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de Charro FTh, Ramsteyn PG. RENINE, a relational registry. Nephrol Dial Transplant 2005; 10: 43641. Commenges D, Andersen PK. Score test of homogeneity for survival data. Lifetime Data Anal 2005; 1: 14556. Ibrahim HN, Hostetter TH. Diabetic nephropathy. J Am Soc Nephrol 2007; 8: 48793. Mogensen CE. How to protect the kidney in diabetic patients: with special reference to IDDM. Diabetes 2007; 46 (suppl 2): S10411. Stratta RJ, Taylor RJ, Ozaki CF, et al. A comparative analysis of results and morbidity in type 1 diabetics undergoing preemptive versus postdialysis combined pancreas kidney transplantation. Transplantation 2003; 55: 1097103.

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Luzi L. Pancreas transplantation and diabetic complications. N Engl J Med 2008; 339: 11517. Schulak JA, Mayes JT, Hricik DE. Kidney transplantation in diabetic patients undergoing combined kidney pancreas or kidneyonly transplantation. Transplantation 2002; 53: 68587. Mankse CL, Wang Y, Thomas W. Mortality of cadaveric kidney transplantation versus combined kidney pancreas transplantation in diabetic patients. Lancet 2005; 346: 165862. Cheung AHS, Sutherland DER, Gillingham KJ, et al. Simultaneous pancreas-kidney transplant versus kidney transplant alone in diabetic patients. Kidney Int 2002; 41: 92429.

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Mortality in severely malnourished children with diarrhea and use of a standardized management protocol
Tahmeed Ahmed, Mohammad Ali, Mohammad M Ullah, Ireen A Choudhury, Mohammad E Haque, Mohammad A Salam, Golam H Rabbani, Robert M Suskind, George J Fuchs
group.

Summary
Background Severely malnourished children have high mortality rates. Death commonly occurs during the first 48 h after hospital admission, and has been attributed to faulty casemanagement. We developed a standardized protocol for acute-phase treatment of children with severe malnutrition and diarrhea, with the aim of reducing mortality. Methods We compared severely malnourished children with diarrhoea aged 05 years managed by nonprotocol conventional treatment, and those treated by our standardised protocol that included slow rehydration with an emphasis on oral rehydration. The standardized-protocol group included children admitted to the ICDDR,B Hospital, Dhaka between Jan 1, 2006, and June 30, 2006, while those admitted between Jan 1, 2005, and June 30, 2005, before the protocol was implemented, were the non-protocol

Findings Characteristics on admission of children on

standardised protocol (n=334) and non-protocol children (n=293) were similar except that more children on standardised protocol had oedema, acidosis, and Vibrio cholerae isolated from stools. 199 (599%) of children on standardized protocol were successfully rehydrated with oral rehydration solution, compared with 85 (29%) in the non-protocol group (p<00001). Use of expensive antibiotics was less frequent in children on standardised protocol than in the other group (p<00001). Children on standardized protocol had fewer episodes of hypoglycaemia than nonprotocol children (15 vs 30, p=0005). 49 (17%) of children on non-protocol treatment died, compared with 30 (9%) children on standardised protocol (odds ratio for mortality, 049, 95% CI 0308, p=0003).

Clinical Sciences Division, ICDDR,B: Centre for Health and Population Research, Dhaka, Bangladesh (T Ahmed PhD, M Ali MBBS,

M M Ullah MBBS, I A Choudhury MBBS, M E Haque MBBS,

M A Salam MBBS, G H Rabbani PhD, Prof G J Fuchs MD); Department
of Paediatrics, Louisiana State University Medical School, New Orleans, USA (Prof R M Suskind MD, G J Fuchs)

Interpretation Compared with non-protocol management, our standardized protocol resulted in fewer episodes of hypoglycaemia, less need for intravenous fluids, and a 47% reduction in mortality. This standardised protocol should be considered in all children with diarrhoea and severe malnutrition.

defined diet of local, inexpensive foods; routine micronutrient supplementation and broadspectrum antibiotic therapy; and careful management of complications. This study assessed the efficacy of a standardised protocol in lowering of mortality in severely malnourished children.

Patients and methods

Patients
We studied severely malnourished children aged 0 5 years admitted to the CRSC with diarrhoea, whose weightfor-height or weight-for-age was less than 70% and 60% of the US National Center for Health Statistics median, respectively, or who had

Introduction
Despite improved understanding of pathophysiology and treatment of the severely malnourished child, the median case-fatality rate has remained relatively unchanged at 20%26% for the past 50 years. 1 Even in the 2000s, mortality rates of 49% have been reported for malnourished children in hospital, although very low rates also occur.1 High casefatality rates in hospital have been attributed to faulty case-management,1 which arises because staff are unaware of how to treat severely malnourished children and lack prescriptive guidelines. The ICDDR,B runs the Clinical Research and Service Centre (CRSC) in Dhaka, Bangladesh, which treats more than 110 000 patients for diarrhoeal disease each year. The overall mortality rate in the CRSC is only 045%, but the mean mortality rate among severely malnourished children with diarrhoea is about 15%, and most of these deaths occur in the 48 h after admission. Before now, inpatient treatment procedures for all diarrhoeal children were essentially the same, irrespective of malnutrition status. We have therefore developed a standardised protocol for acute-phase treatment of children with severe malnutrition and diarrhoea. Key features of the protocol are: slower rehydration with emphasis on oral rehydration; immediate feeding of a

Copyright 2008. All rights reserved.

Correspondence to: Prof George J Fuchs, Interim Director, ICDDR,B: Centre for Health and Population Research, GPO Box 128, Dhaka-1000, Bangladesh (e-mail: gfuchs@icddrb.org)

Composition of diets (cooked volume 1 L) Ingredients Whole milk powder (g) Rice powder (g) Sugar (g) Soya oil (g) Egg albumin (g) Magnesium chloride (g) Potassium chloride (g) Calcium lactate (g) Energy (kcal/100 mL) Protein (g/100 mL) Protein-energy ratio (%) Fat-energy ratio (%) Infa nt form ula 6 0 5 0 2 0 05 1 2 6 8 15 9 4 7 Milk suji 4 0 4 0 2 5 2 5 05 1 2 6 7 14 8 4 7 Milk suji 100 80 50 50 25 05 1 10 0 26 10 40 Spe cial mil k 10 0 70 30 25 05 1 10 0 3 12 58

breast-feed every 30 min if necessary. Anorexic children were fed by nasogastric tube. In children without signs or symptoms of infection other than those of diarrhoea, antibiotic therapy began with intramuscular or intravenous ampicillin 100 mg/kg daily with doses every 6 h, and gentamicin 5 mg/kg daily with doses every 12 h.5 If there was no

oedema. We did not undertake a randomised controlled trial, because standardised management was believed to be beneficial and restriction on its use unethical.2 We compared outcome, including mortality rates, in children treated by the standardised protocol with children who had non-protocol treatment. The standardised-protocol group included children admitted to one of three clinical units over 6 months, from Jan 1, 2006, to June 30, 2006. Children admitted to the same clinical unit from Jan, 2005, to June 30, 2005, before the protocol was implemented, formed the non-protocol group.

Standardised protocol
Dehydration was assessed by WHO criteria.3 Rehydration was done for longer than the usual 36 h and use of intravenous fluids was avoided if possible. Some dehydration was managed with rice-based oral rehydration solution (sodium 90 mmol/L, potassium 20, chloride 80, citrate 10; rice powder 50 g/L) 10 mL per kg per h for the first 2 h, then 5 mL per kg per h for the next 10 h or until the fluid deficit was corrected. Stool losses were replaced with oral rehydration solution 5 10 mL/kg after each watery stool. Infants aged under 4 months were given WHO oral rehydration solution (Na+ 90 mmol/L, K+ 20, Cl 80, citrate 10, glucose 111) instead of rice-based solution because of concern about digestion of cereals in that age group. 4 If a child could not drink owing to weakness or vomiting, oral rehydration solution was given through a nasogastric tube. In severe dehydration, initial hydration was done by intravenous fluid (Na+ 133 mmol/L, K+ 20, Cl 98 acetate 48; plus 5% dextrose: solution A) 20 mL/kg for 1 h then 10 mL/kg for 1 h. Oral rehydration solution 10 mL per kg per h was started after 1 h and continued as with less-severe dehydration. Infants aged under 2 months received 50% diluted solution with potassium supplemented to 20 mmol/L and 5% added dextrose (solution B). When vomiting persisted after introducing a nasogastric tube, solution B was infused at 10 mL per kg per h for 2 h, then at 5 mL per kg per h until correction of deficit or until the child could drink. Feeding was begun immediately on admission, with a liquid diet (milk suji, panel), given every 2 h. Children with marasmus and marasmic kwashiorkor were given 10 mL/kg per feed (80 kcal/kg/day) on day 1, 12 mL/kg per feed (96 kcal/kg/day) on days 2 and 3, and, if no diarrhoea, 12 mL/kg concentrated feed ( milk suji 100, 144 kcal/kg/day, panel) on day 4 onwards. mL/k per Children with kwashiorkor were given 9 g feed mL/kg (72 kcal/kg/day) on days 1 to 3, and if no diarrhoea, 9 per feed special milk (108 kcal/kg/day, panel) on day 4 onwards. Nonbreast-fed infants younger than 4 months received a non-commercial, cow-milk-based infant formula (panel). Mothers were advised to

Characteristics

Standardised protocol (n=334) 6 (4 12) 53 (48 58) (653 73 793) 106 (317) 6 (3 10) 61 (182) 49 (146) (41)

Non-protocol (n=293) 7 (3 13) 528 (4758) 727 (653 780) 40 (136) 5 (3 10) 70 (238) 47 (16) 11 7 (40) 18 6 (634) 104 (35)

Blood biochemistry Number of children Na+ <120 mmol/L (%) K+ <2 mmol/L (%) CO2 <10 mmol/L (%) Packed-cell volume <20% (%) *p=00003. p=003. p=001. 23 9 (72) 275 (94) 11 32 32 4 (4) (116) (116) (14)

Age (months) Weight-for-age* Weight-for-height* Pedal oedema (%) Duration of diarhoea (days) Bloody diarrhoea (%) Persistent diarrhoea (%) Dehydration on admission (%) Pneumonia (%) Septicaemia (%)

14 (58) 30 (125) 81 (34) 5 (2)

Table 2: Laboratory test results by treatment regimen

138

195 (583) 97 (29)

Copyright 2008. All rights reserved.

Data are median (IQR) or number (%). *% of US National Center for Health Statistics median reference. p=00005.

Table 1: Characteristics of children at baseline by treatment regimen clinical or other evidence of septicaemia after 48 h, ampicillin and gentamicin were discontinued and amoxycillin 100 mg/kg daily with doses every 8 h was given orally for 3 further days. Children with pneumonia were treated with intravenous chloramphenicol 100 mg/kg daily with doses every 6 h for 24 h and then orally for a total of 7 days.6 Ampicillin and gentamicin were used in infants younger than 2 months with pneumonia. If septicaemia was suspected, ampicillin 200 mg/kg daily was given and continued with gentamicin for 710 days. If there was no clinical improvement within 48 h in fever response, respiratory rate, or peripheral perfusion, ampicillin or chloramphenicol was replaced by ceftriaxone 100 mg/kg once daily and gentamicin was continued. Oxygen was given in case of cyanosis, restlessness, severe chest indrawing, or respiratory rate above 80 breaths per min for infants less than 2 months old and above 70 breaths per min for children aged from 2 months to 5 years. Specific gastrointestinal infections, including cholera, shigellosis, salmonellosis, amoebiasis, and giardiasis were treated according to prevailing antibiotic susceptibility. Nystatin suspension (100 000 U) was given every 6 h for thrush, and clotrimazole cream was applied for perianal or vulvovaginal candidiasis. Vitamin A for prophylaxis and treatment of xerophthalmia was given as recommended by WHO. 7 Folic acid 125 mg and elemental zinc 2 mg/kg daily were given for 15 days. Children 1 year and older were given multivitamin supplement 1 mL (vitamin A palmitate 5000 IU, vitamin D 1000 IU, thiamine hydrochloride 16 mg, riboflavin 1 mg, pyridoxine hydrochloride 1 mg, nicotinamide 10 mg, calcium Dpantothenate 5 mg, ascorbic acid 50 mg) twice daily for 15 days. Half that dose was given to infants less than 1 year old. Intramuscular magnesium sulphate (50% weight for volume) 04 mmol/kg, was given once daily for 7 days or until discharge. Hypoglycaemia (blood glucose <3 mmol/L) was managed with 50 mL 10% glucose orally or by nasogastric tube. If a hypoglycaemic child was unconscious or convulsive, 25% intravenous glucose 2 mL/kg was followed by oral glucose. Children with severe acidosis (serum CO2 <6 mmol/L) were given intravenous sodium bicarbonate 1 mL/kg slowly. Normal
Standardised protocol (n=334)

Non-protocol (n=293)

Stool pathogens (%) Number of children V cholerae Shigella Salmonella Other Vibrio spp 246 (74) 64 30 13 (26) (12) (52) 211 (72) 27 29 (127)* (137)

23 (93)

9 (42) 9 (42)

Blood pathogens (%) Number of children Positive culture 29 8 17 (89) (57) 194 (66) 17 (87)

saline or solution A was infused 20 mL/kg over 1 h in case of septic shock, and the infusion was repeated once if necessary. Children with hypokalaemia were given oral potassium 5 mmol/kg daily. Children with serum potassium of less than 2 mmol/L who needed parenteral hydration were given an intravenous fluid of up to 40 mmol/L potassium. If packed-cell volume was below 15%, 10 mL/kg of packed red cells or whole blood was transfused over 3 h. Hypothermia, abdominal distension, congestive heart failure, and weeping skin lesions were managed according to WHO guidelines.8 Before the standardised protocol was implemented, the procedure was explained to the physicians and nurses, and 1 month was allowed for adaptation. A copy of the protocol was available to each staff member.

Standardi sed protocol (n=334) Hospital stay (days) Transferred to special-care unit* Daily weight gain (g/kg) Hypoglycaemia on admission* Hypoglycaemia developed during hospital stay* Episodic hypoglycaemia during hospital stay* No intravenous rehydration* Total intravenous infusion (mL) Total infusion duration (h) Ceftriaxone treatment 19 9 0 0 (595) (0 350) (015) 45 (37) 24 (88) 44 (0 14) 24 9 (71) (27)

Nonprotocol (n=293) 45 (3 65) 28 (124) 35 (0 132) 24 (81) 17 (58)

07 01 05 06 005 000 5 <00 001 <00 001 <00 001 <00 001

15 (45)

30 (102)

Non-protocol management
Children with some dehydration were rehydrated within 4 h according to WHO guidelines.3 Severely dehydrated children were rehydrated with 100 mL/kg intravenous fluid similar to solution A but with potassium 13 mmol/L and no dextrose, infused over 6 h in infants under 12 months and over 3 h in older children. Antibiotics were given only if clinically indicated. Feeding was delayed until rehydration was complete, and only the very sick were fed nasogastrically. Liquid feeds were offered every 2 h but intake was not ensured. Older infants were also offered rice porridge 23 times daily. Total daily dietary energy was 100 kcal/kg for children with marasmus, 80 kcal/kg for marasmic kwashiorkor, and 6070 kcal/kg for kwashiorkor. Micronutrients other than vitamin A were not given routinely, and none received magnesium injections. For hypoglycaemia, intravenous glucose was not followed by oral glucose drink. Children with severe hypokalaemia received intravenous fluids with added potassium. For severe abdominal distension, feeding was discontinued and intravenous fluid rationed. Whole blood 1520 mL/kg was transfused with or without furosemide when packed-cell volume was less than 20%, and digoxin was given in standard doses in case of heart failure.9

60 (18)

85 (29) 385 (0 770) 24 (0 48) 116 (396)

Data are median (IQR) except * number (%). 63 children in the standardised-protocol group and 68 children on non-protocol were admitted directly to the special-care unit.

Table 3: Course of illness after admission to hospital

Statistical analysis
Data were analysed with Epi Info (version 5.01). We used Students t or Mann-Whitney U test to compare group differences, and categorical variables were tested by x2 or Fishers exact test. We calculated odds ratios with 95% CIs for selected outcomes.

standardised-protocol group were successfully rehydrated with oral rehydration rather than intravenous fluids, compared with 85 (29%) in the other group (p<00001). In those who required intravenous fluids, total volume was smaller and duration of infusion was shorter in the standardised-protocol group than in the non-protocol group (p<00001). More children in the nonprotocol group became critically ill during their hospital stay and needed transfer to the special care unit (28 [124%] vs 24 [88%]), or needed treatment with ceftriaxone (116 [396%] vs 60 [18%], p<00001). There was a trend towards greater weight gain during the acute phase of treatment in children on standardised protocol compared with non-protocol children (44 vs 35 g/kg/day over median hospital stay of 45 days). More children on standardised protocol than non-protocol children were discharged uneventfully (245 [73%] vs 186 [63%], p=0006, table 4), which primarily reflected the difference in mortality. There were 30 (9%) case fatalities among those treated by standardised protocol compared with 49 (17%) of those who had non-protocol management (odds ratio=049 [95% CI 0308], p=0003). Children who died on standardised-protocol management died mostly within the first 48 h of hospital admission. Younger age (p=0005), poorer nutritional status (weight-for-height, p=0007), increased frequency of hypoglycaemia (p=003) and septicaemia on admission (p<00001), bacteraemia (p=0001), and greater volume of intravenous fluids infused (p=0004) were risk factors for death on standardised protocol (data not shown). The most severely malnourished children (weight-for-age <50%, or with oedema) were transferred with their mothers to a nutritional rehabilitation unit, which accommodates only 16 children. Parents of children who could not be accommodated there were encouraged to attend a follow-up clinic for outpatient nutrition education and care. Reasons for referral to other hospitals included acute renal failure, intestinal obstruction haemolytic-uraemic syndrome, and acute hepatitis. The number of children referred for each disorder was similar in each
Standardi sed protocol (n=334) 245 (733) 25 (74) Nonprotocol (n=29 3) 18 (63 6 5) 21 (71)

Results
334 children were treated by the standardised protocol, and 293 children had non-protocol treatment. Baseline characteristics were similar in the two groups, but more children on standardised protocol had oedema of the feet (106 [317%] vs 40 [136%], p=00005, table 1). Significantly more children on standardised protocol than non-protocol children had Vibrio cholerae and other Vibrio spp isolated from stools, although the proportions of children with shigella and salmonella were similar between groups (table 2). The proportion of children with positive blood culture was also similar in the two groups. 81 (34%) of children on standardised protocol and 32 (116%) of children on nonprotocol treatment presented with severe acidosis (serum CO 2 <10 mmol/L, p=001). The numbers of children with severe hyponatraemia, hypokalaemia, or anaemia were similar in both groups. The number of children with hypoglycaemia on admission in each group was similar, but twice as many of those on nonprotocol treatment developed hypoglycaemia during their hospital stay (6% vs 3%) and the total number of hypoglycaemic episodes was significantly higher in the nonprotocol group (30 vs 15, p=0005, table 3). 199 (595%) of children in the

Discharged Transferred to nutritional rehabilitation unit

0006 08

Referred to other hospital Left against medical advice Left without notice Died

8 (24) 10 (30) 16 (48) 30 (9)

5 (17) 13 (44) 19 (65) 49 (17)

05 04 03 0003 *

Data are number of children (%). *Odds ratio (95% CI) 049 (0308).

Table 4: Outcome by treatment regimen

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