Reversible myocardial dysfunction in critically ill, noncardiac patients: A review*

Manuel Ruiz Bailn; MD, PhD

Objective: To review reversible myocardial dysfunction affecting critically ill patients without cardiac pathology. Data sources: The bibliography for the study was compiled through a search of different databases for the period 1966 2001. References cited in the selected articles also were reviewed. Study Selection: The selection criteria included all articles published on reversible myocardial dysfunction in critically ill patients. Conclusions: Reversible myocardial dysfunction may develop in a situation of critical pathology, but the etiology of reversible

myocardial dysfunction is not fully understood. This dysfunction may be accompanied by increases in enzyme concentrations and electrocardiographic changes. Reversible myocardial dysfunction probably is underdiagnosed, although its presence is associated with a worsening of the prognosis and with more specic therapeutic options. Further studies are necessary to dene its true incidence and clinical implications. (Crit Care Med 2002; 30:1280 1290) KEY WORDS: myocardial stunning; myocardial dysfunction; myocardial depression

Hearts receive different impressions, depending on whether or not time has changed and whether the wind blows the clouds.Virgil, 70 19 BC

n 1975, Heyndrickx and colleagues (1) were the rst to describe the phenomenon of reversible, postischemic, left ventricular dysfunction after observing, in an experimental model in the dog, that myocardial function remained depressed for 3 hrs after occlusion of a coronary artery for 5 mins and for 6 hrs after coronary artery occlusion lasting 15 mins (1). However, Braunwald and Kloner (2), in 1982, were the rst authors to describe the phenomenon of myocardial stunning, on observing that, after a period of ischemia in which necrosis did not take place, a self-limiting phenomenon of ventricular dysfunction may be produced together with a reduction in ventricular compliance. The term myocardial stunning has been used to refer to the reversible myocardial dysfunction (RMD) that persists after myocardial reperfusion, in the absence of any irreversible lesion and after the restoration of normal or almost normal coronary artery ow (3). It currently is recognized that myocardial stunning may occur a) after a single episode of myocardial

ischemia (3, 4); b) after repeated, short, reversible episodes of myocardial ischemia (3, 5 8); c) after a single episode of partially irreversible myocardial ischemia (3, 9); d) in vitro, after global ischemia (3, 10, 11); e) after global ischemia attributable to cardiac arrest maintained with cardioplegic perfusion (12, 13); f) after exercise-induced ischemia (14) or dobutamine-induced stress (15); g) after angioplasty; and h) after acute myocardial infarction, particularly with thrombolysis or angioplasty (16, 17). Hibernating myocardium is a state of persistent myocardial dysfunction caused by a prolonged, severe reduction in coronary blood ow that may be restored to normality by the improvement or normalization of coronary ow (18). Hibernating myocardium and myocardial stunning are the recognized and accepted types of RMD that affect critically ill patients with coronary artery pathology. However, RMD phenomena also occur in cases of critical pathology of noncoronary origin, apart from myocarditis, and may alter the clinical course in these patients. The aim of this article is to review of RMD in cases of critical, noncardiac pathology.

*See also p. 1392. From the Intensive Care Unit, Critical Care and Emergencies Department, Hospital de Poniente, El Ejido, Almera, Spain. Copyright 2002 by Lippincott Williams & Wilkins

METHODS
A search of MEDLINE and EMBASE medical databases was carried out for all articles

published in Spanish, English, French, Italian, or German between 1966 and July 2001. The search used the following keywords: myocardial stunning, reversible, myocardial dysfunction, myocardial depression, trauma, burn injuries, ischemia, reperfusion, anoxia, shock, sepsis, pneumonia, pancreatitis, poisoning, brain injuries, lung injuries, asthma, anaphylaxis, arrhythmias, cardiac arrest, respiratory arrest, cardiopulmonary resuscitation, subarachnoid hemorrhage, stroke, transplantation, acute renal failure, heat stroke, thrombolytic therapy, acute myocardial infarction, shock, cardiogenic shock, complications. A manual search for relevant articles also was carried out. Reversible Myocardial Dysfunction in Critical Pathology. Sharkey et al. (19), in a retrospective study, described 22 cases of myocardial dysfunction with associated electrocardiographic changes consisting of negative T waves in the precordial leads in patients admitted to hospital for acute noncardiac pathologysepsis (n 3), postoperative, noncardiac surgery (n 3), neurologic pathology (n 6), acute pulmonary disease (n 3), and drug overdose or metabolic abnormality (n 7). Both alterations completely resolved before discharge. Iga et al. (20) described eight critically ill patients without coronary artery disease (normal coronary angiographies) presenting similar electrocardiographic changes who developed myocardial dysfunction with alterations of segmental contractility (particularly affecting the apical region) that resolved

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within 1 6 weeks. Recently, Tsuchihashi et al. (21) published a retrospective descriptive study of a syndrome compatible with systolic myocardial dysfunction associated with transient left ventricular apical ballooning and with no signicant angiographic lesions in 88 patients with polyvalent, noncardiac critical pathology. This cardiomyopathy was completely reversible by the time of discharge; 67% of the patients suffered thoracic symptoms. Electrocardiographic changes were observed in the form of T-wave inversion in 97%, ST-segment changes in 90%, and the development of a Q wave in 27%. These three studies are examples of the RMD that may complicate critical pathology that does not involve the coronary artery; however, in addition to these studies, RMD also has been reported in the context of many other pathologies Table 1. Neurogenic Stunned Myocardium. There is a classic and frequent association between cerebral lesions and electrocardiographic changes including P-wave changes, shortening of the PR interval, lengthening of the QTc interval, T-wave inversion, ST-segment changes, and large U waves and Q waves (22). More recently, RMD has been reported in the context of acute cerebrovascular pathology, particularly in association with acute subarachnoid hemorrhage (2331), ischemic stroke (32), subdural hematoma (33), and craTable 1. Causes of reversible myocardial dysfunction described in critically ill patients with no cardiac pathology
Neurogenic stunned myocardium Subarachnoid hemorrhage Stroke Subdural hematoma Cranial trauma Electroconvulsive therapy Acute respiratory failure Upper airway obstruction Asthma Pulmonary embolism Acute lung injury Acute respiratory distress syndrome Anaphylaxis Trauma injuries Pulmonary contusion Multiple trauma patients Hemorrhagic shock Blast injury Burn injuries Postsurgical pathology transplant Sepsis Systemic inammatory response syndrome Pancreatitis Cardiac arrest Poisoning Rhabdomyolysis Episodes of arterial hypertension/pheochromocytoma Thyroid pathology Arrhythmias Hyperthermia/hypothermia Obstructive jaundice Emotional stress Nutrition

nial trauma (34), after electroconvulsive therapy (35), and, possibly, in quadriplegic patients (36). These studies coincide with the nding of myocardial dysfunction affecting seriously ill patients (27) that is reversible within a variable period of time (Table 2). Echocardiography and ventriculography have been used to demonstrate disturbances of global or segmental contractility, which may affect any region but particularly the anterior, septal, and apical regions (Table 2). These disturbances of contractility have been found in 9.4% of acute subarachnoid hemorrhage (31). Zaroff et al. (26) found that this dysfunction was more frequent in women (77%), in smokers, and in hypertensive patients; inotropic drugs are required in most cases. This dysfunction frequently is associated with an increase in concentrations of creatine kinase, particularly the MB fraction (31), and of troponins (31, 32, 37). Furthermore, there are nonspecic electrocardiographic changes such as lengthening of the QT interval (23, 27, 28), T-wave inversion (2729), ST-segment elevation (23, 25, 29, 32, 33), or descent (32) or hemiblocks (24). Kono et al. (25) studied the relationship between the electrocardiographic ndings and alterations in segmental contractility in patients with acute subarachnoid hemorrhage, comparing seven patients presenting ST-segment elevation (V4 V6) with ve patients with no STsegment elevation. The ST-segment elevation was associated with changes in wall motion in the apical region, and it persisted while these changes in segmental contractility were present (29). Mayer et al. (27) found an association between myocardial dysfunction and symmetrical T-wave inversion or an increase in QTc interval (sensitivity 100%, specicity 81%); the T-wave inversion was more sensitive than a long QTc interval. Although the cause of death was related to the acute subarachnoid hemorrhage, RMD could have contributed to mortality by causing complications such as potentially lethal arrhythmias (27, 38), the production of intracavity thrombi and embolic events, hypotension, pulmonary edema (26, 37), or hypoxemia. Any of these complications could potentiate secondary cerebral lesions and worsen the neurologic situation (24, 26, 27, 39). A further interesting aspect is the appearance of myocardial dysfunction after cerebral death. Although studies support the reversibility of myocardial dysfunction after transplant (28, 40, 41), its onset may raise doubts about carrying out heart transplant because it may increase the risk of graft rejection, the dysfunction may persist, or it may even promote infection; the value of dobutamine stress echocardiography has been investigated to assess reversibility (42). The proposed causes of RMD are not fully elaborated and include an active involvement of the cerebral cortex in myocardial contractility (43); a high concentration of catecholamines (31), particularly a catecholaminergic storm at-

tributable to noradrenaline, coronary artery vasospasm, or vasospasm of the coronary microcirculation (42, 44); and reperfusion phenomena (45). Severe Acute Respiratory Failure. Case reports have been published describing RMD in severe episodes of acute respiratory failure attributable to acute upper airway obstruction (46) and in episodes of severe asthma; this RMD is associated with nonspecic STsegment changes in the electrocardiogram (21, 47, 48). These cases initially present a markedly reduced left ventricular ejection fraction (LVEF) with global hypokinesia and segmental alterations affecting the apex (with no effect on the right ventricle); they show rapid recovery but may be complicated by acute pulmonary edema (47) or cardiogenic shock requiring intra-aortic contrapulsation balloon (IACB) assistance until shock resolves or LVEF normalizes (48). This complication is attributed to ischemia, acidosis, hypotension, and hypoxemia (46). Other possible situations of severe acute respiratory failure in which RMD phenomena could develop include human (49, 50) and experimental models of pulmonary embolism (51) and neonatal respiratory distress requiring extracorporeal membrane oxygenation therapy (52); in the latter situation, a clear relationship has been found between the severity of the pulmonary lesion and the RMD, and improvement of the RMD was noted after the use of extracorporeal membrane oxygenation (53). RMD also has been detected in the acute respiratory distress syndrome (54), particularly in experimental models of lung injury attributable to hydrochloric acid (55), oleic acid (56) or pulmonary contusion (57). Anaphylaxis. Anaphylactic shock is characterized classically by a decrease in systemic arterial blood pressure caused, fundamentally, by a reduction in systemic vascular resistances, although, at least initially, cardiac output is normal or high. From this, it may be inferred that cardiac function is normal after anaphylaxis. However, anaphylaxis may induce the onset of arrhythmias, infarcts, or angina (58). Another form of myocardial lesion mediated by anaphylaxis, and which could alter the prognosis, is RMD. Raper and Fisher (59) presented two cases of anaphylaxis complicated by profound, reversible myocardial depression. Both patients developed intractable cardiogenic pulmonary edema, and one patient suffered arrest. The electrocardiograms showed nonspecic ST-segment and T-wave changes. IACB assistance was required in both cases for 72 hrs, a measure that resolved the cardiac failure. The LVEF in the rst case was 15% initially (at 10 hrs) and 29% at 36 hrs; after 10 days it was normal. In the second case, the LVEF was 35% at 3 days and 67% after 2 wks. This complication highlights the utility of the IACB (60). The mechanism of this myocardial dysfunction is not well understood. Mink and colleagues (61, 62), who used experimental models in the dog, recently studied the role of

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Table 2. Neurogenic myocardial stunning

Normalization of Ventricular Function Several days 24 hrs 714 days

Author Kuroiwa et al. (29) Delgado et al. (23) Kono et al. (42) Pollick et al. (24)

n 23 of 226 1 7 of 30 4 of 13

Age 61 70 51.2 62.7

Gender 12 Males/11 females Female 3 Females 4 Females ASH ASH

Pathology

Initial Ventricular Function LVEF 37% SF 17.6%

Cerebral death ASH

Kono et al. (25) Ohtsuka et al. (33) Deibert et al. (28) Tzung-Dau et al. (31) Mayer et al. (27) Zaroff et al. (26)

12 1 1 1 5 of 57 30 of 147

56.9 74 51 65 52 53

3 Females Female Female Female Females Females (77%)

ASH Subdural hematoma ASH Cerebral infarction ASH ASH

LVEF 60% Profound depression LVEF 40% LVEF 42% Moderate to profound depression LVEF 50% in 12 patients, 30% in 3 patients, 1 moderately impaired and 1 with regional dysfunction

23 weeks 3 days 12 hrs 5 days 1444 days 17 days

ECG, electrocardiogram; ASH, acute subarachnoid hemorrhage; LVEF, left ventricular ejection fraction; SF, shortening fraction.

the autacoids in the production of this dysfunction, observing that the H1, H3, and cyclooxygenase receptors are active in the genesis of these compounds; the authors reduced the myocardial dysfunction by blocking these agents. Traumatic Injury. Smail et al. (63) carried out a prospective study in seven patients with severe trauma (Injury Severity Score, 38 9) by using echocardiography to assess LVEF in the initial and early phases of the trauma (the rst 6 hrs, the rst and second days). Myocardial lesion and contusion were excluded. In all cases, there was an initial depression of the LVEF, showing values of 43 2.4%, 51 6%, and 52 4% at 6, 24, and 48 hrs, respectively. No arrhythmias or electrocardiographic changes were found, and there was no elevation of the creatine kinase MB fraction. No alterations in segmental contractility were observed. The systemic blood pressure and the cardiac index improved progressively. Moomey et al. (57) investigated myocardial function after pulmonary contusion in a pig model by using 17 animals, provoking a unilateral lesion of the right hemithorax. They believe that occult ventricular dysfunction and pulmonary contusion play a role in the progression to cardiorespiratory failure, even in the absence of direct cardiac contusion. Raper et al. (64) compared the biventricular function of 69 patients with normotensive sepsis with 18 trauma patients. The study was carried out when the patients blood pressure was stable and vasoactive drugs were not required. These authors found depression of the biventricular contractility in patients with normotensive sepsis, whereas this was maintained in hemodynamically stable trauma patients.

The etiopathogenesis of this dysfunction is not well understood, and the following factors have been implicated: a) hemorrhagic shock (65), demonstrated to cause ventricular dysfunction in animal models (66) attributable to an alteration in the integrity of the cell membrane (67), secondary to the liberation of tumor necrosis factor (TNF)- (68), attributable to subendocardial ischemia (69) or even attributable to coronary vasomotor dysfunction (70); and b) the liberation of cytokines (68), normally associated with the onset of a systemic inammatory response syndrome (SIRS), and in which even testosterone may play an active role (71). Blast injuries (72) and burns (7379) are other types of lesions in which the development of an RMD without compensatory vasoconstriction has been detected. The relationship with burns has been detected both in human models (73) and in experimental animal models (74 76). This dysfunction may appear early, within the rst 24 hrs (77), and may affect both ventricles (73) and even diastolic function (78). Its incidence may be increased in those patients who develop pneumonia (79). This dysfunction may be related to myocardial depression secondary to alteration of the calcium channel function in the myocardial sarcoplasmic reticulum (80) or to the liberation of cytokines, particularly TNF; in pig models of burn shock, prevention of the myocardial dysfunction was achieved by the inhibition of TNF (81). Free radical lesions also may be implicated in this RMD, a theory that could explain the correlation found between myocardial dysfunction and the increase in the troponin concentrations (69, 75 77).

Postoperative Pathology. Sampathkumar et al. (82) found a reversible, idiopathic, dilated myocardiopathy (dilation of all four cavities) occurring in the early posttransplant period, in the absence of sepsis, in seven of 754 patients undergoing liver transplant. With a previously normal echocardiography and with no intraoperative complications, these patients developed pulmonary edema 5 days after liver transplant and presented a mean LVEF of 20% (two patients presented alterations of segmental contractility). Intensive supportive therapy was required, with mechanical ventilation (for a mean of 7 days), and a mean intensive care unit admission of 8 days. One patient required prolonged mechanical ventilation attributable to persistent cardiac failure. In all cases, the cardiac failure resolved and the LVEF normalized except in one patient, in whom it increased from 10% to 30%, causing the death of this patient. Nasraway et al. (83) carried out a retrospective study of the hemodynamic situation in 113 patients undergoing liver transplant. They observed that the nonsurvivors presented an early postoperative myocardial depression, with a lower cardiac index and lower oxygen delivery. These patients were more prone to organ failure and death (83). Anecdotal reports also have been published of episodes of myocardial dysfunction after lung transplant (84) and bone marrow transplant (85). Many mechanisms have been proposed to explain this posttransplant myocardial dysfunction. A possible cause is myocardial depression induced by cytokine liberation (82). Intraoperative manipulation of the viscera and its blood supply could induce endotoxin release, which would initiate a physiologic re-

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Table 2. (Continued)

Disturbances of Segmental Contractility Basal hyperkinesia together with apical hypokinesia or akinesia Anteroapical akinesia, inferoposterolateral hyperkinesia Apical and septal akinesia in all patients, together with other alterations Left ventricular apex Global akinesia, apical aneurysm Global hypokinesia Severe hypokinesia of the inferior wall Diffuse or global or affecting the territory of a single coronary artery Regional (n 21) and global (n 9)

ECG Changes ST elevation I, L, V3V5, T-wave inversion Long QTc; anterior ST segment elevation Inversion and/or attening of the T wave a ST (n 7) QS in II, III, aVF, V3V6; ST elevation in I, II, V3V6 Increased QTc, inverted T waves in I, L ST elevation in II, III, ST descent in V2V4 Long QTc or T-wave inversion

Coronary Angiography Normal Normal Normal

Enzymes a CK in two patients Normal a Troponin a CK-MB

Normal Normal Normal Patent coronary arteries (autopsy) Normal coronary arteries except in one patient

a CK-MB a Troponin I a CK-MB

sponse with the consequent liberation of cytokines; furthermore, these patients may be more susceptible to the effects of the cytokines because of a lower pretransplant reserve (83). Another possible explanation is ischemia or anoxia, which could lead to variable degrees of hepatic and cardiac injury (86); the later reperfusion of the ischemic donor organ has been shown to increase TNF concentrations (83). It has been demonstrated in animal models that hepatic ischemia and reperfusion can induce acute lung injury and reduce myocardial contractility (87, 88). Apart from the processes implicated in myocardial dysfunction, immunosuppressive medication also could be responsible for this cardiodepression (89). RMD phenomena also have been described after other types of surgery. Case reports have been published of unexplained, reversible left ventricular dysfunction in the immediate postoperative period (90) and of right ventricular dysfunction that correlates with the concentration of interleukin-6 after resection of esophageal malignancies (91). This dysfunction could arise because of phenomena of ischemia, reperfusion, or hypoxia or could be attributable to the presence of myocardial depressant substances induced by SIRS caused by the surgical aggression. Sepsis. Sepsis often reduces vasomotor tone, which may cause distributive shock (92). Reversible myocardial dysfunction may occur in up to 40% of cases of sepsis (93). Wiggers (94), during the 1940s, was probably the rst author to describe myocardial depression in shock. A few years later, Weil et al. (95) reported that the intravenous administration of endotoxins caused hypotension secondary to reduced venous return in a dog model. In 1965, Wilson et al. (96) demonstrated that

patients with septic shock usually presented with a hyperdynamic state. Since that time, this myocardial dysfunction has been studied extensively, particularly by the Parrillo group, and may play a decisive role in the genesis of shock (97). Its onset may be extremely early (98), and it is most evident in days 13 of sepsis (97); in the survivors, normalization usually occurs over the following 710 days (99, 100). Myocardial dysfunction may be detected in septic patients (97, 101, 102) and induced in experimental models of healthy humans (103) and animals (104, 105). Nowadays, this dysfunction may be detected easily by echocardiography (100, 101, 106, 107), but it was observed previously by using a otation catheter (94), radionuclide cineangiography, and thermodilution (97, 99, 109). Both systolic and diastolic myocardial dysfunction have been described (104, 106, 108, 109). The right ventricle also may be affected (110), leading to parallel biventricular dysfunction (99, 111, 112, 113). The degree of myocardial dysfunction found during sepsis is very variable, ranging from mild to severe (99, 114, 115), presenting as left ventricular or as biventricular dilation (99, 104, 108). Parker and colleagues (99, 113, 116) found that the biventricular dilation with a decreased ejection fraction is very common in septic shock. Wall motion may be affected globally or this may be observed as disturbances of segmental contractility, particularly at the apex (100, 108), and this may be accompanied by nonspecic electrocardiographic changes (19), although it does not appear to be related to the cardiac index or systemic resistances (97). The appearance of this dysfunction may be associated with a poor prognosis, because it

increases morbidity and mortality rates. However, Parker et al. (117) discovered paradoxically that this dysfunction was less severe in those patients who died, suggesting that this could be an adaptive phenomenon, with the biventricular dilation having a protective effect. The basis for this protective effect is not known. It is possible that the ability to develop ventricular dilation preserves the appropriate ejection volume, despite a signicant reduction in the ejection fraction and the existing vasoplegia (99, 102, 118). Vincent et al. (119) found a greater degree of right ventricular dysfunction in association with a fatal outcome. In any case, the onset of this complication may alter the nal prognosis; dobutamine stress echocardiography has been used as a prognostic indicator in septic shock (101, 102). This lesion has associated biochemical changes in the form of an increase in the cardiac enzymes, particularly troponin I (93, 120) and T (121), and these may prove useful as prognostic markers in sepsis, being associated with a higher mortality rate or with the development of multiorgan failure (93, 105). The physiology of this myocardial dysfunction that occurs in SIRS (122), in sepsis, and in septic shock is not well understood, although there are several possible theories to explain it. The rst theory is myocardial ischemia and reperfusion phenomena (112). This theory has been suggested on the grounds that oxygen requirements increase during sepsis, and there may be a poor distribution of coronary ow, with an imbalance between the oxygen requirements and the increase in the microcirculatory demands, which could cause contractility disturbances (92, 104). This may lead to the increased troponin concentrations

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that are found being interpreted as indicators of myocardial ischemia (121), and the postreperfusion syndrome (123), which appears after organ reperfusion, also could be implicated in the development of this lesion, particularly by the formation of free radicals (114). This etiological possibility has been investigated by three authors. Cunnion et al. (124) assessed coronary sinus blood ow by using thermodilution in seven patients with septic shock. The coronary blood ow of the patients with septic shock was similar to or higher than the control group. Dhainaut et al. (125) found corresponding results in a similar study involving 40 patients with septic shock and 13 control patients. More recently, Solomon et al. (126), in an experimental study in the dog, found that intracellular free energy levels were maintained. Based on the ndings of these studies, it may not be assumed that the myocardial dysfunction associated with septic shock is attributable to generalized myocardial ischemia. The second theory to explain the physiology of myocardial dysfunction is the presence of a circulating agent responsible for this dysfunction. Parrillo et al. (127) presented an elegant study in which the presence of a circulating myocardial depressant substance was demonstrated in septic shock and decreased the contractile velocity of the myocardial cell, which correlated with the reduction in LVEF. Many substances have been implicated in the development of this dysfunction, including particularly cytokines, prostanoids, nitric oxide, and an excess of catecholamines. Cytokines are heat-labile, water-soluble polypeptides or proteins 10 kDa that induce myocardial dysfunction which improves after hemoltration (128, 129). Among the many cytokines related to the onset of myocardial dysfunction, probably the most important is TNF- , a 17-kDa protein found during sepsis (130) that has been shown to be responsible for a deterioration in myocardial function in human and animal models (129, 131). A relationship has been demonstrated in vitro between the concentration of this substance and a shortening of the myocytes; the reduction of TNF- concentrations (129) or the administration of anti-TNF- antibody could improve ventricular function (132). However, recent studies have provided evidence that TNFcauses further effects, some of them potentially benecial, such as the expression of heat shock proteins of 27 and 72 kDa, proteins that could promote tissue repair, maintain an antioxidant effect protecting against oxidative stress, and help initiate ventricular remodeling. Other cytokines implicated in sepsis include interferon- and interleukins-1 , -2, -6, -8, and -10 as well as transforming growth factor- . Synergism between various interleukins could increase the possibility of ventricular dysfunction (114). Regarding prostanoids, in sepsis there is an increased production of platelet activating factor, the thromboxanes, and the prostacyclins,

which are associated with an increased mortality rate (103). This increase in the level of the prostanoids is linked to an increase in the expression of cyclooxygenase enzyme-2 in the endothelial, endocardial, and vascular smooth muscle cells. Although the role of this enzyme in myocardial dysfunction is uncertain, it could alter coronary artery autoregulation, leukocyte activation, and endothelial function. This enzyme may be induced by the action of the lipopolysaccharides on the vascular smooth muscle cells, with the consequent implication in myocardial dysfunction (114). Nitric oxide is induced by the lipopolysaccharides and has been found in very high concentrations in patients who have died because of sepsis. It alters the positive -adrenergic inotropic response, biventricular function, and coronary artery tone. In the heart, nitric oxide may affect the calcium channels by modifying protein kinase activity, thus reducing myobril response to calcium and inhibiting mitochondrial function (97, 114). In addition, an excess of catecholamines has been implicated as a further mechanism that may induce a reversible myocardial injury (92). The leukocytes, particularly the neutrophils activated by the monocytes and macrophages, may be implicated in the development of myocardial dysfunction by migration and liberation of these mediators or even local liberation within the myocardium. A third possible physiopathologic explanation for myocardial dysfunction would be a cytotoxic lesion rather than myocardial depression (120). Various degrees of myocardial lesion and myocyte necrosis (121, 133, 134), myocardial edema, and collagen alterations (104) have been observed that could be caused by a cytotoxic lesion, with increases in the troponin concentrations being a marker of this lesion (120). In practice, all these possibilities may coexist, with RMD being the result of an integration of a reversible cytotoxic lesion and myocardial depression (135, 136). Pancreatitis. Although classically it has been stated that pancreatitis can lead to electrocardiographic changes suggestive of ischemic cardiopathy, it was in the 1970s and at the beginning of the 1980s when Lefer and Lee (137, 138) demonstrated myocardial dysfunction after pancreatitis, in experimental and human models that used isolated papillary muscle preparations. Goldfarb (139) proposed, and demonstrated experimentally, that myocardial dysfunction could develop during pancreatitis, although this nding was disputed by other authors (140 142). Later, ventricular dysfunction was detected in patients with pancreatitis (143) although neither shock nor infection was present (144). Furthermore, it was possible to demonstrate alterations in segmental contractility (particularly septo-apical and septo-basal) that coincided with the electrocardiographic changes and were reversible within 10 days (145). This dysfunction could

eversible myocardial dysfunction may develop in a

situation of critical pathology, but the etiology of reversible myocardial dysfunction is not fully understood.

be explained by metabolic alterations with a similar origin to that occurring in SIRS or in sepsis. Cardiorespiratory Arrest. Many pathologies have been described which, when severe, may be associated with RMD; it is therefore easy to assume that any pathology in its most severe form, the form that may lead to cardiac arrest (CA), or even that caused by CA itself, could lead to RMD. Negovsky (146) introduced the term postresuscitation disease, referring to a syndrome of multiorgan dysfunction that occurred after cardiopulmonary resuscitation (CPR), caused by ischemia secondary to CA and by reperfusion phenomena, and which could be a cause of death. Any system may be affected by this syndrome, which may present with renal failure, acute lung injury, acute respiratory distress syndrome, central nervous system lesions, coagulation disorders, or myocardial dysfunction. Approximately 30% of all patients who are successfully resuscitated die eventually because of cardiac arrhythmias or failure, and almost 50% of deaths attributable to cardiac causes occur in the rst 72 hrs. The onset of RMD in these patients would contribute to increased morbidity and mortality rates. This has been studied in many animal models, and authors have reported that systolic and diastolic dysfunction developed (147149), associated with dilation of the left ventricle (150), after successful resuscitation in studies of experimental CA in rat (147, 148), pig (149 152), and dog (153) models; onset could begin within the rst 10 15 mins, and complete recovery occurred after 48 72 hrs. The degree of ventricular dysfunction has been correlated with the duration of CA (148, 151, 153) and CPR (153); these patients also show an increase in arrhythmias related to the degree of myocardial dysfunction and to the duration of CA and CPR (153). Histologic studies showed macroscopic lesions, particularly in the right ventricle and with the anterolateral free wall being the most severely affected. The longer the ischemia time, the more severe the changes. These lesions consist of isolated or diffuse acute myobrillar necrosis in the subendocardium and, more rarely, in the subepicardium (153).

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Very few studies have evaluated this possible complication of CA in human models. Mllner et al. (154) studied ventricular function in 20 patients resuscitated after CA, comparing the results with those of four control patients. There was a marked depression of contractility after 4 hrs except in three patients, in whom it was normal or increased. Deantonio et al. (155) described three patients surviving ventricular brillation in whom, after resuscitation, a dilated myocardiopathy with an LVEF of 20% to 30% was found on echocardiography. Two weeks later the LVEF had normalized. Tenaglia et al. (156), in a study on survivors of CA attributable to acute myocardial infarction, found a 5 9% recovery of the LVEF in those cases in which CPR lasted 10 mins and a 4 8% recovery of the LVEF after prolonged CPR; in those acute myocardial infarctions not requiring CPR, there were no changes in the LVEF. Hwang et al. (157) found early onset myocardial stunning in three of 11 patients resuscitated after CA, and in two more there was a progressive deterioration; six patients presented no dysfunction. Furthermore, sporadic cases of myocardial stunning have been reported after respiratory (158) or cardiorespiratory (48, 58) arrest. Myocardial stunning is of particular importance in these patients because it may contribute to the onset and persistence of intractable shock and directly cause the patients death. Special measures such as IACB may be required. The causes of this RMD are not clear, and proposed explanations of this phenomenon include myocardial ischemia during or after CA attributable to an increase in coronary artery vascular resistance (158), reperfusion phe-

nomena, coagulation disorders (148), the liberation of cytokines, complement, peroxides, calcium imbalance, and endothelin-1 (149, 159). Another possible etiology is an excess of catecholamines; it has been shown in animal studies that myocardial dysfunction may be more marked after the administration of adrenaline and improves after the administration of esmolol (160). These possible causes of RMD are common to other critical pathologies that cause myocardial dysfunction. In cases of CA, the CPR maneuvers themselves, external cardiac massage and, in particular, cardioversion and debrillation, may cause the RMD. The possible effect on the myocardium of these latter two techniques has been studied in human and animal models and, although it has been reported that there is no myocardial injury (161), these techniques may cause myocardial stunning. Diastolic failure (162), systolic and diastolic dysfunction (163165), and even more severe lesions (165167) have been detected after these techniques have been used, related to the number and energy of the shocks, and these techniques have directly caused death in animals (144, 168). The etiopathogenesis of this dysfunction is related to free radicals, the onset of SIRS, and multiorgan failure (169). Poisoning. Acute poisoning is a recognized and common cause of RMD affecting the left or right ventricle or both ventricles (170, 171), leading to disturbances of segmental contractility, particularly at the level of the septum (172), and electrocardiographic changes, in particular of the ST segment, the T wave, and the QT interval (173, 174). In these cases, complications such as pulmonary edema (174), arrhythmias (172), shock, and even

Table 3. Poisoning related to the onset of RMD Calcium antagonists -blockers -stimulants Catecholamines Chemotherapy Antiarrhythmics Local anesthetics Salicylate toxicity Lithium Iron Hyponatremia because of water intoxication Cocaine Opioid agonists Opioid agonist-antagonists Metamphetamine Tricyclic antidepressants Alcohol Sildenal Non-ionic contrast Aluminum Paraquat Carbon monoxide Hydrocarbon ingestion Scorpion sting Spider bite Bee sting Ipecac Antimony Selenium Nickel

RMD, reversible myocardial dysfunction.

death may occur (175) (Table 3). The etiopathogenesis of this dysfunction could be mediated by direct cardiac toxicity or even could have a multifactorial origin including excess catecholamine release, increased myocardial oxygen requirements, myocardial ischemia, liberation of a myocardial depressant substance, the onset of acute anaphylaxis or SIRS, and acid-base or electrolyte disturbances (176 179). Other Causes of RMD in the Critically Ill Patient. Other causes of RMD in the critically ill patient, described in short series or case reports, include renal failure attributable to rhabdomyolysis (180), episodes of severe arterial hypertension attributable to pheochromocytoma (181, 182), thyrotoxic crisis (183, 184), hypothyroidism (185), hyperthermia (186), hypothermia (187), obstructive jaundice (188), emotional distress (21, 189), and states of malnutrition and refeeding in which a situation of cardiac insufciency may develop with high or low cardiac output and in which hypophosphatemia has been directly implicated (190 195). The majority of these reports coincide with the nding that severe RMD may be associated with electrocardiographic changes, disturbances of segmental contractility, particularly apical, and normal coronary angiographies (180). Other possible causes of RMD include supraventricular arrhythmias which, if prolonged, may lead to myocardial dysfunction that would be reversible after resolution of the arrhythmia (196), and the postpartum cardiomyopathy that may be an abnormal response to pregnancy (197). Clinical Implications of RMD. Although the majority of the studies that have been cited here are case series or noncontrolled studies, it may be inferred from these studies that an RMD may develop in critically ill patients. The possible causes of this RMD are not well understood; it is suspected that the causes of myocardial stunning in the patient with active coronary artery disease may be mediated by ischemia, the postreperfusion lesion (possibly including free radicals), changes in the free intracellular calcium concentration (calcium overload in particular), and modulation of the contractile protein response to calcium with a decreased responsiveness of the contractile laments to calcium (3). Myocardial hibernation is associated with a transient

Table 4. Etiological factors associated with the onset of reversible myocardial dysfunction Cytokines IL-1 IL-2 IL-6 IL-8 IL-10 InterferonTransforming growth factorTNFIL, interleukin; TNF, tumor necrosis factor. Free radicals Nitric oxide Prostanoids Platelet activating factor Thromboxanes Prostacyclins Histamine Testosterone Intracellular calcium concentration Myocardial ischemia Hypoxia/anoxia Coronary artery vasospasm Vasoconstriction of the coronary microcirculation Cardioversion Debrillation Reperfusion phenomena Catecholamines Fasting/refeeding/hypophosphatemia

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decrease in myocardial calcium (18). However, in the critically ill, noncardiac patient, RMD may depend on the causative pathology of the critical illness or may have a multifactorial origin, developing from the combined effects of the tissue hypoxia, reperfusion phenomena, myocardial depressant substance release, SIRS activation, excess circulating catecholamines, or cytotoxicity phenomena; there may even be a genetic basis (198) (Table 4). Although it appears obvious that myocardial stunning is well tolerated in most cases and probably has no signicant effect on the clinical course or prognosis, its onset could increase or directly cause morbidity and mortality (21). Although up to 50% of patients with ventricular dysfunction may be asymptomatic, with no specic diagnosis, RMD may not be considered despite the fact that this dysfunction reduces myocardial reserve, which may, secondarily, cause poor tolerance to uid administration (199). It is conceivable, therefore, that an occult ventricular dysfunction in a critically ill patient may play a role in progression toward cardiorespiratory failure. The diagnosis of RMD could reasonably explain episodes of acute respiratory failure attributable to cardiac failure that otherwise may have been attributed to acute pulmonary lesions, acute respiratory distress syndrome, or even pneumonia. Other problems derived from RMD are those complications it may cause, such as the presence of apical thrombi with the possibility of embolization, an increased length of stay (200), increase in comorbidity, onset of shock (caused either directly or in association with other factors), arrhythmias, and an increase in mortality. Its diagnosis may bring the need for specic measures such as avoidance of anesthetic problems, avoidance of situations of stress, evaluation of the cardiac response and recovery, an estimation of viable myocardium, and later follow-up. Before discussing the possible therapeutic strategies for this RMD, we should remember that this syndrome may represent a subtle manifestation of organ failure in critical illness and may correspond to an adaptive response to the critical pathology (99), or it may even be a complication that increases morbidity and mortality rates (21). The study of how this pathology affects the prognosis of the primary critical pathology is therefore paramount. If an increase in morbidity and mortality rate is demonstrated, a specic therapeutic regimen may be developed for this RMD. This therapeutic regimen may have to be adjusted to include measures such as anticoagulation, cardioprotection, and attempts to recruit stunned myocardium and increase the ejection fraction to reduce the risk of cardiogenic shock by using vasoactive drugs (201) or ventricular assistance methods such as IACB for as long as myocardial stunning lasts; these factors may prevent the death of the patient. One area for study in RMD is the role of the inotropic drugs, such as dobutamine, even in the absence of shock. This drug could improve

myocardial contractility. Recognition of an RMD is therefore important in deciding whether to maintain pharmacologic treatment or mechanical supportive measures such as mechanical ventilation or IACB until the shock recovers or to interpret the LVEF and the segmental contractility disturbances and use this as the basis for decisions on further action (202). Clinical suspicion may be aroused by the electrocardiogram or enzymes (200), and the diagnosis of RMD is easy to make in the ICU by using echocardiography. A further aspect of interest is the possibility for preventing this dysfunction, an area in which there may be a role for drugs such as -blockers, including carvedilol and esmolol, angiotensin converting enzyme inhibitors (203), the prophylactic use of an IACB in situations of stress (203, 204), and, possibly in the future, antioxidants or immunotherapy (132).

5.

6.

7.

8.

CONCLUSIONS
RMD may occur in cases of critical pathology. Its etiology is not fully understood. This dysfunction frequently is associated with an increase in enzyme markers and electrocardiographic changes. It is probably underdiagnosed although it worsens the prognosis and is associated with more specic therapeutic options. Future studies are necessary to assess its true incidence and clinical implications.
9.

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ACKNOWLDEGMENTS
I thank Cosme Ruiz Bailn for help in the preparation of this article and the personnel of the journals libraries of the Virgen de las Nieves University Hospital of Granada and Hospital Torrecrdenas in Almera. I also thank Boehringer Ingelheim Espaa for translation of this text.
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