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Cardiac Contractility Dapo Odujebe, MD Toxicology Fellow NYC Poison Control Center.

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1 Cardiac Contractility Dapo Odujebe, MD Toxicology Fellow NYC Poison Control Center

2 Overview  Review & Cases  Cardiac Electrophysiology  Cardiac Contractility  Cardiac Medications Overdose ManagementOverdose Management  Questions?

3 Case #1  45-year old woman PMHx s/f depression presents to the ED after allegedly ingesting all of her anti-HTN medication.  Prescription filled 3 days prior for 30 tablets of diltiazem CD 240 mg.  Patient alert & oriented, mildly diaphoretic and complaining of generalized weakness.

4 Case #1  Vital signs: BP: 76/36, HR: 46, RR: 14, Temp: 98.6BP: 76/36, HR: 46, RR: 14, Temp: 98.6 pOx: 100% RA, AccuChk: 154pOx: 100% RA, AccuChk: 154  Rest of physical examination is benign.  Patient placed on a cardiac monitor, O 2 via nasal cannular and IV access established.

5 Case #1  What is the next step in her management?

6 Case #3  An 86-year old woman presents with increased confusion and vomiting.  Per family, she’s had increasing weakness, nausea & anorexia over the last 3 days.  PMHx: hypertensionhypertension congestive heart failure (CHF)congestive heart failure (CHF) diabetes mellitusdiabetes mellitus  Medications: hydrochlorothiazidehydrochlorothiazide digoxindigoxin furosemidefurosemide enteric-coated aspirinenteric-coated aspirin metforminmetformin

7 Case #3  In the hospital, she is alert, but oriented only to person.  Vital signs are normal, except for a heart rate of 46 beats/minute. She weighs 143 lbs (65 kg).  Her physical examination demonstrates: bibasilar ralesbibasilar rales irregular S1, S2 with a S3 gallopirregular S1, S2 with a S3 gallop bilateral LE 2+ pitting edema, up to her shinsbilateral LE 2+ pitting edema, up to her shins

8 Case #3  ECG: atrial flutter with variable blockatrial flutter with variable block ventricular rate of beats/minute with occasional premature ventricular contractions (PVCs).ventricular rate of beats/minute with occasional premature ventricular contractions (PVCs).  Laboratory results were within limits except: potassium mEq/Lpotassium mEq/L creatinine mg/dLcreatinine mg/dL glucose mg/dLglucose mg/dL  Initial digoxin serum concentration (SDC): 3.4 ng/mL (> 6 hours since last dose).3.4 ng/mL (> 6 hours since last dose).

9 Case #3  What is the next step in her management?

10 Cardiac Electrophysiology

11  Actions potentials SA nodeSA node Cardiac muscleCardiac muscle  (atria, ventricles & Purkinje fibers)  Channels Ca 2+ channelCa 2+ channel β-adrenergic receptorβ-adrenergic receptor Na + /K + -ATPaseNa + /K + -ATPase

12 Pacemaker Cell Cycle 0 mV -70 mV -50 mV Phase 0 Phase 3 Phase 4 Ca 2+

13 Action potential (SA Node)  Pacemaker of the heart  Unstable resting potential Exhibits automaticityExhibits automaticity AV node & His-Purkinje system are latent pacemakersAV node & His-Purkinje system are latent pacemakers  Phase 1 & 2 are not present in pacemaker action potentials

14 Action potential (SA Node)  Phase 0 Upstroke of action potentialUpstroke of action potential Caused by increase in Ca 2+ conductanceCaused by increase in Ca 2+ conductance Inward Ca 2+ current depolarizes cellInward Ca 2+ current depolarizes cell  Phase 3 RepolarizationRepolarization Caused by outward K + currentCaused by outward K + current

15 Action potential (SA Node)  Phase 4 Slow depolarizationSlow depolarization Caused by increased Na + conductanceCaused by increased Na + conductance Inward Na + currentInward Na + current

16 Cardiac Muscle Cell Cycle Resting Potential -90 mV 0 mV +30 mV -70 mV Phase 0 Phase 1 Phase 2 Phase 3 Phase 4 Ca 2+

17 Action potential (Cardiac Muscle)  Phase 0 Upstroke of action potentialUpstroke of action potential Caused by increase in Na + conductanceCaused by increase in Na + conductance Inward Na + current depolarizes cellInward Na + current depolarizes cell  Phase 1 Brief repolarizationBrief repolarization Caused by outward K + current and decrease in inward Na + currentCaused by outward K + current and decrease in inward Na + current

18 Action potential (Cardiac Muscle)  Phase 2 Plateau of action potentialPlateau of action potential Caused by increase in Ca 2+ conductanceCaused by increase in Ca 2+ conductance Inward Ca 2+ current depolarizes cell ‘balanced’ by outward K + currentInward Ca 2+ current depolarizes cell ‘balanced’ by outward K + current  Phase 3 RepolarizationRepolarization Caused by outward K + current and decrease in inward Ca 2+ currentCaused by outward K + current and decrease in inward Ca 2+ current

19 Action potential (Cardiac Muscle)  Phase 4 Resting membrane potential re- establishedResting membrane potential re- established Inward and outward K + currents are ‘balanced’Inward and outward K + currents are ‘balanced’ Na + /K + -ATPase acts in this phase to re- establish equilibriumNa + /K + -ATPase acts in this phase to re- establish equilibrium Na + /K + -ATPaseNa +,K + -ATPase Na + /K + -ATPase = Na +,K + -ATPase

20 Na + /K + ATPase 3 Na + 2 K + Representative Cardiac Cell Na + channel Voltage dependent L-typeCa 2+ channel L-type Ca 2+ channel Voltage dependent L-typeCa 2+ channel L-type Ca 2+ channel Na + /K + ATPase Na + /Ca 2+ exchanger SR (Mitochondria) Heart muscle K + channel(s) Na + /Ca 2+ Antiporter Ryanodine receptor 3 Na + Ca 2+ β-adrenergic receptor

21 3 Na + 2 K + Normal Cell Physiology SR (Mitochondria) Phase 0 Na + Phase 1 Phase 2 Phase 3 Phase 4 K+K+K+K+ K+K+K+K+ Ca 2+ K+K+K+K+ K+K+K+K+ IK TO IK R K+K+K+K+ Na + 3 Na + Ca 2+ Na +

22 Cardiac Contractility

23 Contractility  Intrinsic ability of cardiac muscle  Also called ‘inotropism’ or ‘inotropy’  Related to the intracellular [Ca 2+ ]  Inotropic agents positive: increase contractilitypositive: increase contractility negative: decrease contractilitynegative: decrease contractility

24 Factors Increasing Contractility  Increased intracellular [Ca 2+ ] increased heart rateincreased heart rate cardiac glycosides (e.g. digoxin)cardiac glycosides (e.g. digoxin)  Stimulation of β 1 -adrenergic receptor sympathomimetic agentssympathomimetic agents catecholaminescatecholamines

25 Contractility - Other Factors  Chronotropy rate of contractionrate of contraction also affected by intracellular [Ca 2+ ]also affected by intracellular [Ca 2+ ]  Dromotropy rate of impulse conductionrate of impulse conduction noted particularly at AV nodenoted particularly at AV node

26 Cardiac Medications & Receptors

27 Cardiac Medications  Some examples: Ca 2+ channel antagonists/blockersCa 2+ channel antagonists/blockers β-adrenergic antagonists/blockersβ-adrenergic antagonists/blockers Cardiac glycosides (digoxin)Cardiac glycosides (digoxin)

28 Ca 2+ Channel Antagonists

29 Calcium Channel  Cardiac calcium channels L-type calcium channelL-type calcium channel ryanodine (RyR2) calcium channelryanodine (RyR2) calcium channel  located on the sarcoplasmic reticulum  Critical for: conduction velocity (AV node)conduction velocity (AV node) duration of depolarizationduration of depolarization cardiac muscle contractioncardiac muscle contraction

30 Ca 2+ Channel Antagonists  Block the L-type calcium channel negative inotropy in cardiac musclenegative inotropy in cardiac muscle  decrease available intracellular Ca 2+ negative chronotropy in pacemaker cellsnegative chronotropy in pacemaker cells negative dromotropy at the AV nodenegative dromotropy at the AV node relaxation of vascular smooth musclerelaxation of vascular smooth muscle  decreased afterload  decreased systemic blood pressure  increased coronary vascular dilatation

31  Phentylalkylamines e.g. verapamile.g. verapamil  Benzothiazepines e.g. diltiazeme.g. diltiazem  Dihydropyridines e.g. nifedipinee.g. nifedipine  Diarylaminopropylethers e.g. bepridile.g. bepridil  Tetralene Derivatives e.g. mibefradile.g. mibefradil Ca 2+ Channel Antagonists

32  Overdose of CCB extension of therapeutic effectsextension of therapeutic effects  Lose their selectivity (mostly) Negative inotropy (bradycardia)Negative inotropy (bradycardia) Negative chronotropy (hypotension)Negative chronotropy (hypotension) Vasodilation (hypotension)Vasodilation (hypotension) Negative dromotropy (AV blocks, brady)Negative dromotropy (AV blocks, brady) +/- hyperglycemia (depressed insulin)+/- hyperglycemia (depressed insulin) Ca 2+ Channel Antagonists CCB = calcium channel blocker

33 β-Adrenergic Antagonists

34 β-Adrenergic Receptors  There are 3 known subtypes of β- adrenergic receptors, namely β 1, β 2 & β 3.  The human heart has predominantly β 1 receptors β 2 & β 3 exist in ‘small’ quantitiesβ 2 & β 3 exist in ‘small’ quantities

35 β-Adrenergic Receptors  Stimulation on β 1 receptors increases heart rateincreases heart rate increases contractilityincreases contractility increases conduction velocityincreases conduction velocity increases automaticityincreases automaticity  The effect of adrenergic agents on the heart is mediated through a secondary messenger – cAMP

36 β-Adrenergic Receptors  Intracellular cAMP concentrations are regulated by 3 components: adrenergic receptor on the cell surfaceadrenergic receptor on the cell surface a “G-protein” complexa “G-protein” complex adenyl cyclase – enzyme synth. cAMPadenyl cyclase – enzyme synth. cAMP  cAMP acts as a secondary messenger interacts with protein kinase A to increase phosphorylating activityinteracts with protein kinase A to increase phosphorylating activity

37 β-Adrenergic Receptors  Protein kinases transfer a phosphate group from ATP to serine  Thereby, phosphorylating various cellular proteins phospholamban ( activity)phospholamban ( activity) troponin ( activity)troponin ( activity) L-type calcium channels ( activity)L-type calcium channels ( activity)

38 β-Adrenergic Receptors Bers DM. Cardiac excitation-contraction coupling. Nature ;

39 β-Adrenergic Antagonists  β-Adrenergic antagonists effects similar to blockade of L-type calcium channeleffects similar to blockade of L-type calcium channel  Clinical effects decrease contraction (hypotension)decrease contraction (hypotension) decrease chronotropy (bradycardia)decrease chronotropy (bradycardia) decrease dromotropy (AV blocks, brady)decrease dromotropy (AV blocks, brady)

40 β-Adrenergic Antagonists  Extra-cardiac signs of toxicity neurological disturbancesneurological disturbances  drowsiness, non-agitated coma dilated pupilsdilated pupils respiratory depressionrespiratory depression  Treatment of toxicity is based on: stimulation of glucagon receptorstimulation of glucagon receptor restoring intracellular Ca 2+ storesrestoring intracellular Ca 2+ stores

41 Overdose Management

42  Decontamination Emesis not recommendedEmesis not recommended Activated charcoal should be consideredActivated charcoal should be considered Gastric lavage with Fr tubeGastric lavage with Fr tube  contraindicated in patients w/ bradycardia  consider particularly in patients a/ SR preps Whole bowel irrigationWhole bowel irrigation  particularly a/ SR preps Overdose Management

43  Atropine Adult: 0.5 – 1.0 mg IVP (max 3 mg)Adult: 0.5 – 1.0 mg IVP (max 3 mg) Children: 0.02 mg/kg IVPChildren: 0.02 mg/kg IVP given every 2 – 3 minutesgiven every 2 – 3 minutes  Should be held in patients getting WBI because of anticholinergic effects Overdose Management

44  Calcium salts increases extracellular Ca 2+increases extracellular Ca 2+ calcium gluconate: 1 gm = 4.3 mEqcalcium gluconate: 1 gm = 4.3 mEq calcium chloride: 1 gm = 13.4 mEqcalcium chloride: 1 gm = 13.4 mEq  Dose 10 – 20 mL of 10% CaCl 210 – 20 mL of 10% CaCl 2 30 – 60 mL of 10% Ca gluconate30 – 60 mL of 10% Ca gluconate Overdose Management

45  Dose (cont’d) effect is transient, redose q15 – 20 minseffect is transient, redose q15 – 20 mins in adults, can give 50 mL of 10% CaCl 2 (5 gm) before having to check a Ca 2+ serum concentrationin adults, can give 50 mL of 10% CaCl 2 (5 gm) before having to check a Ca 2+ serum concentration (i.e. 150 mL of 10% Ca gluconate)(i.e. 150 mL of 10% Ca gluconate) CaCl 2 is causes sclerosis of peripheral veins and should be given centrallyCaCl 2 is causes sclerosis of peripheral veins and should be given centrally Overdose Management

46  Glucagon activates adenyl cyclase directly via glucagon receptoractivates adenyl cyclase directly via glucagon receptor adult dose: 2-5 mg slowly IVadult dose: 2-5 mg slowly IV can be repeated every 5-10 minutescan be repeated every 5-10 minutes total dose should not exceed 10 mgtotal dose should not exceed 10 mg follow bolus with an infusion of the dose that produced an effectfollow bolus with an infusion of the dose that produced an effect Overdose Management

47  Catecholeamines attempt to competitively antagonize β- adrenergic antagonist at the receptorattempt to competitively antagonize β- adrenergic antagonist at the receptor no convincing evidenceno convincing evidence chance of stimulating other receptors in the required dose to produce competive displacementchance of stimulating other receptors in the required dose to produce competive displacement if one is used – norepinephrine is probably the best choiceif one is used – norepinephrine is probably the best choice Overdose Management

48  Insulin & Glucose growing evidence that used correctly, this increases inotropy and chronotropygrowing evidence that used correctly, this increases inotropy and chronotropy theory: improved Ca2+ entry & improved myocardial carbohydrate usetheory: improved Ca2+ entry & improved myocardial carbohydrate use Dose: 0.5 – 1 Unit/kg/hr regular insulinDose: 0.5 – 1 Unit/kg/hr regular insulin give 0.5 gm/kg/hr dextrose (glu > 100)give 0.5 gm/kg/hr dextrose (glu > 100) check glucose every 30 mins initiallycheck glucose every 30 mins initially Overdose Management

49  Amrinone inhibits breakdown of cAMP by phosphodiasterase IIIinhibits breakdown of cAMP by phosphodiasterase III thereby increasing intracellular [] of cAMPthereby increasing intracellular [] of cAMP this increases inotropy and chronotropythis increases inotropy and chronotropy BUT, causes vasodilation & hypotensionBUT, causes vasodilation & hypotension should be used with a vasopressorshould be used with a vasopressor Overdose Management

50 Cardiac glycosides (digoxin)

51 Therapeutic  Digoxin inhibits Na + / K + -ATPase  This increases cytosolic Ca 2+ which increases inotropy.  Therapeutically: digoxin increases automaticitydigoxin increases automaticity shortens the repolarization intervals of the atria and ventriclesshortens the repolarization intervals of the atria and ventricles

52 Therapeutic  Decreases depolarization & conduction through the SA and AV nodes.  These changes are reflected on ECG by: decrease in ventricular response ratedecrease in ventricular response rate PR interval prolongationPR interval prolongation QT interval shorteningQT interval shortening ST segment & T-wave opposite major QRS forcesST segment & T-wave opposite major QRS forces  scooped ST segment  Both these effects result in the characteristic “digitalis effect”

53 Therapeutic  Some characteristic signs of digoxin therapy and toxicity. Digitalis effect Atrial flutter with PVC

54 Clinical Toxicity

55 Toxicologic  Effects mirror its therapeutic actions. BradydysrhythmiasBradydysrhythmias  (from increased VAGAL TONE) Ventricular tachydysrhythmiasVentricular tachydysrhythmias  (from myocardial “irritability”) Rapid atrial rhythms with slow ventricular responseRapid atrial rhythms with slow ventricular response  (slowed AV conduction)

56 3 Na + 2 K + Cell Electrophysiology SR (Mitochondria) Ca 2+ Phase 2 Ca 2+ 3 Na + Ca 2+

57 3 [Na + ] 2 [K + ] Therapeutic & Toxic MoA SR (Mitochondria) Ca 2+ Phase 2 Ca 2+ = Digoxin Ca 2+ Digoxin Na + K+

58 Signs of Toxicity  Metabolic Acute: Hyperkalemia is a marker for severe poisoningAcute: Hyperkalemia is a marker for severe poisoning  Due to blockade of Na+/K+ ATPase  Increases AV blockade and worsens bradydysrhythmias Chronic: Hypokalemia predisposes the patient to dysrhythmias at lower digoxin levelsChronic: Hypokalemia predisposes the patient to dysrhythmias at lower digoxin levels  Higher resting potential increases automaticity

59 Signs of Toxicity  Cardiac Acute or chronicAcute or chronic  Increased automaticity with high-degree AV block  Any dysrhythmia possible….. … EXCEPT a rapidly conducted supraventricular rhythm.

60 Electrocardiogram  PVCs (most common dysrhythmia)  Classic ECG findings: Bidirectional ventricular tachycardiaBidirectional ventricular tachycardia Atrial tachycardia with variable or slow ventricular responseAtrial tachycardia with variable or slow ventricular response Accelerated junctional rhythmsAccelerated junctional rhythms

61 Overdose Management

62 Management of Toxicity  The main goal of treatment is to correct cardiac toxicity.  Treatment of cardiac toxicity usually leads to resolution of CNS and GI symptoms.

63 Treatment  Decontamination Activated charcoal (AC)Activated charcoal (AC)  Adsorbs digoxin well  Decrease absorption  ‘Gut dialysis’  [Boldy DA. et al. 1985, de Silva HA. et al. 2003, Ibanez C. et al. 1995] Multi-dose ACMulti-dose AC  Renal failure  Yellow oleander poisoning

64 Treatment  Dysrhythmias Tachy-Tachy-  Replace K + or Mg ++  Consider Class IB & III antidysrhythmics amiodarone, lidocaine or phenytoin for ventricular dysrhythmiasamiodarone, lidocaine or phenytoin for ventricular dysrhythmias  AVOID Class IA, IC, II and IV antidysrhythmics particularly procainamide and quinidineparticularly procainamide and quinidine  AVOID cardioversion in TOXICITY Brady-Brady-  Atropine  AVOID transvenous/internal pacing

65 Management of Toxicity  GI decontamination Decrease absorptionDecrease absorption ‘Gut dialysis’‘Gut dialysis’ [Boldy DA. et al. 1985, de Silva HA. et al. 2003, Ibanez C. et al. 1995][Boldy DA. et al. 1985, de Silva HA. et al. 2003, Ibanez C. et al. 1995]  Atropine  Correct electrolyte abnormalities  Consider lidocaine or phenytoin for control of dysrhythmias (if definitive therapy unavailable)for control of dysrhythmias (if definitive therapy unavailable)

66 Indications for digoxin-Fab  Symptomatic bradydysrhythmias  Ventricular dysrhythmias  Acute digoxin toxicity & [K + ] >5 mEq/L >5 mEq/L>5 mEq/L  Ingestion >4 mg - child (or 0.1 mg/kg)  Ingestion >10 mg - healthy adult  SDC of ≥10 ng/mL steady state 4-6 hours after ingestion4-6 hours after ingestion  SDC of ≥15 ng/mL at any time

67 Chronic Digoxin Toxicity  More common and more controversial  No absolute indication based on serum concentration  Administer digoxin-Fab if ECG evidence of digoxin toxicityECG evidence of digoxin toxicity Unable to tolerate symptoms of toxicityUnable to tolerate symptoms of toxicity Unable to clear digoxin (BUN/Creat)Unable to clear digoxin (BUN/Creat)

68 Management Empiric Therapy  Acute toxicity: Adults: 10 – 20 vialsAdults: 10 – 20 vials Children: 10 – 20 vialsChildren: 10 – 20 vials  Chronic toxicity: Adults: 3 – 6 vialsAdults: 3 – 6 vials Children: 1 – 2 vialsChildren: 1 – 2 vials ** Should be administered IV over 30 minutes via a 0.22-micron membrane filter.via a 0.22-micron membrane filter. ** Can be given as an IV bolus in a critically ill patient (per manufacturer).(per manufacturer).

69 Management # of vials = amt ingested (mg) x Ingested Dose Known # of vials = SDC (ng/mL) x pt wgt (kg) 100 Serum Drug Concentration (SDC) Known

70 Things Not To Do!!  Calcium “stone heart” in animal models“stone heart” in animal models  Transvenous pacing Taboulet et al. 1993Taboulet et al failure rate of 23% and a 17% mortalityfailure rate of 23% and a 17% mortality increased risk of dysrhythmic deathincreased risk of dysrhythmic death

71 Case Review

72 Case #1  45-year old woman PMHx s/f depression presents to the ED after allegedly ingesting all of her anti-HTN medication.  Prescription filled 3 days prior for 30 tablets of diltiazem CD 240 mg.  Patient alert & oriented, mildly diaphoretic and complaining of generalized weakness.

73 Case #1  Vital signs: BP: 76/36, HR: 46, RR: 14, Temp: 98.6BP: 76/36, HR: 46, RR: 14, Temp: 98.6 pOx: 100% RA, AccuChk: 154pOx: 100% RA, AccuChk: 154  Rest of physical examination is benign.  Patient placed on a cardiac monitor, O 2 via nasal cannular and IV access established.

74 Case #1  What is the next step in her management?

75 Case #3  An 86-year old woman presents with increased confusion and vomiting.  Per family, she complained of increasing weakness, nausea and decreased appetite over the last 3 days.  She has barely kept any of her medications down, and has not been eating.

76 Case #3  PMHx: hypertensionhypertension congestive heart failure (CHF)congestive heart failure (CHF) diabetes mellitusdiabetes mellitus  Medications: hydrochlorothiazidehydrochlorothiazide digoxindigoxin furosemidefurosemide enteric-coated aspirinenteric-coated aspirin metforminmetformin

77 Case #3  In the hospital, she is alert, but oriented only to person.  Vital signs are normal, except for a heart rate of 46 beats/minute. She weighs 143 lbs (65 kg).  Her physical examination demonstrates: bibasilar rales, irregular S1, S2 with an S3 gallopbibasilar rales, irregular S1, S2 with an S3 gallop bilateral lower extremity 2+ pitting edema up to her shinsbilateral lower extremity 2+ pitting edema up to her shins

78 Case #3  ECG: atrial flutter with variable blockatrial flutter with variable block ventricular rate of beats/minute with occasional premature ventricular contractions (PVCs).ventricular rate of beats/minute with occasional premature ventricular contractions (PVCs).  Laboratory results were within limits except: potassium mEq/Lpotassium mEq/L creatinine mg/dLcreatinine mg/dL glucose mg/dLglucose mg/dL  Initial digoxin serum concentration (SDC): 3.4 ng/mL (> 6 hours since last dose).3.4 ng/mL (> 6 hours since last dose).

79 Case #3  What is the next step in her management?

80 Digoxin-Fab Dose  Always round UP whatever answer you get. # of vials = SDC (ng/mL) x pt wgt (kg) 100 Serum Drug Concentration (SDC) Known = 2.21 vials 3.4 ng/mL x 65 kg 100 ≈ 3 vials

81 Case #3  The patient is given 3-vials of digoxin specific antibody fragments (digoxin-Fab).  About 60 minutes after therapy: her heart rate improved to 85 beats/minuteher heart rate improved to 85 beats/minute blood pressure remained stableblood pressure remained stable her ECG demonstratedher ECG demonstrated  rate-controlled atrial fibrillation with no ectopy Her serum potassium concentration had also improvedHer serum potassium concentration had also improved

82 Questions?


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