PoIsOnInG-iNdUcEd HyPoTeNsIoN-wHy NoT tO fOlLoW tHe RuLeS Donna Seger MD Medical Director TN Poison Center Associate Prof of Medicine and Emerg Med Vanderbilt University Medical Center Nashville TN

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PoIsOnInG-iNdUcEd HyPoTeNsIoN-wHy NoT tO fOlLoW
tHe RuLeS Donna Seger MDMedical DirectorTN
Poison CenterAssociate Prof of Medicine and
Emerg MedVanderbilt University Medical
CenterNashville TN
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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

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Inotropic Agents-act on adrenergic receptors at
surface of cardiomyocytes
Protein Kinase A phosphorylates L-Ca
channel?ca influx Troponin1?actinomyosin Ryanodi
ne receptor (RR) ? ca release
RR

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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

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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

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Treatment of Hypotension in the Poisoned Patient

• Glucagon
• Insulin/glucose
• Calcium
• Na HCO3
• Specific Drugs (cases)

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Glucagon

• Does it work?
• Mechamism of action
• side effects

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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

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Intracellular Ca release
?Ca in SR
Cardiac Effects of Glucagon
J Clin Pharm 1999
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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

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Glucagon

• Papillary muscles from patients with heart
  failure
• increased maximum rate of rise of phase 0 of the
  action potential

Clin Pharm Ther 1975
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Clinical Evidence

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

Can Med Assoc 1968
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Glucagon

• Primarily studied in ß-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

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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

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Insulin/Glucose

• Does it work?
• Mechanism of action
• Side effects

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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

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Insulin administration-Regional Segment
Shortening (contraction) did not decrease as CPP
decreased
CPP
Open circles-IV insulin
J Mol Cell Cardiol 1998
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Insulin administration- contraction did not
decrease as CBF decreased
Open circle- IV insulin
Regional SS
J Mol Cell Cardiol 1998
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Glucose uptake important as oxidation of glucose
requires less O2/ATP produced than does oxidation
of fatty acid
Intracoronary Insulin
Anesthetized dogs Cannulated LAD
IV insulin
control
Regional glucose uptake increased by
Intracoronary and IV insulin at all Coronay
Perfusion Pressures
Am Jnl Physiol 1998
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newborn
Insulin-Positive inotropic action
Myocardial oxygen extraction ? from 67 to 48 but
Coronary Flow (CF) ? so that myocardial oxygen
consumption ? only slightly
Oxygen extraction?
Coronary flow?
Myocardial oxygen consumption
Insulin
Am Jnl Ob/Gyn 1977
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• 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
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Intensive Insulin Therapy in Critically Ill
Patients
S u r v i v a l ()
100
Intensive insulin therapy
96
92
Conventional treatment
88
84
80
0 20 40 60 80 100 120
140 160
NEJM 2001
Days after Admission
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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
NEJM 2006
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Myocytes from patients
Voltage-clamped_at_-50 mV to inactivate Na current
L-type Ca current
RESULTS Insulin stimulates L-type Ca
current in dose-dependent manner
Cardiovascular Research 1999
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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
  effect
• Basic Res Cardiol 2002

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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

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Role of calcium administration in hypotensive
poisoned patient is unclear
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L-type Ca channels Heart Vascular smooth
muscle Pancreatic ß-islet
SA node AV node Myocardial contraction Vascular
tone Insulin secretion
C A L C I U M

Ryanodine R
SR
Actin-myosin
Goldfranks
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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

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Treatment

• IV Fluids
• Calcium-does it work?
• Insulin/glucose
• Glucagon
• Hypertonic sodium chloride (animals ?sodium ?
  calcium)

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Calcium in CCB OD

• Beneficial in most animal studies
• Case reports-many note response
• Severely poisoned dont respond
• Not all or none phenomenon
• Assume ? calcium of benefit but If all calcium
  channels blocked, calcium not entering cell

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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
CCM 1995
Diabetes 1975 Jnl Pharm Exp Ther 1993 Tox and
Applied Pharm 1997
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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

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Hypotension in ß-Blocker OD
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Displace catecholamines which reduces activation
of adenylate cyclase
ßB decrease calcium flow through L-type Ca
channels via second messenger systems

?inotropy chronotropy ? hr BP Sodium channel
blocking (MSA) Intrinsic sympathetic
activity Respiratory Depression
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Treatment of Hypotension in ß-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

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Hypotension in sodium channel blocker OD
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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)

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Conformational change-revert to closed during
repolarization
Resting cell-Elec and conc gradients would moveNa
into cell, but Na channels are closed so Na does
not enter
depolarize
Transmembrane potential -90 with help of pumps.
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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 measure of Na ion movement
Vmax
/
Drug Safety 2000
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impermeable
Drug binds and slows recovery
gtgtgtgtgtgtgt
Membrane depolarization
gtgtgtgtgt
? NCBD
?
Cant conduct na or become activated
Influx into cell
ltltltltltltltlt
Increased HR-more activated and inactivated/time
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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

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Reversal of Vmax
In vitro
Effects of antiarrhythmics on Vmax of canine
purkinje fibers
Circulation 1996
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Role of HEART RATEHEART RATEhEArT rAtE in
hypotension
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800 730 660 590 520 450
control alkalotic
Vmax (V/sec)
50
100
200
150
STIMULATION RATE (pulses/min)
AEM 1986
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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 105F

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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

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• Lidocaine
• Was this a good idea?????

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Mean change in QRS duration from baseline for
cocaine and after each antidote
Quinidine
o
control
lidocaine
o
Bicarb
o
Pharmacotherapy 1994
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Hypotensive Cocaine ODIndications for treatments

• BZDP?
• NaHCO3 ?
• Lidocaine?
• Glucagon?
• Insulin/glucose?

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Cocaethylene Hypotension

• Hypotension and lethality is greater with
  cocaethylene than with cocaine

WhAt Is ThE pAtHoPhYsIoLoGy Of ThE
hYpOtEnSiOn??
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etoh???cocaethylene (CEL)

??
Myocardial depressant
Vasoconstrictor Convulsant Na channel
blocker
? by CEL
BChE

UDS
Norcocaethylene
??
EME
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J Pharm Exp Ther 1994
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Max rate of LV pressure increase
CCM 1994
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Max rate of LV pressure decrease
CCM 1994
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NSAID Hypotension

• 3 year-old ingests NSAIDS that are in mothers
  purse
• Unresponsive
• BP unobtainable
• Palpable rapid pulse

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ArE yOu SuRe ThIs Is NSAID-iNdUcEd HyPoTeNsIoN???
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Treatment of TCA-induced Hypotension

• Fluids
• NaHCO3- serum alkalinization (ph not gt 7.6)
• QRS gt120 msec and HR gt120 bpm
• IV push then drip to maintain serum pH 7.55
• Glucagon
• 10 mg over 10 minutes then 3mg/h
• Insulin/glucose
• Catecholamines

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Hypotensive Infant

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

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• 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???

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Differential Diagnosis

• Enteroviral infection causing fulminant hepatitis
• Bacterial sepsis with Disseminated intravascular
  coagulopathy (DIC) secondary to S.Pneumonia
• Disseminated Herpes

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• 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

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• IV NAC ordered 36 hours after admission
• After receiving loading dose, infant became
  mottled, developed respiratory distress, and was
  intubated
• Did NOT become hypotensive

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• 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

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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 dose

Ann Emerg Med 2005
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The management of the hypotensive poisoned
patient should not follow the rules