1. Zohair Al Aseri MD,FRCPC EM & CCM Cardiovascular Meds Intoxication fac.ksu.edu.sa/zalaseri

2. Zohair Al Aseri MD,FRCPC EM & CCM Cardiovascular BB & CCB Intoxication

3. Introduction  a 64-year-old man in the critical bay who took an overdose of his medications. Zohair Al Aseri MD,FRCPC EM & CCM

4.  has a history of hypertension, atrial fibrillation, and depression.  lethargic but arousable  reports he took about 40 tablets of immediate- release metoprolol three hours ago in an attempt to “end it all.” Zohair Al Aseri MD,FRCPC EM & CCM

5.  “Is it too late for gastric decontamination?  If he is symptomatic, which therapy will you try first, and what are your options?” Zohair Al Aseri MD,FRCPC EM & CCM

6.  a 2-year-old child in the pediatric area who was found playing with grandma’s bottle of verapamil controlled release 15 minutes ago.  The grandmother thinks that at most there are three tablets missing. Zohair Al Aseri MD,FRCPC EM & CCM

7. Child looks great  “Are three tablets a big deal?  Can we just watch the child for a couple of hours?  Do we need an IV and blood work? Zohair Al Aseri MD,FRCPC EM & CCM

8.  inhibit endogenous catecholamines such as epinephrine at the beta-receptor. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

9. Selected Characteristics of Common Beta-Blockers Zohair Al Aseri MD,FRCPC EM & CCM

10.  Beta-blockers are rapidly absorbed after oral ingestion, and the peak effect of normal-release preparations occurs in 1 to 4 hours.  Hepatic metabolism on first pass results in significantly less bioavailability after oral dosing than with IV injection (1 : 40 for propranolol).  Volume of distribution for various beta-blockers generally exceeds 1 L/kg, meaning tissue concentrations exceed those of serum. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

11.  Therefore, hemodialysis is not efficacious for most beta-blockers.  Protein binding varies from 0% for sotalol to 93% for propranolol.  Elimination half-lives vary from 8 to 9 minutes for esmolol to as long as 24 hours for nadolol and others Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

12. Zohair Al Aseri MD,FRCPC EM & CCM MANIFESTATIONS AND COMPLICATIONS OF BETA-BLOCKER OVERDOSEIN ORDER OF DECREASING FREQUENCY

13.  Diagnosis and management depend on the clinical picture  Hypoglycemia is common in children Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

14.  IV fluids  Oxygen  Monitoring of card for rhythm and respirations.  Activated charcoal is unproven treatment.  Multiple-dose charcoal without supporting evidence for an improvement in outcome. Zohair Al Aseri MD,FRCPC EM & CCM Management

15.  Onset of toxicity is so uniformly early that absence of symptoms 4 hours after ingestion implies a low risk for subsequent morbidity unless a delayed-release preparation is involved. Zohair Al Aseri MD,FRCPC EM & CCM Management

16. Hypotension, Bradycardia, and Atrioventricular Block  Catecholamines with chronotropic and dromotropic as well as inotropic and vasopressor effects should be chosen. Zohair Al Aseri MD,FRCPC EM & CCM Management

17.  It is rare for one catecholamine to be equally effective against all four toxic effects, so combinations of drugs are often used in severe cases. Zohair Al Aseri MD,FRCPC EM & CCM Management

18. The first step in the treatment of beta-blocker overdose is  Atropine  Glucagon  Crystalloid fluids. Zohair Al Aseri MD,FRCPC EM & CCM Management

19.  A dose of atropine may quickly wear off or be ineffective, so infusion of more potent drugs or cardiac pacing is usually necessary.  Atropine (0.5 mg for adults, 0.02 mg/kg for children, minimum 0.10 mg) should be given before vagal stimuli such as tracheal or gastric intubation. Zohair Al Aseri MD,FRCPC EM & CCM Management

20. Glucagon  Does not depend on beta-receptors for its action, has both inotropic and chronotropic effects.  it helps to counteract the hypoglycemia induced by beta-blocker overdose.  is given as a 5- to 10-mg IV bolus Zohair Al Aseri MD,FRCPC EM & CCM Management

21.  Because of its short (20-minute) half-life, an infusion of 2 to 5 mg/hr (or for children, 0.05– 0.1 mg/kg bolus, then 0.05–0.1 mg/kg/hr) should be started immediately after the bolus.  With cumulative large doses, glucagon should be diluted in 5% glucose in water for constant infusion. Zohair Al Aseri MD,FRCPC EM & CCM Management Glucagon

22.  Side effects include nausea and vomiting in most patients, mild hyperglycemia, hypokalemia, and allergic reactions.  The response to glucagon alone is often inadequate. Zohair Al Aseri MD,FRCPC EM & CCM Management Glucagon

23.  Sodium channel blockade, manifested by QRS widening, occasionally occurs with beta-blocker intoxication and may respond to infusion of sodium bicarbonate. Zohair Al Aseri MD,FRCPC EM & CCM Management sodium bicarbonate

24.  In hypotensive patients, 20 to 40 mL/kg of normal saline or Ringer's lactate solution can be infused and repeated.  If hypotension or bradycardia persists, other cardioactive drugs are indicated.  dopamine, or epinephrine. Zohair Al Aseri MD,FRCPC EM & CCM Management

25.  Other catecholamines include norepinephrine, dobutamine, and phenylephrine.  Often, norepinephrine or dopamine is added to beta-agonists such as isoproterenol that lack vasopressor activity. Zohair Al Aseri MD,FRCPC EM & CCM Management

26.  There are no randomized controlled human trials.  There are multiple case reports of the hemodynamic improvement after institution of HDIE. Zohair Al Aseri MD,FRCPC EM & CCM Stellpflug SJ, Harris CR, Engebretsen KM, et al. Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin. Clin Toxicol 2010;48: 227-229.42 Treatment High-Dose Insulin Euglycemia (HDIE) Therapy

27.  High-dose (0.5–1 unit/kg/hr) insulin infusion for hemodynamically significant toxicity is often given before traditional pressors.  Beta-blocker toxicity shifts myocardial energy preferences from free fatty acids to carbohydrates, and insulin increases myocardial carbohydrate uptake.  Recent canine and porcine models showed the benefit of insulin infusion up to 10 units/kg/hr. Zohair Al Aseri MD,FRCPC EM & CCM Management Insulin

28.  Glucose, usually in 5 to 10% solutions, is infused to maintain a serum glucose of approximately 100 mg/dL.  The combination of glucose and high-dose insulin augments myocardial contraction independent of beta-receptors.  Glucose and potassium should be monitored frequently during infusion and supplemented as needed to maintain euglycemia and eukalemia. Zohair Al Aseri MD,FRCPC EM & CCM Management Insulin

29.  Refractory cases of bradycardia may respond to an external or transvenous pacemaker. Zohair Al Aseri MD,FRCPC EM & CCM Management

30.  Because deleterious effects on calcium transport may contribute to beta-blocker toxicity, IV calcium salts have been suggested for treating hypotension.  calcium should be given cautiously and less aggressively than for cases of calcium channel blocker overdose.  Constant infusions are safer than boluses.  Give 1 to 2 g over 5 to 10 minutes, monitoring closely for effect. Zohair Al Aseri MD,FRCPC EM & CCM Calcium Management

31.  Although uncharacteristic, ventricular tachydysrhythmias do occur sometimes.  Cardioversion and defibrillation are indicated for ventricular tachycardia and ventricular fibrillation, respectively, following American Heart Association guidelines.  Pulsatile ventricular tachycardia or frequent ventricular ectopy can most safely be treated with lidocaine. Zohair Al Aseri MD,FRCPC EM & CCM Ventricular Dysrhythmias Management

32.  Hemodialysis or hemoperfusion may be beneficial for atenolol, nadolol, sotalol, and timolol, the beta-blockers with lower V d, lower protein binding, and greater hydrophilicity. Zohair Al Aseri MD,FRCPC EM & CCM Extracorporeal Elimination and Circulatory Assistance Management

33.  can be lifesaving in cases of refractory hypotension.  To be successful, such heroic measures must be taken before prolonged hypotension leads to multiorgan ischemic injury. Zohair Al Aseri MD,FRCPC EM & CCM Management Extracorporeal Elimination and Circulatory Assistance

34. Zohair Al Aseri MD,FRCPC EM & CCM TREATMENT OF BETA-BLOCKER POISONING

35. Zohair Al Aseri MD,FRCPC EM & CCM

36.  Patients who remain completely asymptomatic for 6 hours after an oral overdose of normal-release preparations can be safely referred for psychiatric evaluation, with medical consultation for the first 24 hours. Zohair Al Aseri MD,FRCPC EM & CCM Disposition

37.  Most fatalities occur with verapamil, but severe toxicity and death have been reported for most drugs of this class. Zohair Al Aseri MD,FRCPC EM & CCM CALCIUM CHANNEL BLOCKERS Perspective

38. Calcium channel antagonists  block the slow calcium channels in the myocardium and vascular smooth muscle, leading to coronary and peripheral vasodilation.  reduce cardiac contractility  depress SA nodal activity  slow AV conduction. Zohair Al Aseri MD,FRCPC EM & CCM Pathophysiology

39.  Both verapamil and diltiazem act on the heart and blood vessels, whereas nifedipine causes primarily vasodilation.  In the pancreas, calcium channel blockade inhibits insulin release, resulting in hyperglycemia.  As with beta-blockers, selectivity is lost in cases of overdose Zohair Al Aseri MD,FRCPC EM & CCM Pathophysiology

40.  All calcium channel blockers are rapidly absorbed  Onset of action and toxicity ranges from less than 30 minutes to 60 minutes  Peak effect of nifedipine can occur as early as 20 minutes after ingestion, Zohair Al Aseri MD,FRCPC EM & CCM Pathophysiology

41.  Peak effect of sustained-release verapamil can be delayed for many hours.  High protein binding and V d greater than 1 to 2 L/kg make hemodialysis or hemoperfusion ineffective.  Fortunately (except with sustained-release preparations), their half-lives are relatively short, limiting toxicity to 24 to 36 hours. Zohair Al Aseri MD,FRCPC EM & CCM Pathophysiology

42. Zohair Al Aseri MD,FRCPC EM & CCM Selected Characteristics of Some Calcium Channel Blockers

43. Zohair Al Aseri MD,FRCPC EM & CCM MANIFESTATIONS AND COMPLICATIONS OF CALCIUM CHANNEL BLOCKER POISONING

44.  Serum levels of calcium antagonists are not available  Glucose and Electrolytes (including calcium and magnesium). Hyperglycemia secondary to insulin inhibition occurs occasionally, but mild and short-lived requires no treatment.  Lactic acidosis occurs with hypotension and hypoperfusion. Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

45.  ECG  A prolonged QRS or QT interval suggests bepridil or a co-ingested cardiac toxin such as a TCA. Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

46.  IV  O2  Cardiac monitoring  Vomiting is a powerful vagal stimulus that can exacerbate bradycardia and heart block.  No evidence for activated charcoal Zohair Al Aseri MD,FRCPC EM & CCM Management

47.  Atropine (0.5–1 mg, up to 3 mg for adults, and 0.02 mg/kg for children, minimum 0.1 mg).  Atropine's effect is short-lived  If symptomatic bradycardia or heart block persists, the next step is a pacemaker or chronotrope such as isoproterenol. Zohair Al Aseri MD,FRCPC EM & CCM Hypotension and Bradycardia

48.  have considerable effect on contractility but their effect on bradycardia, AV block, and peripheral vasodilation is often poor. Zohair Al Aseri MD,FRCPC EM & CCM Hypotension and Bradycardia Intravenous calcium

49.  Epinephrine, norepinephrine, and dobutamine have also led to successful outcomes. Zohair Al Aseri MD,FRCPC EM & CCM Hypotension and Bradycardia

50.  Glucagon has also been used for its inotropic and chronotropic effects. Zohair Al Aseri MD,FRCPC EM & CCM Hypotension and Bradycardia

51.  (0.5–1 iu/kg/hr) infusion has been effective in both animal trials and human cases.  Glucose (5–10% solutions usually suffice) is infused concurrently to maintain serum glucose at 100 mg/dL (usually 10–30 g/hr).  Insulin euglycemia is thought to act by improving myocardial carbohydrate metabolism, thereby augmenting myocardial contraction. Zohair Al Aseri MD,FRCPC EM & CCM Hypotension and Bradycardia Insulin

52.  Serum glucose and potassium levels should be checked frequently to ensure that normal levels are maintained. Zohair Al Aseri MD,FRCPC EM & CCM Hypotension and Bradycardia Insulin

53. Megarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemie/ euglycaemia) therapy in acute calcium channel antagonist and beta-blocker poisoning. Toxicol Rev 2004;23:215-222 Kline JA, Leonova E, Raymond R. Beneficial myocardial metabolic effects of insuin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995;3:1251-63 Tune JD, Mallet RT, Downey HF. Insulin improves contractile function during moderate ischemia in canine left ventricle. Am J Physiol 1998;274:1574-81 High-Dose Insulin Euglycemia (HDIE) Therapy  may be administered to increase inotropy.  Its proposed mechanism of action is by improving calcium use in the myocytes, although the exact mechanism is unclear. Zohair Al Aseri MD,FRCPC EM & CCM Treatment

54. Zohair Al Aseri MD,FRCPC EM & CCM TREATMENT OF CALCIUM CHANNEL BLOCKER INTOXICATION

55. Zohair Al Aseri MD,FRCPC EM & CCM

56.  Because the peak effect occurs in 90 minutes to 6 hours, patients who are totally asymptomatic for 6 hours can be safely discharged  For delayed-release preparations should be admitted for at least 24 hours of continuous cardiac monitoring. Zohair Al Aseri MD,FRCPC EM & CCM Disposition

57.  Widely used as vasodilators in the treatment of heart failure and ischemic heart disease.  augment coronary blood flow as well as reduce myocardial oxygen consumption by reducing afterload.  At lower doses nitrates primarily dilate veins  At higher doses they also dilate arteries. Zohair Al Aseri MD,FRCPC EM & CCM NITRATES AND NITRITES

58.  Hypotension is a common complication, but usually responds to supine positioning, IV fluids, and reduction of dose.  Hypotension is usually transient.  Low-dose pressors are occasionally needed, but it is best to avoid them in the setting of acute coronary syndromes. Zohair Al Aseri MD,FRCPC EM & CCM NITRATES AND NITRITES

59.  Nitrites are also oxidizing agents that convert hemoglobin to methemoglobin, impairing oxygen delivery. Zohair Al Aseri MD,FRCPC EM & CCM NITRATES AND NITRITES

60.  When methemoglobin levels exceed 15%, a venous blood sample appears chocolate brown, and the skin appears blue even while patients look remarkably comfortable.  Unlike most cases of cyanosis, supplemental oxygen does not improve the patient's color. Zohair Al Aseri MD,FRCPC EM & CCM NITRATES AND NITRITES

61.  Pulse oximetry is not reliable, Treatment  IV methylene blue, but this antidote is usually not needed unless methemoglobinemia approaches 30%  The usual dose of methylene blue in adults is 1 to 2 mg IV over 5 minutes. Zohair Al Aseri MD,FRCPC EM & CCM NITRATES AND NITRITES

62. Zohair Al Aseri MD,FRCPC EM & CCM Digitalis Intoxication

63. Zohair Al Aseri MD,FRCPC EM & CCM The foxglove plant, from which digitalis is derived. DIGITALIS Perspective

64. In therapeutic doses, digitalis has two effects: (1) increasing the force of myocardial contraction to increase cardiac output in patients with heart failure. (2) decreasing atrioventricular (AV) conduction to slow the ventricular rate in atrial fibrillation. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

65.  It inhibits membrane sodium-potassium adenosine triphosphatase (ATPase), which increases intracellular sodium and calcium and increases extracellular potassium.  At therapeutic doses, the effects on serum electrolyte levels are minimal. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

66.  With toxic levels, digitalis paralyzes the Na-K pump, potassium cannot be transported into cells, and serum potassium can rise as high as 13.5 mEq/L. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

67.  At therapeutic levels, digitalis indirectly increases vagal activity and decreases sympathetic activity.  At toxic levels, digitalis can directly halt the generation of impulses in the SA node, depress conduction through the AV node, and increase the sensitivity of the SA and AV nodes to catecholamines. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

68.  Digitalis can produce virtually any dysrhythmia or conduction block, and bradycardias are as common as tachycardias. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

69. Zohair Al Aseri MD,FRCPC EM & CCM DYSRHYTHMIAS ASSOCIATED WITH DIGITALIS TOXICITY

70.  The significant protein binding and large volume of distribution suggest that hemodialysis, hemoperfusion, and exchange transfusion are ineffective. Zohair Al Aseri MD,FRCPC EM & CCM Principles of Disease Pathophysiology

71. Zohair Al Aseri MD,FRCPC EM & CCM FACTORS ASSOCIATED WITH INCREASED RISK OF DIGITALIS TOXICITY

72. Zohair Al Aseri MD,FRCPC EM & CCM NONCARDIAC SYMPTOMS OF DIGITALIS INTOXICATION IN ADULTS AND CHILDREN

73.  Serum digoxin levels.  It is the steady state, rather than peak level, that correlates with tissue toxicity and is used to calculate antidote dosages. Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

74.  Peak levels after an oral dose of digoxin occur in 1.5 to 2 hours, with a range of 0.5 to 6 hours.  Steady-state serum concentrations are not achieved until after distribution, or 6 to 8 hours after a dose or overdose, and may be only one fourth to one fifth of the peak level. Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

75.  The ideal serum digoxin concentration for patients with heart failure is considered to be 0.7 to 1.1 ng/mL. Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

76.  After an acute massive overdose in a patient who is rapidly becoming symptomatic, however, it may be impractical to wait 6 to 8 hours for the first reading.  It is unlikely that early levels exceeding 10 to 20 ng/mL will fade to clinical insignificance at 6 to 8 hours after ingestion. Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

77.  Patients taking digitalis therapeutically often take diuretics as well, and they often have low serum and total body potassium levels.  The acutely poisoned patient, in contrast, may have life-threatening hyperkalemia. Zohair Al Aseri MD,FRCPC EM & CCM Diagnostic Strategies

78.  There is no evidence to support gastric emptying for the treatment of digoxin overdose.  Activated charcoal, no improvement in outcome has been established.  Multidose charcoal has no proven benefit Zohair Al Aseri MD,FRCPC EM & CCM Management

79.  In cases of chronic intoxication, often exacerbated by hypokalemia, raising the serum potassium level to 3.5 to 4 mEq/L is an important early treatment.  Potassium can be administered orally (which is safer) or intravenously (IV) although a rate more rapid than 10 to 40 mEq/hour is dangerous. Zohair Al Aseri MD,FRCPC EM & CCM Electrolyte Correction K

80.  In acute poisoning, serum potassium may begin to rise rapidly within 1 to 2 hours of ingestion, potassium should be withheld, even if mild hypokalemia is measured initially. Zohair Al Aseri MD,FRCPC EM & CCM Electrolyte Correction K

81.  A serum potassium level greater than 5 mEq/L warrants consideration of digitalis antibody (ovine Fab fragment) treatment.  If digitalis antibodies are not immediately available, severe hyperkalemia should be treated with IV glucose, insulin, and sodium bicarbonate. Zohair Al Aseri MD,FRCPC EM & CCM Electrolyte Correction K

82.  Many patients on diuretic therapy are also magnesium-depleted, even when the measured serum magnesium level is normal.  If significant magnesium depletion is suggested, 1 to 2 g of magnesium sulfate can be given over 10 to 20 minutes (child: 25 mg/kg), followed by a constant infusion of 1 to 2 g/hour. Zohair Al Aseri MD,FRCPC EM & CCM Electrolyte Correction Mg

83.  Atropine is generally used for severe bradycardia and advanced AV block, with mixed results.  Generally, an external or transvenous pacemaker should be prepared when bradycardia or AV block appears. Zohair Al Aseri MD,FRCPC EM & CCM Atropine

84.  It may be safer to temporize with an external rather than a transvenous pacemaker while waiting for Fab fragments to take effect.  Cardioversion and defibrillation can cause asystole after attempts to treat tachydysrhythmias.  Lower energy settings, such as 25 to 50 J, may be less hazardous. Zohair Al Aseri MD,FRCPC EM & CCM Pacing

85.  Digitalis antibodies are derived from sheep immunized with digoxin. Side Effect  Reactions have included erythema, urticaria, and facial edema, all of which are responsive to the usual treatment.  Hypokalemia  Exacerbation of congestive heart failure  Increase in ventricular rate with atrial fibrillation. Zohair Al Aseri MD,FRCPC EM & CCM Fab Fragments (Digibind or Digifab)

86.  Indicated for serious cardiovascular toxicity  Not for prophylactic administration of higher than expected serum levels.  The primary indication for antibody treatment in cases of acute poisoning is hyperkalemia with a serum potassium level greater than 5.5 mEq/L or ECG changes. Zohair Al Aseri MD,FRCPC EM & CCM Fab Fragments (Digibind or Digifab)

87.  Fab fragment therapy should be used before transvenous pacing, which carries significant risk. Zohair Al Aseri MD,FRCPC EM & CCM Fab Fragments (Digibind or Digifab)

88. Zohair Al Aseri MD,FRCPC EM & CCM RECOMMENDATIONS FOR ADMINISTRATION OF DIGITALIS ANTIBODY FRAGMENTS

89.  All patients who are symptomatic for digitalis intoxication with hyperkalemia, dysrhythmia, AV block, or significant comorbidity should be admitted to the hospital or the emergency department observation unit for at least 12 hours of continuous cardiac monitoring.  All patients treated with antibodies require admission to an intensive care unit. Zohair Al Aseri MD,FRCPC EM & CCM Disposition and Summary

90.  time of ingestion  specific name of the medication  number of pills ingested  formulation (i.e., immediate release vs. sustained release)  dose per tablet  co-ingestants  chronic medications taken as prescribed  alcohol, or illicit drugs. Zohair Al Aseri MD,FRCPC EM & CCM ED Evaluation Important to know:

91. Zohair Al Aseri MD,FRCPC EM & CCM

92. Thank you Zohair Al Aseri MD,FRCPC EM & CCM Main reference is Rosen Text book of EM