Darren M. Roberts

Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study.

Objectives: In critically ill patients receiving continuous renal replacement therapy, we aimed to assess the variability of antibiotic trough concentrations, the influence of effluent flow rates on such concentrations, and the incidence of suboptimal antibiotic dosage. Design: Prospective, observational, multicenter, pharmacokinetic study. Setting: Four tertiary intensive care units within the multicenter RENAL randomized controlled trial of continuous renal replacement therapy intensity. Patients: Twenty-four critically ill adult patients with acute kidney injury receiving ciprofloxacin, meropenem, piperacillin/tazobactam, or vancomycin during continuous renal replacement therapy. Interventions: We obtained trough blood samples and measured antibiotic concentrations. Measurements and Main Results: We obtained data from 40 dosing intervals and observed wide variability in trough concentrations (6.7-fold for meropenem, 3.8-fold for piperacillin, 10.5-fold for tazobactam, 1.9-fold for vancomycin, and 3.9-fold for ciprofloxacin). The median (interquartile range) trough concentrations (mg/L) for meropenem was 12.1 (7.8–18.4), 105.0 (74.4–204.0)/3.8 (3.4–21.8) for piperacillin/tazobactam, 12.0 (9.8–16.0) for vancomycin, and 3.7 (3.0–5.6) for ciprofloxacin. Overall, 15% of dosing intervals did not meet predetermined minimum therapeutic target concentrations, 40% did not achieve the higher target concentration, and, during 10% of dosing intervals, antibiotic concentrations were excessive. No difference, however, was found between patients on the basis of the intensity of continuous renal replacement therapy; this effect may have been obscured by differences in dosing regimens, time off the filter, or altered pharmacokinetics. Conclusions: There is significant variability in antibiotic trough concentrations in critically ill patients receiving continuous renal replacement therapy, which did not only appear to be influenced by effluent flow rate. Here, empirical dosing of antibiotics failed to achieve the target trough antibiotic concentration during 25% of the dosing intervals.

The treatment of acute antibody-mediated rejection in kidney transplant recipients - a systematic review

Background Antibody-mediated rejection (AMR) is a recognized cause of allograft loss in kidney transplant recipients. A range of therapies targeting removal of circulating donor-specific antibodies (DSAs), blocking their effect or reducing production have been reported. Methods We conducted a systematic review to determine the efficacy of treatments for acute AMR in renal allografts. Electronic databases, reference lists, and conference proceedings were searched for controlled trials. Nonrandomized publications were reviewed for the purpose of discussion. Results We identified 10,388 citations, including five randomized and seven nonrandomized controlled trials. The randomized studies were small (median, 13 patients/arm; range, 5–23), of which, four examined plasmapheresis (one suggested benefit) and one for immunoadsorption (also suggesting benefit). Marked heterogeneity was evident, including the definition and severity of AMR and the treatment regimen. The end point of graft survival was common to all studies. Small, nonrandomized controlled studies suggested benefit from rituximab or bortezomib. The effects of dose and regimen on the clinical response to any of the current treatments were not apparent from the available data. Conclusions Data describing the efficacy of treatments for AMR in renal allografts are of low or very low quality. Larger randomized controlled trials and dose-response studies are required.

Prediction of outcome after paraquat poisoning by measurement of the plasma paraquat concentration

Background: Paraquat is a herbicide with a good occupational safety record, but a high mortality after intentional ingestion that has proved refractory to treatment. For nearly three decades paraquat concentration–time data have been used to predict the outcome following ingestion. However, none of the published methods has been independently or prospectively validated. We aimed to use prospectively collected data to test the published predictive methods and to determine if any is superior. Methods: Plasma paraquat concentrations were measured on admission for 451 patients in 10 hospitals in Sri Lanka as part of large prospective cohort study. All deaths in hospital were recorded; patients surviving to hospital discharge were followed up after 3 months to detect delayed deaths. Five prediction methods that are based on paraquat concentration–time data were then evaluated in all eligible patients. Results: All methods showed comparable performance within their range of application. For example, between 4- and 24-h prediction of prognosis was most variable between Sawada and Proudfoot methods but these differences were relatively small [specificity 0.96 (95% CI: 0.90–0.99) vs. 0.89 (0.82–0.95); sensitivity 0.57 vs. 0.79, positive and negative likelihood ratios 14.8 vs. 7.40 and 0.44 vs. 0.23 and positive predictive values 0.96 vs. 0.92, respectively]. Conclusions: All five published methods were better at predicting death than survival. These predictions may also serve as tools to identify patients who need treatment and for some assessment to be made of new treatments that are trialled without a control group.

Rituximab-associated hypogammaglobulinemia: Incidence, predictors and outcomes in patients with multi-system autoimmune disease

Rituximab is a B cell depleting monoclonal antibody used to treat lymphoma and autoimmune disease. Hypogammaglobulinemia has occurred after rituximab for lymphoma and rheumatoid arthritis but data are scarce for other autoimmune indications. This study describes the incidence and severity of hypogammaglobulinemia in patients receiving rituximab for small vessel vasculitis and other multi-system autoimmune diseases. Predictors for and clinical outcomes of hypogammaglobulinemia were explored. We conducted a retrospective study in a tertiary referral specialist clinic. The severity of hypogammaglobulinemia was categorized by the nadir serum IgG concentration measured during clinical care. We identified 288 patients who received rituximab; 243 were eligible for inclusion with median follow up of 42 months. 26% were IgG hypogammaglobulinemic at the time that rituximab was initiated and 56% had IgG hypogammaglobulinemia during follow-up (5-6.9 g/L in 30%, 3-4.9 g/L in 22% and <3 g/L in 4%); IgM ≤0.3 g/L in 58%. The nadir IgG was non-sustained in 50% of cases with moderate/severe hypogammaglobulinemia. A weak association was noted between prior cyclophosphamide exposure and nadir IgG concentration, but not cumulative rituximab dose. IgG concentrations prior to and at the time of rituximab correlated with the nadir IgG post rituximab. IgG replacement was initiated because of recurrent infection in 12 (4.2%) patients and a lower IgG increased the odds ratio of receiving IgG replacement. Rituximab is associated with an increased risk of hypogammaglobulinemia but recovery of IgG level can occur. IgG monitoring may be useful for patients receiving rituximab.

Management of acute organophosphorus pesticide poisoning

Organophosphorus pesticides are used widely for agriculture, vector control, and domestic purposes. Despite the apparent benefits of these uses acute organophosphorus pesticide poisoning is an increasing worldwide problem, particularly in rural areas. Organophosphorus pesticides are the most important cause of severe toxicity and death from acute poisoning worldwide, with more than 200 000 deaths each year in developing countries.1 Although the incidence of severe acute organophosphorus pesticide poisoning is much less in developed countries, many patients with acute low dose unintentional or occupational exposures present to health facilities.2 3 We provide an evidence based review of the management of acute organophosphorus pesticide poisoning. Risk assessment in patients with acute unintentional poisoning is discussed, in addition to special considerations for severe poisoning. #### SUMMARY POINTS #### Sources and selection criteria We searched several resources to identify relevant information on the diagnosis and management of acute organophosphorus poisoning: Medline, Embase, the Cochrane Library, and the Chemical Safety Information for Intergovernmental Organizations database (www.inchem.org/pages/pds.html); websites for registration of clinical trials, including the Current Controlled trials website (http://controlled-trials.com/) using the m RCT search feature; personal archives; and attendance at, and review of abstracts from, workshops and conferences on pesticide poisoning. #### Levels of evidence in the review The evidence supporting specific therapeutic approaches to patients with acute organophosphorus poisoning is listed after each management recommendation. We have adopted the classification used in the BMJ publication Clinical Evidence 4:

Acute Human Self-Poisoning with Imidacloprid Compound: A Neonicotinoid Insecticide

Background Deliberate self-poisoning with older pesticides such as organophosphorus compounds are commonly fatal and a serious public health problem in the developing world. The clinical consequences of self-poisoning with newer pesticides are not well described. Such information may help to improve clinical management and inform pesticide regulators of their relative toxicity. This study reports the clinical outcomes and toxicokinetics of the neonicotinoid insecticide imidacloprid following acute self-poisoning in humans. Methodology/Principal Findings Demographic and clinical data were prospectively recorded in patients with imidacloprid exposure in three hospitals in Sri Lanka. Blood samples were collected when possible for quantification of imidacloprid concentration. There were 68 patients (61 self-ingestions and 7 dermal exposures) with exposure to imidacloprid. Of the self-poisoning patients, the median time to presentation was 4 hours (IQR 2.3–6.0) and median amount ingested was 15 mL (IQR 10–50 mL). Most patients only developed mild symptoms such as nausea, vomiting, headache and diarrhoea. One patient developed respiratory failure needing mechanical ventilation while another was admitted to intensive care due to prolonged sedation. There were no deaths. Median admission imidacloprid concentration was 10.58 ng/L; IQR: 3.84–15.58 ng/L, Range: 0.02–51.25 ng/L. Changes in the concentration of imidacloprid in serial blood samples were consistent with prolonged absorption and/or saturable elimination. Conclusions Imidacloprid generally demonstrates low human lethality even in large ingestions. Respiratory failure and reduced level of consciousness were the most serious complications, but these were uncommon. Substitution of imidacloprid for organophosphorus compounds in areas where the incidence of self-poisoning is high may help reduce deaths from self-poisoning.

A prospective observational study of the clinical toxicology of glyphosate-containing herbicides in adults with acute self-poisoning

Context. The case fatality from acute poisoning with glyphosate-containing herbicides is approximately 7.7% from the available studies but these have major limitations. Large prospective studies of patients with self-poisoning from known formulations who present to primary or secondary hospitals are needed to better describe the outcome from acute poisoning with glyphosate-containing herbicides. Furthermore, the clinical utility of the glyphosate plasma concentration for predicting clinical outcomes and guiding treatment has not been determined. Objective. To describe the clinical outcomes, dose–response, and glyphosate kinetics following self-poisoning with glyphosate-containing herbicides. Methods. This prospective observational case series was conducted in two hospitals in Sri Lanka between 2002 and 2007. We included patients with a history of acute poisoning. Clinical observations were recorded until discharge or death. During a specified time period, we collected admission (n = 216, including five deaths) and serial (n = 26) blood samples in patients. Severity of poisoning was graded using simple clinical criteria. Results. Six hundred one patients were identified; the majority ingested a concentrated formulation (36%, w/v glyphosate). Twenty-seven percent were asymptomatic, 63.7% had minor poisoning, and 5.5% of patients had moderate to severe poisoning. There were 19 deaths (case fatality 3.2%) with a median time to death of 20 h. Gastrointestinal symptoms, respiratory distress, hypotension, altered level of consciousness, and oliguria were observed in fatal cases. Death was strongly associated with greater age, larger ingestions, and high plasma glyphosate concentrations on admission (>734 μg/mL). The apparent elimination half-life of glyphosate was 3.1 h (95% CI = 2.7–3.6 h). Conclusions. Despite treatment in rural hospitals with limited resources, the mortality was 3.2%, which is lower than that reported in previous case series. More research is required to define the mechanism of toxicity, better predict the small group at risk of death, and find effective treatments.

Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement.

Objective:Methanol poisoning can induce death and disability. Treatment includes the administration of antidotes (ethanol or fomepizole and folic/folinic acid) and consideration of extracorporeal treatment for correction of acidemia and/or enhanced elimination. The Extracorporeal Treatments in Poisoning workgroup aimed to develop evidence-based consensus recommendations for extracorporeal treatment in methanol poisoning. Design and Methods:Utilizing predetermined methods, we conducted a systematic review of the literature. Two hundred seventy-two relevant publications were identified but publication and selection biases were noted. Data on clinical outcomes and dialyzability were collated and a two-round modified Delphi process was used to reach a consensus. Results:Recommended indications for extracorporeal treatment: Severe methanol poisoning including any of the following being attributed to methanol: coma, seizures, new vision deficits, metabolic acidosis with blood pH ⩽7.15, persistent metabolic acidosis despite adequate supportive measures and antidotes, serum anion gap higher than 24 mmol/L; or, serum methanol concentration 1) greater than 700 mg/L (21.8 mmol/L) in the context of fomepizole therapy, 2) greater than 600 mg/L or 18.7 mmol/L in the context of ethanol treatment, 3) greater than 500 mg/L or 15.6 mmol/L in the absence of an alcohol dehydrogenase blocker; in the absence of a methanol concentration, the osmolal/osmolar gap may be informative; or, in the context of impaired kidney function. Intermittent hemodialysis is the modality of choice and continuous modalities are acceptable alternatives. Extracorporeal treatment can be terminated when the methanol concentration is <200 mg/L or 6.2 mmol/L and a clinical improvement is observed. Extracorporeal Treatments in Poisoning inhibitors and folic/folinic acid should be continued during extracorporeal treatment. General considerations: Antidotes and extracorporeal treatment should be initiated urgently in the context of severe poisoning. The duration of extracorporeal treatment extracorporeal treatment depends on the type of extracorporeal treatment used and the methanol exposure. Indications for extracorporeal treatment are based on risk factors for poor outcomes. The relative importance of individual indications for the triaging of patients for extracorporeal treatment, in the context of an epidemic when need exceeds resources, is unknown. In the absence of severe poisoning but if the methanol concentration is elevated and there is adequate alcohol dehydrogenase blockade, extracorporeal treatment is not immediately required. Systemic anticoagulation should be avoided during extracorporeal treatment because it may increase the development or severity of intracerebral hemorrhage. Conclusion:Extracorporeal treatment has a valuable role in the treatment of patients with methanol poisoning. A range of clinical indications for extracorporeal treatment is provided and duration of therapy can be guided through the careful monitoring of biomarkers of exposure and toxicity. In the absence of severe poisoning, the decision to use extracorporeal treatment is determined by balancing the cost and complications of extracorporeal treatment to that of fomepizole or ethanol. Given regional differences in cost and availability of fomepizole and extracorporeal treatment, these decisions must be made at a local level.

Overcoming apathy in research on organophosphate poisoning.

High rates of pesticide poisoning in developing countries and increasing risk of nerve gas attacks in the West mean effective antidotes for organophosphates should be a worldwide priority

The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology

Abstract Extracorporeal treatments (ECTRs), such as hemodialysis and hemoperfusion, are used in poisoning despite a lack of controlled human trials demonstrating efficacy. To provide uniform recommendations, the EXTRIP group was formed as an international collaboration among recognized experts from nephrology, clinical toxicology, critical care, or pharmacology and supported by over 30 professional societies. For every poison, the clinical benefit of ECTR is weighed against associated complications, alternative therapies, and costs. Rigorous methodology, using the AGREE instrument, was developed and ratified. Methods rely on evidence appraisal and, in the absence of robust studies, on a thorough and transparent process of consensus statements. Twenty-four poisons were chosen according to their frequency, available evidence, and relevance. A systematic literature search was performed in order to retrieve all original publications regardless of language. Data were extracted on a standardized instrument. Quality of the evidence was assessed by GRADE as: High = A, Moderate = B, Low = C, Very Low = D. For every poison, dialyzability was assessed and clinical effect of ECTR summarized. All pertinent documents were submitted to the workgroup with a list of statements for vote (general statement, indications, timing, ECTR choice). A modified Delphi method with two voting rounds was used, between which deliberation was required. Each statement was voted on a Likert scale (1–9) to establish the strength of recommendation. This approach will permit the production of the first important practice guidelines on this topic.