Toxic Toxic Bradycardia Bradycardia

and and HypotensionHypotension

Alyssa Reed, R1Alyssa Reed, R1

Thanks to Dr Mark Yarema

CASECASE

It is 330 am when the paramedics patch to It is 330 am when the paramedics patch to tell you they are on scene with a man who tell you they are on scene with a man who has a pulse of 45 and SBP of 80has a pulse of 45 and SBP of 80

What medical conditions could cause this? What medical conditions could cause this?

Medical Causes of Medical Causes of BradycardiaBradycardia

MIMI

Sick Sinus SyndromeSick Sinus Syndrome

HyperkalemiaHyperkalemia

HypothermiaHypothermia

Increased ICPIncreased ICP

VasovagalVasovagal

Physiologic (athletes)Physiologic (athletes)

CASE CONTINUED…CASE CONTINUED…

The patient arrives. Vitals are unchanged The patient arrives. Vitals are unchanged after 2L N/S and 2 mg of atropine. He is after 2L N/S and 2 mg of atropine. He is obtunded but breathing spontaneously. His obtunded but breathing spontaneously. His wife says he has a history or atrial wife says he has a history or atrial fibrillation, angina, hypertension and fibrillation, angina, hypertension and depression. The paramedics found a lot of depression. The paramedics found a lot of pill bottles beside him and suspect an pill bottles beside him and suspect an overdose. They left the bottles behind. overdose. They left the bottles behind.

What medications cause bradycardia?What medications cause bradycardia?

TOXIC BRADYCARDIATOXIC BRADYCARDIA Beta BlockersBeta Blockers

Calcium Channel BlockersCalcium Channel Blockers

Cardiac glycosides (digoxin)Cardiac glycosides (digoxin)

Cholinergic agents Cholinergic agents

Clonidine/Imidazolines (alpha2 agonists)Clonidine/Imidazolines (alpha2 agonists)

Opioids/Sedative HypnoticsOpioids/Sedative Hypnotics

Phenylpropanolamine (alpha1 agonists)Phenylpropanolamine (alpha1 agonists)

Sodium channel blockersSodium channel blockers

Can we eliminate any of these based on clinical presentation? Can we eliminate any of these based on clinical presentation?

TOXIC BRADYCARDIATOXIC BRADYCARDIA

Beta BlockersBeta Blockers

Calcium Channel BlockersCalcium Channel Blockers

Cardiac glycosides (digoxin)Cardiac glycosides (digoxin)

Cholinergic agents Cholinergic agents

Clonidine/Imidazolines (alpha2 agonists)Clonidine/Imidazolines (alpha2 agonists)

Opioids/Sedative HypnoticsOpioids/Sedative Hypnotics

Phenylpropanolamine (alpha1 agonists)Phenylpropanolamine (alpha1 agonists)

Sodium channel blockersSodium channel blockers

THE “BIG FOUR”THE “BIG FOUR”

Beta BlockersBeta Blockers

Calcium Channel BlockersCalcium Channel Blockers

Cardiac GlycosidesCardiac Glycosides

Sodium Channel BlockersSodium Channel Blockers

IntroductionIntroduction

Maybe put in some physiology and table Maybe put in some physiology and table 17.11 page 393 of lilly17.11 page 393 of lilly

CASECASE

40M brought by EMS after an OD. Drug 40M brought by EMS after an OD. Drug unknown. Pulse is 50 and SBP is 90.unknown. Pulse is 50 and SBP is 90.

Which of the four do you think is most likely Which of the four do you think is most likely responsible? responsible?

Na Channel BlockersNa Channel Blockers

Class IA Class IA AntiarrhythmicsAntiarrhythmics• QuinidineQuinidine• ProcainamideProcainamide• DisopyramideDisopyramide

Class IC Class IC AntiarrhythmicsAntiarrhythmics• FlecainideFlecainide• PropafenonePropafenone

CocaineCocaine

TCAsTCAs Diltiazem/Diltiazem/

VerapamilVerapamil PropranololPropranolol CarbamazepineCarbamazepine

PresentationPresentation

QRS wideningQRS widening

HypotensionHypotension

SeizuresSeizures

Altered Mental StatusAltered Mental StatusMembrane Stabilizing ActivityMembrane Stabilizing ActivityDecreased perfusionDecreased perfusion

ManagementManagement

Sodium BicarbonateSodium Bicarbonate 50ml = 50mEq = 1ampule50ml = 50mEq = 1ampule IndicationsIndications

11 QRS > 100msQRS > 100ms

22 Persistent hypotension despite adequate Persistent hypotension despite adequate fluid resusfluid resus

33 DysrhythmiasDysrhythmias DosingDosing• Bolus 3 ampsBolus 3 amps• 3 amps in a bag of D5W and infuse and 3 amps in a bag of D5W and infuse and

2-3x maintenance2-3x maintenance

Hypertonic SalineHypertonic Saline

CASECASE

A 55M is brought in by the paramedics with A 55M is brought in by the paramedics with a pulse of 40 and SBP of 78. His BG is 18. He a pulse of 40 and SBP of 78. His BG is 18. He is AOx3.is AOx3.

He has a history of “heart problems” and no He has a history of “heart problems” and no other medical historyother medical history

K 4.0 K 4.0

Which of the “big four” is likely responsible? (see Which of the “big four” is likely responsible? (see next ECG to help eliminate)next ECG to help eliminate)

Put in ECG that is slow and narrowPut in ECG that is slow and narrow

Beta Blockers Calcium Channel Blockers

Vitals HypotensiveBradycardic

HypotensiveBradycardicTachycardic

Mental Status Depressed Preserved

Blood Glucose Low-Normal High

Calcium Channel Calcium Channel BlockersBlockers

All block L-type calcium channelsAll block L-type calcium channels Heart*Heart*• Contractile TissueContractile Tissue• Pacemaker cellsPacemaker cells

Vascular Smooth Muscle*Vascular Smooth Muscle* Endocrine (including beta pancreatic Endocrine (including beta pancreatic

cells)cells) RetinaRetina Skeletal muscleSkeletal muscle

Put in a pic of the channels and Put in a pic of the channels and depolarizationdepolarization

1) Myocyte depolzn triggers opening of LTCC

2) Causes release of stored Ca from SR

3) Contract

Calcium Channel Calcium Channel BlockersBlockers

2 Major Clasess2 Major Clasess DihydropyridinesDihydropyridines• Preferentially block L-type calcium Preferentially block L-type calcium

channels in the vasculaturechannels in the vasculature• Potent vasodilators with little negative Potent vasodilators with little negative

effect upon cardiac contractillity or effect upon cardiac contractillity or conductionconduction

Non-dihydropyridinesNon-dihydropyridines• Preferentially block L-type calcium Preferentially block L-type calcium

channels in the myocardiumchannels in the myocardium• Negative inotropic effects and decrease Negative inotropic effects and decrease

AV node conductionAV node conduction

Q: Why is brady not listed as complication of the dihydropyridines?

CCB OD PresentationCCB OD Presentation HypotensionHypotension

Bradydysrhythmias (or reflex tachycardia)Bradydysrhythmias (or reflex tachycardia)

Normal mental statusNormal mental status

HyperglycemiaHyperglycemia disruption of fatty acid metabolism creating disruption of fatty acid metabolism creating

relative insulin resistance and decreased relative insulin resistance and decreased release of insulin from β panc cellsrelease of insulin from β panc cells

Pulmonary EdemaPulmonary Edema Heart failure + vasodilation and extravasationHeart failure + vasodilation and extravasation

IleusIleus Decreased smooth muscle function in bowelDecreased smooth muscle function in bowel

CCB OD DxCCB OD Dx

No urine or serum test readily availableNo urine or serum test readily available

ECGECG

CXRCXR

Lytes (including Ca, Mg)Lytes (including Ca, Mg)

Blood GlucoseBlood Glucose

ABGABG

What are some of the ECG findings/rhythms in CCB OD?

CCB OD and the ECGCCB OD and the ECG

BradysrhythmiasBradysrhythmias• AV block of all degreesAV block of all degrees• Sinus arrestSinus arrest• AV dissociationAV dissociation• Junctional rhythmJunctional rhythm• AsystoleAsystole

Reflex Sinus TachReflex Sinus Tach• Nifedipine ODNifedipine OD

OD General ApproachOD General Approach

1.1. ABCsABCs

2.2. GI DecontaminationGI Decontamination• Activated charcoal (50G in adult, 1g/kg in Activated charcoal (50G in adult, 1g/kg in

peds)peds)• Gastric LavageGastric Lavage• Whole Bowel Irrigation (polyethylene Whole Bowel Irrigation (polyethylene

glycol 2L/hr adults, 500cc/hr peds)glycol 2L/hr adults, 500cc/hr peds)

3.3. Enhanced EliminationEnhanced Elimination• HemodialysisHemodialysis

4.4. AntidotesAntidotes

5.5. Supportive careSupportive care

CCB OD MxCCB OD Mx

HYPOTENSIONHYPOTENSION• Fluids Fluids • CalciumCalcium• GlucagonGlucagon• PressorsPressors

BRADYCARDIABRADYCARDIA• AtropineAtropine• CalciumCalcium• GlucagonGlucagon• PacerPacer

AtropineAtropine

Given routinely to symptomatic Given routinely to symptomatic bradycardic patientsbradycardic patients

Often ineffectiveOften ineffective

AdultsAdults: 0.5-1 mg IV Q3min to a max : 0.5-1 mg IV Q3min to a max of 3mgof 3mg

PedsPeds: 0.02mg/kg IV with a min dose : 0.02mg/kg IV with a min dose of 0.1mg and a max of 1mg of 0.1mg and a max of 1mg

Calcium Calcium

CALCIUM CHLORIDECALCIUM CHLORIDE• 10% solution10% solution• 1g/10ml1g/10ml• 1g = 13.6 mEq1g = 13.6 mEq• Central lineCentral line• DoseDose: 1g over 10 : 1g over 10

min (10cc) Q15 to min (10cc) Q15 to a max of 6 g and a max of 6 g and can infuse 1-2g/hr can infuse 1-2g/hr if responsiveif responsive

CALCIUM CALCIUM GLUCONATEGLUCONATE• 10% solution10% solution• 1g/10ml1g/10ml• 1g = 4.5 mEq1g = 4.5 mEq• Peripheral linePeripheral line• DoseDose: 3g (30cc) : 3g (30cc)

over 10 minover 10 min

GlucagonGlucagon Increases intracellular levels of cAMPIncreases intracellular levels of cAMP• Opens Ca channelsOpens Ca channels

Animal modelsAnimal models• increase in heart rateincrease in heart rate• Little effect on MAPLittle effect on MAP

Bolus: 5mg over 1-2 min, to max of 15mg Bolus: 5mg over 1-2 min, to max of 15mg (this is diluted in 10cc N/S)(this is diluted in 10cc N/S)

Maintenance: infusion of response dose Maintenance: infusion of response dose mg/hrmg/hr

Vomiting and aspiration riskVomiting and aspiration risk

Phenol toxicity Phenol toxicity

ATP cAMP

Gs

GlucagonGlucagon

Phosphodiesterase

AMP

Amrinone

GlucagonCatecholaminepressors

PressorsPressors

Q: What would be the ideal properties of a pressor in CCB Q: What would be the ideal properties of a pressor in CCB tox? tox?

A: Direct-acting agent with +chronotropy, inotropy, A: Direct-acting agent with +chronotropy, inotropy, and vasoconstrictive effectsand vasoconstrictive effects

Q: What would you use? Q: What would you use?

A: Norepinenphrine is initial choice A: Norepinenphrine is initial choice

Dopamine not because indirect effects and little Dopamine not because indirect effects and little alpha alpha

Can increase pulmonary edema and ischemic Can increase pulmonary edema and ischemic vascular dz and renal failure vascular dz and renal failure

Insulin and GlucoseInsulin and Glucose CJEM 2006 Prediger and YaremaCJEM 2006 Prediger and Yarema

Systematic review of 13 papersSystematic review of 13 papers 20 cases of CCB OD (17 adult, 3 pediatric)20 cases of CCB OD (17 adult, 3 pediatric) Most effective at treating hypotension Most effective at treating hypotension

(n=15)(n=15) 3 patients converted to sinus from AV block3 patients converted to sinus from AV block Dosing and length of treatment varied Dosing and length of treatment varied

widelywidely AE: asymptomatic hypoglycemia AE: asymptomatic hypoglycemia

(n=8),hypokalemia (n=4)(n=8),hypokalemia (n=4) Conclusion: HDIG is safe and effective Conclusion: HDIG is safe and effective

treatment of CCB overdose treatment of CCB overdose

Insulin and Glucose Insulin and Glucose

The heart usually metabolizes free fatty acids The heart usually metabolizes free fatty acids but in shock state it needs glucosebut in shock state it needs glucose

In CCB OD cardiac glucose uptake is impaired In CCB OD cardiac glucose uptake is impaired b/cb/c1.1. Decreased insulin release (calcium mediated)Decreased insulin release (calcium mediated)

2.2. CCB toxicity induces a state of insulin CCB toxicity induces a state of insulin resistance (myocardium and rest of body)resistance (myocardium and rest of body)

3.3. Acidosis and low perfusion limits glycolysis and Acidosis and low perfusion limits glycolysis and carbohydrte delivery to the heart carbohydrte delivery to the heart

Insulin acts as a pressorInsulin acts as a pressor Improved glucose delivery and uptake to the Improved glucose delivery and uptake to the

heart and improving cardiac performanceheart and improving cardiac performance

Insulin and GlucoseInsulin and Glucose Disrupt state of carbohydrate dependence Disrupt state of carbohydrate dependence

and insulin resistance and insulin resistance

Animal modelsAnimal models• Improved survival with Improved survival with

hyperinsulinemia/euglycemia compared to hyperinsulinemia/euglycemia compared to calcium, pressors and glucagoncalcium, pressors and glucagon

• Positive inotropic effects Positive inotropic effects

Bolus: 0.1U/kg IV of regular insulin Bolus: 0.1U/kg IV of regular insulin

Infusion: 0.2-0.5 U/kg/hrInfusion: 0.2-0.5 U/kg/hr

Glucose: 25-50 g of dextrose at beginning or Glucose: 25-50 g of dextrose at beginning or can infuse at 0.5 g/kg/hr can infuse at 0.5 g/kg/hr

Other TherapiesOther Therapies Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors• Amrinone , milrinoneAmrinone , milrinone• Increase cAMP by preventing degradation Increase cAMP by preventing degradation

of it by phosphodiesterase enzymeof it by phosphodiesterase enzyme• May exacerbate hypotensionMay exacerbate hypotension• ICU setting with pulmonary artery ICU setting with pulmonary artery

cathetercatheter

Sodium BicarbonateSodium Bicarbonate• Prolonged QRS or lactic acidosisProlonged QRS or lactic acidosis• 1amp= 50mEq1amp= 50mEq• Put 3 amps in 1L D5W and infuse and Put 3 amps in 1L D5W and infuse and

two times maintenancetwo times maintenance

Invasive MxInvasive Mx

Transvenous pacingTransvenous pacing• Does not counteract negative Does not counteract negative

inotropic effectsinotropic effects• Successful capture may not Successful capture may not

correct hypotensioncorrect hypotension

Intraaortic balloon pumpIntraaortic balloon pump

Cardiopulmonary bypassCardiopulmonary bypass

SummarySummary Block L-type channelsBlock L-type channels• Vascular smooth muscleVascular smooth muscle• Cardiac muscle cells and pacemaker cellsCardiac muscle cells and pacemaker cells

Hypotension, brady or tachy, preserved Hypotension, brady or tachy, preserved mental status, hyperglycemicmental status, hyperglycemic

MxMx• Early WBIEarly WBI• Fluids/atropineFluids/atropine• CalciumCalcium• GlucagonGlucagon• PressorsPressors• Insulin and glucoseInsulin and glucose

CASECASE

50F brought in by EMS. Patient is altered. 50F brought in by EMS. Patient is altered. T= 37, P= 50, RR= 12, SBP= 74, O2=90%RA, T= 37, P= 50, RR= 12, SBP= 74, O2=90%RA, BG 3.5BG 3.5

Hx of “heart problems” and hypertensionHx of “heart problems” and hypertension

Which of the big four do you suspect? Which of the big four do you suspect?

Beta ReceptorsBeta ReceptorsBeta 1Beta 1

Primarily in the heartPrimarily in the heart Increase 1) heart rate, 2) contractility, and Increase 1) heart rate, 2) contractility, and

3) AV conduction3) AV conduction Decrease AV node refractoriness Decrease AV node refractoriness

Beta 2Beta 2 Primarily in bronchial and peripheral Primarily in bronchial and peripheral

smooth musclesmooth muscle Also in liver, uterus, heartAlso in liver, uterus, heart Vasodilation, bronchodilation, Vasodilation, bronchodilation,

gluconeogenesis, glycogenolysis gluconeogenesis, glycogenolysis Beta 3Beta 3

Adipose tissue and heartAdipose tissue and heart Thermogenesis Thermogenesis

Beta BlockersBeta Blockers

Structurally resemble isoproterenol (pure β Structurally resemble isoproterenol (pure β agonist)agonist)

Competitively inhibit endogenous Competitively inhibit endogenous catecholamines (ex. Epinephrine) at the B-catecholamines (ex. Epinephrine) at the B-receptorreceptor

These catecholamines normally bind to the These catecholamines normally bind to the receptor and result in activation of adenyl receptor and result in activation of adenyl cyclase, resulting in cAMPcyclase, resulting in cAMP

cAMP augments:cAMP augments:1.1. InotropyInotropy (myocardial contraction) (myocardial contraction)

2.2. DromotropyDromotropy (cardiac conduction) (cardiac conduction)

3.3. Chronotropy Chronotropy (heart rate)(heart rate)

How would you expect the patient to present?

Clinical PresentationClinical Presentation

BradycardiaBradycardia HypotensionHypotension UnconsciousnessUnconsciousness Respiratory Respiratory

arrest or arrest or insufficiencyinsufficiency

Hypoglycemia Hypoglycemia (uncommon in (uncommon in adults)adults)

Seizures (esp. Seizures (esp. propranolol)propranolol)

Symptomatic Symptomatic BronchospasmBronchospasm

VT or VFVT or VF Mild hyperK Mild hyperK

Rosen’s Table 150-8

βB PropertiesβB Properties

1.1. Membrane-Stabilizing Activity (MSA)Membrane-Stabilizing Activity (MSA)• Inhibition of myocardial fast sodium channelsInhibition of myocardial fast sodium channels• Can result in wide QRS and other Can result in wide QRS and other

dysrhythmiasdysrhythmias

2.2. LipophilicityLipophilicity• High lipid solubility= rapidly cross BBBHigh lipid solubility= rapidly cross BBB• Cause altered LOC (independent of Cause altered LOC (independent of

hypoperfusion)hypoperfusion)

3.3. Intrinsic Sympathomimetic Activity (ISA)Intrinsic Sympathomimetic Activity (ISA) Partial agonist effect at beta receptor sitePartial agonist effect at beta receptor site Cause less bradycardia and hypotension Cause less bradycardia and hypotension DO NOT completely protect DO NOT completely protect

Noncardioselective βBNoncardioselective βB

MSA Lipophilic ISA ½ life (hr) Comments

Propranolol ++ + - 4 Most deaths

Nadolol - - - 10-20 Dialyzable

Labetalol + - - 4-6 α blocker too

Sotalol - + - 7-18 Class III/II

Rosen’s Table 150-3

Cardioselective βBCardioselective βB

MSE Lipohilic ISA ½ life (hr) Comments

Metoprolol - + - 3-4

Atenolol - - - 5-8 Dialyzable

Esmolol - - - 0.13

Acebutolol ++ + + 2-4 QT long

Rosen’s Table 150-3

βB OD and the ECGβB OD and the ECG

Increased PR Increased PR from decreased from decreased conduction velocity down AV nodeconduction velocity down AV node

BradycardiaBradycardia from decreased from decreased automaticity within SA nodeautomaticity within SA node

Ventricular tachydysrhythmiasVentricular tachydysrhythmias with with MSA βBMSA βB

Wide QRS Wide QRS with MSA βBwith MSA βB

QT prolongation QT prolongation with sotalol ODwith sotalol OD

Which beta blocker might Which beta blocker might cause this dysrhythmia?cause this dysrhythmia?

βB OD MxβB OD Mx

HYPOTENSIONHYPOTENSION• FluidsFluids• GlucagonGlucagon• EpinephrineEpinephrine• IsoproterenolIsoproterenol

BRADYCARDIA*BRADYCARDIA*• AtropineAtropine• GlucagonGlucagon• PacemakerPacemaker• EpinephrineEpinephrine• IsoproterenolIsoproterenol

* Only tx if third degree block or symptomatic

AtropineAtropine

Symptomatic bradycardia onlySymptomatic bradycardia only

Adults: O.5-1mg IV to a max of 3mgAdults: O.5-1mg IV to a max of 3mg

Peds: 0.02mg/kg with a min of 0.1mg Peds: 0.02mg/kg with a min of 0.1mg and max of 1mgand max of 1mg

Poor effect on improving bradycardia Poor effect on improving bradycardia and hypotension and hypotension

GlucagonGlucagon

Remember glucagon activates adenylate Remember glucagon activates adenylate cyclase at a site independent from beta-cyclase at a site independent from beta-adrenergic sitesadrenergic sites• Increases cAMP= increases intracellular Increases cAMP= increases intracellular

Ca= increasing contractility Ca= increasing contractility

Considered first line (“antidotal”) Considered first line (“antidotal”)

DoseDose• 2-5mg (50mcg/kg in peds) diluted in 2-5mg (50mcg/kg in peds) diluted in

10cc N/S over 1-2 min to a max of 15mg10cc N/S over 1-2 min to a max of 15mg• Maintenance: response dose in mg/hrMaintenance: response dose in mg/hr

ATP cAMP

Gs

Beta blocker Beta blocker “antidotes” “antidotes”

Phosphodiesterase

AMP

Amrinone

GlucagonCatecholaminepressors

InsulinInsulin

Animal models show promiseAnimal models show promise• Improved cardio and hemodynamic Improved cardio and hemodynamic

parameters and decreased mortalityparameters and decreased mortality

No definite dosing regimenNo definite dosing regimen• Regular insulin infusion starting at Regular insulin infusion starting at

0.1U/kg/hr combined with glucose at 0.1U/kg/hr combined with glucose at 1g/kg/hr1g/kg/hr

• Check glucose levels every 30-60minCheck glucose levels every 30-60min• Less than in CCB OD (0.2-0.5U/kg/hr Less than in CCB OD (0.2-0.5U/kg/hr

after a bolus)after a bolus)

OthersOthers

CalciumCalcium• Shown to reverse hypotension in animal and Shown to reverse hypotension in animal and

human modelshuman models• Dosing: see CCB OD section (Calcium chloride Dosing: see CCB OD section (Calcium chloride

vs. gluconate) vs. gluconate)

PressorsPressors• Epinephrine and norepinephrine have both Epinephrine and norepinephrine have both

been used been used • Poor outcomesPoor outcomes

IsoproterenolIsoproterenol• Should be ideal because B1 and B2 agonist Should be ideal because B1 and B2 agonist

effectseffects• However, can worsen hypotensionHowever, can worsen hypotension

OthersOthers Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors• Inhibit breakdown of cAMP by Inhibit breakdown of cAMP by

phosphodiesterasesphosphodiesterases• Case reports onlyCase reports only• Use only after other therapies have failedUse only after other therapies have failed

Sodium BicarbonateSodium Bicarbonate• Safe adjunctSafe adjunct• Use if QRS wideUse if QRS wide• 1-2mEq/kg IV push1-2mEq/kg IV push

MagnesiumMagnesium• Ventricular arrhythmiasVentricular arrhythmias• Sotalol OD Sotalol OD

OthersOthers

Intravenous pacingIntravenous pacing• Profound bradycardiaProfound bradycardia• Frequently cannot captureFrequently cannot capture• Can increase heart rate without a Can increase heart rate without a

corresponding increase in perfusioncorresponding increase in perfusion

Intraaortic balloon pumpIntraaortic balloon pump• Successful case reports in failed Successful case reports in failed

pharmacological tx of propranolol and pharmacological tx of propranolol and atenolol ODatenolol OD

HemodialysisHemodialysis• Nadolol, sotalol, atenolol Nadolol, sotalol, atenolol

SummarySummary

BETA BLOCKER ODBETA BLOCKER OD

1. GI Decontamination1. GI Decontamination

2. Atropine/Fluids2. Atropine/Fluids

3. Glucagon3. Glucagon

4. Calcium4. Calcium

5. Insulin/Glucose5. Insulin/Glucose

6. Pressors (with 6. Pressors (with caution)caution)

7. Phosphodiesterase 7. Phosphodiesterase inhibitorsinhibitors

8. Invasive tx8. Invasive tx

CCB ODCCB OD

1. GI decontamination1. GI decontamination

2. Atropine/Fluids2. Atropine/Fluids

3. Calcium3. Calcium

4. Glucagon4. Glucagon

5. Insulin/glucose5. Insulin/glucose

6. Pressors (with 6. Pressors (with caution)caution)

7. Invasive tx7. Invasive tx

CASECASE

55M brought in by EMS. Pulse is 45, SBP is 55M brought in by EMS. Pulse is 45, SBP is 95. Patient complaint of nausea and 95. Patient complaint of nausea and vomiting for several days and difficulty vomiting for several days and difficulty seeing for the last day. seeing for the last day.

Hx: HTN, AfibHx: HTN, Afib

Vomiting and PVCsVomiting and PVCs

What did he likely take?

Cardiac GlycosidesCardiac Glycosides

Na-K ATPase Na-K ATPase InhhibitorsInhhibitors

DigoxinDigoxin, Digitoxin, Ouabain, Foxglove, Lilly , Digitoxin, Ouabain, Foxglove, Lilly of the valley, oleanderof the valley, oleander

2 desired effects of Digoxin2 desired effects of Digoxin

1.1. Improve the contractility of the failing heartImprove the contractility of the failing heart• By blocking the Na-K ATPase pump and By blocking the Na-K ATPase pump and

ultimately increasing intracellular Ca ultimately increasing intracellular Ca which increases the force of which increases the force of contractioncontraction

2.2. Prolong the refractory period of the AV node Prolong the refractory period of the AV node in pts with SVTin pts with SVT• By enhancing vagal tone and reducing By enhancing vagal tone and reducing

sympathetic activitysympathetic activity

Clinical PresentationClinical Presentation ACUTEACUTE

Few initial signs Few initial signs and symptomsand symptoms

Cardiac Cardiac instabilityinstability

HyperKHyperK

CHRONICCHRONIC FatigueFatigue VisionVision• Blurred visionBlurred vision• Color Color

disturbancesdisturbances GIGI• Abdo painAbdo pain• DiarrheaDiarrhea• Nausea/Nausea/

VomitingVomiting CNSCNS• HeadacheHeadache• DizzinessDizziness• ConfusionConfusion

* Usually preserve BP and not significantly hypotensive like βB and CCBs

DiagnosisDiagnosis

ECGECG

ElectrolytesElectrolytes

Serum digoxin levelSerum digoxin level Measure at least 6 hrs after last dose Measure at least 6 hrs after last dose

(time needed to reach steady state)(time needed to reach steady state) False + elevated levels (no SSx)False + elevated levels (no SSx)• Pregnant womenPregnant women• Chronic renal failure or hepatobiliary Chronic renal failure or hepatobiliary

dz dz False – normal levels (sig SSx) False – normal levels (sig SSx) • Foxglove or oleander ingestionFoxglove or oleander ingestion

Increased vagal tone.

Increased automaticity

Digoxin and the ECGDigoxin and the ECG

What are common digoxin toxic arrhythmias?

Dig Tox and the ECGDig Tox and the ECG

NONSPECIFICNONSPECIFIC PVCs PVCs 11st,st, 2 2ndnd (type 1), 3 (type 1), 3rdrd

degree AV blockdegree AV block Sinus bradycardiaSinus bradycardia Sinus tachycardiaSinus tachycardia Sinoatrial block or Sinoatrial block or

arrestarrest Afib with slow Afib with slow

ventricular ventricular responseresponse

Junctional escape Junctional escape rhythmrhythm

AV dissociationAV dissociation Ventricular Ventricular

bigeminy and bigeminy and trigeminytrigeminy

VTach/VFibVTach/VFib Torsades de Torsades de

pointespointes

Dig Tox and the ECGDig Tox and the ECG

MORE SPECIFICMORE SPECIFIC Afib with slow, regular ventricular Afib with slow, regular ventricular

rate (AV dissociation)rate (AV dissociation) Nonparoxysmal junctional Nonparoxysmal junctional

tachycardia (70-130 bpm)tachycardia (70-130 bpm) Atrial tachycardia with block (150-Atrial tachycardia with block (150-

200 bpm)200 bpm) Bidirectional VTachBidirectional VTach

Dig Tox and the ECGDig Tox and the ECG

Very rarely seeVery rarely see Mobitz Type II blockMobitz Type II block Afib or Aflutter with rapid Afib or Aflutter with rapid

ventricular responseventricular response Unimorphic VtachUnimorphic Vtach

AFIB with Slow AFIB with Slow Ventricular ResponseVentricular Response

Nonparoxysmal Junctional Nonparoxysmal Junctional TachycardiaTachycardia

Bidirectional VTBidirectional VT

Potassium and Dig Potassium and Dig ToxicityToxicity

Acute ToxicityAcute Toxicity• Correlates with hyperkalemiaCorrelates with hyperkalemia• K level determines prognosis and K level determines prognosis and

treatmenttreatment

Chronic ToxicityChronic Toxicity• K normal or lowK normal or low• Slow rise over time allows kidneys to Slow rise over time allows kidneys to

balancebalance• Patients often also on diuretic which Patients often also on diuretic which

reduce the K levelreduce the K level

Potassium and acute Potassium and acute digoxin toxicitydigoxin toxicity

3

8

5

7

6

4

SurvivedDied

Bismuth, C., et al. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol 1973; 6:153.

K<5.0, 0% mortalityK 5-5.5, 50% mortalityK>5.5 100% mortality

Predisposing FactorsPredisposing Factors

Advanced ageAdvanced age WomenWomen Renal InsufficiencyRenal Insufficiency Heart DiseaseHeart Disease• Congenital Heart Congenital Heart

DzDz• Ischemic heart Ischemic heart

DzDz• CHFCHF• MyocarditisMyocarditis

AlkalosisAlkalosis HypothyroidismHypothyroidism

Electrolyte ImbalanceElectrolyte Imbalance• Hypo or hyper kalemiaHypo or hyper kalemia• HypomagnesemiaHypomagnesemia• HypercalcemiaHypercalcemia

Sympathomimetic DrugsSympathomimetic Drugs Cardiotoxic CoingestantsCardiotoxic Coingestants• BBBB• CCBCCB• Tricyclic Tricyclic

antidepressantsantidepressants Drug InteractionsDrug Interactions• Quinidine, amiodaroneQuinidine, amiodarone• ErythromycinErythromycin

Management of Dig Management of Dig ToxicityToxicity

GI DecontaminationGI Decontamination

Electrolyte CorrectionElectrolyte Correction

BradycardiasBradycardias

Ventricular DysrhythmiasVentricular Dysrhythmias

Fab FragmentsFab Fragments

GI DecontaminationGI Decontamination

Digoxin is absorbed effectively by Digoxin is absorbed effectively by activated charcoalactivated charcoal Within one hour of ingestionWithin one hour of ingestion 50g for adults50g for adults 1g/kg for peds 1g/kg for peds

No improvement in outcome has No improvement in outcome has been provenbeen proven

Electrolyte CorrectionElectrolyte Correction KK

Hypo: in chronic tox want to replace (goals of Hypo: in chronic tox want to replace (goals of 3.5 to 4mEq/L)3.5 to 4mEq/L)• Oral repletion preferredOral repletion preferred• Don’t replace in acuteDon’t replace in acute

Hyper: in acute tox want to reduce itHyper: in acute tox want to reduce it• Insulin glucoseInsulin glucose• Beta agonistBeta agonist• Sodium bicarbonateSodium bicarbonate• NOTNOT Calcium Calcium

MgMg• Hypomag often reportedHypomag often reported• Replace with 2-4g magnesium sulfate Replace with 2-4g magnesium sulfate

BradycardiasBradycardias

AtropineAtropine• Reverses dig induced vagal toneReverses dig induced vagal tone• More effective than in other cardiac More effective than in other cardiac

drug toxicity (acute toxicity)drug toxicity (acute toxicity)• 0.5mg-1mg to a max of 3mg Q2-3 min 0.5mg-1mg to a max of 3mg Q2-3 min

PacingPacing• If fail atropine treatmentIf fail atropine treatment• Catheter may induce ventricular Catheter may induce ventricular

dysrhythmiasdysrhythmias• External pacing safer but not as External pacing safer but not as

effectiveeffective

Ventricular Ventricular DysrhythmiasDysrhythmias

Vagal ManeuversVagal Maneuvers• NO!!! Can cause asystole and cardiac arrest NO!!! Can cause asystole and cardiac arrest

PhenytoinPhenytoin• SafeSafe• May enhance AV conductionMay enhance AV conduction• Load with 10-15mg/kg Infuse at 25-Load with 10-15mg/kg Infuse at 25-

50mg/min50mg/min

LidocaineLidocaine• SafeSafe• Load with 1-3mg/kg Infuse at 1-4mg/minLoad with 1-3mg/kg Infuse at 1-4mg/min

Fab FragmentsFab Fragments

Digibind™Digibind™

Purified from sheepPurified from sheep

Rapidly bind to digoxin in the Rapidly bind to digoxin in the tissuestissues

Efflux of intracellular digoxin Efflux of intracellular digoxin

Further binding of free digoxinFurther binding of free digoxin

Renally excretedRenally excreted

Indications for Indications for Digibind™Digibind™

1.1. Vetricular dysrhythmiasVetricular dysrhythmias

2.2. Severe bradycardia unresponsive to Severe bradycardia unresponsive to atropineatropine

3.3. Serum K > 5 mEq/L (acute ingestion)Serum K > 5 mEq/L (acute ingestion)

4.4. Serum digoxin levelSerum digoxin level >10 mmol/L at any time>10 mmol/L at any time >12.5 mmol/L 6 hours after ingestion >12.5 mmol/L 6 hours after ingestion

5.5. Acute Ingestion of > 10mg (4mg peds)Acute Ingestion of > 10mg (4mg peds)

6.6. Presence of a digoxin-toxic rhythm in the Presence of a digoxin-toxic rhythm in the setting of an elevated digoxin levelsetting of an elevated digoxin level

Effectiveness of Effectiveness of DigibindDigibind

Antman, EM, et al. Antman, EM, et al. CirculationCirculation 1990 1990 N=150 (cases of life-threatening digitalis tox)N=150 (cases of life-threatening digitalis tox) ResultsResults• 80% complete resolution of all signs and 80% complete resolution of all signs and

symptomssymptoms• 10% improved10% improved• 10% showed no response10% showed no response• Median time to initial response was 19 min Median time to initial response was 19 min • Time to complete response was 88 minTime to complete response was 88 min• 54% of cardiac arrest patients survived 54% of cardiac arrest patients survived

hospitalizationhospitalization

Nonresponders to Nonresponders to DigibindDigibind

1.1. Underlying heart disease (that Underlying heart disease (that causes some of the causes some of the manifestations)manifestations)

2.2. Too low a dose of FabToo low a dose of Fab

3.3. Moribund on presentationMoribund on presentation

4.4. Co-ingestion of other cardiac toxic Co-ingestion of other cardiac toxic drugsdrugs

Dosing of DigibindDosing of Digibind

Given IV over 30 minutesGiven IV over 30 minutes Unless arrested, then give as a bolusUnless arrested, then give as a bolus

Vials of Fab= (Dig level ng/ml x Mass Vials of Fab= (Dig level ng/ml x Mass kg)/ 100kg)/ 100

Always round upAlways round up

Example: how many vials would you need for Example: how many vials would you need for a 70kg woman with a digoxin level of 3 and a 70kg woman with a digoxin level of 3 and frequent PVCs?frequent PVCs?Vials= (3 x 70) / 100 = 2.1 so you would give 3

What if you don’t know the dig level right away???

Dosing of DigibindDosing of Digibind

ACUTEACUTE Stable- 5 vialsStable- 5 vials Unstable- 15 vialsUnstable- 15 vials

CHRONICCHRONIC Stable- 1 vialStable- 1 vial Unstable- 4 vialsUnstable- 4 vials

*1 vial costs approx 400$*1 vial costs approx 400$

Summary- Acute vs Summary- Acute vs ChronicChronic

CHRONICCHRONIC

1.1. Higher mortalityHigher mortality

2.2. K normal or lowK normal or low

3.3. Ventricular Ventricular dysrhythmias more dysrhythmias more commoncommon

4.4. Usually elderly Usually elderly patientspatients

5.5. Often need Fab Often need Fab fragment therapyfragment therapy

6.6. Underlying heart dz Underlying heart dz increases morbidity increases morbidity and mortalityand mortality

ACUTEACUTE

1.1. Lower mortalityLower mortality

2.2. K normal or highK normal or high

3.3. Bradycardia and AV Bradycardia and AV block more commonblock more common

4.4. Usually younger Usually younger patientspatients

5.5. Often do well Often do well without Fab without Fab fragment therapyfragment therapy

6.6. Absence of heart dz Absence of heart dz decreases morbidity decreases morbidity and mortalityand mortality

Bradycardia and Bradycardia and HypotensionHypotension

Sodium channel blockersSodium channel blockers Wide QRS. Wide QRS. Rx = bicarbonateRx = bicarbonate

DigoxinDigoxin Blocks, increased automaticity. Blocks, increased automaticity. Rx = digibind.Rx = digibind.

Calcium channel blockersCalcium channel blockers Increased glucose, preserved mental status Increased glucose, preserved mental status Rx - Calcium, pressors, insulin / glucoseRx - Calcium, pressors, insulin / glucose

Beta blockersBeta blockers Altered mental status, normal glucoseAltered mental status, normal glucose Rx - Glucagon, insulin / glucose, pressorsRx - Glucagon, insulin / glucose, pressors