Refractoriness of drug-induced hypotension: Prediction and management Bruno Mégarbane

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1 Refractoriness of drug-induced hypotension: Prediction and management Bruno Mégarbane Department of Medical and Toxicological Critical Care, INSERM, U1144, Paris Diderot University Lariboisière Hospital, Paris, France

2 Poisonings with cardiotoxicants In the USA: AAPCC-NPDS 2013 Cardiovascular agents: 7 th cause of exposures (3.9%) and 2 th cause of death (fatality rate: 0.29%) Cardiovascular pharmaceuticals Sodium-channel blockers (Class I) Beta-blockers (class II) Potassium channel blockers (sotalol) (class III) Calcium-channel antagonists (class IV) Cardioglycosides (class V) Non-cardiovascular pharmaceuticals Drugs Industrial toxicants Plants and over-the-counter, and household toxicants,

3 Is it possible to suspect the onset of severe cardiovascular failure on hospital admission? To admit the patient into the adequate ward To prevent toxicity using the optimal therapies and antidotes

4 The predictive value of the ingested dose: The example of ajmaline poisoning Delay for symptom occurrence: 1-3 h All patients in cardiac arrest died Ingested tablets N Cardiac arrest 1 g g g 16 8 Conso F. Press Med 1980

Dextropropoxyphen Dosulepine Flecainide Maprotiline Propranolol > 1.

5 Doses resulting in severe cardiovascular failure Acebutolol Amitritptyline Carbamazepine Chloroquine Clomipramine Dextropropoxyphen Dosulepine Flecainide Maprotiline Propranolol > 1.5 g > 2 g > 10 g > 4 g > 2 g > 500 mg > 1.25 g > 1.5 g > 3 g > 2 g Baud FJ. Crit Care 2007

6 Probability of epinephrine infusion rate >3 mg/h (%) The predictive value of the ingested dose: Example of chloroquine poisoning Simulated probability over time for having an epinephrine infusion rate >3 mg/h Reported ingested dose of chloroquine Time from reported ingestion (h) Mégarbane B. Clin Tox 2011

Serum lactate is an excellent prognosticator - Despite of absence of specificity, the serum lactate concentration had an excellent prognostic utility to

8-fold increase in odds of fatality (p < 0.001). ROC-AUC: 0.87 (95% CI: 0.81 0.94) Manini AF.

7 Serum lactate is an excellent prognosticator - Despite of absence of specificity, the serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality. - The optimal lactate cut-point was 3.0 mmol/l (84% sensitivity, 75% specificity), which conferred a 15.8-fold increase in odds of fatality (p < 0.001). ROC-AUC: 0.87 (95% CI: ) Manini AF. ClinTox 2010 Lactate is a marker of all types of SHOCK A marker of inadequate perfusion or cellular O 2 consumption A marker of inadequate resuscitation and management A predictor of patient bad outcome and development of organ dysfunction

8 Serum lactate concentrations (mmol/l) Serum lactate concentrations (mmol/l) Beta-blocker poisonings Predictive value of lactate concentration on admission 30 p< p< Survivors Fatalities On admission values Peak values The ROC-AUC of initial lactate for predicting mortality was 0.84 ( ). The cutoff point maximizing the sum of sensitivity and specificity was 2.7 mmol/l. For the 3.0 mmol/l selected lactate cutoff point: 55% sensitivity, 80% specificity. Mégarbane B. Clin Tox 2010

9 Calcium-channel antagonist poisonings Predictive value of hyperglycemia Levine M. Crit Care Med 2007

10 Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias Boehnert MT. N Engl J Med 1985

11 Chloroquine poisoning: prognosis assessment Supposed ingested dose Systolic BP QRS duration Severe > 4 g or < 100 mmhg or > 0.10 s Mild < 2 g and > 100 mmhg and < 0.10 s Plasma chloroquine concentration 12 M No death µm death rate: 2% > 25 µm death rate: 22% > 50 µm death rate: 60% Clemessy JL, et al. Crit Care Med 1996

12 Predictive factors in digitalis poisoning Age AV block K + >4.5 Death rate Female Male < 55 > 55 < 55 > 55 Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Dally S. Press Med 1981

Plasma Flecainide Concentrations (mg/l) Prognostic value of plasma concentrations in acute poisonings Relationship Between Plasma Flecainide Concentration and

13 Plasma Flecainide Concentrations (mg/l) Prognostic value of plasma concentrations in acute poisonings Relationship Between Plasma Flecainide Concentration and Outcome Flecainide poisonings Verapamil poisonings Survivors Fatalities Outcome of Acute Poisonings Mégarbane B. Clin Tox 2007 Mégarbane B. BCPT 2010

14 Once admitted to the ICU, how is it possible to assess cardiovascular failure refractoriness? Definition of refractoriness Patient monitoring in the ICU

$mechanism of shock Definition of the optimal treatment Diagnosis of the refractoriness of$

15 Strategy of management of toxic cardiovascular failure Diagnosis of shock Determination of the mechanism of shock Definition of the optimal treatment Diagnosis of the refractoriness of shock

16 Hemodynamic monitoring of cardiotoxicant poisonings Macrocirculation level: - Measurement of blood pressure and cardiac index Microcirculation level: - Simple signs: dizziness, transitory consciousness loss and collapse, skin discoloration, or even chest pain. - More sophisticated signs requiring a close and repeated assessment of any change in the mental status, low urine output and routine clinical chemistry (lactate, creatinine and liver function tests).

17 Evaluation of the mechanism of the toxic shock 1- Hypotension: systolic BP < 90 mm Hg or systolic BP decrease > 40 mmhg or mean BP < 65 mmhg 2- Unresponsive to fluids 3- At least one sign of organ hypoperfusion Peripheral Shock Cardiogenic Failure Cardiac Index (l.min -1.m- 2 ) > 3.5 < 2.5 Systemic Resistance (d.s -1.cm -5.m 2 ) < 1500 > 2000 P aw (mmhg) < 10 > 18 LVEF (%) > 70 < 60

18 Echocardiography Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation, myocardium thickness, valve diseases). However, it remains operator-dependent Echocardiography aspects Hypovolemia or vasoplegia Cardiogenic shock Severe dysrhythmia

SvO 2 versus cardiac index relationships 90 SvO 2 = SaO 2 - VO 2 IC x Hb x 1.

19 SvO 2 versus cardiac index relationships 90 SvO 2 = SaO 2 - VO 2 IC x Hb x SvO 2 (%) VO 2 : 110 ml/min/m 2 - SaO 2 : 95 % - Hb : 11 g/dl Cardiac index (L/min/m 2 ) 5 6 7

20 Predictive value of the mechanism of cardiovascular failure in colchicine poisoning Sauder P. Hum Toxicol, 1983

21 Refractoriness requires failure of optimal supportive treatments in the ICU Intubation and mechanical ventilation : Severe arrhythmias and associated collapse Coma, convulsions, respiratory failure Treatment of collapse/shock Fluids + adequate catecholamines Treatment of torsade-de-pointes Defibrillation, MgSO 4, titrated isoproterenol, cardiac pacing Correction of electrolyte imbalance (K +, Mg 2+ ) Treatment of monomorphic ventricular tachycardia Defibrillation, MgSO 4, lidocaine infusion Cardiac pacing High degree AV block with preserved inotropism

22 Refractoriness requires failure of the optimal administration of antidotes in the ICU (1) Beta-blockers Dobutamine 5-20 µg/kg/min Isoprenaline 1-5 mg/h (Sotalol) Calcium channel blockers Calcium chloride 1 g IV bolus /15 min 4 doses, mg/kg/h infusion Glucagon 2-5 mg IV bolus 2-10 mg/h continuous infusion Insulin 1 IU/kg IV bolus 1-10 IU/kg/h continuous infusion Epinephrine mg/h ± Cardiac Pacing Epinephrine mg/h Norepinephrine mg/h Methylene blue 2 mg/kg bolus 1 mg/kg/h infusion

23 Refractoriness requires failure of the optimal administration of antidotes in the ICU (2) Sodium channel blockers Sodium bicarbonates 8.4% 250 ml to be repeated 3 times + 2g KCl / 250 ml (cocaine: Lidocaine IV) Epinephrine mg/h Norepinephrine mg/h Cardioglycosides Atropine mg to be repeated Anti-digoxin Fab fragments Semi-molar or molar dose (if not available: ventricular pacing)

24 Dobutamine infusion (µg/kg/min) Assessment of catecholamine limitations in cardiotoxicant poisonings Dobutamine infusion Epinephrine infusion 10.0 Patient Flecainide concentration (mg/l) 0.50 Mégarbane B. Clin Tox 2005 (abstract)

25 PK/PD population modeling in chloroquine poisonings Mégarbane B. Clin Tox2010

26 Difficulty to manage catecholamines - epinephrine versus dobutamine - F, 17 years, severe propranolol poisoning Sedation + mechanical ventilation + FiO 2 100% Epinephrine 1.5 mg/h Dobutamine 15 µg/kg/min BP S mmhg D mmhg M mmhg P RA 7 6 cmh 2 0 P AP S cmh 2 0 D cmh 2 0 M cmh 2 0 P cw cmh 2 0 Cardiac Index l/min/m 2 Systemic resistances UI 30 min later Dramatic decrease in BP...

27 What to do if refractoriness to pharmacological treatments is suspected? 1- Lipid Emulsion 2- Veno-arterial ECMO 3- Molecular adsorbent recirculating system (MARS )

25 ml/kg/min infusion Mechanisms: - Lipid sink / sponge: alteration of tissue distribution - Modulator of myocardial energy, overcoming the

28 Lipid emulsion for local anesthetic toxicity To treat severe anesthetics side-effects in the OR as well as membrane-stabilizing agent or calcium-channel blocker poisonings. Dose regimen: 1.5 ml/kg IV bolus then 0.25 ml/kg/min infusion Mechanisms: - Lipid sink / sponge: alteration of tissue distribution - Modulator of myocardial energy, overcoming the inhibition of fatty acid-dependent metabolism - Activator of myocardial Ca 2+ channel increasing Ca 2+ current - Other toxin-specific mechanisms? Sirianni AJ. Ann Emerg Med 2008 Finn SD. Anesthesia 2009 Weinberg GL. Anesthesiology 2009

29 Percent of decrease in serum concentration Percent of decrease in serum concentration Partition constant and volume of distribution as predictors of ILE efficacy for toxicological emergencies Serum drug concentration decrease plotted against the partition constant and the volume of distribution of eleven drugs with 2% Intralipid added to the sample Partition constant Volume distribution French D. Clin Tox 2011

30 Agents with positive bench evidence for class effect and reported clinical use associated with a positive outcome Na + -channel antagonists - Local anesthetics - Tricyclic antidepressants: Doxepin Imipramine Amitryptilline Dothiepin - Flecainide [bench model evidence equivocal] - Propafenone - Cocaine Ca 2+ -channel blockers Verapamil Diltiazem Beta-blockers Propranolol Carvedilol Nebivolol Miscellaneous Haloperidol

Lipid emulsion: state of the Art Pro: Experimental data: good basis Endorsed by anesthetists for local anesthetics-induced toxicity Readily available at a much lower cost Rapid reversion of

31 Lipid emulsion: state of the Art Pro: Experimental data: good basis Endorsed by anesthetists for local anesthetics-induced toxicity Readily available at a much lower cost Rapid reversion of cardiotoxicity, easier use than cardiopulmonary bypass. While the evidence base for ILE use in drug intoxication is evolving, the Con: present evidence supports its use only in local anesthetic systemic Experimental conditions different from the scenarios of oral overdose toxicity and lipophilic cardiotoxin intoxication when there is an Human cases: anecdotal, biased reporting, no comparison with other antidotes immediate threat to life, and other therapies have proven ineffective. No consensus on indications in drug poisonings Optimal dose (High doses)? Dose adjustment for patient population? Duration? Delay to administration after ingestion? Limited safety data: adverse effects? Long-term outcome? Interactions?

32 va-ecmo in cardiogenic schock The purpose of va-ecmo is to take over heart function until recovery can occur, minimizing myocardial work, improving organ perfusion, and maintaining the renal and biliary elimination of the toxicant. Baud FJ. Crit Care 2007

33 Cannulation of femoral vessels in medical ICU Femoral arcade Femoral artery Femoral vein 5 6 Mégarbane B. Intensive Care Med 2007

34 va-ecmo in the ICU Superficial femoral shunt Arterial cannula Venous cannula Babatasi G. Arch Mal Cœur Vx 2001 Mégarbane B. Intensive Care Med 2007

35 va-ecmo monitoring in the ICU Spontaneous cardiac rhythm ECLS completely dependent cardiac flow (around 5-6 l/min) Severe hypotension despite high dose catecholamine Spontaneous cardiac flow

Monitoring of an ECMO-treated poisoned patient

obtain ACT = 2N Catecholamines for mean BP =

36 Monitoring of an ECMO-treated poisoned patient in ICU Efficient anticoagulation: heparin to obtain ACT = 2N Catecholamines for mean BP = mmhg + dobutamine to facilitate LV discharge Adequate transfusions Adapted Mechanical ventilation Temperature control Canulated lower limb monitoring (NIRS) Echocardiography: weaning criteria Neurological evaluation (EEG, clinical) Care, nursing

37 Published cases of va-ecmotreated acute poisonings: - Beta-blockers - CCB - Sodium channel blockers De Lange DW. Clin Tox 2013

38 A comparison of survival with and without ECMO support treatment for severe poisoning due to drug intoxication Masson R. Resuscitation 2012

39 Toxicokinetics in severe poisonings requiring ECMO Propafenone poisoning Carbamazepine poisoning Mégarbane B. Intensive Care Med T 1/2 : 30 h (pharmacology: 4 h) - Vd: 151 l/kg - Clearance: 262 l/h - Concentration on admission: 224 μmol/l - Peak concentration: 338 μmol/l at 101 h - Prolonged absorption despite MDAC - T 1/2 : 22.6 h (pharmacology: h)

$Assessment of MARS usefulness in diltiazem and verapamil poisonings with refractory$

40 Assessment of MARS usefulness in diltiazem and verapamil poisonings with refractory vasoplegic shock Time-course of PD parameters Time-course of PK Pichon N. Ann Emerg Med 2011

$refractory cardiovascular failure$

41 Assessment of MARS usefulness in amlodipine/valsartan overdose with refractory cardiovascular failure Time-course of PD parameters Time-course of PK Gérard L. Clin Tox 2015

42 Conclusions Shock and arrhythmias following poisonings with cardiotoxicants (especially with digitalis, sodium-channel, and calcium channel blockers) may lead to life-threatening symptoms and death. Adequate monitoring of severity and assessment of prognostic criteria are mandatory to improve patient management. Treatment is mainly supportive. Despite the absence of high-level of evidence, administration of antidotes is life-saving. Lipid emulsion, ECLS (cardiogenic shock) and MARS should be considered in refractory cardiovascular failure although their definitive benefit still needs to be evaluated.

ECMO for treatment of cardiotoxic intoxications

ECMO for treatment of cardiotoxic intoxications Bruno Mégarbane, MD, PhD Medical and Toxicological Critical Care Department Lariboisiere Hospital, INSERM UMRS-1144, Paris-Diderot University Paris France