Shock

1. 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

2. 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

3. 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 ###

4. 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

5. 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

6. Treatment of Hypotension in the Poisoned Patient • Glucagon • Insulin/glucose • Calcium • Na HCO3 • Specific Drugs (cases)

7. Glucagon • Does it work? • Mechamism of action • side effects

8. 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

9. Intracellular Ca release ↑Ca in SR Cardiac Effects of Glucagon J Clin Pharm 1999

10. 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

11. Glucagon • Papillary muscles from patients with heart failure • increased maximum rate of rise of phase 0 of the action potential Clin Pharm Ther 1975

12. Clinical Evidence • 50 µg/kg (10 patients) • Increased cardiac output • Increased heart rate (4 minutes) Can Med Assoc 1968

13. 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

14. 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

15. Insulin/Glucose • Does it work? • Mechanism of action • Side effects

16. 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

17. Insulin administration-Regional % Segment Shortening (contraction) did not decrease as CPP decreased CPP Open circles-IV insulin J Mol Cell Cardiol 1998

18. Insulin administration- contraction did not decrease as CBF decreased Open circle- IV insulin Regional % SS J Mol Cell Cardiol 1998

19. 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 Physiol1998

20. 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

21. 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

22. 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

23. 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

24. Myocytes from patients Voltage-clamped@-50 mV to inactivate Na current; L-type Ca++ current RESULTS : Insulin stimulates L-type Ca++ current in dose-dependent manner Cardiovascular Research 1999

25. 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

26. 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

27. Role of calcium administration in hypotensive poisoned patient is unclear

28. L-type Ca channels ■Heart ■Vascular smooth muscle ■Pancreatic β-islet SA node; AV node Myocardial contraction Vascular tone Insulin secretion C A L C I U M *** Ryanodine R SR Actin-myosin Goldfranks

29. 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

30. Treatment • IV Fluids • Calcium-does it work? • Insulin/glucose • Glucagon • Hypertonic sodium chloride (animals; ↑sodium ↓ calcium)

31. 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

32. 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

33. 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

34. Hypotension in β-Blocker OD

35. Displace catecholamines which reduces activation of adenylate cyclase*** βB 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

36. 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

37. Hypotension in sodium channel blocker OD

38. 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)

39. 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.

40. 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

41. impermeable Drug binds and slows recovery >>>>>>> Membrane depolarization >>>>> ☻ NCBD ☻ Can’t conduct na or become activated Influx into cell <<<<<<<< Increased HR-more activated andinactivated/time

42. 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

43. Reversal of Vmax In vitro Effects of antiarrhythmics on Vmax of canine purkinje fibers Circulation 1996

44. Role of HEART RATEHEART RATEhEArT rAtE in hypotension

45. 800 730 660 590 520 450 control alkalotic Vmax (V/sec) 50 100 150 200 STIMULATION RATE(pulses/min) AEM 1986

46. 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

47. 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

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

49. Mean % change in QRS duration from baseline for cocaine and after each antidote Quinidine o control lidocaine o Bicarb o Pharmacotherapy 1994

50. Hypotensive Cocaine ODIndications for treatments • BZDP? • NaHCO3 ? • Lidocaine? • Glucagon? • Insulin/glucose?