Age-related changes in microvascular permeability: a significant factor in the susceptibility of children to shock?

During studies of the pathogenesis of dengue shock syndrome, a condition largely confined to childhood and characterized by a systemic increase in vascular permeability, we observed that healthy controls, age-matched to children with dengue shock syndrome, gave high values of filtration capacity (K(f)), a factor describing vascular permeability. We hypothesized that K(f) might be age dependent. Calf K(f) was studied in 89 healthy Vietnamese subjects aged 5 to 77 years. The K(f) was highest in the youngest children [7. 53 (1.96-15.46) K(f)U; median (range); where the units of K(f), K(f)U=ml.min(-1).100 ml(-1).mmHg(-1)]. Values were 3- to 4-fold lower towards the end of the second decade [4.69 (1.91-7.06) K(f)U]. Young mammals are known to have a larger microvascular surface area per unit volume of skeletal muscle than adults. During development the proportion of developing vessels is greater. Moreover, the novel microvessels are known to be more permeable to water and plasma proteins than when mature. These factors may explain why children more readily develop hypovolaemic shock than adults in dengue haemorrhagic fever and other conditions characterized by increased microvascular permeability

Reactive nitrogen intermediates and outcome in severe adult malaria.

The role of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in the pathophysiology of severe falciparum malaria remains unclear. We conducted a retrospective case-control study of Vietnamese adults with severe malaria to determine the relationship between outcome and admission plasma reactive nitrogen intermediates (RNI), the stable metabolites of NO. The study was designed to take into account the potential confounders of recent dietary nitrogen intake and renal function. Seventy-six patients who died from severe malaria were matched for age and sex with 76 survivors from a prospectively studied series of 560 patients. Median untransformed unadjusted plasma RNI levels were slightly higher in fatal cases (45 mumol/L, range 0-482) than in survivors (24.1 mumol/L, range 1.4-466) (P = 0.031, Wilcoxon signed-rank). There was a significant positive correlation between RNI levels and plasma creatinine (Spearman's rho = 0.35, P < 0.0001), and the addition of plasma creatinine as a covariate in a multivariate analysis abolished the trend towards higher RNI levels in fatal cases (P for the coefficient for RNI = 0.96). There was no association between RNI levels and either depth of coma on admission or time to regain consciousness. These findings do not support a pivotal role for systemic generation of NO in the pathogenesis of severe malaria in general, or cerebral malaria in particular

Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam.

BACKGROUND: In some parts of the world, peritoneal dialysis is widely used for renal replacement in acute renal failure. In resource-rich countries, it has been supplanted in recent years by hemodialysis and, most recently, by hemofiltration and associated techniques. The relative efficacy of peritoneal dialysis and hemofiltration is not known. METHODS: We conducted an open, randomized comparison of pumped venovenous hemofiltration and peritoneal dialysis in patients with infection-associated acute renal failure in an infectious-disease referral hospital in Vietnam. RESULTS: Seventy adult patients with severe falciparum malaria (48 patients) or sepsis (22 patients) were enrolled; 34 were assigned to hemofiltration and 36 to peritoneal dialysis. The mortality rate was 47 percent (17 patients) in the group assigned to peritoneal dialysis, as compared with 15 percent (5 patients) in the group assigned to hemofiltration (P=0.005). The rates of resolution of acidosis and of decline in the serum creatinine concentration in the group assigned to hemofiltration were more than twice those in the group assigned to peritoneal dialysis (P<0.005), and renal-replacement therapy was required for a significantly shorter period. In a multivariate analysis, the odds ratio for death was 5.1 (95 percent confidence interval, 1.6 to 16) and that for a need for future dialysis was 4.7 (95 percent confidence interval, 1.3 to 17) in the group assigned to peritoneal dialysis. The cost of hemofiltration per survivor was less than half that of peritoneal dialysis, and the cost per life saved was less than one third. CONCLUSIONS: Hemofiltration is superior to peritoneal dialysis in the treatment of infection-associated acute renal failure

The pathophysiologic and prognostic significance of acidosis in severe adult malaria.

OBJECTIVE: To investigate the pathophysiology and prognostic significance of acidosis in severe adult malaria. DESIGN: Cohort study. SETTING: The intensive care unit of an infectious diseases hospital in southern Vietnam. PATIENTS: Three hundred forty-six consecutive adult patients with severe falciparum malaria. INTERVENTIONS: Measurements of baseline venous lactate and pyruvate concentrations and an extensive range of clinical and laboratory variables were made, and patients were followed up carefully until death or discharge from the hospital. Admission arterial blood pH and gas tensions were recorded in 296 patients, and hepatic venous sampling was done in 12 patients. MEASUREMENTS AND MAIN RESULTS: Overall, 198 (67%) patients were acidotic (standard base deficit [SBD], >3.3 mmol/L [n = 196], or arterial Pco2, >45 torr [6 kPa] [n = 3]). Hyperlactatemia (plasma lactate, >4 mmol/L) occurred in 120 (35%) of the 346 patients and was associated significantly with acidosis (p < .0001). The hepatosplanchnic lactate extraction ratio was negatively correlated with mixed venous plasma lactate (r2 = .50; p = .006). Hyperlactatemia, metabolic acidosis (SBD, >3.3), and acidemia (pH <7.35) were strongly positively associated with a fatal outcome (relative risks [95% confidence interval], 4.3 [range, 1.8-10.6], 5.0 [range, 3.0-8.1], and 2.7 [range, 1.8-4.1], respectively). The SBD was the single best clinical or laboratory predictor of fatal outcome. The overall median lactate/pyruvate ratio was raised at 30.6 (range, 20.6-62.3; normal range, <15), suggesting hypoxia and anaerobic glycolysis, and was significantly higher in fatal cases (p < .0001). In an additive multivariate model, the two main independent contributors to metabolic acidosis were plasma creatinine, as a measure of renal dysfunction, and venous plasma lactate, together accounting for 63% of the variance in SBD. In univariate analyses, they contributed 29% and 38%, respectively. CONCLUSIONS: These results confirm the importance of acidosis in the pathophysiology of severe adult malaria and suggest a multifactorial origin involving tissue hypoxia, liver dysfunction, and impaired renal handling of bicarbonate

An open randomized comparison of intravenous and intramuscular artesunate in severe falciparum malaria.

An open paired randomized comparison of intramuscular and intravenous artesunate was conducted in 28 adult patients with severe falciparum malaria. The dose regimen in both groups was 2 mg/kg given immediately followed by 1 mg/kg at 12 and 24 h, and then daily until the patient could swallow. Both routes of administration were well tolerated and there was no evidence of toxicity. One patient in each treatment group died. Clinical and parasitological measures of recovery in survivors were similar in the 2 groups with mean fever clearance times of 37.3 h (standard deviation [SD] = 26.1 h) and 31.5 h (SD = 24.2 h) and mean parasite clearance times of 33.4 h (SD = 13.9 h) and 29.4 h (SD = 12.7 h) in the intravenous and intramuscular groups respectively. Artesunate is equally effective and well tolerated when given by the intravenous or intramuscular routes

The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria.

Pro- and antiinflammatory cytokines were measured on admission in 287 consecutive Vietnamese adults with severe falciparum malaria. Plasma interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations and the IL-6: IL-10 ratio were significantly higher in patients who died than in survivors (P<.001). On multivariate analysis, hyperparasitemia, jaundice, and shock were all associated independently with raised IL-6, IL-10, and interferon-gamma, and acute renal failure specifically with raised TNF-alpha levels. Cerebral malaria patients, particularly those without other vital organ dysfunction, had significantly lower levels of these cytokines (P=.006), reflecting a more localized pathology. Serial IL-6 and IL-10 measurements made on 43 patients who died and matched survivors indicated a relative deficiency in IL-10 production as death approached. Elevated plasma cytokines in severe malaria are associated with systemic pathologic abnormalities, not cerebral involvement. Both the overall magnitude of the cytokine responses and the eventual imbalance between the pro- and antiinflammatory responses are important determinants of mortality

Unidentified acids of strong prognostic significance in severe malaria.

OBJECTIVE: To calculate, using the Stewart approach to acid-base disorders, the strong anion gap as an estimate for the contribution of unmeasured plasma anions other than lactate to the metabolic acidosis that characterizes severe falciparum malaria and to assess its relative prognostic significance. DESIGN: Cohort study. SETTING: The intensive care unit of an infectious diseases hospital in southern Vietnam. PATIENTS: Consecutive adult patients (n = 268) with severe falciparum malaria. INTERVENTIONS: The intervention was clinical management in a dedicated unit. We measured baseline venous lactate, electrolytes, biochemical variables, admission arterial blood pH, and gas tensions for calculation of the strong anion gap. MEASUREMENTS AND MAIN RESULTS: The mean (95% confidence interval) admission strong anion gap was 11.1 (10.4-11.9) mEq/L, compared with lactate (geometric mean, 95% confidence interval) at 2.9 (2.7-3.2) mmol/L. Strong anion gap had a high predictive value for mortality (area under the receiver operating characteristic curve 0.73 (95% confidence interval, 0.65-0.82), which was independent of plasma lactate and creatinine concentrations. Renal failure and hepatic dysfunction were both associated with, but were not the sole determinants of, high levels of strong anion gap. CONCLUSIONS: In severe malaria, unidentified anions other than lactate are the most important contributors to metabolic acidosis, a major cause of death. The strong anion gap is a powerful prognostic indicator in patients with severe malaria

Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients.

The qinghaosu (artemisinin) group of drugs is the most important new class of antimalarials developed in the last fifty years. Although there has been no clinical evidence of neurotoxicity, an unusual pattern of damage to specific brain-stem nuclei has been reported in experimental animals receiving high doses of arteether or artemether. Detailed clinical examinations, audiometry, and brain stem auditory evoked potentials (BSAEPs) were assessed in 242 Vietnamese subjects who had previously received up to 21 antimalarial treatment courses of artemisinin or artesunate alone and 108 controls from the same location who had not received these drugs. There was no evidence of a drug effect on the clinical or neurophysiological parameters assessed. In this population there was no clinical or neurophysiological evidence of brain-stem toxicity that could be attributed to exposure to artemisinin or artesunate

Effects of dopamine and epinephrine infusions on renal hemodynamics in severe malaria and severe sepsis.

OBJECTIVE: To describe and compare the effects of dopamine and epinephrine in various doses on renal hemodynamics and oxygen transport in patients with severe malaria and severe sepsis. DESIGN: Prospective, controlled, crossover trial. SETTING: The intensive care unit of an infectious diseases hospital in Viet Nam. PATIENTS: Fourteen patients with severe falciparum malaria and five with severe sepsis. INTERVENTIONS: In an open, crossover design, we observed the effects on renal and systemic hemodynamics and oxygen transport of separate stepped infusions of epinephrine and dopamine. We measured renal blood flow (RBF) and cardiac output by the thermodilution method using fluoroscopically guided catheters. Creatinine clearance at each time point was calculated from the renal plasma flow and the renal arteriovenous difference in plasma creatinine. MEASUREMENTS AND MAIN RESULTS: Dopamine at a "renal" dose (2.5 microg/kg/min) was associated with a mean (95% confidence interval) fractional increase in the absolute renal blood flow index (RBFI) of 37% (13% to 61%) and in RBF as a fraction of cardiac output (RBF/CO) of 35% (10% to 59%; p = .007 and p = .014, respectively). The consequent 39% (14% to 64%) increase in renal oxygen supply (p = .002) was accompanied by a 32% (20% to 44%) decrease in the renal oxygen extraction ratio (p = .0003), leading to no net change in renal oxygen consumption. At higher doses (10 microg/kg/min), both RBF and RBF/CO were not significantly different from baseline values and decreased further as the dose was reduced again. There was no obvious explanation for this hysteresis. There was no change in renal oxygen consumption throughout the study. Because lactic acidosis developed, epinephrine was only given to eight of the 19 patients, and the full stepped epinephrine infusion was given to four patients. Epinephrine infusion was associated, both in absolute terms and when compared with dopamine, with a significant increase in renal vascular resistance (p = .0008 and .0005, respectively), a decrease in RBF/CO (p = .002 and .03), and a compensatory increase in the renal oxygen extraction ratio (p = .005 and .0001). RBFI and renal oxygen consumption remained constant throughout the epinephrine infusion profile. Neither epinephrine nor dopamine significantly affected creatinine clearance or urine output. Twelve patients (63%) were in established renal failure (plasma creatinine, >3 mg/dL) at the time of the study, although the presence or absence of renal failure did not significantly influence the effects of the study drugs. However, overall, the presence of renal failure was associated with a lower mean renal oxygen consumption, a lower mean renal oxygen consumption as a fraction of systemic oxygen consumption, and a higher mean renal vascular resistance. CONCLUSION: Although dopamine increased and epinephrine decreased fractional renal blood flow, there was no evidence that either drug produced either a beneficial or a deleterious effect on renal oxygen metabolism or function at any of the doses investigated