4)
14.4 (3.4)t (12.9, 15.9) 16.6 (4.0)* (14.8, 18.4)
15.1 (3.3)t (13.6, 16.6) 14.0 (4.1) (12.2, 15.8)
0.73 (0.07)t (0.70, 0.76) 0.80 (0.12)** (0.75, 0.85)
0.75 (O.ll)t (0.70, 0.80) 0.67 (0.14) (0.61, 0.73)
6.51 (l.Ol)t (6.07, 6.95) 7.03 (0.92)** (6.63, 7.43)
6.84 (1.04)tt (6.38, 7.30) 5.91 (1.30) (5.34, 6.48)
7.20 (1.53) 7.31 (1.62) 88.2 (27.4)b (76.2, 100.2) 8.8 (4.0)' (7.0, 10.6)
7.12 (1.8) 7.14 (2.0) 108.6 (45.8) (88.5, 128. 7) 11.2 (4.3) (9.3, 13.1)
'Values in age- and nutritionally-matched healthy controls (mean (SD) ). Serum zinc: 0.94 (0.16) mg/1 and rectal mucosal zinc: 10.11 (1.77) f.lg/g dry weight. bDiarrhoeal duration was defined as the time in hours from sampling for zinc to the passage of first formed stool (t= 1.71, 38 d.f.,p=0.078). 'Average diarrhoea! frequency/24 h during course of therapy was calculated as: Total number of diarrhoea! stools till recovery -------------------------------x24 diarrhoea! duration (t = 1.83, 38 d.f., p = 0.076).
t, ttSignificantly different from recovery values (paired r-test) (tp
ISSN: 0272-4936 (Print) 1465-3281 (Online) Journal homepage: http://www.tandfonline.com/loi/ypch19
Oral zinc supplementation in persistent diarrhoea in infants H. P. S. Sachdev, N. K. Mittal & H. S. Yadav To cite this article: H. P. S. Sachdev, N. K. Mittal & H. S. Yadav (1990) Oral zinc supplementation in persistent diarrhoea in infants, Annals of Tropical Paediatrics, 10:1, 63-69, DOI: 10.1080/02724936.1990.11747411 To link to this article: http://dx.doi.org/10.1080/02724936.1990.11747411
Published online: 13 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 27 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ypch19 Download by: [Australian Catholic University]
Date: 25 August 2017, At: 16:51
Annals of Tropical Paediatrics (1990) 10, 63-69
Oral zinc supplementation in persistent diarrhoea in infants H.P. S. SACHDEV,N. K.MITTAL&H. S. YADAV*
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Department of Pediatrics, Maulana Azad Medical College, New Delhi and* Institute of Nuclear Medicine and Allied Sciences, Delhi (Received 13 September 1989)
Summary. A controlled randomized trial was conducted in 40 infants (6-18 months old) with persistent diarrhoea ( > 2 weeks' duration) to evaluate the effect of oral zinc supplementation. After completion of rehydration, 20 infants in group A received oral zinc sulphate (20 mg elemental zinc twice daily) and an equal number in group B were given a placebo (glucose). Each child was given oral nalidixic acid and a similar milk-free feeding schedule. Both the groups were comparable with respect to various initial characteristics including nutrition, diarrhoea! disease, serum alkaline phosphatase and serum and rectal mucosal zinc content. During therapy, all the assessed parameters of zinc status (serum alkaline phosphatase and serum and rectal zinc) recorded significant elevation and reduction in groups A and B, respectively. At recovery, the zinc status of group A was significantly higher than that of group B. The diarrhoea! duration and frequency in the zinc-supplemented group were lower but the differences were not statistically significant (p=0.078 and p=0.076, respectively). Weight gain in both groups was comparable. It is concluded that in persistent diarrhoea there is depletion of zinc with the progression of disease and oral zinc administration can improve the zinc status. The possible anti-diarrhoeal effect of zinc, however, merits further study.
Introduction The majority of children with acute gastroenteritis have a self-limiting illness, and the diarrhoea diminishes after a few days. However, it is estimated that in the developing world almost 5-20% of episodes of diarrhoea that begin acutely persist beyond the expected period of recovery . 1' 2 Diarrhoea lasting for longer than 2-3 weeks is usually considered 'persistent'. Many of these children have growth failure, but this is not an inherent part of the definition. Also, certain well defined prolonged diarrhoea! illnesses such as coeliac disease, inflammatory bowel disease, genetically-determined illnesses, familial lethal diarrhoeas, and blind loop
syndromes owing to known causes are excluded. 1 The factors responsible for the persistence of diarrhoea are probably many, some of which are not entirely clear. There is, presently, no uniformly effective therapy for persistent diarrhoea, except for patients with known aetiologies (persistent bacterial and parasitic enteric infection, carbohydrate malabsorption, and protein intolerance). Conflicting results have been reported with antimicrobials, cholestyramine, antimotility agents and diverse diets. 1 Termination of diarrhoea is crucial for reducing mortality and preventing the vicious cycle of diarrhoea and malnutrition. Children with prolonged diarrhoea may be zinc-deficient since they have a significantly
Reprint requests to: Dr H. P. S. Sachdev, Associate Professor in Pediatrics, DII/145, West Kidwai Nagar, New Delhi 110 023, India.
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
64
H. P. S. Sachdev et al.
reduced content of serum zinc, serum alkaline phosphatase (a zinc-dependent enzyme) and rectal mucosal zinc.3-5 It should, however, be acknowledged that a low serum zinc concentration could also arise as a result of the infection itself. A recent balance study provides conclusive evidence of zinc depletion in diarrhoea. 6 Zinc is a constituent of several important enzymes in the human body. It is essential for DNA, RNA and protein synthesis and, as such, is important for cell division. 7 A deficiency may thus limit regeneration of gut epithelium and consequently delay recovery from diarrhoea. It has also been shown that the absorption of water and electrolytes is significantly diminished in zinc-deficient animals, 8•9 and that the transport of water and electrolytes is restored to normal following zinc repletion. 9 An earlier trial we conducted in infants with acute diarrhoea suggested that oral zinc administration can replenish body 'zinc status' (as assessed by serum zinc, serum alkaline phosphatase and rectal mucosal zinc) and this may shorten the diarrhoeal duration and frequency in children with relatively lower rectal mucosal zinc content. 10 A controlled, randomized study was therefore designed to evaluate the effect of oral zinc supplementation in 'persistent' diarrhoea.
Materials and methods The study population comprised 40 infants aged 6-18 months hospitalized with the diagnosis of'persistent diarrhoea', i.e. an episode of diarrhoea ( > 4 loose watery stools/24 h) that began acutely but persisted for at least 2 weeks with no intervening period of remission. Children with the following features were not included in the study: (i) a history of another diarrhoeal episode 1 month prior to the onset of the present illness; (ii) critically sick infants, i.e. infants requiring a life-support system, blood transfusion or total parenteral nutrition; (iii) obvious parenteral infections, e.g. septicaemia, meningitis, pneumonia or urinary tract infection: if the initial bacteriological screening showed
a patient to have parenteral infection, the child was excluded from the study and the next infant to be studied was allocated to the treatment group from which the infant had been excluded; (iv) severe malnutrition (grades Ill and IV), in order to minimize the effect of malnutrition-a known zincdeficient stateu-on zinc status. At admission, the infants were clinically assessed for the degree of dehydration and randomized to either of the two treatment groups. Informed consent was obtained from the parents or guardians at the time of admission. Irrespective of the assigned treatment group, infants who were considered to be severely dehydrated on admission (estimated dehydration > 10%) were given intravenous normal saline (2~30 ml/kg/h) until the blood pressure and pulse returned to normal. Subsequently, they completed rehydration and maintenance therapy with the World Health Organization (WHO) recommended oral rehydration solution (ORS). Those who were mildly to moderately dehydrated on admission were initially rehydrated and maintained with the WHOORS. The initially calculated deficit was replaced over the 1st 6-8 h on the basis of clinical assessment of dehydration on admission. The ORS was administered by the attendants in a supervised ad libitum fashion. Once clinical assessment indicated that hydration had been achieved (usually within 8 h), this treatment regimen was discontinued and only continuing stool losses were replaced on 1:1 approximation with the WHO-ORS. At this juncture, the infants were started on syrup nalidixic acid (50 mg/ kg per day in three divided doses) and half strength rice-dal mixture (vide infra). For every infant, enteral feeding was instituted in a sequential manner, viz. intravenous fluids (if required) followed by WHO-ORS, followed by half strength rice-dal mixture (RDM) on rehydration. The half strength RDM was upgraded to full strength after 24--36 h; simultaneously, solid food in the form of khichri (cooked mixture of rice, mung lentils and vegetable oil in solid form)
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Oral zinc in persistent diarrhoea and mashed ripe banana was allowed. The feeding was given in a supervised ad libitum manner; guidelines, however, were given to the parents regarding the desirable food intake per 24 h. Cow's milk, breast-milk and wheat products were strictly avoided. If, during any phase of enteral feeding, the diarrhoea worsened the infant was switched back to the earlier feeding sequence and the same food was retried only after a further 12-24 h. The decision to use nalidixic acid in every child was prompted by reports of frequent abnormal overgrowth of micro-organisms in the small bowel of infants with persistent diarrhoea, 1•12 and the use of oral gentamicin in this condition. 13 Earlier experience had revealed a uniform in vitro susceptibility of a vast majority of bacterial enteropathogens (E. coli, Shigella, Salmonella) to nalidixic acid. The full strength RDM consisted of rice powder 50 g, mung lentils 33 g, sugar 20 g, vegetable oil30 g, and NaC11 gin 1litre of water. 2 RD M was used for feeding in every case as facilities for laboratory diagnosis of cow's milk protein intolerance were not available and, furthermore, local experience had documented its acceptability and use in chronic diarrhoea. 2 The infants were closely monitored at regular intervals for hydration status, weight, and frequency and consistency of stools. The serum and rectal tissue samples for assessing the zinc status (vide infra) were taken at a fixed time of day following admission (9-10 a.m.) in the rehydrated state. Subsequently, in a randomized, doubleblind manner, the patients received twice daily either oral powdered zinc (group A) or placebo, i.e. glucose (group B). Oral zinc was given as 55 mg zinc sulphate (equivalent to 20 mg of elemental zinc) twice daily. The zinc supplementation dose was calculated on the basis of the following considerations: (a) stool zinc losses can be exceedingly high in infants with diarrhoea; values up to 2-3 mg per day are reported. 14 •15 Intravenous zinc supplementation in a dose of 300-500 f.lg/kg per day was required to reverse the clinical features of zinc deficiency
65
in these infants. The absorption of zinc in healthy individuals is reported to range from 5 to 25%,. 7 •16 In diarrhoea, the absorption is expected to be lower. Assuming an absorption of 50% and a parenteral requirement of 300 f.Ig/kg, the oral dose requirement would be 6 mg/kg. Similarly, for values of 10% and 500 f.Ig/kg, the oral dose works out at 5 mg/kg; (b) an oral zinc supplementation study in adults with non-responsive coeliac syndrome utilized 4-5.2 mg/kg elemental zinc; 17 (c) prior to the initiation of the study, it was estimated that the average rehydration weight would range between 7 and 8 kg. A supplementation dose of 5-6 mg/kg was therefore given as 20 mg elemental zinc twice daily. The pertinent investigations performed included haemogram; serum protein, albumin, zinc and alkaline phosphatase; stool sampling for pH, reducing substances, microscopic examination and bacteriological culture; urine sampling for microscopy and culture; blood culture; chest X-ray; and rectal biopsy for histopathology and rectal mucosal zinc content. Zinc estimations were performed on an atomic absorption spectroscope, taking adequate precautions to prevent contamination. The rectal biopsy samples were also collected in plastic tubes (pretested to be zinc-free). They were gently shaken with de-ionized water (pre-tested to be zinc-free) until they were blood- and stool-free. These were then stored in a deep freeze until analysis. The rectal tissue was dried to a constant weight (hot air oven for 30 min at 100°C) and acid digested (1 ml zinc-free concentrated nitric acid) before zinc estimation. For reasons outlined subsequently, 'zinc status' was assessed by concurrent measurement of three laboratory parameters, namely, serum zinc, rectal mucosal zinc and serum alkaline phosphatase. Similarly, the term 'nutritional status' refers to weight-for-age, length, mid-arm circumference, and serum protein and serum albumin levels. Statistical analyses were performed using the Student's t-test, paired t-test, chi-square test and Mann-Whitney U test.
66
H. P. S. Sachdev et al.
TABLE I. Initial characteristics of the treatment groups' Group A (zinc supplement)
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Feature No. Males/females Age (months) Duration of diarrhoea (days) Frequency (per 24 h) of diarrhoea before admission Range Weight for ageb Length (cm) Mid-arm circumference (cm) Degree of hydration Mild(10%) Weight gain during rehydration(%) Stool examination a. PMN leucocytes (per HPF) 10-20 >20 b. Red blood cells c. pH :,;;;; 5 and reducing substances Organisms isolated in stool: Shigella Salmonella EPEC E. coli' Klebsiella Rectal histology: moderate to severe colitis Heamoglobin (g/dl) Time (h) from hospitalization to zinc sampling No. requiring earlier sequence of feeding after starting therapy"
13/7
20 13 (65~ 0 ) 9.3 (2.2) 18.2 (2.4) 9.5 (6.0) (6-14) 73.4 (9.1) 66.2 (3.7) 11.1 (1. 7)
GroupB (placebo)
12/8
20 12 (60%) 9.5 (2.8) 19.0 (3.02) 10.1 (5.0) (7-13) 71.9 (10.0) 67.5 (4.1) 11.5 (1.9)
13 (65° 0 ) 6 (30°, 0 ) 1 (5%) 4.1 (3.8)
11 (55%) 8(40%) 1 (5%) 4.4 (3.3)
4 (20° 0 ) 8 (40° 0 ) 6(30%) 5 (25%)
5 (25%) 9(45%) 5 (25%) 6(30%)
6 (30° 0 ) 2 (10° 0 ) 3 (15%) 8 (40%) 4 (16~'0 )
4(20%) 3(15%) 2 (10%) 10 (50%) 3 (15%)
10 (50° 0 ) 9.1 (1.1) 15.7 (2.4)
8 (40° 0 ) 9.3 (1.2) 14.8 (2.0)
2 (10° 0 )
1 (5%)
'Values denote mean (SD). None of the differences between the groups was significant (p > 0.05). bExpressed as percentage of 50th centile ofNCHS standards. 'Non-enteropathogenic E. coli. •For details see 'Materials and methods'.
Results There were 20 cases each in groups A and B. The initial characteristics of the two treatment groups were comparable (Tables I and 11). The various characteristics of the treatment groups during the course of therapy are summarized in Table 11. The oral zinc supplements were well tolerated and none of the infants developed emesis secondary to zinc ingestion. Serum protein, serum albumin
and body weight were comparable within and between the treatment groups. During therapy all the assessed parameters of zinc status (serum alkaline phosphatase, serum zinc and rectal zinc) recorded a statistically significant elevation in the zinc-supplemented group, and a statistically significant reduction in the placebo group. Also, at recovery these parameters were significantly greater in the zinc-supplemented group. The diarrhoea! duration and average frequency in
Oral zinc in persistent diarrhoea
67
TABLE 11. Features of the treatment groups during therapy (mean (SD))
Feature
Downloaded by [Australian Catholic University] at 16:51 25 August 2017
Serum protein (g/dl) Initial Recovery Serum albumin (g/dl) Initial Recovery Serum alkaline phosphatase (KAU) Initial (Cl, 95° 0 ) Recovery (Cl, 95° 0 ) Serum zinc (mg/1)' Initial (Cl, 95° 0 ) Recovery (Cl, 95° 0 ) Rectal mucosal zinc (Jig/g dry weight)' Initial (Cl, 95° 0 ) Recovery (Cl, 95° 0 ) Weight(kg) Rehydration Recovery Diarrhoea! duration (h) (Cl, 95'Yu) Average diarrhoea! frequency/24 h (Cl, 95° 0 )
Group A (zinc supplement)
GroupB (placebo)
5.3 (0.4) 5.3 (0.4)
5.1 (0.5) 5.1 (0.5)
3.4 (0.3) 3.4 (0.3)
3.3 (0.4) 3.3 (0.4)
14.4 (3.4)t (12.9, 15.9) 16.6 (4.0)* (14.8, 18.4)
15.1 (3.3)t (13.6, 16.6) 14.0 (4.1) (12.2, 15.8)
0.73 (0.07)t (0.70, 0.76) 0.80 (0.12)** (0.75, 0.85)
0.75 (O.ll)t (0.70, 0.80) 0.67 (0.14) (0.61, 0.73)
6.51 (l.Ol)t (6.07, 6.95) 7.03 (0.92)** (6.63, 7.43)
6.84 (1.04)tt (6.38, 7.30) 5.91 (1.30) (5.34, 6.48)
7.20 (1.53) 7.31 (1.62) 88.2 (27.4)b (76.2, 100.2) 8.8 (4.0)' (7.0, 10.6)
7.12 (1.8) 7.14 (2.0) 108.6 (45.8) (88.5, 128. 7) 11.2 (4.3) (9.3, 13.1)
'Values in age- and nutritionally-matched healthy controls (mean (SD) ). Serum zinc: 0.94 (0.16) mg/1 and rectal mucosal zinc: 10.11 (1.77) f.lg/g dry weight. bDiarrhoeal duration was defined as the time in hours from sampling for zinc to the passage of first formed stool (t= 1.71, 38 d.f.,p=0.078). 'Average diarrhoea! frequency/24 h during course of therapy was calculated as: Total number of diarrhoea! stools till recovery -------------------------------x24 diarrhoea! duration (t = 1.83, 38 d.f., p = 0.076).
t, ttSignificantly different from recovery values (paired r-test) (tp
