Latest articles in clinical Toxicology

1. Latest articles in clinical Toxicology

2. Are vasopressors useful in toxin-induced cardiogenic shock? Clin Toxicol (Phila). 2017;55(4):285-304. [PubMed] • The authors’ search identified 130 human case reports and 14 animal studies that met their inclusion criteria. • Surprisingly (at least to me), human case report data showed vasopressors didn’t work more often than they did work • In the majority of animal studies, vasopressor treatment failed to improve hemodynamic function and resulted in decreased survival.

3. Application in clinical practice • Don’t throw out vasopressors as an option in these incredibly sick patients, but understand that other therapies, such as insulin, may be more effective. • Expert consensus recommendations for management of calcium channel blocker poisoning still list norepinephrine and/or epinephrine among their first-line recommendation. • Human cases suggest that even though vasopressors are not often effective, they don’t seem to be harmful (unlike in theanimal data). The largest series of 48 patients (not included in this review article), demonstrated effectiveness in most cases.

4. McCabe D, Lu J. The association of hemodialysis and survival in intubated salicylate-poisoned patients. Am J Emerg Med. 2017;35(6):899-903. • Retrospective, observational study of poison center records.Intubated patients with a salicylate level > 50 mg/dL were included. Survival was compared to measured serum salicylate level and the administration of HD. Overall survival rate was 73% in the 56 cases reported • Survival rate in patients that didnotreceive HD • ASA level > 50 mg/dL had a 56%(14/25) • ASA level > 80 mg/dL had a0% (0/9) • Survival rate when patients received HD: • ASA level > 50 mg/dL had an83.9% (26/31) • ASA level > 80 mg/dL had an83.3% (15/18)

5. Application in clinical practice : • Even taking into account the retrospective nature and incomplete data sets from voluntary reporting to poison centers,there is an association between hemodialysis and survival in mechanically-ventilated, salicylate-poisoned patients with levels > 50 mg/dL. • Early hemodialysis should be arranged in salicylate-poisoned patients who require intubation (or are headed in that direction).

6. Safety and effectiveness of physostigmine: a 10-year retrospective review Clin Toxicol(Phila). July 2017:1-7 • The California Poison Control System published a 10-year retrospective cohort study of 191 hospitalized patients who received physostigmine to reverse an anticholinergic toxidrome • 142 patients (74.3%) were treated with physostigmine alone.36 patients (18.8%) were discharged directly from the ED (57.6% of patients were admitted to the ICU) • 182 patients (95.3%) had no documented adverse effects • 4 patients experienced emesis,2 patients experienced QTc prolongation,2 patients experienced seizures, 1 patient died (unrelated)

7. Application in clinical practice : • Physostigmine appeared effective in the majority of cases. • Most patients still were admitted to the ICU (contradicting the findings of the2010 Rosenbaum study). • We should stop fearing physostigmine and use it in cases of anticholinergic poisoning (as long as TCAs are not the causeandthere is no intraventricular conduction defects, no QRS/QTc prolongation or AV block on ECG) • Stock physostigmine in your ED to ensure timely administration

8. How to use physostigmine • Physostigmine controlled agitation and reversed delirium in 96% and 87% of patients, respectively (Ann Emerg Med 2000). Benzodiazepines controlled agitation in 24% of patients but were ineffective in reversing delirium • Dose : 1 to 2 mg in adults and 0.02 mg/kg (maximum, 0.5 mg) in children IV infused over at least 5minutes. • Onset is within minutes (Anesth Analg 1973) • Can be repeated after 10 to 15 minutes

9. Flumazenil in BDZ overdose? 1. Do we need to reverse BZD overdose in adult patients ? Overall complication rate with benzodiazepine overdose is low: Of 702 patients who had takenbenzodiazepines alone or in combination with ethanol or other drugs, 0.7% died and 9.8% had complications (​Hojer 1988​). 2. Attempts to Prove Safety In the first study there were 904 adult patients with 13 reported seizures and 1 death (​Kreshak 2012​). A second study specific to pediatric patients reported 83 patients with no seizures and no deaths (​Kreshak2012​). A third study found 80 patients with 1 seizure and 0 deaths (​Veiraiah 2012​). A fourth small retrospective study 23 ED patients found that there were no seizures (​Nguyen 2015​).

10. Clinical application • A 2016 systematic review and meta-analysis of randomized trials summed it up perfectly: "Flumazenilshould not be used routinely, and the harms and benefits should be considered carefully in every patient(​Penninga 2016​, ​Sivilotti 2016​)." • Cases in which to consider flumazenil are pediatric patients and reversalof procedural sedation if needed

11. EARLY High dose insulin therapy • Dose: Regular insulin bolus 1 unit/kg IV, then infusion 0.5-1 unit/kg/hour. Before initiating measure serum glucose and supplement if less than 200. • Monitor potassium hourly and then once every 6 hours once stable. • Monitor glucose every 10 minutes and then every 30-60 minutes once stable. • A recommended starting dose of dextrose is 0.5 g/kg/hr delivered as D​25​W orD​50​W (by central venous access). • Insulin receptors are saturable, meaning that the hypoglycemia is limited at a certain point. You may end up needing less dextrose than you think! • Dextrose may be required up to 24 hours after insulin is discontinued

12. IV lipid emulsion • Work like a shuttle to accelerate redistribution from targets to reservoir organs. • .Consider lipid emulsion for local anesthetics, CCB, BB, TCA, bupropion, chloroquine, andother lipid soluble, cardio-/neurotoxic agents (​French 2011​ • ‘Best’ dose for oral poisonings: 20% lipid emulsion - 1.5 mL/kg bolus, 0.25 mL/kg/min X 3min, 0.025 mL/kg/min up to 6.5 hrs (​Fettiplace 2015​)f. • Possible adverse effects include ALI, pancreatitis, allergic reaction, fat emboli, and DVT(​Hayes 2016​).g. • Beware of laboratory interference and incompatibilitywith other resuscitation medications Labs should be drawn before lipid is given and it should be administered in its own line.

13. Reversing Dabigatran with Idarucizumab : Skepticism is always welcome when the same company makes the drug and the antidote. • The Lancet study was conducted in healthy volunteers, while the NEJM study was conducted in patients needing reversal but lacked a control group. • Idarucizumab seems to reverse laboratory markers of anticoagulation from dabigatran rapidly and completely, including dilute thrombin time and ecarin clotting time. Not all institutions have these assays available. • The dose that seems to 'work' the best is 5 gm given IV (two-2.5 gm infusions given no more than 15 minutes apart).Median investigator-reported time to cessation of bleeding was 11.4 hours in the NEJM study. • 21 / 90 patients in the NEJM study had 'serious adverse effects' including thrombotic events.

14. Siegal DM, et al. Andexanet Alfa for the Reversal of FactorXa Inhibitor Activity. N Engl J Med 2015;373(25)2413-25. • Two parallel randomized, placebo-controlled trials (ANNEXA-A [apixaban] and ANNEXA-R [rivaroxaban]) were conducted in healthy vounteers to evaluate the ability of andexanet to reverse anticoagulation, as measured by the percent change in anti factor Xa activity after administration. What they Found • Compared to placebo, andexanet significantly reduced anti-factor Xa activity, increased thrombin generation, and decreased unbound drug concentration in both the apixaban and rivaroxaban groups.

15. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM Apr 2019 Evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. • In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours.

16. Murthy MS, et al. Blood glucose response to rescue dextrose in hypoglycemic, critically ill patients receiving an insulin infusion. Ann pharm2015; This retrospective study was conducted in critically ill patients who experienced hypoglycemia while receiving an insulin infusion. While it may not directly apply to all Emergency Department patients, an estimation of the expected blood glucose increase from rescue dextrose is helpful. The study found a median increase of 4 mg/dL (0.2 mmol/L) per gram of D50 administered. If the blood glucose doesn’t respond as anticipated, it can help us troubleshoot possible issues (eg, line access).