the clinical value of the ecg in noncardiac conditionscardioland.org/ecg/clinical value of the ecg...

DOI 10.1378/chest.125.4.1561 2004;125;1561-1576 Chest

Carlos Van Mieghem, Marc Sabbe and Daniel Knockaert

ConditionsThe Clinical Value of the ECG in Noncardiac

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The Clinical Value of the ECG inNoncardiac Conditions*

Carlos Van Mieghem, MD; Marc Sabbe, MD, PhD; andDaniel Knockaert, MD, PhD

The ECG is an indispensable tool in the ICU for the detection and diagnosis of heart disease.ECG abnormalities however can be present in a wide variety of noncardiac conditions,complicating the differential diagnosis with primary cardiac pathology. This overview discussesthe ECG abnormalities and their pathophysiologic basis in the most frequently encounterednoncardiac conditions, such as electrolyte abnormalities, pulmonary embolism, CNS diseases,esophageal disorders, hypothermia, and drug-related and other conditions. Knowledge of thecharacteristic ECG changes may provide early clues to the presence of these disorders, theprompt recognition of which can be life saving. (CHEST 2004; 125:1561–1576)

Key words: CNS disease; drugs; ECG; electrolyte abnormalities; esophageal disorders; hypothermia; noncardiacconditions; poisoning; pulmonary embolism; QT syndrome

Abbreviations: CAD � coronary artery disease; CO � carbon monoxide; LQTS � long QT syndrome;MI � myocardial infarction; PE � pulmonary embolism; QTo � observed QT interval; SAH � subarachnoid hemor-rhage; TCA � tricyclic antidepressant; TdP � torsades de pointes

T he critical care physician is confronted daily withpatients who present with a great variety of

complaints. In patients either suspected of having orbeing at high risk of cardiac disease, an ECG is asimple, useful, and readily available part of thediagnostic workup. A history of prolonged retroster-nal and oppressing pain in combination with ST-segment elevation on the ECG will suggest thediagnosis of a myocardial infarction (MI). However,ST-segment elevation and tall T waves do not invari-ably mean myocardial ischemia. They can also occurin hyperkalemia, hypothermia, and intracranial hem-orrhage. Particularly in the latter case, a wrongdiagnosis of ischemic cardiac disease could be dev-

astating for the patient if thrombolytic therapyshould be started inappropriately. It therefore maybe a challenging and sometimes difficult task tointerpret an ECG correctly.

In this review, we will discuss the ECG manifes-tations of electrolyte disorders and acute pulmonaryembolism (PE) only briefly, as these are well known.More attention will be given to ECG changes in thefollowing disorders: CNS pathology, esophageal dis-orders, hypothermia, ECG changes caused by drugsor poisoning, and finally some unusual conditions.

Electrolyte Disorders

Potassium

The potassium ion plays a key role in the normalfunction of the cells of the human body. In the heart,specific levels of intracellular and extracellular po-tassium are essential for normal electrical pulsegeneration and conduction. Disturbances in cardiacconduction, which can lead to ventricular fibrillationor asystole, pose the greatest danger to the patientwith hyperkalemia. Hyperkalemia is associated witha distinctive sequence of ECG changes. The rela-tionship between the degree of hyperkalemia and

*From the Departments of Cardiology (Dr. Van Mieghem),Emergency Medicine (Dr. Sabbe), and General Internal Medi-cine (Dr. Knockaert), University Hospital Gasthuisberg, Leuven,Belgium.Manuscript received February 12, 2003; revision accepted Octo-ber 23, 2003.Reproduction of this article is prohibited without written permis-sion from the American College of Chest Physicians (e-mail:[email protected]).Correspondence to: Carlos Van Mieghem, MD, Department ofCardiology, Thoraxcenter, Bd 404, Erasmus MC, Dr. Molewa-terplein 40, 3015 GD Rotterdam, The Netherlands; e-mail:[email protected]

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the ECG changes, however, is variable, and in rarecases of severe hyperkalemia the ECG may even benormal or near normal.1 The earliest changes are theappearance of peaked, narrow T waves and a short-ened QT interval, which reflect abnormally rapidrepolarization (Fig 1).2 Occasionally, this may beconfused with the tall T waves of myocardial isch-emia (Fig 2). However, the QT interval is usuallynormal or prolonged during ischemic episodes.2

Further changes of the ECG occur at a plasma K�

concentration � 7 to 8 mEq/L, and these changesare primarily due to delayed depolarization: widen-ing of the QRS complex (the ECG manifestation ofslowed ventricular depolarization) and decreasedamplitude with widening and eventual loss of the Pwave. PR prolongation can also occur, followedsometimes by second-degree or third-degree AVblock. ST-segment elevation in leads V1 and V2,mimicking acute MI, has occasionally been reportedin severe hyperkalemia.3 The ST-segment deviationprobably is caused by nonhomogenous depolariza-tion in different portions of the myocardium. Ac-cording to this hypothesis, a voltage gradient iscreated between normal myocardial cells and thosedepolarized by potassium, resulting in current flowbetween these regions. Since dialysis rapidly normal-izes the ST-segment elevation, it is also known as the

dialyzable current of injury.4 The final changes are asine-wave pattern, in which the widened QRS com-plex merges with the T wave. This is followed byventricular fibrillation or asystole.

Hypokalemia produces characteristic changes inthe ECG that are primarily due to delayed ventric-ular repolarization. The result is ST-segment depres-sion with decreased amplitude or inversion of the Twave and increased U wave prominence. In severehypokalemia, an increase in amplitude of the P wave,prolongation of the PR interval, and widening of theQRS complex may all occur.2

Hypokalemia is an important cause of acquiredlong QT syndrome (LQTS), a condition that predis-poses to torsades de pointes (TdP), since it delaysventricular repolarization and sets the stage forre-entrant arrhythmias. Hypokalemia also causes ar-rhythmias due to enhanced automaticity. The risk ofhypokalemia-induced arrhythmia is increased in pa-tients with either myocardial ischemia or who arereceiving digitalis.5

Calcium

Hypercalcemia and hypocalcemia predominantlyalter the action potential duration (phase 2 of theaction potential), which results in either shortening

Figure 1. 12-lead ECG from a patient with hyperkalemia (K� concentration of 7.1 mEq/L). Note theclassic peaked T waves in the precordial leads. The QTc interval (341 ms) is shortened.

1562 Critical Care Review



(hypercalcemia) or prolongation (hypocalcemia) ofthe QT interval. The influence on the QT interval isentirely due to a modification of the ST-segmentduration. Both conditions can affect T-wave mor-phology.2

In severe hypercalcemia, QRS complex and PRintervals frequently are prolonged, and second-degree or third-degree AV block has been reported.2The J wave, also referred as the Osborn wave, whichis considered pathognomonic of hypothermia, hasoccasionally been reported in hypercalcemia.6 Thecombination of hypocalcemia and hyperkalemia, asseen in patients with renal insufficiency, produces acharacteristic ECG pattern of ST-segment prolonga-tion (from hypocalcemia) with a “tented” T wave(from hyperkalemia).2

Magnesium

Magnesium concentrations within the range en-countered in clinical practice do not produce specificECG patterns, at least at normal K and Ca concen-tration.2 Hypomagnesemia usually is associated withpotassium depletion, and the ECG abnormalities arethose of hypokalemia.7 Magnesium is essential forthe control of intracellular potassium concentrationand thus contributes to the electrical stability of thecardiac cell. Its antiarrhythmic potential is well es-tablished in the treatment of TdP. Hypermag-

nesemia is an uncommon clinical condition and isusually encountered in patients with renal failurewho have other electrolyte disturbances, particularlyhyperkalemia and hypocalcemia, which in them-selves produce characteristic ECG changes.7

Sodium

Isolated hypernatremia or hyponatremia has noconsistent effect on the ECG, but in patients withintraventricular conduction disturbances caused byhyperkalemia, hypernatremia shortens and hypona-tremia prolongs the QRS duration.2

PE

PE continues to be considered both an underdi-agnosed and overdiagnosed, potentially fatal disor-der. In recent years, the diagnostic contribution ofrelatively new techniques such as echocardiographyand spiral CT has been studied intensively. The“classical” S1Q3T3 ECG pattern was described asearly as 1935, yet the diagnostic role of ECG in acutePE continues to arouse clinical interest. A number ofexcellent reviews on this subject have been pub-lished in recent years.8,9 In the acute phase of PE,numerous ECG changes may be seen. These includearrhythmias, alteration in conduction, a shift in axisof the QRS complex, and changes in morphology ofthe P wave, the QRS complex, the ST segment, andthe T wave. As shown in Table 1, the ECG findingscan be extremely variable, with poor sensitivity andspecificity (Fig 3,4). Indeed the ECG may be normal

Figure 2. Similar changes are found in the initial stage of anacute coronary occlusion (hyperacute, tall T-wave changes in theprecordial leads). The QTc interval (399 ms) in this patient, whopresented with an occlusion of the left anterior descendingcoronary artery, is normal.

Table 1—Reported ECG Findings in Acute PE*

Variables %

Normal ECG 9–27Rhythm disturbances

Sinus tachycardia 8–69Premature beats (atrial or ventricular) 4–23Atrial fibrillation or flutter 0–35

P-wave abnormalitiesP pulmonale 6–18

QRS complex changesRight-axis deviation 3–66Left-axis deviation 2–14Right bundle-branch block pattern 6–67Q waves in leads III and aVF 14–49S waves in leads I and aVL 28–73Clockwise rotation of the heart 7–51S1Q3T3 11–50

ST-segment and T-wave abnormalities 49–77ST-segment elevation in leads V1, aVR, and IIIT-wave inversion in precordial leads V1 through V5

T-wave negativity in leads III and aVF

*Adapted from Chan et al9 and Panos et al.10




in up to 27% of the patients.8 Pre-existing cardiopul-monary disease can mimic several of the abnormal-ities associated with PE and this decreases thespecificity of the ECG. In a recent study, the S1Q3T3pattern, considered pathognomonic for acute PE bymany clinicians, was equally prevalent in patientswith and without PE.9

The identification of right ventricular dysfunctionin patients with PE is an important finding as itcorrelates with outcome.11 Only a few reports12–15

exist on the relation between the ECG and rightventricular overload. We particularly mention thestudy of Sreeram et al,12 as this report includes mostof the ECG signs suggested by other investigators asindicative of right ventricular strain. In 49 consecu-tive patients with proven PE, right ventricular over-load, as defined by echocardiography, was identifiedon 76% of ECGs obtained at hospital admission ifthree or more of the following ECG findings werefound: (1) incomplete or complete right bundle-branch block; (2) S waves in leads I and aVL � 1.5mm; (3) transition zone shift to V5; (4) Q waves inleads III and aVF but not in lead II; (5) QRS axis� 90° or indeterminate axis; (6) low limb leadvoltage � 5 mm; and (7) T wave inversion in leadsIII and aVF or in leads V1 to V4. The majorshortcomings of these studies are their retrospectivenature, the lack of a control group, and the exclusionof most patients with preexisting cardiac or pulmo-

nary disease. In addition, the study of Sreeram et al12

underscores the poor diagnostic performance of theECG as a single study, since 26% of patients withsevere PE do not demonstrate any ECG abnormalityat all. Their message is nevertheless relevant, as thiscombination of ECG findings assists the clinician inrapidly identifying some patients with severe PE,who may have ECG manifestations of right heartstrain.

In conclusion, the role of the ECG as an indepen-dent marker for the diagnosis, severity and prognosisof PE is limited. There are no ECG findings that areunequivocally diagnostic of PE. However, the com-bination of certain ECG findings, in particular thosedescribed by Sreeram et al,12 within the clinicalcontext of a probable PE should raise a high degreeof suspicion, and the diagnosis can be confirmed orrejected by a more specific diagnostic test.

CNS Disease

The association of specific ECG changes withintracranial disease has been recognized for � 5decades.16 ECG abnormalities occur most often inpatients with subarachnoid hemorrhage, but alsohave been described in cases of ischemic stroke,intracranial hemorrhage, head trauma, neurosurgicalprocedures, acute meningitis, intracranial space-occupying tumors, and epilepsy.17

Cerebrovascular disorders mainly cause abnormal-ities of ventricular repolarization. The most common

Figure 4. This patient also demonstrated signs of major PE: alarge thrombus in both main pulmonary arteries (chest CT) andright ventricular dysfunction (echocardiography) were docu-mented. The ECG only revealed sinus tachycardia.

Figure 3. 12-lead ECG from a patient with a massive PE.Echocardiography confirmed the ECG signs of right ventricularstrain (symmetrical T-wave inversion in the precordial leads V1through V4).




findings are depressed ST segments, flat or invertedT waves, prominent U waves, and prolongation ofthe QTc.16 Prolonged QT intervals are associatedwith the risk of TdP. The most striking ECG changesare usually associated with subarachnoid hemor-rhage (SAH). The prevalence of ECG abnormalitiesin this group of patients varies from 50 to 90%.18 Asshown in Figure 5, these changes sometimes cannotbe differentiated from the changes noted in an acutecoronary syndrome and are sometimes interpreted assuch. Pathologic Q waves also can develop.16 Boththe ST-T wave abnormalities and Q waves are oftentransient but may persist as long as 8 weeks.19

Besides changes in ECG morphology, rhythm disor-ders also occur in CNS disorders. The incidence hasbeen estimated to be � 75%.16 Both tachyarrhyth-mias and bradyarrhythmias can occur. Most of theserhythm problems are benign and include sinus tachy-cardia and premature atrial and ventricular contrac-tions. Clinically significant arrhythmias, however, arenot unusual. New-onset atrial fibrillation has beenreported in as many as one third of patients withacute stroke, although it is not always clear whetherthe atrial fibrillation associated with a stroke is acause or an effect.17 TdP has been detected in 4% ofpatients with SAH.18,20 Cerebrovascular accidentsmay also be associated with all degrees of AV block.21

Complete AV dissociation, however, is rare, and ifpresent is usually of short duration.

The pathophysiology of these ECG abnormalitiesis not entirely clear, and several mechanisms have

been proposed. Substantial evidence endorses thehypothesis that the ECG changes are the result ofmyocardial injury. Definite proof of myocardial dam-age was first demonstrated by autopsy studies andsubsequently in reports showing the presence ofregional wall abnormalities on two-dimensionalechocardiography or at left ventriculography.22-24 Ina recent study, laboratory confirmation of cardiacinjury has been provided by the finding of elevatedcardiac troponin I levels in a considerable proportionof patients with acute neurologic disease.25

The next question is how CNS pathology gives riseto ischemic cardiac injury? It is hypothesized thatCNS injury may result in excessive sympathetic toneand catecholamine production. The most importantcontrol sites of the sympathetic nervous system arefound to be the insular cortex, amygdala, and lateralhypothalamus.26 In stroke patients, in whom thelikelihood of concomitant coronary artery disease(CAD) is high, it is plausible that an increase insympathetic tone results in increased oxygen de-mand and hence myocardial damage. However, traf-fic accident victims and young patients with SAHalso demonstrate myocardial damage in the presenceof normal coronary arteries. This has been shown inautopsy series.26,27 Experimental models and clinicaldata lend further support to the hypothesis of sym-pathetic overactivity. Myocardial damage can beproduced experimentally by the parenteral adminis-tration of catecholamines or by electrical stimulationof specific regions of the brain as the hypothalamusand insula.16 The lesions are similar to those found inpatients who have either a pheochromocytoma or arecocaine abusers.28 Catecholamines probably eitherhave a direct toxic effect on myocardial cells ormediate the vasoconstriction of coronary arterieswith subsequent myocardial damage.28

In a substantial number of patients with ECGchanges, no evidence of myocardial damage ispresent. It is likely that reflex mechanisms that giverise to transient electrophysiologic changes in theheart are responsible for the ECG changes observedin these cases.29

Esophageal Disorders

The ECG is a standard test in the investigation ofthe patient with chest pain. The main aim of theevaluation is to exclude cardiac disease. Esophagealdisorders are well recognized among the noncardiaccauses of chest pain.

Chest pain of esophageal origin is frequentlyclinically indistinguishable from that of cardiac originand responds equally well to nitroglycerine. Thissimilarity can be explained by the convergence of

Figure 5. ECG from a patient with an acute subarachnoidhemorrhage. Note the inverted T waves in the precordial andlateral leads, which can mimic the changes seen with myocardialischemia. In this patient, the QT interval was markedly prolonged(QTc � 613 ms).




afferent signals from heart and esophagus to thesame dorsal neurons of the spinal cord.30

Between 10% and 50% of patients with anginalpain who are referred for arteriography are found tohave normal coronary arteries.31 An esophageal sourceof noncardiac chest pain is found in up to 60% of cases,and ECG abnormalities may be found in these pa-tients.31 Changes in T wave morphology and ST seg-ments, characteristic manifestations of myocardial isch-emia, may be misleading. Three studies based on eithermethacholine or ergonovine provocation tests in pa-tients with noncardiac chest pain have reported theoccurrence of chest pain associated with esophagealmotility abnormalities and ischemic changes on theECG.34–36 Because of negative cardiac investigationfindings (often including coronary angiography), theesophagus was presumed to be the origin of chest painand ECG abnormalities. This hypothesis however canbe questioned since acetylcholine can also inducespasm of the large coronary arteries.37 Even in theabsence of large vessel spasm, acetylcholine can pro-voke angina-like chest pain with ischemic ECGchanges, as has been shown in a study of patients withchest pain and normal or near-normal (� 50% reduc-tion in lumen diameter) coronary arteriograms.38 Theinvestigators hypothesized that these findings were theresult of myocardial ischemia due to coronary micro-vascular spasm.

Gastroesophageal reflux is a more important causeof angina-like pain than esophageal motility disor-ders.39 Acid installation in the esophagus may triggermyocardial ischemia and ECG changes in patientswith concomitant CAD.40,41 An elevated sympatheticdischarge with a resultant increase in myocardialoxygen demand and reduction in coronary bloodflow (as measured by intracoronary Doppler cathe-ter) have been proposed as the underlying mecha-nism.40,41 These experimental findings, however,have not been supported by clinical studies. The roleof gastroesophageal reflux and motility disorders ininducing chest pain in patients with CAD has beenstudied by correlating episodes of chest pain withfindings of esophageal manometry, measurement ofpH and ECG recording.30,42 Most pain episodeswere not associated with acid reflux or ECG signs ofmyocardial ischemia, and pain was rarely precededby a reflux episode. Hence, acid reflux does not seemto induce myocardial ischemia. Furthermore, in agroup of patients with no underlying cardiac disease,reflux did not produce any ECG changes.43

In conclusion, both cardiac and esophageal diseasemay produce similar chest pain, and these twoentities frequently coexist, thereby confusing theclinician. The documentation of ECG abnormalitiesis an important finding, as it makes the diagnosis ofan esophageal disorder unlikely.

Hypothermia

Accidental hypothermia is not uncommon duringthe winter months. Elderly people are particularly atrisk, as they often live alone in inadequately heatedrooms. One study in Scotland suggested that hypo-thermia probably accounts for � 4,000 hospital ad-missions and � 1,000 deaths per year.44

Characteristic ECG changes occur in patients withhypothermia (Fig 6). Knowledge of these changesmay facilitate a rapid diagnosis. The Osborn wave,also known as the J wave, is the most striking ECGfeature in hypothermia. It is a “hump-like” deflectionbetween the QRS complex and the early part of theST segment.45 The amplitude and the duration of thewave increase with decreasing body temperature.The J wave is most prominent in leads facing the leftventricle and in the inferior limb leads.45 Withrewarming, the amplitude decreases but the J wavecan persist 12 to 24 h after restoration of bodytemperature.46 The electrophysiologic origin of the Jwave was recently clarified.47 It is caused by atransmural voltage gradient created by the presenceof a prominent action potential notch in the epicar-dium but not endocardium. The notched configura-tion of the action potential is explained by moreprominent transient outward potassium current inepicardial compared to endocardial layers. As such, adistinct J wave or elevated J point has been describedin subjects with the “early repolarization syndrome,”a normal variant. Under hypothermic conditions, thechannel remains open longer. This causes an increasein the amplitude and width of the action potentialnotch in the epicardium but not in the endocardium,giving rise to the Osborn wave on the ECG. TheOsborn wave is not specific for hypothermia, as it maybe seen in hypercalcemia, certain CNS lesions, partic-ularly of the hypothalamus and, as already mentioned,can appear as a normal variant.6,47,48

Other ECG features of hypothermia include shiv-ering artifacts due to muscular tremor (which maynot be evident clinically), sinus bradycardia, QRSprolongation, and prolongation of the PR intervaland QTc.48 With decreasing body temperature,rhythm abnormalities are a cause for concern. Atrialfibrillation is common below 32°C, and the risk ofventricular fibrillation is high when body tempera-ture is lower than 28°C.49

Drugs Associated With Acquired LQTS

Both cardiac drugs and other medications cancause ECG changes. Many antiarrhythmic drugsdisplay a proarrhythmic effect. In recent years, re-ports of TdP and syncope or cardiac arrest duringtherapy with antihistamines, antibiotics, GI proki-




netic drugs, and others have drawn attention to thepotential proarrhythmic effects of noncardiovasculardrugs.50,51 TdP is a specific type of proarrhythmiaand is classically described as a pause-dependentpolymorphic ventricular tachycardia occurring in thesetting of the congenital or acquired LQTS. We willmainly discuss the acquired form. LQTS is a disorderof cardiac repolarization that is characterized byprolongation of the QTc.51 The QT interval is theECG measure of the total duration of the depolar-ization and repolarization phases of the ventricularaction potential. Lengthening of the repolarization

phase results in the LQTS. The acquired LQTS isalmost always associated with drugs that prolong theQT interval, although other causes have been re-ported (Table 2). An extensive list of these drugs canbe found at http://www.torsades.org.

Different ion currents contribute to the repolar-ization phase of the ventricular action potential.Current knowledge underscores the importance ofthe potassium ion channels. Congenital LQTS is aheritable ion channel disease caused by one ofseveral mutations in the genes coding for the sodiumor potassium ion channel proteins. Mutations of the

Figure 6. Top, A: ECG from a patient with severe hypothermia (23.8°C at presentation). Osbornwaves (as depicted by the arrows) are present in all leads. Bottom, B: After patient rewarming (35.9°C),the Osborn waves disappeared. The QT interval was still prolonged (QTc � 591 ms).




potassium genes KvLQT1 and HERG, which under-lie the LQT1 and LQT2 genotypes, together causesome 90% of cases.52 TdP may occur with all antiar-rhythmic drugs that block sodium or potassiumchannels and thus result in myocardial repolarizationabnormalities. However, it is mainly described forclass Ia and III antiarrhythmic drugs, which blockthe delayed rectifier potassium current. Noncardiacdrugs, capable of prolonging the QTc interval, act byblocking a cardiac potassium channel, most com-monly the Ikr-subtype, the rapidly activating potas-sium-delayed rectifier, which is the channel affectedby mutations that underlie the LQT2 and LQT6genotypes.53 This has been demonstrated in studieswith terfenadine, a antihistaminergic agent, anderythromycin, a macrolide antibiotic.54,55

In the majority of cases of drug-induced LQTS,predisposing factors can be identified. In an analysisof 250 patients treated with cisapride who acquiredQT prolongation, risk factors were identified in 74%of cases: inhibition of cytochrome P-450 3A4 byother drugs was the most frequent (47%), followedby electrolyte abnormalities (32%), and co-adminis-tration of other QT-prolonging drugs (23%).56

Drugs that inhibit the hepatic cytochrome P-450enzyme (ketoconazole, itraconazole, erythromycin)can decrease the metabolism of drugs such as terfe-nadine, astemizole, or cisapride, and may result inadditive effects. Similarly, hepatic or renal failuremay enhance the QT interval-prolonging effect ofvarious drugs. This explains the increased incidenceof sotalol-associated TdP reported in patients with

impaired renal function.57 Other drugs that prolongaction potential duration, such as phenothiazines andhaloperidol, may play a role. Older age, female sex,structural heart disease (including left ventricular hy-pertrophy, low left ventricular ejection fraction, myo-cardial ischemia), and slow heart rate also facilitatedrug-induced prolongation of the QTc.53 Finally, insome patients with drug-induced LQTS, an underlyinggenetic predisposition has been demonstrated.52

LQTS has several ECG manifestations. The mainfeature is QTc prolongation. The QT interval ismeasured from the beginning of the QRS complex tothe end of the T wave, preferably at a paper speed of� 50 mm/s. A discrete and separate U wave shouldnot be included in the measurement of the QTinterval. Methods for QT measurement have severallimitations and vary among investigators. It is recom-mended to measure the QT interval in leads in whichthe T wave is most distinct, in lead II or aVL, or inleads with the longest QT interval, usually V2 or V3.To increase precision, the QT interval should bemeasured in three or more consecutive beats (ex-cluding those preceded by premature beats) andshould be averaged.58

The QT interval shows considerable intraindi-vidual and interindividual variability and varies withheart rate, gender, age, autonomic tone, and time ofthe day. QT measurements should be corrected forheart rate. QTc may be calculated from the observedQT interval (QTo) using the formula of Bazett,where the QTc is equal to the QTo divided by thesquare root of the RR interval in seconds(QTc � QTo/�RR).58 QTc is prolonged when it is� 450 ms in men or � 470 ms in women. In childrenaged 1 to 15 years, � 460 ms represents the upperlimit of normal.59 Two caveats should be noted. First,the suggested QTc values are an arbitrary cut-off, asQTc values � 500 ms have been observed in healthyindividuals.58 Second, QTc prolongation does notoccur in 6 to 12% of patients who carry a geneticmutation.53 Nevertheless, a prolonged QTc interval,especially values � 500 ms, should be a reason forconcern and should be considered as a contraindica-tion for the use of drugs capable of prolonging thecardiac repolarization.

Other ECG features include increased QT disper-sion and T wave and U wave abnormalities. T waveand U wave changes are more frequent in thecongenital form of the LQTS.53

The patient with LQTS is at risk for TdP. Theclinical picture of TdP can range from a brief,asymptomatic, self-terminating arrhythmia episodeto one of single or recurrent syncope or suddencardiac death. The arrhythmia is characterized by acontinuous alteration in morphology, amplitude, andpolarity of the QRS complexes, whose peaks twist

Table 2—Main Causes of Acquired LQTS*

DrugsCardiac

Quinidine, disopyramide, procainamide, sotalol, ibutilide,azimilide, amiodarone, phenylamine, bepridil

NoncardiacErythromycin, grepafloxacin, moxifloxacin, pentamidine,

amantadine, chloroquine, trimethoprim-sulfamethoxazole,phenothiazines, haloperidol, tricyclic antidepressants,terfenadine, astemizole, ketoconazole, itraconazole,probucol, ketanserin, cisapride, papaverine, tacrolimus,arsenic trioxide

Electrolyte disturbancesHypokalemia, hypomagnesemia, hypocalcemia

Severe bradycardiaSick sinus syndrome, high-grade AV block

Poisons and recreational drugsCocaine, organophosphorus compounds

Cerebrovascular diseasesIntracranial and subarachnoid hemorrhage, stroke, encephalitis

Other causesHypothyroidism, hypothermia, myocardial ischemia, protein-

sparing fasting, autonomic neuropathy, HIV disease

*Adapted from Kahn52 and Hohnloser.61




around the isoelectric baseline (hence the termtorsades de pointes or twisting of the points) asoriginally described by Dessertenne.60 The rhythmranges between 100 beats/min and 250 beats/min,and usually terminates spontaneously but maydegenerate into ventricular fibrillation or morerarely monomorphic ventricular tachycardia.61

TdP typically occurs after a prolonged QTc in thepreceding sinus beats. Especially in acquiredLQTS, TdP is triggered by a typical short-long-short QRS complex interval initiation sequence(Fig 7). To explain this feature, we quote thebrilliant description of Khan52:

The initiation of TdP is dependent on a pause in theelectrical activity created by a longer cycle length, whichmay be secondary to an extrasystole or bradycardia. Thelonger cycle length usually precedes the last supraventric-ular beat before the initiation of TdP. In a typical short-long-short sequence, a supraventricular beat is followed byan extrasystole (short cycle). This extrasystole is followedby a supraventricular beat after a long postextrasystolicpause (long cycle); this supraventricular beat, which has alonger QT interval than the preceding supraventricularbeats, is followed by a ventricular beat that is the first beatof the TdP.

Drug-Induced ECG Changes and CardiacToxicity

In this section, we highlight the typical ECGabnormalities associated with the use, or mainlyabuse, of the psychotropic agents lithium and tricy-clic antidepressants (TCAs), and the stimulants co-caine and amphetamines. A short discussion of thecardiovascular side effects of chemotherapeuticagents is also provided.

TCAs were previously the mainstay of antidepres-sant pharmacotherapy, but they have been largely

replaced by selective serotonin reuptake inhibitors asfirst-choice agents. The main reasons are the com-parable efficacy of both agents and the better safetyprofile of selective serotonin reuptake inhibitors,including minimal cardiovascular effects. TCAsblock the reuptake of several neurotransmitters inthe CNS, such as norepinephrine, serotonin, anddopamine. Their anticholinergic activity, and (espe-cially) a quinidine-like effect on the heart, explainthe cardiovascular effects.62 Sinus tachycardia is afrequent finding and is ascribed to the anticholin-ergic effect. The quinidine-like effect consists ofblockade of the fast sodium channel in the cellmembrane (class I effect) and interaction with theoutward delayed rectifier potassium current (classIII activity).63 This results respectively in conductiondefects (PR prolongation, QRS widening, and heartblock) and repolarization abnormalities (QTc prolon-gation). As with quinidine, second-degree or third-degree AV block, ventricular arrhythmias (TdP), andsick sinus syndrome are toxic effects of TCAs.64 Thenegative inotropic effect contributes to hypotensionin TCA overdose. Rhythm and conduction abnor-malities in addition to hypotension are the clinicalmanifestations of cardiac toxicity.62 Impending car-diovascular toxicity in adult patients is usually pre-ceded by specific ECG abnormalities: the majority ofpatients at significant risk will have a QRS intervalduration � 100 ms or a rightward shift (130° to 270°)of the terminal 40 ms of the frontal plane QRS vector(Fig 8). The latter finding is characterized by anegative deflection of the terminal portion of theQRS complex in lead I and a positive deflection ofthe same portion in lead aVR.64 The documentationof these ECG abnormalities is important, as itmandates ICU monitoring for at least 24 h.65 ECG

Figure 7. Bradycardia-associated TdP in a patient who presented initially with complete atrioventric-ular block. Note the typical short-long-short QRS complex interval initiation sequence: a supraventric-ular escape beat (A) is followed by two premature ventricular extrasystoles (B) after a short couplinginterval, which is followed, after a long AV block-induced pause after the ventricular extrasystoles, bya supraventricular beat (C) and another short-coupled premature ventricular depolarization (D), whichis the first beat of the TdP. The QTc in the preceding supraventricular beats is 480 ms.




changes are rare at therapeutic levels and more likelyin those with preexisting heart disease.

Lithium exerts minimal cardiac effects at thera-peutic doses in most patients. Benign, reversibleT-wave changes (including inversion and flattening)are seen in approximately 20 to 30% of patientstreated with lithium.66 ECG abnormalities of clinicalsignificance are mainly documented at toxic levels:they include all kinds of arrhythmias (sinus nodedysfunction is well documented) and QTc prolonga-tion.67,68

Cocaine and amphetamines are common drugs ofabuse. In a 1999 survey in the United States, anestimated number of 1.5 million people were activeusers of cocaine.69 Both drugs act as powerful sym-pathomimetic agents and may induce the typicalECG changes of myocardial ischemia and MI due tocoronary spasm even in the absence of risk factorsfor atherosclerosis.69

The intensive care physician is increasingly beinginvolved in the management of patients with cancer.The adverse effect of chemotherapeutic agents isone of the main reasons for admitting a patient withcancer to the ICU. Although the toxic effects to thebone marrow and GI tract are well recognized,physicians are less familiar with the cardiovasculartoxicity from antitumor drugs. A wide variety of ECGchanges, including arrhythmias, nonspecific ST andT-wave abnormalities, decreased QRS voltage, andprolongation of the QTc interval, have been de-scribed.70 Instead of being specific for a class of

chemotherapeutic agents, ECG changes in generalare a reflection of the drug-mediated toxic action onthe heart.

Anthracyclines are the chemotherapeutic agentsmost widely recognized for causing cardiac toxicity.71

Acute toxicity, occurring during or just after a singledose, is rare, and consists of nonspecific ECG ab-normalities and all kinds of arrhythmias. Rare causesof sudden death, acute heart failure, or fatal myocar-ditis have been reported. Chronic anthracycline-induced cardiotoxicity is more common, usually ap-pears within 1 year of treatment, but also maybecome apparent only many years after completionof therapy. It manifests clinically as congestive heartfailure or life-threatening arrhythmias. The mostcommon risk factor for the development of chronicanthracycline-induced cardiomyopathy is total cu-mulative dose of the drug.

Several other anticancer drugs have been associ-ated with cardiotoxicity, although less frequentlythan anthracyclines. 5-Fluorouracil is typically asso-ciated with angina-like chest pain, often accompa-nied by ischemic changes on the ECG.72 Less fre-quent manifestations include arrhythmias, MI,contractile dysfunction, and sudden death. Mostcardiac effects are acute, occurring during 5-fluorou-racil infusion or shortly afterwards, and are usuallyreversible when the drug is withdrawn. Of the severalproposed mechanisms, coronary vasospasm has beensuggested to be a main contributing factor. Myocardialischemia and infarction have also been attributed tocisplatin.73 Of the many observed cardiac events, pac-litaxel has been reported most commonly to causeasymptomatic bradycardia.70 High doses of cyclophos-phamide and ifosfamide may cause acute severe heartfailure and malignant arrhythmias with sometimes fataloutcome.70,74 The most serious cardiovascular effects ofthe interferons and interleukin-2 include systemic hy-potension, supraventricular and ventricular arrhyth-mias, MI, and severe, usually reversible, congestivecardiomyopathy.75

Poisons That Result in ECG Changes

Cardiac toxicity is a common finding in patientswho have been poisoned with a wide variety ofchemical agents. Poisons that result in ECG changesinclude carbon monoxide (CO), cyanide, organo-phoshates, arsenic, or even specified herbal thera-pies. Poisoning with cardiovascular drugs is relativelyrare and will not be discussed, as the ECG effectsand toxicity of these agents can generally be pre-dicted based on their class effect.

CO poisoning is considered one of the mostcommon acute intoxications, with an average of

Figure 8. ECG showing sinus tachycardia with widened QRScomplex (110 ms) and marked deviation of the terminal portionof the QRS complex in lead I (deep S wave) and aVR (large Rwave). Findings are consistent with TCA poisoning (plasmaconcentration of 1,258 ng/mL).




40,000 cases per year in the United States.76,77 Thetoxic effects of CO are the result of tissue hypoxia.CO has an affinity for hemoglobin, which is 200times as great as that of O2 and interferes with therelease of O2 from oxyhemoglobin, thus decreasingthe amount of O2 available to the tissues. By bindingto mitochondrial cytochrome oxidase, CO also inhib-its cellular respiration. The ECG is a useful tool toevaluate possible myocardial toxicity. Alterations ofthe ST segment and T wave are the most commonabnormalities. They reflect the oxygen deficit at thelevel of the myocardial cell and are frequentlyaccompanied by biochemical and pathologic evi-dence of necrosis (Fig 9).76 Ischemic ECG changesrepresent one of the standard indications for hyper-baric O2 in a patient with CO poisoning, in additionto chest pain, metabolic acidosis, and significantneurologic impairment.77

Cyanide poisoning often occurs in the setting ofsmoke inhalation, where combined CO and cyanidetoxicity occurs. Cyanide binds to cellular cytochromeoxidase and thus interferes with aerobic O2 utiliza-tion. The ECG abnormalities are similar to those ofCO poisoning.

Organophosphates complex with the acetylcho-linesterase enzymes, leading to phosphorylation anddeactivation. The resultant accumulation of acetyl-choline causes initial stimulation, then exhaustion ofcholinergic synapses. The toxicity mainly resultsfrom muscarinic and nicotinic symptoms. The car-diovascular symptoms are bradycardia, following a

tachycardia compensating the hypoxia due to respi-ratory muscle weakness, rare atrial fibrillation, orventricular tachycardia.78

ECG changes resulting from heavy metal poison-ing are mainly described in arsenic exposure. QTcprolongation and T-wave inversion may persistmonths after clinical recovery. Rarely, TdP andventricular fibrillation occur during acute toxicity.79

Herbal therapies are increasingly being used: in arecent survey, the use of self-prescribed herbalmedicines within the United States general popula-tion increased from 2.5% in 1990 to 12.1% in 1997.80

Many herbal remedies have proven beneficial ef-fects, but some have the potential to cause serioustoxic effects, either directly or through herb/druginteractions. Cardiac adverse effects are typical afterthe ingestion of oleander, a plant containing cardiacglycosides. The clinical picture resembles digitalistoxicity, which includes life-threatening ventriculartachyarrhythmias, bradycardia, and heart block.81 Anexample of herb/drug interaction includes the de-creased bioavailability of digoxin and cyclosporinewhen these drugs are combined with St John’swort.82 This interaction can have serious conse-quences, as has been reported.83 Another source oftoxicity is contamination of herbal preparations withheavy metals, including arsenic.84

ECG Abnormalities Related to ElectricalInjury

An estimated 1,100 to 1,300 deaths occur annuallyin the United States from electrical injury (includinglightning strike).85 One third of patients presentingwith an electrical injury manifest a cardiac compo-nent, and death from electrical injury most com-monly stems from cardiac arrest. Changes in theECG are frequently observed and may be trivial orlife threatening. The most commonly reported ECGabnormalities are sinus tachycardia and nonspecificchanges in the ST segment and T wave.85 Numerousrhythm and conduction disturbances may occur, themajority of which run a benign course. Direct myo-cardial injury, anoxia secondary to cardiopulmonaryarrest, and autonomic instability explain many of thecardiac manifestations of electrical injury, includingthe above-mentioned ECG changes.86

Electroconvulsive therapy is mainly used in thetreatment of depression that has proved resistant tomedications. The electrically induced seizure pro-duces autonomic nervous system activation, whichunderlies the cardiovascular complications.87 TypicalECG abnormalities include ischemia-like changes(T-wave inversion, ST-segment depression, and newpathologic Q waves) and various arrhythmias. Signifi-

Figure 9. 12-lead ECG from a patient with severe CO poisoning(CO hemoglobin of 39.1%) showing signs of myocardial ischemiaas suggested by T-wave inversion in the precordial and inferiorlimb leads. An elevated troponin level (troponin I level of 11.8�g/L) confirmed the presence of myocardial injury.




cant and persistent ECG changes are especially prev-alent among patients with preexisting cardiac disease.88

Miscellaneous Conditions

Misplacement of ECG electrodes is a common causefor errors in ECG interpretation. Reversal of the right

arm with the left leg electrode creates the pattern of aninferior MI.89 Placing the precordial electrodes toohigh on the chest may mimic an anterior MI (poor R-wave progression) or the pattern of right bundle-branch block (rSR� complex).89 ECG artifact such asproduced by body movement or a poor skin-electrodecontact can simulate life-threatening arrhythmias and

Figure 10. ECG before (top, A) and after (bottom, B) thoracentesis for tension pneumothorax. Notethe presence of sinus tachycardia and signs suggestive of right ventricular strain (right-axis deviation,clockwise rotation of the heart, and concomitant Q waves in leads II, III and aVF, a rSR� pattern in leadV1, and large S waves in leads I, aVL, and the lateral precordial leads).




as a result expose patients to unnecessary diagnosticand therapeutic procedures, including cardiac catheter-ization and the implantation of cardiac devices.90

The finding of nonspecific ST-T wave abnormali-ties, defined as � 1-mm ST-segment depression orST-segment elevation with or without an abnormal Twave on the ECG, is a frequent cause for concern.Indeed, up to 8% of adult patients with chest paintreated in the emergency department who presentedwith either a normal ECG or nonspecific ST-Tabnormalities had a final hospital diagnosis of acuteMI.91 However, transient ST-segment changes havebeen documented during ambulatory monitoring inup to 8% of patients without obstructive CAD.92

Nonspecific repolarization abnormalities have beendescribed during ambulatory ECG monitoring fol-lowing a meal, after a change in body position, orafter a Valsalva maneuver.93 Up to 15% of apparentlyhealthy subjects with hyperventilation have nonspe-cific ST-T changes.94

Correct interpretation of ST-T changes requiresknowledge of the clinical context and the cardiac riskprofile of the patient. Overreliance on a normal ECGfinding in a patient with a classical history of anginalchest pain is dangerous. Conversely, nonspecificST-T wave abnormalities in a patient with atypicalchest pain and a low probability of CAD allows earlydischarge from the emergency department. A con-siderable number of these patients probably have apanic attack or hyperventilation.

Most of the ECG changes that occur duringpregnancy can be explained by the physiologic adap-tations in response to pregnancy. As the heart movestoward a horizontal position because of uterineenlargement, there is a (leftward or rightward) shiftof the QRS axis.95 The increase in size and leftventricular mass, as documented by echocardiogra-phy, may result in increased left ventricular voltage.Sinus tachycardia and premature atrial and ventric-ular beats are also considered as normal. Minor ST-Twave changes have also been reported in pregnancyand are interpreted as normal in an asymptomaticwoman.96

The use of contrast agents during cardiac cathe-terization is frequently accompanied by ECGchanges. These include prolongation of the QRScomplex, increase in the QT interval, marked shiftsin the ST segment, and T-wave morphology (T-waveinversion or peaking in the inferior leads).97 Theinhibitory action on the sinoatrial and atrioventricu-lar node explains the transient bradycardia in manypatients and the occasional effect of complete AVblock or sinus arrest. Also ventricular fibrillation,reported in 0.6 to 1.3% of patients, is often attrib-uted to the use of contrast material.98

Contrast agent toxicity is at least partly mediatedby hyperosmolarity. In predisposing to ventricularfibrillation, contrast-induced transient hypocalcemiamay be another contributing factor.99 The lowerincidence of significant arrhythmias and other ECGchanges when using low-osmolarity contrast materialand the reduction of the calcium-binding potentialfor newer agents have further reduced the incidenceof ventricular fibrillation. This would appear tosubstantiate the postulated mechanisms.100

Pulmonary emphysema, a condition characterizedby lung hyperinflation, produces several anatomicchanges that affect the ECG in unique ways.101 Thedownward displacement of the diaphragm and theheart produces a rightward shift of the QRS axis inthe frontal plane and poor progression of the R wavein the precordial leads, simulating anterior MI. Thislatter finding is explained by the relatively highposition of the precordial electrodes in relation tothe heart. They are often at the level of the base ofthe heart and therefore record a negative ventricularpotential.102 Compression of the heart into a morevertical position explains the prominent P waves inleads II, III, and aVF, and as a result of exaggeratedatrial repolarization PR-segment and ST-segmentdepression in the same leads.101 Low voltage of theQRS complexes, especially in the left precordialleads, is the effect of the lowered electrical transmis-sion resulting from the hyperinflated lungs.101

Tension pneumothorax is mostly diagnosed earlyon a purely clinical basis. Unexpected ECG findings,due to positional changes of the heart, may give riseto confusion, particularly suspicion of PE (Fig 10).

Conclusion

Although most of the ECG abnormalities detectedin patients in the emergency department or ICU arecaused by primary cardiac diseases, ECG changes donot invariably imply a cardiac abnormality. A thor-ough knowledge of the ECG manifestations of non-cardiac conditions, commonly seen in critical caresettings, may result in rapid diagnosis and correcttreatment of potentially life-threatening disorders.Misinterpretation of the ECG may even expose thepatient to wrong therapeutic options, with seriousrisks.

ACKNOWLEDGMENT: The authors are grateful to GeorgeSutherland, MD, PhD, for his review of the manuscript, and toStian Langeland and Gerda Ceulenaere for their assistance in itspreparation.

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DOI 10.1378/chest.125.4.1561 2004;125;1561-1576 Chest

Carlos Van Mieghem, Marc Sabbe and Daniel Knockaert The Clinical Value of the ECG in Noncardiac Conditions

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