Case-control study of drug monitoring of ß-lactams in obese critically ill patients.

Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum ß-lactams (meropenem, ceftazidime/cefepime, and piperacillin-tazobactam), resulting in inappropriate serum concentrations. Obesity may further modify the pharmacokinetics of these agents. We reviewed our data on critically ill obese patients (body mass index of ≥ 30 kg/m(2)) treated with a broad-spectrum ß-lactam in whom therapeutic drug monitoring was performed and compared the data to those obtained in critically nonobese patients (body mass index of <25 kg/m(2)) to assess whether there were differences in reaching optimal drug concentrations for the treatment of nosocomial infections. Sixty-eight serum levels were obtained from 49 obese patients. There was considerable variability in ß-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard drug regimens of ß-lactams resulted in insufficient serum concentrations in 32% of the patients and overdosed concentrations in 25%. Continuous renal replacement therapy was identified by multivariable analysis as a risk factor for overdosage and a protective factor for insufficient ß-lactam serum concentrations. The serum drug levels from the obese cohort were well matched for age, gender, renal function, and sequential organ failure assessment (SOFA) score to 68 serum levels measured in 59 nonobese patients. The only difference observed between the two cohorts was in the subgroup of patients treated with meropenem and who were not receiving continuous renal replacement therapy: serum concentrations were lower in the obese cohort. No differences were observed in pharmacokinetic variables between the two groups. Routine therapeutic drug monitoring of ß-lactams should be continued in obese critically ill patients.

Development and Delphi validation of a Best Possible Medication History form.

OBJECTIVE: To develop and validate a standardized Best Possible Medication History (BPMH) form that could be used by clinical pharmacists. METHODS: The draft version was presented to a focus group and was adapted following their comments. A three-rounds e-Delphi method was used to validate content, usability and face validity of the BPMH form. We supplemented the quantitative analysis with a qualitative analysis of comments for each Delphi round. RESULTS: The draft BPMH form contained 23 items grouped into eight tabs. Refinement of these tabs and items by the focus group resulted in 7 tabs and 21 items, which were included in the Delphi survey. The consensus was obtained for all tabs within the second round (p=0.072). Consensus was reached on 76% (16/21) of items in the third round. 20 items were included following the qualitative analysis of the experts' comments in the third round. CONCLUSIONS: The findings of this study provide data on the content of the BPMH form. This form can be used to help clinical pharmacists to collect a complete and accurate medication list on admission. It could have an impact on inpatient safety and improve inpatient management. Studies with an international e-Delphi should be conducted for wider use.

Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock.

OBJECTIVE: Supplementation with tetrahydrobiopterin, a nitric oxide synthase cofactor, may reduce microvascular endothelial dysfunction in severe sepsis. We studied whether tetrahydrobiopterin administration exerts beneficial effects in an ovine septic shock model. DESIGN: Randomized animal study. SETTING: University hospital animal research laboratory. SUBJECTS: Fourteen adult female sheep. INTERVENTIONS: Fecal peritonitis was induced, and the sheep were randomized to receive tetrahydrobiopterin (n=7), given intravenously as 20 mg/kg boluses at 4 and 12 hrs after sepsis induction, or placebo (n=7). All animals were fluid resuscitated. The experiment was continued until death or for a maximum of 30 hrs. MEASUREMENTS AND MAIN RESULTS: In addition to standard hemodynamic assessment, the sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. The first bolus of tetrahydrobiopterin blunted the increase in heart rate and cardiac index seen in the control group without affecting mean arterial pressure, and the second bolus of tetrahydrobiopterin prevented the decreases in cardiac index and mean arterial pressure. The reduction in mixed venous blood oxygen saturation and the increase in blood lactate seen in the control group were also delayed. Tetrahydrobiopterin significantly attenuated the deterioration in perfused small vessel proportion and density, microvascular flow index, and the increase in microvascular heterogeneity observed in the control group. Tetrahydrobiopterin was associated with better preserved lung compliance and PaO2/FIO2 ratio, which were associated with a lower lung wet/dry weight ratio at the end of the study. Median survival time was significantly prolonged in the tetrahydrobiopterin group (25.0 vs. 17.8 hrs, p<.01). CONCLUSION: In this clinically relevant model of sepsis, tetrahydrobiopterin supplementation attenuated the impairment in sublingual microvascular perfusion and permeability, which was accompanied by better preserved gas exchange, renal flow and urine output, and prolonged survival.

Hemoadsorption to treat severe iatrogenic intoxication with Patent Blue: a case report.

BACKGROUND: Intoxication with Patent Blue V [sodium compound of (diethylamino-4-phenyl)(hydroxy-5-disulfo-2,4-phenyl) methanol] can lead to high levels of methemoglobin and metabolic acidosis. In severe cases and if not rapidly eliminated from the plasma, this can lead to multiple organ failure and death. CASE REPORT: A 27-year-old Asian woman (original from Vietnam) was admitted after ecstasy intoxication resulting in multi-organ failure (acute respiratory distress syndrome, metabolic acidosis, capillary leakage syndrome, renal failure, shock refractory to standard resuscitation). As a consequence, continuous renal replacement therapy and veno-venous extracorporeal membrane oxygenation were started. Methylene blue administration to reverse vasoplegia was decided, but unfortunately, Patent Blue V was erroneously administered, resulting in a severe clinical picture of methemoglobinemia and tissue hypoxia. As a therapeutic intervention, CytoSorb hemoadsorption was initiated, and rapid and significant reduction in plasma methemoglobin, accompanied by improved hemodynamics and normalization in plasma lactate levels, was observed. CONCLUSIONS: This is the first case describing the application of CytoSorb hemoadsorption in a patient with ecstasy intoxication complicated by iatrogenic administration of Patent Blue V. There is a potential role for CytoSorb in drug intoxication, which needs to be confirmed in larger series.

Expansion of the mangrove species Rhizophora mucronata in the Western Indian Ocean launched contrasting genetic patterns.

Estimates of population structure and gene flow allow exploring the historical and contemporary processes that determine a species' biogeographic pattern. In mangroves, large-scale genetic studies to estimate gene flow have been conducted predominantly in the Indo-Pacific and Atlantic region. Here we examine the genetic diversity and connectivity of Rhizophora mucronata across a > 3,000 km coastal stretch in the Western Indian Ocean (WIO) including WIO islands. Based on 359 trees from 13 populations and using 17 polymorphic microsatellite loci we detected genetic breaks between populations of the (1) East African coastline, (2) Mozambique Channel Area (3) granitic Seychelles, and (4) Aldabra and northern Madagascar. Genetic structure, diversity levels, and patterns of inferred connectivity, aligned with the directionality of major ocean currents, driven by bifurcation of the South Equatorial Current, northward into the East African Coastal Current and southward into the Mozambique Channel Area. A secondary genetic break between nearby populations in the Delagoa Bight coincided with high inbreeding levels and fixed loci. Results illustrate how oceanographic processes can connect and separate mangrove populations regardless of geographic distance.

Implementation of a new health information technology for the management of cancer chemotherapies.

BACKGROUND: Cancer chemotherapy drugs are classified as high-risk molecules. Safety of the cancer chemotherapy process is often achieved with the implementation of a health information technology to each step or to the entire process. However, computerisation could lead to the emergence of new unintended medication errors. The aim of the study was to evaluate the impact of new software designed for the management of anticancer chemotherapies. METHOD: The cartography of the process and the failure modes, effects and criticality analysis were performed by a multidisciplinary team. Criticality indexes were calculated considering or not the implementation of the commercial software (CytoWeb). Quality and satisfactory indicators were measured before the implementation and during the use of the software. RESULTS: Our results demonstrated the complexity of the cancer chemotherapy process in the hospital. Risk analysis highlighted the positive impact of CytoWeb on the process safety but pointed out some steps that were not positively influenced by the software. Although a decrease of 38.6% of error rate was observed with the electronic system, new unintended medication errors emerged. These errors were due to inadequate use of the software (encoding of the wrong drug, the wrong dose, the wrong patient parameters or lab results and lack of prescriber adherence). Our satisfaction survey showed that the hospital pharmacists and doctors were less satisfied by the software than the nurses, mostly in terms of task achievement and time saving. Survey's results highlighted some weaknesses in the user training and in the collaboration between the medical staff. CONCLUSIONS: Our work showed the emergence of unintended medication errors linked to computerisation that were due to an inadequate use of the software. Other issues were highlighted such as the lack of collaboration between the medical staff, the lack of prescriber implication and weaknesses in the user training or in the information related to CytoWeb.

Improved venous thromboembolism prophylaxis by pharmacist-driven interventions in acutely ill medical patients in Belgium.

BACKGROUND: Forty to 50 % of hospitalized patients with an acute medical illness have risk factors for venous thromboembolism (VTE) and it has been shown that VTE prophylaxis reduced the incidence of VTE events in these patients. However, a large multinational survey, the ENDORSE study, showed that only 37 % of medical patients with VTE risk factors actually received VTE prophylaxis. OBJECTIVE: To evaluate the impact over time of pharmacist-driven interventions aiming at increasing the appropriate use of VTE prophylaxis in acutely ill medical hospitalized patients. SETTING: A Belgian urban academic hospital. METHOD: First, during 1 month, medical and nurse reports of all hospitalized medical patients were reviewed to evaluate the proportion of patients who were on prophylaxis according to clinical practice guidelines. Second, interventions were conducted and included unit-specific physician and nurse education, diffusion of educational tools summarizing VTE prophylaxis guidelines, and reminders. Third, the impact of the interventions on the proportion of patients receiving VTE prophylaxis according to clinical practice guidelines was evaluated after 3 months and 1 year. MAIN OUTCOME MEASURE: Proportion of hospitalized medical patients receiving VTE prophylaxis according to clinical practice guidelines. RESULTS: The baseline evaluation showed that 36 % (26/72) of the patients at risk of VTE received VTE prophylaxis according to clinical practice guidelines. Three months and one year after the interventions, 68 % (55/81), and 72 % (58/81) of the patients at risk of VTE received VTE prophylaxis according to clinical practice guidelines. Among patients not at risk of VTE, 15 % (21/141), 8 % (24/290), and 8 % (27/330) respectively at baseline evaluation, 3 months and 1 year after the interventions, received VTE prophylaxis. CONCLUSION: Pharmacist-driven interventions improved the proportion of acutely ill medical patients receiving VTE prophylaxis according to clinical practice guidelines and the benefit of the interventions was maintained after 1 year.

Strongyloides disseminated infection successfully treated with parenteral ivermectin: case report with drug concentration measurements and review of the literature.

We report the case of an immunosuppressed patient with Strongyloides disseminated infection who was successfully treated with the veterinary parenteral form of ivermectin. A kidney transplant recipient developed disseminated infection with Strongyloides stercoralis. Because oral treatment with ivermectin was not possible, subcutaneous ivermectin (75 µg/kg/day, then 200 µg/kg/day) was given for 9 days, with clinical improvement and disappearance of all larvae. Serum ivermectin concentrations were between 15.6 ng/mL and 19.7 ng/mL during the 9 days of therapy; however, drug accumulation (plasma levels >40 ng/mL) 48 h after discontinuation of therapy was associated with the development with encephalopathy. We also review all cases of human disseminated Strongyloides infection treated with parenteral ivermectin.

Continuous epileptiform discharges in patients treated with cefepime or meropenem.

OBJECTIVE: To test the hypothesis that treatment with cefepime hydrochloride leads to higher incidence of periodic epileptiform discharges compared with treatment with other ß-lactams. DESIGN: Data from hospital pharmacy databases of patients treated with cefepime or meropenem during a 42-month period (from January 1, 2007, through June 30, 2010) were retrospectively crossed with data from the electroencephalography database for the same period. SETTING: Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. PATIENTS: Patients who underwent electroencephalographic testing while taking cefepime or meropenem were selected. Only electroencephalographic tests performed during the antibiotic treatment period were considered. Matches were compared with nurses' medication records to ensure that the antibiotic considered was effectively given. MAIN OUTCOME MEASURE: Proportions of patients with continuous epileptiform discharges in the 2 groups were compared using the Fisher exact test. RESULTS: A total of 1120 patients were treated with cefepime and 1572 patients with meropenem. Electroencephalographic testing was performed during treatment in 59 patients treated with cefepime and 80 treated with meropenem (5.26% vs 5.08%, P = .85). Continuous epileptiform discharges were present in 14 patients in the cefepime group and 3 in the meropenem group (1.25% vs 0.19%, P < .001). Blood creatinine concentration was elevated in 5 of the 17 patients (range, 1.5-4.2 mg/dL; reference range, 0.7-1.2 mg/dL), and liver enzyme levels were elevated in 5 patients. No patient had major electrolyte disturbances. CONCLUSIONS: Our study showed a prevalence of electroencephalographic test results with continuous epileptiform discharges in 14 of 1120 patients receiving cefepime (1.25%) but only 3 of 1572 patients receiving meropenem (0.19%). Contrary to the results of previous case series, these electroencephalographic patterns occurred, in most cases, in patients with normal renal function. These results suggest that cefepime may be an independent risk factor for periodic epileptiform discharges, which are associated with worse outcomes. This finding could provide a partial explanation for the higher mortality rates reported in patients treated with cefepime compared with other ß-lactams.

Drotrecogin alfa (activated) for severe sepsis: could we consider a shorter treatment period in patients with a favorable course?

PURPOSE: The objective of this study was to develop a model to identify patients in whom drotrecogin alfa (activated) (DAA) might be administered for periods shorter than the recommended 96 hours. METHODS: We did a retrospective chart review of all 124 patients treated with a standard 96-hour infusion of DAA in a 31-bed department of intensive care. Using a stepwise approach, we identified and combined parameters that could help predict outcomes to achieve the best sensitivity associated with 100% specificity. RESULTS: Twenty-one (17%) of the 124 patients had a favorable outcome (left the intensive care unit within 5 days of DAA initiation); of these, 11 had an increase in arterial pH in the first 24 hours of treatment compared with 22 (21%) of the 103 patients with intermediate (intensive care unit stay >5 days after DAA initiation) or unfavorable (died within 5 days of DAA initiation) outcomes (P = not significant). Eight (72.7%) of these 11 patients and no other patient showed a decrease in sequential organ failure assessment score of at least 50% during the first 24 hours (P < .001). By combining these 2 variables, we could identify, with 100% specificity, 8 of the patients with a favorable outcome (38%) who made a prompt recovery. CONCLUSIONS: A simple model based on sequential organ failure assessment score and arterial pH can help identify patients with a rapid favorable course in whom a shorter duration of DAA treatment may be justified.