Andrea Penaloza

Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well tolerated, but rare serious complications may occur in some patients receiving VPA chronically, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity (VHT) and VPA-induced hyperammonaemic encephalopathy (VHE). Some data suggest that VHT and VHE may be promoted by carnitine deficiency. Acute VPA intoxication also occurs as a consequence of intentional or accidental overdose and its incidence is increasing, because of use of VPA in psychiatric disorders. Although it usually results in mild central nervous system depression, serious toxicity and even fatal cases have been reported. Several studies or isolated clinical observations have suggested the potential value of oral L-carnitine in reversing carnitine deficiency or preventing its development as well as some adverse effects due to VPA. Carnitine supplementation during VPA therapy in high-risk patients is now recommended by some scientific committees and textbooks, especially paediatricians. L-carnitine therapy could also be valuable in those patients who develop VHT or VHE. A few isolated observations also suggest that L-carnitine may be useful in patients with coma or in preventing hepatic dysfunction after acute VPA overdose. However, these issues deserve further investigation in controlled, randomized and probably multicentre trials to evaluate the clinical value and the appropriate dosage of L-carnitine in each of these conditions.

Pyridoxine in clinical toxicology: a review

Pyridoxine (vitamin B6) is a co-factor in many enzymatic pathways involved in amino acid metabolism: the main biologically active form is pyridoxal 5-phosphate. Pyridoxine has been used as an antidote in acute intoxications, including isoniazid overdose, Gyromitra mushroom or false morrel (monomethylhydrazine) poisoning and hydrazine exposure. It is also recommended as a co-factor to improve the conversion of glyoxylic acid into glycine in ethylene glycol poisoning. Other indications are recommended by some sources (for example crimidine poisoning, zipeprol and theophylline-induced seizures, adjunct to d-penicillamine chelation), without significant supporting data. The value of pyridoxine or its congener metadoxine as an agent for hastening ethanol metabolism or improving vigilance in acute alcohol intoxication is controversial. This paper reviews the various indications of pyridoxine in clinical toxicology and the supporting literature. The potential adverse effects of excessive pyridoxine dosage will also be summarized.

Bench-to-bedside review: Hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers

Hyperinsulinaemia/euglycaemia therapy (HIET) consists of the infusion of high-dose regular insulin (usually 0.5 to 1 IU/kg per hour) combined with glucose to maintain euglycaemia. HIET has been proposed as an adjunctive approach in the management of overdose of calcium-channel blockers (CCBs). Indeed, experimental data and clinical experience, although limited, suggest that it could be superior to conventional pharmacological treatments including calcium salts, adrenaline (epinephrine) or glucagon. This paper reviews the patho-physiological principles underlying HIET. Insulin administration seems to allow the switch of the cell metabolism from fatty acids to carbohydrates that is required in stress conditions, especially in the myocardium and vascular smooth muscle, resulting in an improvement in cardiac contractility and restored peripheral resistances. Studies in experimental verapamil poisoning in dogs have shown that HIET significantly improves metabolism, haemodynamics and survival in comparison with conventional therapies. Clinical experience currently consists only of a few isolated cases or short series in which the administration of HIET substantially improved cardiovascular conditions in life-threatening CCB poisonings, allowing the progressive discontinuation of vasoactive agents. While we await further well-designed clinical trials, some rational recommendations are made about the use of HIET in severe CBB overdose. Although the mechanism of action is less well understood in this condition, some experimental data suggesting a potential benefit of HIET in β-adrenergic blocker toxicity are discussed; clinical data are currently lacking.

Comparison of the Unstructured Clinician Gestalt, the Wells Score, and the Revised Geneva Score to Estimate Pretest Probability for Suspected Pulmonary Embolism

STUDY OBJECTIVE The assessment of clinical probability (as low, moderate, or high) with clinical decision rules has become a cornerstone of diagnostic strategy for patients with suspected pulmonary embolism, but little is known about the use of physician gestalt assessment of clinical probability. We evaluate the performance of gestalt assessment for diagnosing pulmonary embolism. METHODS We conducted a retrospective analysis of a prospective observational cohort of consecutive suspected pulmonary embolism patients in emergency departments. Accuracy of gestalt assessment was compared with the Wells score and the revised Geneva score by the area under the curve (AUC) of receiver operating characteristic curves. Agreement between the 3 methods was determined by κ test. RESULTS The study population was 1,038 patients, with a pulmonary embolism prevalence of 31.3%. AUC differed significantly between the 3 methods and was 0.81 (95% confidence interval [CI] 0.78 to 0.84) for gestalt assessment, 0.71 (95% CI 0.68 to 0.75) for Wells, and 0.66 (95% CI 0.63 to 0.70) for the revised Geneva score. The proportion of patients categorized as having low clinical probability was statistically higher with gestalt than with revised Geneva score (43% versus 26%; 95% CI for the difference of 17%=13% to 21%). Proportion of patients categorized as having high clinical probability was higher with gestalt than with Wells (24% versus 7%; 95% CI for the difference of 17%=14% to 20%) or revised Geneva score (24% versus 10%; 95% CI for the difference of 15%=13% to 21%). Pulmonary embolism prevalence was significantly lower with gestalt versus clinical decision rules in low clinical probability (7.6% for gestalt versus 13.0% for revised Geneva score and 12.6% for Wells score) and non-high clinical probability groups (18.3% for gestalt versus 29.3% for Wells and 27.4% for revised Geneva score) and was significantly higher with gestalt versus Wells score in high clinical probability groups (72.1% versus 58.1%). Agreement between the 3 methods was poor, with all κ values below 0.3. CONCLUSION In our retrospective study, gestalt assessment seems to perform better than clinical decision rules because of better selection of patients with low and high clinical probability.

Performance of age-adjusted D-dimer cut-off to rule out pulmonary embolism

Summary:  Background:  Age‐adjusted D‐dimer cut‐off has recently been proposed to increase D‐dimer usefulness in older patients suspected of pulmonary embolism (PE).

Comparison of the Wells score with the simplified revised Geneva score for assessing pretest probability of pulmonary embolism

INTRODUCTION The Wells score is widely used in the assessment of pretest probability of pulmonary embolism (PE). The revised Geneva score is a fully standardized clinical decision rule that was recently validated and further simplified. We compared the predictive accuracy of these two scores. METHODS Data from 339 patients clinically suspected of PE from two prospective management studies were used and combined. Pretest probability of PE was assessed prospectively by the Wells score. The simplified revised (SR) Geneva score was calculated retrospectively. The predictive accuracy of both scores was compared by area under the curve (AUC) of receiver operating characteristic (ROC) curves. RESULTS The overall prevalence of PE was 19%. Prevalence of PE in the low, moderate and high pretest probability groups assessed by the Wells score and by the simplified revised Geneva score was respectively 2%(95% CI (CI) 1-6) and 4% (CI 2-10), 28% (CI 22-35) and 25% (CI 20-32), 93% (CI 70-99) and 56% (CI 27-81). The Wells score performed better than the simplified revised Geneva score in patients with a high suspicion of PE (p<0.05). The AUC for the Wells score and the simplified revised Geneva score was 0.85 (CI: 0.81 to 0.89) and 0.76 (CI: 0.71 to 0.80) respectively. The difference between the AUCs was statistically significant (p=0.005). CONCLUSIONS In our population the Wells score appeared to be more accurate than the simplified revised Geneva score. The impact of this finding in terms of patient outcomes should be investigated in a prospective study.

Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population.

INTRODUCTION PERC rule was created to rule out pulmonary embolism (PE) without further exams, with residual PE risk<2%. Its safety is currently not confirmed in high PE prevalence populations even when combined with low clinical probability assessed by revised Geneva score (RGS). As PERC rule and RGS are 2 similar explicit rules with many redundant criteria, we hypothesized that the combination of PERC rule with gestalt clinical probability could resolve this limitation. METHODS We collected prospectively documented clinical gestalt assessments and retrospectively calculated PERC rules and RGS from a prospective study of PE suspected patients. We analyzed performance of combinations of negative PERC with low clinical probability assessed by both methods in high overall PE prevalence population. RESULTS Among the final study population (n = 959), the overall PE prevalence was 29.8%. Seventy-four patients (7.7%) were classified as PERC negative and among them, 4 patients (5.4%) had final diagnosis of PE. When negative PERC was combined with low pretest probability assessed by RGS or gestalt assessment, PE prevalence was respectively 6.2% and 0%. This last combination reaches threshold target of 2% and unnecessary exams could easily have been avoided in this subgroup (6%). However, it confidence interval was still wide (0%; CI 0-5). CONCLUSIONS PERC rule combined with low gestalt probability seems to identify a group of patients for whom PE could easily be ruled out without additional test. A larger study is needed to confirm this result and to ensure safety.

Derivation and validation of a multivariate model to predict mortality from pulmonary embolism with cancer: the POMPE-C tool

BACKGROUND Clinical guidelines recommend risk stratification of patients with acute pulmonary embolism (PE). Active cancer increases risk of PE and worsens prognosis, but also causes incidental PE that may be discovered during cancer staging. No quantitative decision instrument has been derived specifically for patients with active cancer and PE. METHODS Classification and regression technique was used to reduce 25 variables prospectively collected from 408 patients with AC and PE. Selected variables were transformed into a logistic regression model, termed POMPE-C, and compared with the pulmonary embolism severity index (PESI) score to predict the outcome variable of death within 30 days. Validation was performed in an independent sample of 182 patients with active cancer and PE. RESULTS POMPE-C included eight predictors: body mass, heart rate >100, respiratory rate, SaO2%, respiratory distress, altered mental status, do not resuscitate status, and unilateral limb swelling. In the derivation set, the area under the ROC curve for POMPE-C was 0.84 (95% CI: 0.82-0.87), significantly greater than PESI (0.68, 0.60-0.76). In the validation sample, POMPE-C had an AUC of 0.86 (0.78-0.93). No patient with POMPE-C estimate ≤ 5% died within 30 days (0/50, 0-7%), whereas 10/13 (77%, 46-95%) with POMPE-C estimate >50% died within 30 days. CONCLUSION In patients with active cancer and PE, POMPE-C demonstrated good prognostic accuracy for 30 day mortality and better performance than PESI. If validated in a large sample, POMPE-C may provide a quantitative basis to decide treatment options for PE discovered during cancer staging and with advanced cancer.

Bench-to-bedside review: Antidotal treatment of sulfonylurea-induced hypoglycaemia with octreotide.

The major potential adverse effect of use of sulfonylurea agents (SUAs) is a hyperinsulinaemic state that causes hypoglycaemia. It may be observed during chronic therapeutic dosing, even with very low doses of a SUA, and especially in older patients. It may also result from accidental or intentional poisoning in both diabetic and nondiabetic patients. The traditional approach to SUA-induced hypoglycaemia includes administration of glucose, and glucagon or diazoxide in those who remain hypoglycaemic despite repeated or continuous glucose supplementation. However, these antidotal approaches are associated with several shortcomings, including further exacerbation of insulin release by glucose and glucagon, leading only to a temporary beneficial effect and later relapse into hypoglycaemia, as well as the adverse effects of both glucagon and diazoxide. Octreotide inhibits the secretion of several neuropeptides, including insulin, and has successfully been used to control life-threatening hypoglycaemia caused by insulinoma or persistent hyperinsulinaemic hypoglycaemia of infancy. Therefore, this agent should in theory also be useful to decrease glucose requirements and the number of hypoglycaemic episodes in patients with SUA-induced hypoglycaemia. This has apparently been confirmed by experimental data, one retrospective study based on chart review, and several anecdotal case reports. There is thus a need for further prospective studies, which should be adequately powered, randomized and controlled, to confirm the probable beneficial effect of octreotide in this setting.

European and American suspected and confirmed pulmonary embolism populations: comparison and analysis

Summary.  Background: If the prevalence of pulmonary embolism (PE) differs significantly between the US and Europe, this observation could reduce the generalizability of diagnostic protocols for PE derived in either location.Objective: To determine possible causes and potential clinical consequences of these PE prevalence differences.Methods: Secondary analysis of three prospectively collected multicenter samples (two French and one from the US) including 3174 European and 7940 American PE‐suspected patients in Emergency departments (ED) (117 for Europe and 12 for US). Comparison of clinical features, resource use and outcomes of European‐ and US‐suspected PE populations in ED.Results: European patients evaluated for PE were significantly older and had a higher clinical pretest probability (CPP) for PE. The final PE prevalence was significantly higher in Europe, in the overall sample (26.5% vs. 7.6%) and in each level of CPP. Suspected European patients categorized as low CPP had a higher posttest probability than US low CPP patients. Suspected US patients categorized as high CPP had a much lower posttest probability of PE than in Europe. The mean number of tests performed for one PE diagnosis was lower in Europe (7.4 vs. 21.6). Among patients diagnosed with PE, European patients had a higher mean severity of illness score and a higher PE‐mortality rate (3.4% vs. 0.7%).Conclusions: Among patients suspected of a PE and those ultimately diagnosed with a PE, European patients had higher acuity, a higher pretest probability and worse outcome than US patients. The present study underscores the importance of disease prevalence for pretest probability scoring approaches and for significance interpretation of imaging tests.