AACN Advanced Critical Care Volume 25, Number 3, pp. 297-304 © 2014 AACN
ECG
Challenges
Gerard B. Hannibal, RN, MSN, PCCN Department Editor
Influence of Calcium Abnormalities on the ECG Sonya Moore, MSN, CRNA Chris Winkelman, RN, PhD Barbara Daum, MSN, CNP
E
lectrolyte disorders are a significant cause of morbidity and mortality for adults in the intensive care unit and hospital. Hypocalcemia occurs in 15% to 88% of hospital admissions. The incidence of ionized hypocalcemia has been reported at 15% to 50% in patients in the intensive care unit.1 Another 15% of hospitalized adults demonstrate hypercalcemia.2 The purpose of this column is to explain the actions of calcium on cardiac depolarization and repolarization and explore the manifestations of serum calcium derangements in a 12-lead electrocardiograph (ECG) tracing. We report the diagnosis and management of 2 composite scenarios that illustrate hypocalcemia and hypercalcemia with illustrative ECGs. Case Report 1 M.K., a 50-year-old white woman, presented to the preadmission testing area prior to a scheduled surgery for an elective tonsillectomy for airway obstruction. During the review of systems, she reported feeling “weak and tired,” with new muscle cramps and circumoral paresthesia. Her surgeon was not aware of these symptoms. Vital signs at this time were heart rate (HR) 60/min, regular; blood pressure 90/40 mm Hg, respiratory rate 14/min, and peripheral oxygen saturation 98% on room air. On physical examination, a speech hesitation/tremor was noticed, and hyperreflexia was observed in all 4 extremities. With manual muscle testing, the patient demonstrated 4/5 strength in upper extremities. A complete blood cell count, basic metabolic panel, and calcium, magnesium, phosphorous, and troponin levels were collected. A preoperative ECG was done. Laboratory values were as follows: sodium, 159 mEq/L; chloride, 111 mEq/L; potassium, 3.2 mEq/L; blood urea nitrogen, 20 mg/dL; creatinine, 0.7 mg/dL; glucose, 90 mg/dL; total calcium, 6.2 mg/dL; ionized calcium, 3.0 mg/dL; phosphorous, 4.8 mg/dL (1.6 mmol/L); magnesium, 1.0 mg/dL (0.5 mmol/L); and albumin, 4.5 mg/dL. The ECG demonstrated sinus rhythm with a prolonged corrected QT (QTc) interval and prolonged ST segment (Figure 1). An ECG from 14 months ago in
Sonya Moore is Instructor, Frances Payne Bolton School of Nursing, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106 ([email protected]). Chris Winkelman is Associate Professor, Frances Payne Bolton School of Nursing, Case Western Reserve University, and MetroHealth Medical Center, Cleveland, Ohio. Barbara Daum is CNP, MSN, Cardiology, University Hospitals Case Medical Center, Cleveland, Ohio. The authors declare no conflicts of interest. DOI: 10.1097/NCI.0000000000000038
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Figure 1: 12-lead electrocardiograph of a patient with severe hypocalcemia. Ventricular rate = 60; PR = 0.19 seconds (190 ms); QRS = 0.06 seconds (60 ms); QT/corrected QT = 0.410/0.558 seconds (410/558 ms); ST segment = 0.2 seconds (200 ms).
her primary care office had none of these features and was interpreted as sinus rhythm, rate 72/min, PR 0.18 seconds, QRS 0.06 seconds, and QTc 0.41 seconds. Case Report 2 A.B., a 56-year-old Hispanic woman, presented for preoperative testing for a parathyroidectomy. The patient was confused about time and complained of muscle weakness, lethargy, and increasing abdominal pain. The following pertinent findings were collected during physical examination: blood pressure 160/96 mm Hg, HR 52/min with regular, normal heart sounds, and clear lung sounds bilaterally. Deep tendon reflexes were diminished on bilateral lower extremities. Admitting laboratory work revealed a serum parathyroid hormone (PTH) level of 9.2 pmol/L (normal = 1.0-6.8), a total calcium level of 14.4 mg/dL, and an ionized calcium level of 10.9 mg/dL. Complete blood cell count and other laboratory findings were essentially normal. The ECG demonstrated sinus bradycardia with a shortened QTc and nonspecific T-wave abnormalities (Figure 2). Overview: Serum Calcium The normal serum calcium level ranges from 9.0 to 10.5 mg/dL (2.25-2.62 mmol/L).3 Ionized calcium is the active physiological form of this essential electrolyte, with a normal range of 4.5 to 5.6 mg/dL (1.05-1.30 mmol/L).3 Half of serum calcium is ionized, while 40% of the remaining amount is bound to proteins (90% to albumin) or anions of phosphate,
carbonate, citrate, lactate, or sulfate. As a result, the total serum calcium level is decreased in the presence of a reduced serum albumin level. However, adjusting the value of total calcium by correcting for albumin is not useful for critically ill patients, and assessing ionized calcium is recommended for diagnosis and treatment.4 In addition to its effects on the heart and ECG, ionized calcium is necessary for several physiological processes. Ionized calcium is essential to neurotransmitter release and muscle contraction and relaxation in the heart and systemically.5 Calcium is a cofactor in the clotting cascade and required for bone mineralization.6 Calcium has regulatory capabilities, including digestive enzyme activation, cytokine release, free radical production, and inhibition of adenosine triphosphate synthesis.5 Serum calcium derangements often are accompanied by concurrent alterations in phosphorus, potassium, and magnesium.5 Calcium Ion Channels Ion channels have 2 properties: ion passage through cell membranes and gating.7 Ion channel passage is selective but not exclusive, as illustrated by sodium-calcium channels that allow sodium (Na) and calcium (Ca) to bind and pass through at a rate of 3Na:1Ca.6 Gating refers to the opening and closing of ion channels, and gates can be open, closed, or inactive. Inactive gates are the basis for the cardiac cell refractory period and prevention of premature excitation. Mechanisms of gating in ion channels include
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Figure 2: 12-lead electrocardiograph of a patient with severe hypercalcemia.
voltage (charge)-dependent, ligand (chemical or neurotransmitter)-dependent, and mechanosensitive (pressure or stretch)-dependent.6,7 Two types of calcium channels exist in the heart, and both are voltage-dependent: the L(low threshold) and T-(transient) types. The L-type calcium channels are in all cardiac cells; they are associated with low voltage for activation and contribute to intracellular signaling and excitation-contraction coupling. The Ttype calcium channels are in pacemaker, atrial, and Purkinje cells and require a higher voltage to open. Both channels are affected by hypocalcemia and hypercalcemia.7 Both L-type and T-type calcium channels mediate the shape of the action potential.8 Calcium channels also are involved in supplying calcium for contractile myocytes, but myocardial contractions are not reflected in the ECG.9 Calcium and the Action Potential Five phases of the cardiac action potential, numbered 0 to 4, in ventricular myocytes form the contractile tissue of the heart. Pacemakers are specialized cardiac cells with 3 phases to the action potential, numbered 0, 3, and 4. Calcium plays a role in all phases as described in Table 1. ECG waveforms occur as electrolytes flow through ionic channels in contractile tissue.6 The particular influence of calcium on an ECG tracing generally affects the QRS duration and shape, the slope of the ST segment, and the length of the QT interval. Heart rate and rhythm also are affected by calcium via the actions on pacemaker cells, resulting in both
brady- and tachy-dysrhythmias during serum calcium derangements.8 Phase 0 corresponds to the initial upward slope of the action potential, signaling depolarization of ventricular myocytes. Phase 1 of the cardiac action potential is sometimes called the overshoot and represents the closure of the sodium and potassium channels. Phases 0, 1, and 2 are associated with the duration of the QRS. During phase 1, calcium slows the inactivation of sodium channels (gating).9 During phase 2, calcium channels open, sustaining the depolarization of ventricular myocytes and creating the plateau of the ventricular action potential, which appears as the continuation of the QRS into the ST segment on the ECG.8 Phase 3 of the cardiac action potential is repolarization. When calcium reaches a threshold of accumulation within the cell during the plateau phase, the potassium channels open. During phase 3 of the cardiac action potential, intracellular calcium sequesters in the vicinity of the potassium channel, influencing outflow of potassium and repolarization.8 Phase 3 is generally manifested as the T wave on the ECG. At the end of phase 3, sodium channels may open with a larger than normal stimulus, which is called the relative refractory period. High and low serum calcium levels can influence the ability of sodium channels to open, changing the requisite stimulus needed to overcome the relative refractoriness of sodium channels to open during this period.9 Phase 3 ends with the return of the resting or baseline potential, phase 4. During phase 4, calcium channels in the ventricle are closed, and the ECG returns to the isoelectric line.6
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Table 1: The Action Potential of Cardiac Pacemaker Cells and Myocytes (Contractile Cells) and Changes Related to Abnormal Serum Calcium Phase
Polarization
Conductance
Hypocalcemia
Hypercalcemia
Phase 0
Pacemaker cells: depolarization
L-type calcium ion channels open; calcium and sodium flow inward to pacemaker cells
Altered automaticity and conduction; dysrhythmias
Altered automaticity and conduction; dysrhythmias
Ventricular myocytes: rapid depolarization
Voltage-gated sodium channels open; fast sodium flow inward to contractile myocytes
Phase 1 (phase 1 is not present in pacemaker cells)
Ventricular myocytes: initial repolarization
Inactivation of sodiumpotassium ion channels results in a net inward flow of potassium
Increased amplitude of the action potential
Decreased amplitude of the action potential
Phase 2 (phase 2 is not present in pacemaker cells)
Ventricular myocytes: plateau
Slow inflow of calcium through L-type channels and outflow of potassium occurs
Lengthened action potential
Shortened action potential
Phase 3
Pacemaker cells: rapid repolarization
Minor sodium-potassium exchange contributes to the flow of current
Ventricular myocytes: rapid repolarization Phase 4
Inflow of potassium through voltage-gated potassium channels and slow outflow of calcium occurs; note that the rate of repolarization is faster in myocytes compared to pacemaker cells
Pacemaker cells: Inward flow of sodium, slow (diastolic) inward flow of calcium depolarization through both L- and T-type ion channels and Ventricular slow potassium outward myocytes: flow resting Minimal electrolyte exchange; ion homeostasis
ECG Signs of Calcium Derangements Abnormal serum calcium has primary effects on the ST segment and QT interval on the ECG.10 These effects and others are listed in Table 2. The ST segment connects the QRS and T waveforms. It is characterized by a duration of 0.07 to 0.12 seconds and is isoelectric or has a slight upward slope in physiologically normal states.5,10 It represents the period from the end of depolarization to the beginning of repolarization. The ST segment is not typically
Prolonged action potential can trigger dysrhythmias (after depolarization) Relaxed slope; longer duration of repolarization
Steeper slope; speeds repolarization
Altered automaticity and conduction
Altered automaticity and conduction
Loss of sino-atrial node activity Slowed repolarization
measured in time interval, but its length influences the duration of the QT interval. The QT interval is the summation of ventricular depolarization and repolarization and depends on HR, age, and sex. Because the QT interval varies by HR, a corrected measure of the QT interval, the QTc, is used to determine the actual duration of repolarization. A mathematical approach, commonly Bazett’s formula,10 is used to calculate a QTc. The clinical significance of a shortened or prolonged QTc is that it is associated with increased risk for
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Table 2: Electrocardiographic Changes Associated With Abnormal Serum Calcium Values Calcium Level Mild derangement
Severe derangement
Hypocalcemia
Hypercalcemia
Prolonged QT
Shortened QT
Flattened T waves
Broad, tall T waves
Reduced PR
Wide QRS
Narrowed QRS
Low R wave
Prolonged ST duration
Shortened ST duration
Long QT, QTc
Shortened QT, QTc
Altered ST slope (low, depressed, inverted)
Tall, peaked T wave
Broad U wave, particularly with associated hypokalemia
life-threatening ventricular dysrhythmias and sudden cardiac death.11 A prolonged QTc is greater than 0.43 seconds in men and 0.45 seconds in women.11,12 A shortened QTc is generally less than 0.37 seconds.13 In the presence of hypocalcemia, calcium diffuses across channels into the cell at a slower rate. Reduced extracellular calcium also alters outflow of potassium. These changes in electrolyte transfer across cardiac cell membranes cause a prolongation of the plateau phase of the cardiac action potential and result in a QTc in excess of 0.45 seconds.2,8 Other abnormal ECG findings with hypocalcemia are bradyand tachy-dysrhythmias and atrial fibrillation.14 These changes in rate and rhythm are linked to calcium effects on pacemaker cells; hypocalcemia alters sodium slow channel dynamics and the threshold of pacemaker depolarization. In general, the prolongation of the QTc is attributed to the increased ST-segment duration. However, the interaction between calcium and potassium channels affects depolarization and the duration of the QRS and T waves. In the presence of hypercalcemia, calcium diffuses into the myocyte at an increased rate or quantity. High intracellular calcium, in turn, influences the opening of potassium-calcium channels during depolarization (and depolarization). The most common ECG change is a shortened ST segment, resulting in a short QT interval. With hypercalcemia, the plateau phase is shortened and a narrow QRS may be noted on an ECG.7,8 Other ECG changes associated with high serum calcium are a prolonged PR interval, low R-wave amplitude, ST eleva-
tion, and mild peaking of T waves as a result of changes in conduction across the AV node and the effects of calcium altering sodium channel dynamics in the ventricles.15,16 With severe hypercalcemia, P waves may disappear.9 Hypothermia also has been noted in severe hypercalcemia, which results in Osborne waves (notching of the upslope in V1) on the ECG tracing.17 Calcium channel activity also is regulated by the autonomic nervous system. Epinephrine and norepinephrine activate adenyl cyclase by triggering a guanosine triphosphate binding protein, ultimately activating protein kinase, to open the calcium channel allowing calcium influx.18 During periods of sympathetic nervous system activation, ECG changes associated with hypocalcemia and hypercalcemia may be exaggerated. Causes and Treatment of Serum Calcium Derangements Hypocalcemia
The cause of hypocalcemia can be determined by assessing serum levels of PTH, magnesium, creatinine, phosphate, vitamin D, amylase, lipase, and creatine kinase.5 The causes of hypocalcemia are typically categorized by comorbid presentation, occurring during hospital-based treatments, and as a result of rare conditions. Table 3 describes the causes of hypocalcemia, listing physiological and iatrogenic conditions. The treatment of hypocalcemia is controversial in critically ill patients. Experts suggest that patients without symptoms should not be treated. Patients with signs of symptomatic
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Table 3: Causes of Hypocalcemia Physiological Causes
Iatrogenic Causes
Pancreatitis
Multiple blood transfusions (citrate chelation)
Sepsis
Chemotherapy agents: cisplatin, cyclophosphamide, 5-fluorouracil, leucovorin
Severe burns Hypophosphatemia Vitamin D deficiency Rhabdomyolysis Milk-alkali syndrome Stage 5 chronic kidney disease/kidney failure Congenital hypoparathyroidism Hemochromatosis Lactate, acidemia Hypomagnesemia or severe hypermagnesemia Widespread osteoblastic metastases
Antibiotics: dactinomycin, amikacin, gentamicin, tobramycin Anticonvulsant drugs: phenytoin, phenobarbital Antifungal agents: amphotericin B, ketoconazole High-dose loop diuretics: furosemide, butamide Biphosphonate administration (Foscanart) Acquired kidney failure Parathyroidectomy Tumor lysis syndrome Phosphate administration Magnesium depletion
hypocalcemia such as tetany, laryngospasm, or ventricular arrhythmias as a consequence of a prolonged QT should be treated.5 Presenting conditions and concurrent electrolyte derangements must be treated simultaneously. In severe symptomatic hypocalcemia, 10 ml of 10% calcium gluconate can be given intravenously (IV) over 10 minutes. This dose can be given every 60 minutes until symptoms resolve.2 Moderate to severe hypocalcemia, manifested with an ionized calcium level of less than 4 mg/dL, can be treated with 4 g of calcium gluconate IV over 4 hours. Mild hypocalcemia, with an ionized calcium level of 4 to 5 mg/dL, can be treated with calcium gluconate 1 to 2 g administered IV over 2 hours.2 Hypercalcemia
Hypercalcemia symptoms correlate with the acuity and magnitude of the increase in ionized serum calcium levels.2 With mild hypercalcemia (serum values 10.4-12 mg/dL), no symptoms may occur. Moderate hypercalcemia (serum values of 12-14 mg/dL) may be associated with gastrointestinal complaints of nausea, loss of appetite, thirst, and constipation. Lethargy, polyuria, polydipsia, and nocturia may be present. More severe hypercalcemia (>14 mg/dL) symptoms include confusion, muscle weakness and muscle or joint pain, and abdominal pain. On physical examination, hypertension and hyperreflexia can be observed. The most common cause of hypercalcemia is increased calcium absorption from renal disease
coupled with the inability to excrete excess calcium.2 Gradual increases of serum calcium as occurs with malignancy may be asymptomatic, as seen in 20% to 30% of patients with cancer.2 Common causes of hypercalcemia are listed in Table 4. The focus of management of hypercalcemia is correcting the underlying problem. Hydration with sodium chloride with continuous ECG and hemodynamic monitoring should be implemented. Once rehydration is achieved, loop diuretics to promote calciuresis may be added.5 Intravenous bisphosphonates are useful in hypercalcemia from osteoclastic bone resorption, but these drugs may cause renal failure. Glucocorticoids, calcitonin, mithramycin, and gallium nitrate also may be used to block bone resorption from chronic conditions and reduce malignant hypercalcemia.5 Case Report 1 Follow-up The patient in case report 1 had both hypocalcemia and hypomagnesium. With calcium and magnesium repletion, the ECG returned to normal (Figure 3), and the circumoral paresthesia resolved. Normoreflexia was demonstrated on return physical examination, with muscle weakness improving to 5/5 on a manual muscle test. The patient reported “feeling better but not quite back to baseline.” She was discharged from preadmission testing, and advised to obtain follow-up serum tests for electrolytes including calcium, magnesium, and phosphorus, a vitamin D level, and parathyroid level. Three
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Table 4: Causes of Hypercalcemia Physiological Causes
Iatrogenic Causes
Primary hyperparathyroidism
Prolonged immobilization
Malignancy; most commonly breast, renal, ovarian/endometrial, multiple myeloma, lymphomas, and squamous cell cancers of the head, neck, cervix, and lungs
Calcium administration Medications including lithium, tamoxifen, thiazide diuretics
Granulomatous disease (sarcoidosis) Thyrotoxicosis Familial hypocalciuric hypercalcemia Vitamin D toxicity
days later, her repeat electrolytes and parathyroid values were normal, but her vitamin D was low. Her repeat ECG returned to baseline. At the follow-up visit to her primary care provider to obtain an ECG and review the follow-up laboratory values, she reported using diuretics for weight loss. Diuretic use, coupled with a newly diagnosed vitamin D deficiency, was determined to be the source of her hypocalcemia and concerning ECG changes. Oral vitamin D was prescribed using current guidelines, and the patient was instructed to avoid self-treatment with diuretics. Case Report 2 Follow-up A.B. received a bolus of 1 L of sodium chloride over 1 hour, followed by sodium chloride at a
rate of 250 mL/hour to improve fluid balance and provide sufficient fluid for the kidneys to excrete calcium. After 2 L were infused, 20 mg of furosemide was administered to accelerate calcium excretion. With no signs of fluid overload or kidney injury noted, the patient remained alert and became oriented. Four hours later, following a total of 2 L of IV fluid and a urine output of 2 L, a new serum analysis showed a PTH of 8 pmol/L and an ionized calcium level of 6.9 mg/dL. A repeat ECG demonstrated normal sinus rhythm with an improved QTc interval of 0.41 seconds. Consultation with the surgeon resulted in a plan to schedule parathyroid removal in the next 24 hours; the patient was admitted and continued to receive IV fluids. The surgery proceeded without
Figure 3: 12-lead electrocardiograph after treatment for hypocalcemia and other electrolyte derangements. Ventricular rate = 59; PR = 0.16 seconds (160 ms); QRS = 0.07 seconds (70 ms); QT/corrected QT = 0.322/0.438 seconds (322/438 ms); ST = 0.16 seconds (160 ms). 303 Copyright © 2014 American Association of Critical-Care Nurses. Unauthorized reproduction of this article is prohibited.
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incident. Parathyroid and calcium levels were within normal limits on discharge home 48 hours later. Conclusion Serum calcium abnormalities can contribute to abnormal ECG tracings. In the first case report, hypocalcemia led to concerning QTc prolongation and delayed surgery. Laboratory results and more detailed questioning led to additional findings of low serum vitamin D and self-administered intermittent diuretic use as causes of hypocalcemia. In the second case report, the patient had a symptomatic bradycardia that influenced the surgeon to move up her planned parathyroidectomy to avoid recurrent complications from hypercalcemia caused by hyperparathyroid disease. Electrolyte imbalances are common in hospitalized patients. Although treatment includes restoring electrolyte and fluid balance, clinicians also need to diagnose the underlying cause of electrolyte-induced ECG changes to prevent recurrence and avoid complications from dysrhythmias or unnecessary cardiac interventions. Application of physiological knowledge contributes to understanding the ECG changes associated with hypocalcemia and hypercalcemia. REFERENCES 1. Egi M, Kim I, Nichol A, et al. Ionized calcium concentration and outcome in critical illness. Crit Care Med. 2011;39(2):314–321. 2. French S, Subauste J, Geraci S. Calcium abnormalities in hospitalized patients. South Med J. 2012;105(4):231–237.
3. Pagana KD, Pagana T. Mosby’s Manual of Diagnostic and Laboratory Tests. 5th ed. St Louis, MO: Elsevier; 2014. 4. Slomp J, van der Voort PH, Gerritsen RT, Berk JA, Bakker AJ. Albumin-adjusted calcium is not suitable for diagnosis of hyper- and hypocalcemia in the critically ill. Crit Care Med. 2003;31(5):1389–1393. 5. Marik PE. Handbook of Evidence-Based Critical Care. 2nd ed. New York: Springer; 2010. 6. Hall JE. Guyton and Hall Textbook of Physiology. 12th ed. Philadelphia, PA: Elsevier; 2011. 7. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2(2):185–194. 8. Fearnley CJ, Roderick HL, Bootman MD. Calcium signaling in cardiac myocytes. Cold Spring Harb Perspect Biol. 2011;3(11):a004242. 9. Bers DM. Calcium cycling and signaling in cardiac myocytes. Ann Rev Physiol. 2008;70:23–49. 10. Wagner GS, Strauss DG. Marriott’s Practical Electrocardiography. 12th ed. Philadelphia, PA: Wolters Kluwer (Lippincott Williams & Wilkins); 2013. 11. Ma H, Smith B, Dmiterienko A. Statistical analysis methods for QT/QTc prolongation. J Biopharm Stat. 2008:18(3):553–563. 12. Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47(2): 362–367. 13. Moss AJ. QTc prolongation and sudden cardiac death: the association is in the detail. J Am Coll Cardiol. 2006;47(2):368–369. 14. Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57(7):802–812. 15. Balci A, Koksal O, Kose A, Armagan E, Ozdemir F, Inal T. General characteristics of patients with electrolyte imbalance admitted to emergency department. World J Emerg Med. 2013;4(2):113–116. 16. Falk RH. Severe hypercalcaemia mimicking acute myocardial infarction. Clin Med. 2009;9(5):503–504; author reply 504. 17. Nishi SP, Barbagelata NA, Atar S, Birnbaum Y, Tuero E. Hypercalcemia-induced ST-segment elevation mimicking acute myocardial infarction. J Electrocardiol. 2006;39 (3):298–300. 18. Otero J, Lenihan DJ. The “normothermic” Osborn wave induced by severe hypercalcemia. Tex Heart Inst J. 2000;27(3):316–317.
304 Copyright © 2014 American Association of Critical-Care Nurses. Unauthorized reproduction of this article is prohibited.
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ECG
Challenges
Gerard B. Hannibal, RN, MSN, PCCN Department Editor
Influence of Calcium Abnormalities on the ECG Sonya Moore, MSN, CRNA Chris Winkelman, RN, PhD Barbara Daum, MSN, CNP
E
lectrolyte disorders are a significant cause of morbidity and mortality for adults in the intensive care unit and hospital. Hypocalcemia occurs in 15% to 88% of hospital admissions. The incidence of ionized hypocalcemia has been reported at 15% to 50% in patients in the intensive care unit.1 Another 15% of hospitalized adults demonstrate hypercalcemia.2 The purpose of this column is to explain the actions of calcium on cardiac depolarization and repolarization and explore the manifestations of serum calcium derangements in a 12-lead electrocardiograph (ECG) tracing. We report the diagnosis and management of 2 composite scenarios that illustrate hypocalcemia and hypercalcemia with illustrative ECGs. Case Report 1 M.K., a 50-year-old white woman, presented to the preadmission testing area prior to a scheduled surgery for an elective tonsillectomy for airway obstruction. During the review of systems, she reported feeling “weak and tired,” with new muscle cramps and circumoral paresthesia. Her surgeon was not aware of these symptoms. Vital signs at this time were heart rate (HR) 60/min, regular; blood pressure 90/40 mm Hg, respiratory rate 14/min, and peripheral oxygen saturation 98% on room air. On physical examination, a speech hesitation/tremor was noticed, and hyperreflexia was observed in all 4 extremities. With manual muscle testing, the patient demonstrated 4/5 strength in upper extremities. A complete blood cell count, basic metabolic panel, and calcium, magnesium, phosphorous, and troponin levels were collected. A preoperative ECG was done. Laboratory values were as follows: sodium, 159 mEq/L; chloride, 111 mEq/L; potassium, 3.2 mEq/L; blood urea nitrogen, 20 mg/dL; creatinine, 0.7 mg/dL; glucose, 90 mg/dL; total calcium, 6.2 mg/dL; ionized calcium, 3.0 mg/dL; phosphorous, 4.8 mg/dL (1.6 mmol/L); magnesium, 1.0 mg/dL (0.5 mmol/L); and albumin, 4.5 mg/dL. The ECG demonstrated sinus rhythm with a prolonged corrected QT (QTc) interval and prolonged ST segment (Figure 1). An ECG from 14 months ago in
Sonya Moore is Instructor, Frances Payne Bolton School of Nursing, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106 ([email protected]). Chris Winkelman is Associate Professor, Frances Payne Bolton School of Nursing, Case Western Reserve University, and MetroHealth Medical Center, Cleveland, Ohio. Barbara Daum is CNP, MSN, Cardiology, University Hospitals Case Medical Center, Cleveland, Ohio. The authors declare no conflicts of interest. DOI: 10.1097/NCI.0000000000000038
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Figure 1: 12-lead electrocardiograph of a patient with severe hypocalcemia. Ventricular rate = 60; PR = 0.19 seconds (190 ms); QRS = 0.06 seconds (60 ms); QT/corrected QT = 0.410/0.558 seconds (410/558 ms); ST segment = 0.2 seconds (200 ms).
her primary care office had none of these features and was interpreted as sinus rhythm, rate 72/min, PR 0.18 seconds, QRS 0.06 seconds, and QTc 0.41 seconds. Case Report 2 A.B., a 56-year-old Hispanic woman, presented for preoperative testing for a parathyroidectomy. The patient was confused about time and complained of muscle weakness, lethargy, and increasing abdominal pain. The following pertinent findings were collected during physical examination: blood pressure 160/96 mm Hg, HR 52/min with regular, normal heart sounds, and clear lung sounds bilaterally. Deep tendon reflexes were diminished on bilateral lower extremities. Admitting laboratory work revealed a serum parathyroid hormone (PTH) level of 9.2 pmol/L (normal = 1.0-6.8), a total calcium level of 14.4 mg/dL, and an ionized calcium level of 10.9 mg/dL. Complete blood cell count and other laboratory findings were essentially normal. The ECG demonstrated sinus bradycardia with a shortened QTc and nonspecific T-wave abnormalities (Figure 2). Overview: Serum Calcium The normal serum calcium level ranges from 9.0 to 10.5 mg/dL (2.25-2.62 mmol/L).3 Ionized calcium is the active physiological form of this essential electrolyte, with a normal range of 4.5 to 5.6 mg/dL (1.05-1.30 mmol/L).3 Half of serum calcium is ionized, while 40% of the remaining amount is bound to proteins (90% to albumin) or anions of phosphate,
carbonate, citrate, lactate, or sulfate. As a result, the total serum calcium level is decreased in the presence of a reduced serum albumin level. However, adjusting the value of total calcium by correcting for albumin is not useful for critically ill patients, and assessing ionized calcium is recommended for diagnosis and treatment.4 In addition to its effects on the heart and ECG, ionized calcium is necessary for several physiological processes. Ionized calcium is essential to neurotransmitter release and muscle contraction and relaxation in the heart and systemically.5 Calcium is a cofactor in the clotting cascade and required for bone mineralization.6 Calcium has regulatory capabilities, including digestive enzyme activation, cytokine release, free radical production, and inhibition of adenosine triphosphate synthesis.5 Serum calcium derangements often are accompanied by concurrent alterations in phosphorus, potassium, and magnesium.5 Calcium Ion Channels Ion channels have 2 properties: ion passage through cell membranes and gating.7 Ion channel passage is selective but not exclusive, as illustrated by sodium-calcium channels that allow sodium (Na) and calcium (Ca) to bind and pass through at a rate of 3Na:1Ca.6 Gating refers to the opening and closing of ion channels, and gates can be open, closed, or inactive. Inactive gates are the basis for the cardiac cell refractory period and prevention of premature excitation. Mechanisms of gating in ion channels include
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Figure 2: 12-lead electrocardiograph of a patient with severe hypercalcemia.
voltage (charge)-dependent, ligand (chemical or neurotransmitter)-dependent, and mechanosensitive (pressure or stretch)-dependent.6,7 Two types of calcium channels exist in the heart, and both are voltage-dependent: the L(low threshold) and T-(transient) types. The L-type calcium channels are in all cardiac cells; they are associated with low voltage for activation and contribute to intracellular signaling and excitation-contraction coupling. The Ttype calcium channels are in pacemaker, atrial, and Purkinje cells and require a higher voltage to open. Both channels are affected by hypocalcemia and hypercalcemia.7 Both L-type and T-type calcium channels mediate the shape of the action potential.8 Calcium channels also are involved in supplying calcium for contractile myocytes, but myocardial contractions are not reflected in the ECG.9 Calcium and the Action Potential Five phases of the cardiac action potential, numbered 0 to 4, in ventricular myocytes form the contractile tissue of the heart. Pacemakers are specialized cardiac cells with 3 phases to the action potential, numbered 0, 3, and 4. Calcium plays a role in all phases as described in Table 1. ECG waveforms occur as electrolytes flow through ionic channels in contractile tissue.6 The particular influence of calcium on an ECG tracing generally affects the QRS duration and shape, the slope of the ST segment, and the length of the QT interval. Heart rate and rhythm also are affected by calcium via the actions on pacemaker cells, resulting in both
brady- and tachy-dysrhythmias during serum calcium derangements.8 Phase 0 corresponds to the initial upward slope of the action potential, signaling depolarization of ventricular myocytes. Phase 1 of the cardiac action potential is sometimes called the overshoot and represents the closure of the sodium and potassium channels. Phases 0, 1, and 2 are associated with the duration of the QRS. During phase 1, calcium slows the inactivation of sodium channels (gating).9 During phase 2, calcium channels open, sustaining the depolarization of ventricular myocytes and creating the plateau of the ventricular action potential, which appears as the continuation of the QRS into the ST segment on the ECG.8 Phase 3 of the cardiac action potential is repolarization. When calcium reaches a threshold of accumulation within the cell during the plateau phase, the potassium channels open. During phase 3 of the cardiac action potential, intracellular calcium sequesters in the vicinity of the potassium channel, influencing outflow of potassium and repolarization.8 Phase 3 is generally manifested as the T wave on the ECG. At the end of phase 3, sodium channels may open with a larger than normal stimulus, which is called the relative refractory period. High and low serum calcium levels can influence the ability of sodium channels to open, changing the requisite stimulus needed to overcome the relative refractoriness of sodium channels to open during this period.9 Phase 3 ends with the return of the resting or baseline potential, phase 4. During phase 4, calcium channels in the ventricle are closed, and the ECG returns to the isoelectric line.6
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Table 1: The Action Potential of Cardiac Pacemaker Cells and Myocytes (Contractile Cells) and Changes Related to Abnormal Serum Calcium Phase
Polarization
Conductance
Hypocalcemia
Hypercalcemia
Phase 0
Pacemaker cells: depolarization
L-type calcium ion channels open; calcium and sodium flow inward to pacemaker cells
Altered automaticity and conduction; dysrhythmias
Altered automaticity and conduction; dysrhythmias
Ventricular myocytes: rapid depolarization
Voltage-gated sodium channels open; fast sodium flow inward to contractile myocytes
Phase 1 (phase 1 is not present in pacemaker cells)
Ventricular myocytes: initial repolarization
Inactivation of sodiumpotassium ion channels results in a net inward flow of potassium
Increased amplitude of the action potential
Decreased amplitude of the action potential
Phase 2 (phase 2 is not present in pacemaker cells)
Ventricular myocytes: plateau
Slow inflow of calcium through L-type channels and outflow of potassium occurs
Lengthened action potential
Shortened action potential
Phase 3
Pacemaker cells: rapid repolarization
Minor sodium-potassium exchange contributes to the flow of current
Ventricular myocytes: rapid repolarization Phase 4
Inflow of potassium through voltage-gated potassium channels and slow outflow of calcium occurs; note that the rate of repolarization is faster in myocytes compared to pacemaker cells
Pacemaker cells: Inward flow of sodium, slow (diastolic) inward flow of calcium depolarization through both L- and T-type ion channels and Ventricular slow potassium outward myocytes: flow resting Minimal electrolyte exchange; ion homeostasis
ECG Signs of Calcium Derangements Abnormal serum calcium has primary effects on the ST segment and QT interval on the ECG.10 These effects and others are listed in Table 2. The ST segment connects the QRS and T waveforms. It is characterized by a duration of 0.07 to 0.12 seconds and is isoelectric or has a slight upward slope in physiologically normal states.5,10 It represents the period from the end of depolarization to the beginning of repolarization. The ST segment is not typically
Prolonged action potential can trigger dysrhythmias (after depolarization) Relaxed slope; longer duration of repolarization
Steeper slope; speeds repolarization
Altered automaticity and conduction
Altered automaticity and conduction
Loss of sino-atrial node activity Slowed repolarization
measured in time interval, but its length influences the duration of the QT interval. The QT interval is the summation of ventricular depolarization and repolarization and depends on HR, age, and sex. Because the QT interval varies by HR, a corrected measure of the QT interval, the QTc, is used to determine the actual duration of repolarization. A mathematical approach, commonly Bazett’s formula,10 is used to calculate a QTc. The clinical significance of a shortened or prolonged QTc is that it is associated with increased risk for
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Table 2: Electrocardiographic Changes Associated With Abnormal Serum Calcium Values Calcium Level Mild derangement
Severe derangement
Hypocalcemia
Hypercalcemia
Prolonged QT
Shortened QT
Flattened T waves
Broad, tall T waves
Reduced PR
Wide QRS
Narrowed QRS
Low R wave
Prolonged ST duration
Shortened ST duration
Long QT, QTc
Shortened QT, QTc
Altered ST slope (low, depressed, inverted)
Tall, peaked T wave
Broad U wave, particularly with associated hypokalemia
life-threatening ventricular dysrhythmias and sudden cardiac death.11 A prolonged QTc is greater than 0.43 seconds in men and 0.45 seconds in women.11,12 A shortened QTc is generally less than 0.37 seconds.13 In the presence of hypocalcemia, calcium diffuses across channels into the cell at a slower rate. Reduced extracellular calcium also alters outflow of potassium. These changes in electrolyte transfer across cardiac cell membranes cause a prolongation of the plateau phase of the cardiac action potential and result in a QTc in excess of 0.45 seconds.2,8 Other abnormal ECG findings with hypocalcemia are bradyand tachy-dysrhythmias and atrial fibrillation.14 These changes in rate and rhythm are linked to calcium effects on pacemaker cells; hypocalcemia alters sodium slow channel dynamics and the threshold of pacemaker depolarization. In general, the prolongation of the QTc is attributed to the increased ST-segment duration. However, the interaction between calcium and potassium channels affects depolarization and the duration of the QRS and T waves. In the presence of hypercalcemia, calcium diffuses into the myocyte at an increased rate or quantity. High intracellular calcium, in turn, influences the opening of potassium-calcium channels during depolarization (and depolarization). The most common ECG change is a shortened ST segment, resulting in a short QT interval. With hypercalcemia, the plateau phase is shortened and a narrow QRS may be noted on an ECG.7,8 Other ECG changes associated with high serum calcium are a prolonged PR interval, low R-wave amplitude, ST eleva-
tion, and mild peaking of T waves as a result of changes in conduction across the AV node and the effects of calcium altering sodium channel dynamics in the ventricles.15,16 With severe hypercalcemia, P waves may disappear.9 Hypothermia also has been noted in severe hypercalcemia, which results in Osborne waves (notching of the upslope in V1) on the ECG tracing.17 Calcium channel activity also is regulated by the autonomic nervous system. Epinephrine and norepinephrine activate adenyl cyclase by triggering a guanosine triphosphate binding protein, ultimately activating protein kinase, to open the calcium channel allowing calcium influx.18 During periods of sympathetic nervous system activation, ECG changes associated with hypocalcemia and hypercalcemia may be exaggerated. Causes and Treatment of Serum Calcium Derangements Hypocalcemia
The cause of hypocalcemia can be determined by assessing serum levels of PTH, magnesium, creatinine, phosphate, vitamin D, amylase, lipase, and creatine kinase.5 The causes of hypocalcemia are typically categorized by comorbid presentation, occurring during hospital-based treatments, and as a result of rare conditions. Table 3 describes the causes of hypocalcemia, listing physiological and iatrogenic conditions. The treatment of hypocalcemia is controversial in critically ill patients. Experts suggest that patients without symptoms should not be treated. Patients with signs of symptomatic
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Table 3: Causes of Hypocalcemia Physiological Causes
Iatrogenic Causes
Pancreatitis
Multiple blood transfusions (citrate chelation)
Sepsis
Chemotherapy agents: cisplatin, cyclophosphamide, 5-fluorouracil, leucovorin
Severe burns Hypophosphatemia Vitamin D deficiency Rhabdomyolysis Milk-alkali syndrome Stage 5 chronic kidney disease/kidney failure Congenital hypoparathyroidism Hemochromatosis Lactate, acidemia Hypomagnesemia or severe hypermagnesemia Widespread osteoblastic metastases
Antibiotics: dactinomycin, amikacin, gentamicin, tobramycin Anticonvulsant drugs: phenytoin, phenobarbital Antifungal agents: amphotericin B, ketoconazole High-dose loop diuretics: furosemide, butamide Biphosphonate administration (Foscanart) Acquired kidney failure Parathyroidectomy Tumor lysis syndrome Phosphate administration Magnesium depletion
hypocalcemia such as tetany, laryngospasm, or ventricular arrhythmias as a consequence of a prolonged QT should be treated.5 Presenting conditions and concurrent electrolyte derangements must be treated simultaneously. In severe symptomatic hypocalcemia, 10 ml of 10% calcium gluconate can be given intravenously (IV) over 10 minutes. This dose can be given every 60 minutes until symptoms resolve.2 Moderate to severe hypocalcemia, manifested with an ionized calcium level of less than 4 mg/dL, can be treated with 4 g of calcium gluconate IV over 4 hours. Mild hypocalcemia, with an ionized calcium level of 4 to 5 mg/dL, can be treated with calcium gluconate 1 to 2 g administered IV over 2 hours.2 Hypercalcemia
Hypercalcemia symptoms correlate with the acuity and magnitude of the increase in ionized serum calcium levels.2 With mild hypercalcemia (serum values 10.4-12 mg/dL), no symptoms may occur. Moderate hypercalcemia (serum values of 12-14 mg/dL) may be associated with gastrointestinal complaints of nausea, loss of appetite, thirst, and constipation. Lethargy, polyuria, polydipsia, and nocturia may be present. More severe hypercalcemia (>14 mg/dL) symptoms include confusion, muscle weakness and muscle or joint pain, and abdominal pain. On physical examination, hypertension and hyperreflexia can be observed. The most common cause of hypercalcemia is increased calcium absorption from renal disease
coupled with the inability to excrete excess calcium.2 Gradual increases of serum calcium as occurs with malignancy may be asymptomatic, as seen in 20% to 30% of patients with cancer.2 Common causes of hypercalcemia are listed in Table 4. The focus of management of hypercalcemia is correcting the underlying problem. Hydration with sodium chloride with continuous ECG and hemodynamic monitoring should be implemented. Once rehydration is achieved, loop diuretics to promote calciuresis may be added.5 Intravenous bisphosphonates are useful in hypercalcemia from osteoclastic bone resorption, but these drugs may cause renal failure. Glucocorticoids, calcitonin, mithramycin, and gallium nitrate also may be used to block bone resorption from chronic conditions and reduce malignant hypercalcemia.5 Case Report 1 Follow-up The patient in case report 1 had both hypocalcemia and hypomagnesium. With calcium and magnesium repletion, the ECG returned to normal (Figure 3), and the circumoral paresthesia resolved. Normoreflexia was demonstrated on return physical examination, with muscle weakness improving to 5/5 on a manual muscle test. The patient reported “feeling better but not quite back to baseline.” She was discharged from preadmission testing, and advised to obtain follow-up serum tests for electrolytes including calcium, magnesium, and phosphorus, a vitamin D level, and parathyroid level. Three
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Table 4: Causes of Hypercalcemia Physiological Causes
Iatrogenic Causes
Primary hyperparathyroidism
Prolonged immobilization
Malignancy; most commonly breast, renal, ovarian/endometrial, multiple myeloma, lymphomas, and squamous cell cancers of the head, neck, cervix, and lungs
Calcium administration Medications including lithium, tamoxifen, thiazide diuretics
Granulomatous disease (sarcoidosis) Thyrotoxicosis Familial hypocalciuric hypercalcemia Vitamin D toxicity
days later, her repeat electrolytes and parathyroid values were normal, but her vitamin D was low. Her repeat ECG returned to baseline. At the follow-up visit to her primary care provider to obtain an ECG and review the follow-up laboratory values, she reported using diuretics for weight loss. Diuretic use, coupled with a newly diagnosed vitamin D deficiency, was determined to be the source of her hypocalcemia and concerning ECG changes. Oral vitamin D was prescribed using current guidelines, and the patient was instructed to avoid self-treatment with diuretics. Case Report 2 Follow-up A.B. received a bolus of 1 L of sodium chloride over 1 hour, followed by sodium chloride at a
rate of 250 mL/hour to improve fluid balance and provide sufficient fluid for the kidneys to excrete calcium. After 2 L were infused, 20 mg of furosemide was administered to accelerate calcium excretion. With no signs of fluid overload or kidney injury noted, the patient remained alert and became oriented. Four hours later, following a total of 2 L of IV fluid and a urine output of 2 L, a new serum analysis showed a PTH of 8 pmol/L and an ionized calcium level of 6.9 mg/dL. A repeat ECG demonstrated normal sinus rhythm with an improved QTc interval of 0.41 seconds. Consultation with the surgeon resulted in a plan to schedule parathyroid removal in the next 24 hours; the patient was admitted and continued to receive IV fluids. The surgery proceeded without
Figure 3: 12-lead electrocardiograph after treatment for hypocalcemia and other electrolyte derangements. Ventricular rate = 59; PR = 0.16 seconds (160 ms); QRS = 0.07 seconds (70 ms); QT/corrected QT = 0.322/0.438 seconds (322/438 ms); ST = 0.16 seconds (160 ms). 303 Copyright © 2014 American Association of Critical-Care Nurses. Unauthorized reproduction of this article is prohibited.
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incident. Parathyroid and calcium levels were within normal limits on discharge home 48 hours later. Conclusion Serum calcium abnormalities can contribute to abnormal ECG tracings. In the first case report, hypocalcemia led to concerning QTc prolongation and delayed surgery. Laboratory results and more detailed questioning led to additional findings of low serum vitamin D and self-administered intermittent diuretic use as causes of hypocalcemia. In the second case report, the patient had a symptomatic bradycardia that influenced the surgeon to move up her planned parathyroidectomy to avoid recurrent complications from hypercalcemia caused by hyperparathyroid disease. Electrolyte imbalances are common in hospitalized patients. Although treatment includes restoring electrolyte and fluid balance, clinicians also need to diagnose the underlying cause of electrolyte-induced ECG changes to prevent recurrence and avoid complications from dysrhythmias or unnecessary cardiac interventions. Application of physiological knowledge contributes to understanding the ECG changes associated with hypocalcemia and hypercalcemia. REFERENCES 1. Egi M, Kim I, Nichol A, et al. Ionized calcium concentration and outcome in critical illness. Crit Care Med. 2011;39(2):314–321. 2. French S, Subauste J, Geraci S. Calcium abnormalities in hospitalized patients. South Med J. 2012;105(4):231–237.
3. Pagana KD, Pagana T. Mosby’s Manual of Diagnostic and Laboratory Tests. 5th ed. St Louis, MO: Elsevier; 2014. 4. Slomp J, van der Voort PH, Gerritsen RT, Berk JA, Bakker AJ. Albumin-adjusted calcium is not suitable for diagnosis of hyper- and hypocalcemia in the critically ill. Crit Care Med. 2003;31(5):1389–1393. 5. Marik PE. Handbook of Evidence-Based Critical Care. 2nd ed. New York: Springer; 2010. 6. Hall JE. Guyton and Hall Textbook of Physiology. 12th ed. Philadelphia, PA: Elsevier; 2011. 7. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2(2):185–194. 8. Fearnley CJ, Roderick HL, Bootman MD. Calcium signaling in cardiac myocytes. Cold Spring Harb Perspect Biol. 2011;3(11):a004242. 9. Bers DM. Calcium cycling and signaling in cardiac myocytes. Ann Rev Physiol. 2008;70:23–49. 10. Wagner GS, Strauss DG. Marriott’s Practical Electrocardiography. 12th ed. Philadelphia, PA: Wolters Kluwer (Lippincott Williams & Wilkins); 2013. 11. Ma H, Smith B, Dmiterienko A. Statistical analysis methods for QT/QTc prolongation. J Biopharm Stat. 2008:18(3):553–563. 12. Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47(2): 362–367. 13. Moss AJ. QTc prolongation and sudden cardiac death: the association is in the detail. J Am Coll Cardiol. 2006;47(2):368–369. 14. Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57(7):802–812. 15. Balci A, Koksal O, Kose A, Armagan E, Ozdemir F, Inal T. General characteristics of patients with electrolyte imbalance admitted to emergency department. World J Emerg Med. 2013;4(2):113–116. 16. Falk RH. Severe hypercalcaemia mimicking acute myocardial infarction. Clin Med. 2009;9(5):503–504; author reply 504. 17. Nishi SP, Barbagelata NA, Atar S, Birnbaum Y, Tuero E. Hypercalcemia-induced ST-segment elevation mimicking acute myocardial infarction. J Electrocardiol. 2006;39 (3):298–300. 18. Otero J, Lenihan DJ. The “normothermic” Osborn wave induced by severe hypercalcemia. Tex Heart Inst J. 2000;27(3):316–317.
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