PoIsOnInG-iNdUcEd HyPoTeNsIoN-wHy NoT tO fOlLoW tHe RuLeS

Donna Seger MDMedical DirectorTN Poison Center

Associate Prof of Medicine and Emerg MedVanderbilt University Medical Center

Nashville TN

Shock• Clinically defined as hypotension (cardinal sign

of circulatory dysfunction) tachycardia, decreased mentation and oliguria

• Circulatory Shock in ICU– Hypovolemic– Cardiogenic– Obstructive– Distributive

Impaired Oxidative Metabolism

Rules suggest treatment with fluids, catecholamines

Inotropic Agents-act on adrenergic receptors at surface of cardiomyocytes

Protein Kinase A ###phosphorylates:*L-Ca channel→ca influx*Troponin1→actinomyosin*Ryanodine receptor (RR)→ ca release

###RR

Hypotension in ICU Patients• Fluids, catecholamines are standard treatment• Basis for recommending catecholamine pressors

– Treatment in elderly; chronically ill; acutely ill with an infectious process

• Poisoned patient is young, healthy– Responds to hypotension with adrenal outpouring of

catecholamines– Catecholamine receptors are sensitive in young– Exogenous catecholamines may be of little benefit

Causes of Hypotension in Poisoned Patient

– Receptor blockade– Ion channel blockade– Myocardial depression– Drug-induced vasodilation– Volume loss– Arrhythmias– Interruption of oxygen use at the molecular level– Inhibition of oxidative phosphorylation– Seizures

• Treat the Cause of Hypotension-treatment may not follow the rules

Treatment of Hypotension in the Poisoned Patient

• Glucagon

• Insulin/glucose

• Calcium

• Na HCO3

• Specific Drugs (cases)

Glucagon

• Does it work?

• Mechamism of action

• side effects

Glucagon

• Polypeptide that interacts with catecholamine-independent receptors to stimulate adenyl cyclase and increase cAMP

• Ionotropic effect of glucagon occurs before production of cAMP which may be due to movement of calcium into cardiac cells via arachidonic acid pathway

• Increases slope of phase zero of action potential

• Increases conduction velocity through AV node• Enhances membrane responsiveness

J Clin Pharm 1999

Cardiac Effects of Glucagon

↑Ca in SR

Intracellular Ca release

Glucagon

• Open-chest anesthesized dogs

• Quinidine caused dose-dependent decrease in heart rate, blood pressure and contractility which was reversed within 2 minutes by Glucagon

CV Research 1977

Glucagon

• Papillary muscles from patients with heart failure

• increased maximum rate of rise of phase 0 of the action potential

Clin Pharm Ther 1975

Clinical Evidence

• 50 µg/kg (10 patients)– Increased cardiac output– Increased heart rate (4 minutes)

Can Med Assoc 1968

Glucagon• Primarily studied in β-blocker and CCB OD

– Animal evidence • Beta Blocker OD-treatment of choice• CCB OD- ↑ HR, Cardiac Output and reversed

AV blocks but no ↑↑ MAP • Addition of other pressors not better

• Response reported in TCA OD cases • Case reports-inconsistent response

following administration of multiple drugs• Loading dose and drip not consistent• Hospital supplies variable

–Clinical Ramifications

Glucagon

• Dose-10mg/10 min followed by drip of

1-5 mg/h

Half-life 6.6 minutes

Side effects-vomiting, ↑glucose, ↓potassium

• Need to study as first-line therapy and compare it to catecholamine pressors and insulin/glucose in hypotensive poisoned patient

Insulin/Glucose

• Does it work?

• Mechanism of action

• Side effects

Insulin and Glucose (Toxicologist perspective)

• Mechanism ????• Insulin increases glucose uptake and allows

myocardial metabolism of CHO instead of fatty acids during stress

• Improves cardiac compression independent of myocardial CHO usage (calcium signaling)

Jnl CV Pharm 1996

• Insulin is positive inotrope • Difficult to determine if improves survival in

hypotensive OD patient

J Mol Cell Cardiol 1998

Open circles-IV insulin

Insulin administration-Regional % Segment Shortening (contraction) did not decrease as CPP decreased

CPP

J Mol Cell Cardiol 1998

Open circle- IV insulin

Regional % SS

Insulin administration- contraction did not

decrease as CBF decreased

Am Jnl Physiol 1998

Intracoronary Insulin

IV insulin

control

Regional glucose uptake increased by Intracoronary and IV insulin at all Coronay Perfusion Pressures

Anesthetized dogsCannulated LAD

Glucose uptake important as oxidation of glucose requires less O2/ATP produced than does oxidation of fatty acid

Myocardial oxygen extraction ↓ from 67 to 48% but Coronary Flow (CF) ↑ so that myocardial oxygen consumption ↑ only slightly

Am Jnl Ob/Gyn 1977

Insulin-Positive inotropic action

newborn

Insulin

Oxygen extraction↓

Coronary flow↑

Myocardial oxygen consumption

• 20201 patients with ST-Segment elevation Myocardial Infarction (MI)

• Randomized to GIK versus supportive care

• GIK had neutral effect on mortality, cardiac arrest, and cardiogenic shock

JAMA 2005

Intensive Insulin Therapy in Critically Ill Patients

Survival

(%)

Days after Admission

0 20 40 60 80 100 120 140 160

100

96

92

88

84

80

Intensive insulin therapy

Conventional treatment

NEJM 2001

NEJM 2006

Insulin reduced morbidity but not mortality among all ICU patients. Mortality was decreased in patients treated 3 or more days, but these pts could not be identified before therapy

L-type Ca++ current

Cardiovascular Research 1999

Myocytes from patients

RESULTS : Insulin stimulates L-type Ca++ current in dose-dependent manner

Voltage-clamped@-50 mV to inactivate Na current;

Insulin• Improves cardiac contractile function

without increasing myocardial oxygen consumption

• Stimulates L-type Ca current BUT

Guinea pig and rat hearts↑↑ Insulin and ↑↑ Calcium-negative

inotropic effectBasic Res Cardiol 2002

DOSE????

10 mg insulin with 50 cc 50% dextrose

• ??? 0.1 IU/kg/hour– Considered a timid approach as case reports

have demonstrated response to administration of hi dose insulin BUT

– When insulin receptors are saturated, does excess insulin decrease inotropy???

» Basic Res Cardiol 2002

Role of calcium administration in hypotensive

poisoned patient is unclear

L-type Ca channels■Heart■Vascular smooth muscle■Pancreatic β-islet

***

Ryanodine R

SR

Goldfranks

Actin-myosin

SA node; AV nodeMyocardial contractionVascular toneInsulin secretion

CALCIUM

Hypotension in CCB OD• Hyperglycemia, metabolic acidosis, bradycardia,

vasodilation• Block L-type Ca channels in myocardial, smooth

muscle, and beta cells• Negative inotropy• Decreases HR • Slow AV conduction• Decrease rate of recovery of channel-use

dependent• Decrease coronary vascular resistance• Increase coronary blood flow• Vasodilation• Decrease Insulin secretion

Treatment

• IV Fluids

• Calcium-does it work?

• Insulin/glucose

• Glucagon

• Hypertonic sodium chloride (animals; ↑sodium ↓ calcium)

Calcium in CCB OD

• Beneficial in most animal studies

• Case reports-many note response

• Severely poisoned don’t respond

• Not all or none phenomenon– Assume ↑ calcium of benefit but If all calcium

channels blocked, calcium not entering cell

HIE for treatment of hypotension in CCB OD

• Canine Verapamil OD-– Glucagon increased HR and cardiac output although

not MAP AEM 1995

– Insulin is superior to glucagon and catecholamines

– Heart changes from FFA to glucose metabolism in shock; increased insulin allows max CHO utilization

• Hypoinsulinemia may be a factor as CCB OD causes dose-related inhibition of glucose-induced insulin release (rat pancreas)

Jnl Pharm and Exp Ther 1993

Diabetes 1975Jnl Pharm & Exp Ther 1993Tox and Applied Pharm 1997

CCM 1995

Insulin/glucose v glucagon

• Physicians more familiar with insulin/glucose

• Glucagon not as readily available

• Cost– 5 mg glucagon infusion costs pharmacy

$150/hour– 70 IU insulin infusion costs $0.63/hour

Hypotension in β-Blocker OD

Displace catecholamines which reduces activation of adenylate cyclase***

βB decrease calciumflow through L-typeCa channels via secondmessenger systems

***

↓inotropy & chronotropy↓ hr & BPSodium channel blocking (MSA)Intrinsic sympathetic activityRespiratory Depression

Treatment of Hypotension in β-Blocker OD

• Fluids• Atropine-does it work?

– Transiently improves bradycardia 25% of time with no effect on blood pressure (muscurinic anticholinergic)

Clin Tox 1993

• Glucagon• Insulin/glucose• Calcium• Catecholamine

Hypotension in sodium channel blocker OD

Sodium Channel Blockers

• Cardiac Na channels are voltage sensitive proteins belonging to a family of ion channels that are gated (open and closed) by changes in membrane potential (depolarization)

Transmembrane potential –-90 with help of pumps.

Resting cell-Elec and conc gradients would moveNa into cell, but Na channels are closed so Na does not enter

Conformational change-revert to closed during repolarization

depolarize

Drug Safety 2000

Cardiac Action Potential

Sodium influx causes upstroke of phase 0 of action potential- responsible for rapid conduction thru ventricle and narrow QRS,

Drugs that block Na channel depress upstroke of phase 0 and QRS widens

/Vmax

Vmax measure of Na ion movement

impermeable Drug binds and slows recovery

Membrane depolarization

Can’t conduct na or become activatedInflux into cell

Increased HR-more activated and inactivated/time

>>>>>>>

>>>>>

<<<<<<<<

☻

NCBD☻

Administration of NaHCO3 in Na Channel Blocker toxicity

• Increase dissociation of drug from Na channel and/or decrease recovery time– increased extracellular Na+ concentration;

increased pH; or combination

• Relative role of Na+ and pH varies between drugs (as evidenced by Vmax )

Circulation 1996

Circulation 1996

Reversal of VmaxIn vitro

Effects of antiarrhythmics on Vmax of canine purkinje fibers

Role of HEART RATE

HEART RATEhEArT rAtE

in hypotension

Vmax

(V/sec)

STIMULATION RATE (pulses/min)

50 100 200150

800

730

660

590

520

450

control

alkalotic

AEM 1986

Cocaine Hypotension

• 35 yo male admitted to ED with known cocaine OD.

• Pre-hospital seizure-received 2mg Ativan

• BP 80/40

• Wide-complex tachcardia (HR 150 bpm)

• Temp 105°F

Cocaine OD

• On arrival in Hospital, Endotracheal intubation with Vecuronium

• VT/VF which would narrow and HR would drop to 90 with administration of NaHCO3

• 2 liters normal saline

• 8 amps bicarb

• pH-7.1

• Still hypotensive

• Lidocaine

• Was this a good idea?????

Pharmacotherapy 1994

Mean % change in QRS duration from baseline for cocaine and after each antidote

oo

o

Bicarb

control

Quinidine

lidocaine

Hypotensive Cocaine ODIndications for treatments

• BZDP?

• NaHCO3 ?

• Lidocaine?

• Glucagon?

• Insulin/glucose?

Cocaethylene Hypotension

• Hypotension and lethality is greater with cocaethylene than with cocaine

WhAt Is ThE pAtHoPhYsIoLoGy Of ThE

hYpOtEnSiOn??

BChE

UDS

EME

****

***

+etoh→→→cocaethylene (CEL)

Norcocaethylene

↑↑

↑↑

Myocardial depressant***Vasoconstrictor

***Convulsant***Na channel blocker

↑ by CEL

J Pharm Exp Ther 1994

CCM 1994

Max rate of LV pressure increase

CCM 1994

Max rate of LV pressure decrease

NSAID Hypotension

• 3 year-old ingests NSAIDS that are in mother’s purse

• Unresponsive

• BP unobtainable

• Palpable rapid pulse

ArE yOu SuRe ThIs Is NSAID-iNdUcEd HyPoTeNsIoN???

Treatment of TCA-induced Hypotension

• Fluids

• NaHCO3- serum alkalinization (ph not > 7.6)

– QRS >120 msec and HR >120 bpm – IV push then drip to maintain serum pH 7.55

• Glucagon– 10 mg over 10 minutes then 3mg/h

• Insulin/glucose

• Catecholamines

Hypotensive Infant

• 4 month-old born to HIV + Mother• One week history of fever to 102°F,vomiting,

diarrhea• Rx Amoxacillin• O/A BP 69/46; HR 146; RR 46; sat 96%; 992 F • PE: dry mucous membranes, neck supple;

bilateral bulging TM; tone normal; skin without rash; liver-5.5 cm below right costal margin

• Treatment?

• Fluids• Rocephin, Acyclovir• Dobutamine- BP increased to 88/63; HR 194• Vancomycin-2 hours later• Blood cultures obtained• Lab: SGPT 25,644 U/L; SGOT 12, 544 U/L;• TBili 0.8 mg/dL; INR-6; plt-957,000• Glucose 74mg/dL; Ca 7.6 ; Cr 0.8

• CO2 15

• Differential Diagnosis???

Differential Diagnosis

• Enteroviral infection causing fulminant hepatitis

• Bacterial sepsis with Disseminated intravascular coagulopathy (DIC) secondary to S.Pneumonia

• Disseminated Herpes

• APAP level obtained 7 hours after admission because intern erroneously ordered it

• 28 mg/L

• Mother, Grandmother, and babysitter had been administering APAP for fever

• IV NAC ordered 36 hours after admission

• After receiving loading dose, infant became mottled, developed respiratory distress, and was intubated

• Did NOT become hypotensive

• Cr increased to 1.8 mg/dL (day 3),

2.4 mg/dL (day 5), with decreasing urine output and evidence of fluid overload. Diuretics administered

• Cr 1.2 mg/dL (day 7)

• Liver enzymes rapidly decreased

Reaction to Nac• Anaphylactoid reaction (6-23%)

– Rash– Pruritus– Angioedema– Nausea, vomiting– Bronchospasm– Tachycardia– hypotension

• Occur within first 30 minutes after 15 minute load

• Not related to infusion time of loading doseAnn Emerg Med 2005

The management of the hypotensive poisoned patient should not follow the rules