Endotoxaemia is common in children with Plasmodium falciparum malaria.

BACKGROUND: Children presenting to hospital with recent or current Plasmodium falciparum malaria are at increased the risk of invasive bacterial disease, largely enteric gram-negative organisms (ENGO), which is associated with increased mortality and recurrent morbidity. Although incompletely understood, the most likely source of EGNO is the bowel. We hypothesised that as a result of impaired gut-barrier function endotoxin (lipopolysaccharide), present in the cell-wall of EGNO and in substantial quantities in the gut, is translocated into the bloodstream, and contributes to the pathophysiology of children with severe malaria. METHODS: We conducted a prospective study in 257 children presenting with malaria to two hospitals in Kenya and Uganda. We analysed the clinical presentation, endotoxin and cytokine concentration. RESULTS: Endotoxaemia (endotoxin activity ≥0.4 EAA Units) was observed in 71 (27.6%) children but its presence was independent of both disease severity and outcome. Endotoxaemia was more frequent in children with severe anaemia but not specifically associated with other complications of malaria. Endotoxaemia was associated with a depressed inflammatory and anti-inflammatory cytokine response. Plasma endotoxin levels in severe malaria negatively correlated with IL6, IL10 and TGFß (Spearman rho: TNFα: r=-0.122, p=0.121; IL6: r=-0.330, p<0.0001; IL10: r=-0.461, p<0.0001; TGFß: r=-0.173, p<0.027). CONCLUSIONS: Endotoxaemia is common in malaria and results in temporary immune paralysis, similar to that observed in patients with sepsis and experimentally-induced endotoxaemia. Intense sequestration of P. falciparum-infected erythrocytes within the endothelial bed of the gut has been observed in pathological studies and may lead to gut-barrier dysfuction. The association of endotoxaemia with the anaemia phenotype implies that it may contribute to the dyserythropoesis accompanying malaria through inflammation. Both of these factors feasibly underpin the susceptibility to EGNO co-infection. Further research is required to investigate this initial finding, with a view to future treatment trials targeting mechanism and appropriate antimicrobial treatment.

Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome.

BACKGROUND: Severe acute malnutrition (SAM) accounts for two million deaths worldwide annually. In those hospitalised with SAM, concomitant infections and diarrhoea are frequent complications resulting in adverse outcome. We examined the clinical and laboratory features on admission and outcome of children with SAM and diarrhoea at a Kenyan district hospital. METHODS: A 4-year prospective descriptive study involving 1,206 children aged 6 months to 12 years, hospitalized with SAM and managed in accordance with WHO guidelines. Data on clinical features, haematological, biochemical and microbiological findings for children with diarrhoea (≥ 3 watery stools/day) were systematically collected and analyzed to identify risk factors associated with poor outcome. RESULTS: At admission 592 children (49%) had diarrhoea of which 122 (21%) died compared to 72/614 (12%) deaths in those without diarrhoea at admission (Χ(2) = 17.6 p<0.001). A further 187 (16%) children developed diarrhoea after 48 hours of admission and 33 died (18%). Any diarrhoea during admission resulted in a significantly higher mortality 161/852 (19%) than those uncomplicated by diarrhoea 33/351 (9%) (Χ(2) = 16.6 p<0.001). Features associated with a fatal outcome in children presenting with diarrhoea included bacteraemia, hyponatraemia, low mid-upper arm circumference <10 cm, hypoxia, hypokalaemia and oedema. Bacteraemia had the highest risk of death (adjusted OR 6.1; 95% C.I 2.3, 16.3 p<0.001); and complicated 24 (20%) of fatalities. Positive HIV antibody status was more frequent in cases with diarrhoea at admission (23%) than those without (15%, Χ(2) = 12.0 p = 0.001) but did not increase the risk of death in diarrhoea cases. CONCLUSION: Children with SAM complicated by diarrhoea had a higher risk of death than those who did not have diarrhoea during their hospital stay. Further operational and clinical research is needed to reduce mortality in children with SAM in the given setting.

Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation.

BACKGROUND: Severe malnutrition is frequently complicated by sepsis, leading to high case fatality. Oral ciprofloxacin is a potential alternative to the standard parenteral ampicillin/gentamicin combination, but its pharmacokinetics in malnourished children is unknown. METHODS: Ciprofloxacin (10 mg/kg, 12 hourly) was administered either 2 h before or up to 2 h after feeds to Kenyan children hospitalized with severe malnutrition. Four plasma ciprofloxacin concentrations were measured over 24 h. Population analysis with NONMEM investigated factors affecting the oral clearance (CL) and the oral volume of distribution (V). Monte Carlo simulations investigated dosage regimens to achieve a target AUC(0-24)/MIC ratio of ≥125. RESULTS: Data comprised 202 ciprofloxacin concentration measurements from 52 children aged 8-102 months. Absorption was generally rapid but variable; C(max) ranged from 0.6 to 4.5 mg/L. Data were fitted by a one-compartment model with first-order absorption and lag. The parameters were CL (L/h) = 42.7 (L/h/70 kg) × [weight (kg)/70](0.75) × [1 + 0.0368 (Na(+) - 136)] × [1 - 0.283 (high risk)] and V (L) = 372 × (L/70 kg) × [1 + 0.0291 (Na(+) - 136)]. Estimates of AUC(0-24) ranged from 8 to 61 mg·h/L. The breakpoint for Gram-negative organisms was <0.06 mg/L with doses of 20 mg/kg/day and <0.125 mg/L with doses of 30 or 45 mg/kg/day. The cumulative fraction of response with 30 mg/kg/day was ≥80% for Escherichia coli, Klebsiella pneumoniae and Salmonella species, but <60% for Pseudomonas aeruginosa. CONCLUSIONS: An oral ciprofloxacin dose of 10 mg/kg three times daily (30 mg/kg/day) may be a suitable alternative antibiotic for the management of sepsis in severely malnourished children. Absorption was unaffected by the simultaneous administration of feeds.

Determination of ciprofloxacin in human plasma using high-performance liquid chromatography coupled with fluorescence detection: application to a population pharmacokinetics study in children with severe malnutrition.

Clinical pharmacokinetic studies of ciprofloxacin require accurate and precise measurement of plasma drug concentrations. We describe a rapid, selective and sensitive HPLC method coupled with fluorescence detection for determination of ciprofloxacin in human plasma. Internal standard (IS; sarafloxacin) was added to plasma aliquots (200 µL) prior to protein precipitation with acetonitrile. Ciprofloxacin and IS were eluted on a Synergi Max-RP analytical column (150 mm×4.6 mm i.d., 5 µm particle size) maintained at 40°C. The mobile phase comprised a mixture of aqueous orthophosphoric acid (0.025 M)/methanol/acetonitrile (75/13/12%, v/v/v); the pH was adjusted to 3.0 with triethylamine. A fluorescence detector (excitation/emission wavelength of 278/450 nm) was used. Retention times for ciprofloxacin and IS were approximately 3.6 and 7.0 min, respectively. Calibration curves of ciprofloxacin were linear over the concentration range of 0.02-4 µg/mL, with correlation coefficients (r(2))≥0.998. Intra- and inter-assay relative standard deviations (SD) were <8.0% and accuracy values ranged from 93% to 105% for quality control samples (0.2, 1.8 and 3.6 µg/mL). The mean (SD) extraction recoveries for ciprofloxacin from spiked plasma at 0.08, 1.8 and 3.6 µg/mL were 72.8±12.5% (n=5), 83.5±5.2% and 77.7±2.0%, respectively (n=8 in both cases). The recovery for IS was 94.5±7.9% (n=15). The limits of detection and quantification were 10 ng/mL and 20 ng/mL, respectively. Ciprofloxacin was stable in plasma for at least one month when stored at -15°C to -25°C and -70°C to -90°C. This method was successfully applied to measure plasma ciprofloxacin concentrations in a population pharmacokinetics study of ciprofloxacin in malnourished children.

Phase II trial of isotonic fluid resuscitation in Kenyan children with severe malnutrition and hypovolaemia.

BACKGROUND: Children with severe malnutrition who develop shock have a high mortality. Contrary to contemporaneous paediatric practice, current guidelines recommend use of low dose hypotonic fluid resuscitation (half-strength Darrows/5% dextrose (HSD/5D). We evaluated the safety and efficacy of this guideline compared to resuscitation with a standard isotonic solution. METHODS: A Phase II randomised controlled, safety and efficacy trial in Kenyan children aged over 6 months with severe malnutrition and shock including children with severe dehydration/shock and presumptive septic shock (non-diarrhoeal shock). Eligible children were randomised to HSD/5D or Ringer's Lactate (RL). A maximum of two boluses of 15 ml/kg of HSD/5D were given over two hours (as recommended by guidelines) while those randomised to RL received 10 ml/kg aliquots half hourly (maximum 40 ml/kg). Primary endpoint was resolution of shock at 8 and 24 hours. Secondary outcomes included resolution of acidosis, adverse events and mortality. RESULTS: 61 children were enrolled: 41 had shock and severe dehydrating diarrhoea, 20 had presumptive septic shock; 69% had decompensated shock. By 8 hours response to volume resuscitation was poor with shock persisting in most children:-HSD/5D 15/22 (68%) and RL14/25 (52%), p = 0.39. Oliguria was more prevalent at 8 hours in the HSD/5D group, 9/22 (41%), compared to RL-3/25 (12%), p = 0.02. Mortality was high, HSD/5D-15/26(58%) and RL 13/29(45%); p = 0.42. Most deaths occurred within 48 hours of admission. Neither pulmonary oedema nor cardiogenic failure was detected. CONCLUSIONS: Outcome was universally poor characterised by persistence of shock, oliguria and high case fatality. Isotonic fluid was associated with modest improvement in shock and survival when compared to HSD/5D but inconclusive due to the limitations of design and effectiveness of either resuscitation strategy. Although isotonic fluid resuscitation did not result in cardiogenic heart failure, as previously feared, we conclude that the modest volumes used and rate of infusion were insufficient to promptly correct shock. The adverse performance of the recommended fluid resuscitation guideline for severe malnutrition should prompt clinical investigation of isotonic fluids for resuscitation of compensated shock, defining rate and volumes required to inform future guidelines. TRIAL REGISTRATION: The trial is registered as ISCRTN: 61146418.

The prognostic value of dipstick urinalysis in children admitted to hospital with severe malnutrition.

BACKGROUND: Children with severe malnutrition (SAM) present to hospital with an array of complications, resulting in high mortality despite adherence to WHO guidelines. Diagnostic resources in developing countries are limited and bedside tests could help identify high-risk children. Dipstick urinalysis is a bedside screening test for urinary tract infections (UTIs). UTIs are common in SAM and can lead to secondary invasive bacterial sepsis. Very few studies have examined the usefulness of dipstick screening of urine specimens in SAM and none has explored its prognostic value. PATIENTS AND METHODS: A 2-year prospective study on children admitted in Kilifi District Hospital, Kenya, with SAM. Freshly voided, clean catch urine samples were tested using Multistix reagent test strips. Positive samples were sent for culture. RESULTS: Of the 667 children admitted, 498 children (75%) provided urine samples; of these, 119 (24%) were positive for either leucocyte esterase (LE) or nitrites. Culture-proven UTI was detected in 28 children (6% overall). All isolates were coliforms and were >50% were resistant to cotrimoxazole and gentamicin. There was no difference in severity signs between those with positive dipstick and those without. Case fatality was higher among children with a positive dipstick (29% vs 12%). Presence of a positive dipstick was a strong predictor of mortality (adjusted HR 2.5). CONCLUSIONS: A urine dipstick positive for either LE or nitrites is a useful predictor of death in children admitted with SAM. Prospective studies to determine the role of untreated UTI in these deaths are needed before any treatment recommendations can be made.

Hypothermia in children with severe malnutrition: low prevalence on the tropical coast of Kenya.

Hypothermia is stated as a common complication of severe malnutrition although there are little primary data to support this. We performed a prospective study of children with severe acute malnutrition (SAM) admitted to a district hospital in Kenya. We documented the prevalence of hypothermia and examined its association with outcome and ambient temperature. During a 2-year period 667 children were recruited. Hypothermia was recorded in only 12 out of 15 191 (0.08%) temperature observations and as a single event in 12 children (2% of cases). There was no correlation with ambient temperature. Although mortality rates were higher in children with hypothermia (4/12, 33%) than those without (121/655, 18%), the timing of hypothermia did not coincide with clinical deterioration. Hypothermia was a rare marker of severity in our setting. We recommend that other observations be highlighted to identify high risk groups and that routine temperature observations be reduced wherever staff are few.