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Transcript of Shock
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
• 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
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 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
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
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
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
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
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
NSAID Hypotension
• 3 year-old ingests NSAIDS that are in mother’s purse
• Unresponsive
• BP unobtainable
• Palpable rapid pulse
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