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Suhail Allaqaband Sinai Samaritan Medical Center Milwaukee, WI Digitalis Intoxication Cardiac glycoside poisoning is a potentially life-threatening problem In a series of 150 severely affected patients • 50 % were receiving long-term digitalis therapy, • 10 %had taken an accidental large overdose, and • 40 % had ingested an overdose with suicidal intent Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation 1990; 81:1744 Digitalis Intoxication The mortality in different studies has ranged from 3 to 40 percent Recent advances have considerably lowered the incidence of digitalis overdose in patients receiving chronic therapy. These include: • A better understanding of pharmacokinetics, leading to more appropriate maintenance dosing • Increasing awareness of drugs that can affect digoxin metabolism • The development of radioimmunoassays for plasma digoxin levels PHARMACOLOGY Digitalis acts at the subcellular level by inhibiting the membrane-bound Na-K-ATPase pump The net effect is the intracellular loss of potassium and the gain of sodium and calcium Drug action depends on the tissue conc., which is relatively constant in relation to plasma levels Thus, plasma levels can be used to monitor compliance and toxicity PHARMACOLOGY The two digitalis preparations used in clinical practice today are digoxin and digitoxin The bioavailability of digoxin is about 80 % and plasma half-life is 1.6 days Major depot for digitalis in humans is skeletal muscle As a result, dosage requirements and the likelihood of toxicity are related to muscle mass rather than total body weight Approximately one-third of the body stores of digoxin is excreted per day – 30 % unchanged in the urine, and 3 % as metabolites in stool PREDISPOSING FACTORS TO TOXICITY Drug Interactions • A number of drugs can raise digitalis levels by interfering with its metabolism or renal excretion Renal insufficiency • End-stage renal disease, prolongs the half-life of digoxin and reduces its volume of distribution • There must be reductions both in the loading dose (by about 40 percent) and in the maintenance dose (by 50 to 75 percent) in this setting PREDISPOSING FACTORS TO TOXICITY Finally, there are a number of factors that can increase the sensitivity to digoxin and predispose to toxicity at plasma levels at the upper limits of normal • old age, • certain cardiac diseases - active ischemia, myocarditis, cardiomyopathy, cardiac amyloidosis, cor pulmonale • metabolic factors - hypokalemia, hypomagnesemia, hypoxemia, hypernatremia, hypercalcemia, and acidbase disturbances CLINICAL MANIFESTATIONS There are multiple, mostly nonspecific manifestations of digitalis toxicity These include fatigue, blurred vision, disturbed color perception, anorexia, nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, confusion, delirium, and occasionally hallucinations Cardiac arrhythmias are responsible for mortality in this setting and may take almost any form CLINICAL MANIFESTATIONS The combination of SVT and AV block, for example, is highly suggestive of digitalis toxicity Although hypokalemia predisposes to digitalis toxicity, massive overdose can lead to hyperkalemia as inhibition of the Na-K-ATPase pump impairs potassium entry into cells Plasma digoxin levels are markedly elevated in these patients, usually being above 10 ng/mL Other signs of toxicity can occur at lower levels of 3 to 5 ng/mL PLASMA DIGOXIN LEVELS Plasma digoxin levels should be measured at least 6 hours after the last dose, since this is the time required for attainment of the steady state The plasma digoxin concentration should be used only as a guide to appropriate therapeutic dosing Several factors (importantly hypokalemia) can predispose to toxicity at levels below 2 ng/mL, which is considered the upper limit of normal On the other hand, clearly elevated levels (above 3 ng/mL) can be seen in asymptomatic patients PLASMA DIGOXIN LEVELS False positive elevations of plasma digoxin can occur in newborns, pregnant women, and patients with chronic renal failure or hepatobiliary disease This problem is thought to result from increased levels of endogenous digoxin-like substances The highest values (up to 4 ng/mL) are seen in neonates Smaller errors of 0.6 to 1.8 ng/mL have been described in the third trimester of pregnancy, renal failure, and combined hepatic and renal failure Large doses of steroid derivatives, such as spironolactone and methylprednisolone, can cross react with the digoxin radioimmunoassay GENERAL PRINCIPLES OF THERAPY Gastrointestinal decontamination • ipecac-induced emesis or lavage is carried out with care to avoid vagal stimulation which may worsen existing conduction block • activated charcoal effectively adsorbs digitalis, if ingestion has occurred within 6-8 hours • repeated doses can be given to adsorb active metabolites as they are excreted by the biliary tract • cholestyramine is an alternative to activated charcoal GENERAL PRINCIPLES OF THERAPY Correction of electrolyte imbalances • Hypokalemia, hypomagnesemia, and other electrolyte disorders should be corrected • Potassium replacement should be given carefully, since raising the plasma potassium concentration can increase atrioventricular block • Some acutely intoxicated patients present with severe hyperkalemia, requiring therapy with glucose and insulin and sodium bicarbonate GENERAL PRINCIPLES OF THERAPY Management of cardiac arrythmias • Severe bradyarrhythmias are treated with atropine, electrical pacing is used in unresponsive patients • Therapy of cardiac ectopy is reserved for more complex forms • Lidocaine and phenytoin are antiarrhythmic drugs of first choice • Verapamil is useful for SVT’s • Cardioversion should be limited to patients with life-threatening arrhythmias and used at the lowest effective energy level DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS Digoxin-specific antibody Fab fragments (Digibind®), purified from sheep IgG, rapidly bind to circulating digoxin and are indicated in • Ingestion of more than 10 mg of digoxin in adults or 4 mg in children • Plasma digoxin concentration above 10 ng/mL • A plasma potassium concentration above 5 meq/L in the presence of life-threatening arrhythmia – ventricular tachycardia or fibrillation, progressive bradycardia, or high degree AV nodal block Mechanism of action of Digibind The proposed sequence of events that occurs after infusion of Fab fragments begins with rapid binding of intravascular digoxin and is followed by diffusion of the fragments into the interstitial space to bind free digoxin at that site The affinity of the fragments for digoxin is greater than the affinity of digoxin for Na-K ATPase The Fab fragments are relatively small (mol wt 50,000) which allows them and bound digoxin to be rapidly excreted by glomerular filtration in patients with nearnormal renal function The elimination half-life of the fragments is 15 to 20 hours in this setting Digibind Digibind can also be successfully in patients with renal insufficiency, including those on maintenance dialysis In the largest study, 18 patients had a pretreatment plasma creatinine concentration of more than 5 mg/dL, including five who were on dialysis These patients responded to Digibind in a manner similar to patients with normal renal function Efficacy of Digibind In the largest series of 150 patients with lifethreatening digitalis toxicity, • 80 percent had resolution of all signs and symptoms, • 10 percent improved, and • 10 percent showed no response The median time to initial response was 19 minutes and the time to complete response was 88 minutes Of the patients who experienced cardiac arrest, 54 percent survived hospitalization Several factors which contribute to partial responses or resistance include, • underlying heart disease that was the true cause of some of the presumed manifestations of digitalis toxicity, • too low a dose of Fab, and • treatment of patients who were already moribund A dramatic fall in the plasma potassium concentration can occur after digibind therapy The decline in the plasma potassium concentration begins within one hour and is complete within 4 hrs Thus, monitoring of the plasma potassium concentration should be performed in all patients receiving this therapy Side effects of digibind therapy Despite the improvement induced by digibind, potentially important side effects can occur • exacerbation of congestive heart failure, • increased ventricular response in patients with A-fib. • hypokalemia Idiosyncratic allergic manifestations are very rare, occurring in less than one percent of cases Plasma digoxin measurements are unreliable for one to two weeks after fragment therapy Dosing regimen for digoxin-specific antibody fragments Total body load of digitalis (TBL, in mg) = SDC (serum digitalis concentration) x volume of distribution x weight (kg) The serum digitalis concentration is measured in ng/mL and for digoxin, the volume of distribution is 5.6 L/kg, therefore • TBL = (SDC x 5.6 x weight) ÷ 1000 One vial of digibind contains 40 mg, which neutralizes approximately 0.6 mg of digoxin Dosing regimen for digoxin-specific antibody fragments Number of vials = TBL ÷ 0.6 Or Number of vials = (SDC x weight) ÷ 100 If the amount ingested is known, then the TBL can be calculated directly: TBL = Dose ingested (mg) x 0.8 for digoxin which has 80 percent bioavailability If the SDC and the amount ingested are not known, then digibind is given empirically according to the following regimen For an acute overdose in adults: • Give 10 vials; repeat with another 10 vials if indicated With chronic toxicity: • Give 6 vials to an adult, one vial to a child EXTRACORPOREAL TECHNIQUES Hemodialysis or hemoperfusion can help control hyperkalemia or volume overload in patients with concurrent renal failure They are, however, of limited utility in removal of digoxin because of its extensive tissue binding and very large volume of distribution (5.6 L/kg)