Incidence of surgical site infections and accompanying risk factors in Vietnamese orthopaedic patients.

A cohort study of surgical site infections (SSIs) was conducted in 582 orthopaedic surgical patients at Cho Ray Hospital, a reference hospital in Ho Chi Minh City, Vietnam, in order to determine the incidence and analyse risk factors for SSIs in this population. The SSI incidence rate was 12.5% (73 of 582); 3.6% incisional SSIs, 6.8% deep incisional SSIs and 2.1% organ/space SSIs. The incidence increased from 2% in clean wounds to 44.6% in dirty wounds, or 1.3% in patients with a National Nosocomial Infections Surveillance (NNIS) risk index of 0 to 75% in patients with an NNIS risk ratio of 3. In multi-variate analysis, having a dirty wound [odds ratio (OR) 8.7; 95% confidence intervals (CI) 4.6--16.4], American Society of Anesthesiologists' score >2 (OR 3.9; 95%CI 1.8-8.8), procedures with external fixation (OR 2.9; 95%CI 1.4-5.9), emergency surgery with motor-vehicle-related trauma (OR 2.1; 95%CI 1.2-3.9), or duration of procedure >2h (OR 2.1; 95%CI 1.1-4.2) were independent risk factors for SSI. Lack of appropriate prophylaxis was of borderline significance (OR 3.2; 95%CI 0.9-11.1, P=0.06). Among 76 patients with SSIs, 22 patients were discovered during postdischarge follow-up. These late SSIs had age as an additional risk factor (OR 2.8; 95%CI 1.1-7.2). Our data show that SSIs were frequent and differed widely by wound class. The NNIS risk index was predictive of SSI for this population. With a high number of motor vehicle accidents in Vietnam, the majority of orthopaedic operations are trauma related. Emergency surgery for injuries sustained in these accidents, and procedures with external fixation were especially prone to infections.

Mineral homoeostasis in acute renal failure complicating severe falciparum malaria.

Disturbances in calcium metabolism in acute renal failure (ARF) remain incompletely understood. Most data are from patients with rhabdomyolysis. As renal impairment commonly accompanies severe malaria in the absence of rhabdomyolysis, falciparum malaria provides an alternative model of mineral homoeostasis in ARF. We studied 25 Vietnamese subjects, aged 18-63 yr, with severe malaria and 10 controls. Fourteen patients had a serum creatinine level of 250 mumol/L or less during treatment (group 1), five developed ARF but were not dialyzed (group 2a), and six required dialysis (group 2b). Group 1 patients presented with mild hypocalcemia (mean +/- SD serum ionized calcium, 1.18 +/- 0.05 vs. 1.23 +/- 0.02 mmol/L in controls; P = 0.01) that persisted until discharge in the presence of normal serum phosphate, PTH, and vitamin D metabolite levels. Group 2 patients were more hypocalcemic on admission (1.10 +/- 0.08 mmol/L; P < 0.0001 vs. controls), especially those in group 2b whose serum ionized calcium fell to 0.88 +/- 0.13 mmol/L when renal dysfunction was maximal. In group 2 patients, the admission serum PTH level was raised (5.4 +/- 3.8 vs. 2.7 +/- 0.9 pmol/L in controls; P < 0.02) and changed reciprocally with calcemia. Significant rises in serum phosphate occurred only in group 2b patients who had depressed serum free 1,25-dihydroxyvitamin D levels throughout. Hypercalcemia did not accompany the diuretic phase of ARF. These data suggest that parathyroid gland dysfunction is a cause of hypocalcemia in severe malaria without ARF, as seen in group 1 patients; in patients with ARF, the effect of the combination of phosphate retention and altered vitamin D metabolism on skeletal PTH sensitivity is of prime significance.

Glucose metabolism in severe malaria: minimal model analysis of the intravenous glucose tolerance test incorporating a stable glucose label.

Basal plasma glucose is usually increased in uncomplicated malaria, implying insulin resistance. If the infection progresses, the risk of hypoglycemia will increase as host glucose production becomes insufficient for host/parasite demand. To assess the relative contribution of insulin-mediated and non-insulin-mediated glucose disposal to plasma glucose levels in severe malaria, we studied six healthy controls (two males and four females; mean age, 38 years) and eight patients with complicated falciparum malaria (five males and three females; mean age, 31 years) who had a frequently sampled intravenous glucose tolerance test (FSIVGTT) in which 10% of the dextrose bolus was 6,6-D2-glucose. The minimal model was applied to native and labeled plasma glucose and serum insulin profiles over 4 hours postinjection. Basal plasma glucose concentrations in the patients were significantly greater than in the controls (median [range], 6.1 [2.1 to 8.5] v 4.3 [3.9 to 4.7] mmol/L, P = .03). Malaria-associated insulin resistance was confirmed by a lower insulin sensitivity index (SI) in patients (5.6 [2.4 to 17.4] v 16.0 [2.5 to 22.3] x 10(-4).min-1 per microU/mL in controls, P = .026). Glucose effectiveness ([SG] the ability of glucose to reduce its own plasma concentration) was higher in the patients (0.015 [0.006 to 0.024] v 0.008 [0.007 to 0.010] min-1 in controls, p = .019). Glucose disappearance at basal concentration was increased by a median of 42% in severe malaria patients, with the insulin-independent component comprising 81%, versus 67% in controls. Indices of beta-cell function were normal in malaria patients. These data demonstrate that basal plasma glucose utilization is increased approximately 50% in severe malaria, consistent with previously published isotope-turnover studies. Altered SG plays a major role. Prevention and treatment of early hypoglycemia should be based on adequate glucose replacement. Strategies that reduce insulin secretion or effects appear to be of minor importance.

Selective high-performance liquid chromatographic determination of artesunate and alpha- and beta-dihydroartemisinin in patients with falciparum malaria.

A novel solid-phase extraction and a robust high-performance liquid chromatographic (HPLC) separation procedure for artesunate and alpha- and beta-dihydroartemisinin, using post-column alkali decomposition and UV detection is described. Extraction was performed with Bond-Elut Phenyl solid-phase extraction cartridges and analysis by HPLC was carried out using a Waters Symmetry C8 5-microns 150 x 3.9 mm I.D. column. The mobile phase was 50% acetonitrile in 0.1 M acetate buffer (pH 4.8) delivered at a flow-rate of 0.7 ml/min. The column eluate was mixed with 1.2 M potassium hydroxide in 90% methanol delivered at 0.3 ml/min, in a 1-ml reaction coil at 69 degrees C, to form UV-absorbing chromophores which were detected at 290 nm. The recovery of all analytes was greater than 80%. There was no significant difference in the peak-area ratio of alpha- and beta-dihydroartemisinin in plasma. Preliminary pharmacokinetic data from six adult Vietnamese patients who received 120 mg of artesunate by intravenous injection for the treatment of acute falciparum malaria are presented. Despite limited data, the mean half-life of artesunate was approximately 3.5 min while that for dihydroartemisinin was 34 min. These data confirm the relatively rapid clearance of both artesunate and its principle active metabolite, dihydroartemisinin.

Pharmacokinetics of retinyl palmitate and retinol after intramuscular retinyl palmitate administration in severe malaria.

Retinol (vitamin A alcohol) is an accepted adjunctive treatment in infections such as measles. There is also indirect evidence from in vitro, animal and human studies that retinol supplementation may be beneficial in severe malaria. There have, however, been no studies that have examined the pharmacokinetics of acute retinol supplementation in severe illness. To establish whether mobilization of intramuscular retinyl palmitate (RP) and its availability as retinol are adequate in complicated falciparum malaria, we administered a single dose of 400000 i.u. of RP to six Vietnamese adults with severe malaria. Another 28 patients were not given RP. All patients had blood samples taken over 96 h for RP and retinol assay using HPLC, and received conventional anti-malarial and supportive therapy. Admission serum retinol concentrations were below the lower limit of the reference range (<1.0 micromol/l) in 74% of the 34 patients. In supplemented patients, analysis of serum RP between 0 and 96 h using a multi-compartmental model revealed a median (range) delay in mobilization of 6.9 h (0.7-15.1 h), a bioavailability of 55% (19-100%) and an elimination half-life of 13.5 h (4.2-23.7 h). The area under the serum retinol curve expressed as an absolute or percentage change from baseline was greater in supplemented than in unsupplemented patients (P<0.05). The separation in median serum retinol concentrations in the two groups was maximal at 48 h. The model-derived retinol half-life [1.5 (0.7-15.8) h] suggested rapid uptake, metabolism and/or excretion. In conclusion, there is variable RP bioavailability in severe malaria, but a significant if delayed increase in serum retinol over that associated with recovery from the infection. In severe infections, RP supplementation appears simple, well tolerated and of potential benefit once anti-microbial and supportive therapy have been established.

Oral bioavailability of dihydroartemisinin in Vietnamese volunteers and in patients with falciparum malaria.

AIMS: To obtain comprehensive bioavailability data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following their separate oral administration to Vietnamese volunteers and to patients with acute, uncomplicated falciparum malaria. METHODS: Volunteers were randomized to receive either i.v. ARTS (120 mg) followed by oral ARTS (150 mg) 8 h later (Group 1, n = 10), or i.v. ARTS (120 mg) followed by oral DHA (120 mg) 8 h later. Patients, also received oral ARTS (150 mg; Group 3, n = 8) or DHA (120 mg; Group 2, n = 7), in a randomized cross-over study design. Multiple blood samples were collected after each administration and plasma ARTS and/or DHA concentrations were determined by h.p.l.c. Pharmacokinetic descriptors were obtained from noncompartmental analysis and bioavailability was calculated from AUC data. In the patients, the time to 50% parasite clearance (PCT50) and fever clearance time (FCT) also were measured. RESULTS: In Group 1 (volunteers), the mean (95% CI) absolute bioavailability of oral ARTS was 80% (62,98%), while in Group 2 (volunteers), the bioavailability of oral DHA was 45% (34,56%). In the patients (Group 3), the bioavailability of oral DHA relative to oral ARTS was 88% (49,127%). The median PCT50 and FCT were 2.3 and 28 h, respectively. CONCLUSIONS: The study shows that the absolute bioavailability of DHA was significantly lower than that for ARTS in healthy volunteers. The bioavailability of ARTS in volunteers was consistent with previous studies in patients with uncomplicated falciparum malaria. The dose-normalized Cmax and AUC(0,infinity) for DHA were significantly greater in patients with falciparum malaria than in healthy volunteers. The high relative bioavailability of DHA in the patients may have been due to lower first-pass clearance. We conclude that, for the treatment of malaria, DHA is likely to be a suitable oral substitute for ARTS. Based on our mean AUC measurements, it appears that equal doses of DHA and ARTS (mg basis) should give equivalent systemic exposure to bioactive DHA in uncomplicated falciparum malaria.

A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria.

AIMS: To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria. METHODS: Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT50) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic-pharmacodynamic relationships. RESULTS: Following i.v. bolus, ARTS had a peak concentration of 29.5 microM (11 mg l[-1]), elimination t1/2 = 2.7 min, CL = 2.33 l h(-1) kg(-1) and V = 0.14 l kg(-1). The Cmax for DHA was 9.3 microM (2.64 mg l[-1]), t1/2 = 40 min, CL =0.75 l h(-1) kg(-1) and V = 0.76 l kg(-1). Following oral ARTS, relative bioavailability of DHA was 82%, Cmax was 2.6 microM (0.74 mg l[-1]), t1/2 = 39 min, and MAT = 67 min. Overall, the PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT50 or FCT and AUC, Cmax or MRT for DHA. CONCLUSIONS: Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.