- Email: [email protected]
Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2019) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT
Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report Abdellah Hedjoudje a, Jean-Paul Cervoni a,∗, Cyrille Patry b, Marion Chatot c, Morgan Faivre a, Thierry Thévenot a a
Service d’hépatologie, CHRU Jean-Minjoz, Besanc¸on, France Service de réanimation médicale, CHRU Jean-Minjoz, Besanc¸on, France c Service de cardiologie, CHRU Jean-Minjoz, Besanc¸on, France b
KEYWORDS Takotsubo cardiomyopathy; Transient apical ballooning; Stress-induced cardiomyopathy; Alcohol withdrawal; Delirium tremens; Autonomic Hyperactivity; liver cirrhosis; case report.
Summary A 64-year-old cirrhotic woman was admitted for alcoholic hepatitis associated with renal failure. Subsequently, she displayed symptoms of alcohol withdrawal progressing to delirium tremens. During hospitalization, she developed acute respiratory distress. The electrocardiogram showed diffuse anteroseptal ST elevation. Transthoracic echocardiography revealed systolic left ventricular apical balloon-like dilation, hypokinesis of the left ventricular mid- and apical segments, and a left ventricular ejection fraction of 30%. Coronary angiography was normal and led to the diagnosis of Takotsubo cardiomyopathy. This report describes a singular case of Takotsubo cardiomyopathy precipitated by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure. © 2019 Published by Elsevier Masson SAS.
Introduction Takotsubo cardiomyopathy (TCM) is a reversible cardiomyopathy frequently precipitated by acute emotional or
Abbreviations: AWS, alcohol withdrawal syndrome; CI, confidence interval; TCM, Takotsubo cardiomyopathy; ULN, upper limit of normal. ∗ Corresponding author at: Hepatology department, Besanc ¸on Uni¸on-cedex, 25030, versity Hospital, 3, rue Alexandre Fleming, Besanc France. E-mail address: [email protected] (J.-P. Cervoni).
physical stressors through excessive catecholamine release [1]. Both alcohol withdrawal (and subsequent development of delirium tremens) and liver failure are associated with a hyperadrenergic state predisposing to cardiovascular complications. We report herein the case of a 64-year-old woman presenting a TCM triggered synergistically by alcohol withdrawal and acute-on-chronic liver failure.
Case report A 64-year-old woman was admitted to our Hepatology intensive care unit after being diagnosed with Child-Pugh C10
https://doi.org/10.1016/j.clinre.2019.11.010 2210-7401/© 2019 Published by Elsevier Masson SAS.
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
2
A. Hedjoudje et al.
liver cirrhosis complicated by acute kidney failure and likely acute alcoholic hepatitis. Her past medical history included liver cirrhosis diagnosed two months previously, and breast adenocarcinoma treated in 1993 by surgery. She was a smoker with a history of 38 pack-years, and had a history of alcohol abuse, with self-reported consumption of 80 g of wine per day. On admission, vital signs were as follows: temperature 36.5 ◦ C, pulse 71 beats per minute, respiratory rate 16 breaths per minute, blood pressure 125/85 mmHg, and peripheral capillary oxygen saturation was 96% in room air. Physical examination revealed jaundice, and spider angiomas on the trunk, but there was no clinical sign of hepatic encephalopathy, no ascites or peripheral edema. Cardiopulmonary and neurological physical examinations were considered normal. Digital rectal exam found no blood. Laboratory test results were as follows: total bilirubin 6 mg/dL, aspartate aminotransferase (AST) 182 IU/mL (5.3 × ULN), alanine aminotransferase (ALT) 65 IU/mL (1.2 × ULN), international normalized ratio (INR) 1.53, white blood cells 6.5 109 /L, platelets 250 × 109 /L, hemoglobin 10 g/dL, creatinine 3.2 mg/dL, blood urea nitrogen 65.5 mg/dL, natremia 131 mmol/L, kalemia 3.3 mmol/L and C-reactive protein 36.7 mg/L. Electrocardiogram and chest X-ray on admission were normal. In addition, the abdominal ultrasound found morphologic features suggestive of liver cirrhosis with no ascites, no lesion suggestive of hepatocellular carcinoma and no urinary tract obstruction. After three days of sobriety, the patient developed alcohol withdrawal syndrome (AWS) with delirium tremens. She was managed using standard practices, including use of oral benzodiazepines and fluid balance. On day five, she developed acute respiratory distress with chest wall retraction and paradoxical breathing. Her vital signs were as follows: temperature 37 ◦ C, pulse 140 beats per minute, respiratory rate 25 breaths per minute, blood pressure 125/85 mmHg, and oxygen saturation 92% with 10 L/min of oxygen. The Glasgow score was 15/15. The patient did not report chest pain, chest discomfort, or palpitations. Chest X-ray found alveolar edema (Fig. 1). ECG revealed sinus tachycardia with antero-apical ST-segment elevation (Fig. 2). Serum electrolyte values (sodium, potassium, phosphorus and magnesium) were normal and kidney function was improved (serum creatinine level was 0.75 mg/dL). Arterial blood gases with 8L/min of oxygen revealed pH = 7.47, pO2 = 7.4 kPa, pCO2 = 3.43 kPa, lactates = 3.40 mmol/L; troponin I was found to be elevated at 3.96 ng/mL (normal range below 0.016), and decreased progressively thereafter (3.66 and 0.66 ng/mL respectively 6 and 24 hours later). Brain Natriuretic Peptide was elevated at 1393 ng/L (normal range; 0—100). The patient was subsequently transferred to the critical care unit. Bedside echocardiography showed left ventricular dilatation with apical ballooning on systole, hypokinesis of the left ventricular mid-segments and apex, a left ventricular ejection fraction of 30% and normal pulmonary artery pressures. Left ventriculogram during systole showed apical ballooning suggestive of TCM (Fig. 3) and cardiac catheterization further confirmed the characteristic pattern of apical ballooning in the absence of coronary atherosclerosis and no significant lesions of the coronary arteries (Fig. 4). Three days later, another echocardiography showed
Figure 1 Chest X-ray at admission and at day 5. Chest X-ray at day 5 during respiratory distress showing alveolar oedema.
normal systolic function without wall motion abnormalities. The diagnosis of TCM was retained, and supportive therapy was initiated. The respiratory distress syndrome was successfully treated with nasal high-flow therapy (OptiflowTM system), which delivered a fraction of inspired oxygen of 40% with a flow rate up to 50 L/min. Respiratory symptoms promptly improved after one-hour session associated with diuretics. Thereafter, oxygen supply was gradually reduced and was removed seven hours later. The electrocardiogram returned to normal 8 hours after the admission in the critical care unit. The patient remained confused with auditory and visual hallucinations, but he was no longer agitated and did not display other cardiac or renal complications. He returned to our hepatology intensive care unit two days later, and blood cultures remained negative and no infection occurred until the end of its hospital stay.
Discussion This case highlights the risk of TCM in the context of liver cirrhosis with acute-on-chronic liver failure associated with delirium tremens. The diagnosis of TCM is clinically challenging and can be made only after ruling out several other possible causes of respiratory distress in a cirrhotic patient with delirium tremens. First, patients with cirrhosis may develop progressive impairment of circulatory and cardiac function during the course of their illness, independently of alcohol cardiotoxicity, termed ‘‘cirrhotic cardiomyopathy’’ (CCM). This term denotes a condition of infra-clinical, chronic cardiac dysfunction in a patient with established cirrhosis, characterized by a blunted contractile response to stress (pharmacological, surgical or inflammatory) and altered diastolic relaxation in the absence of any other cardiac disease [1]. Second, respiratory depression is a common side effect of high dose benzodiazepine treatment. The primary initial pharmacologic therapy for AWS involves gammaaminobutyric acid receptor inhibition, most often achieved
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient
3
Figure 2 12-lead electrocardiogram at day 6. This electrocardiogram shows ST-segment elevation at derivations V3, V4, V5, and T-wave inversion at V6.
Figure 3 Left ventriculogram during diastole (A) and systole (B). These figures show the characteristic apical ballooning suggestive of Takotsubo cardiomyopathy.
Figure 4
Coronary angiogram. Coronary angiogram shows no obstruction of the coronary arteries.
with intermittent administration of benzodiazepines, to replace the neurodepressant activity of alcohol [2]. The decreased hepatic clearance of drugs observed in cirrhotic patients can result in drug accumulation, which may potentially increase hazardous side effects, such as over-sedation and respiratory depression in an already debilitated patient [3]. Third, excessive hydration may lead to respiratory distress syndrome due to iatrogenic pulmonary edema. Fourth, electrolyte imbalance (such as hypokalemia or hypomagnesemia) are common in AWS, and can increase the risk of acute coronary syndrome [4]. Electrophysiological alterations, such as prolongation of the QT interval, are observed in up to 63% of patients with AWS [5]. Other arrhythmogenic
events reported include torsade de pointes, sustained ventricular tachycardia, atrial fibrillation and supraventricular tachycardia [4]. Finally, in case of respiratory failure with sepsis, a diagnosis of pneumonia should be considered, since it is a frequent complication that accounts for the majority of deaths [6]. In our case, TCM was diagnosed by the absence of coronary artery disease and the presence of characteristic transient left ventricular apical ballooning. While no consensus on the diagnostic criteria for TCM exists, the most widely accepted diagnostic criteria have been proposed by the Mayo Clinic [7]. Their suggested diagnostic criteria are the presence of all of the following features, which were all present in our patient:
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
4
A. Hedjoudje et al.
transient hypokinesis, akinesis or dyskinesis in the left ventricular mid segments with or without apical involvement; regional wall motion abnormalities that extend beyond that expected from a single epicardial vascular distribution; and frequently, but not always, a stressful trigger: • the absence of obstructive coronary artery disease or angiographic evidence of acute plaque rupture; • new ECG abnormalities (ST-segment elevation and/or Twave inversion); • the absence of pheochromocytoma and myocarditis or other reason for left ventricular dysfunction. TCM is becoming an increasingly recognized clinical disorder first reported in 1990 in the Japanese population [8]. It remains an under-diagnosed condition that may account for 1% to 2% of all cases of suspected acute myocardial infarction [9]. Clinically, patients display signs and symptoms that often mimic acute coronary syndrome, such as chest pain, dyspnea, occasional syncope and abnormal ECG findings. Most often, the diagnosis is made after exclusion of other cardiac disease, and in the presence of normal cardiac catheterization. Treatment is only supportive since no definitive benefit was yielded from pharmacologic therapy [10]. Recently, a novel clinical score has been developed to help distinguish between TCM and acute coronary syndrome [11]. The physiopathology of TCM is not yet fully elucidated. However, the most likely hypothesis remains catecholamine cardiotoxicity. In more than 85% of cases, TCM is provoked by either a physically or emotionally stressful event that precedes the onset of symptoms, leading to overproduction of endogenous catecholamine [12]. It has been found that catecholamine surges exert positive inotropic and lusitropic effects on cardiomyocytes. Catecholamine-mediated stimulation of myocardial 1- and 2- adrenergic receptors induces coupling with intracellular stimulatory G protein (Gs) and subsequent activation of adenylyl cyclase, which increase cyclic adenosine monophosphate (cAMP), which secondarily activates protein kinase A. This in turn stimulates several downstream intracellular targets resulting in a positive inotropic response [13] . At supraphysiological levels, catecholamines have a negative inotropic effect due to a switch in the 2-adrenergic receptors coupling from Gs protein to Gi protein signaling in the ventricular myocardium, a mechanism known as ‘‘biased agonism’’ or ‘‘stimulus trafficking’’. Consequently, the 2-adrenergic receptors-Gi signaling predominantly located at the apex can then cause direct myocyte injury, leading to acute myocardial stunning and transient hypokinesis[14]. This effect appears to be greatest at the apex, where -adrenergic receptors are most predominant, with an apical—basal gradient of -adrenergic receptor leading to the typical ampulla-shaped cardiomyopathy. This hyperadrenergic status is well established in AWS. The first association of TCM with AWS was described in 2004 by Suzuki et al. [15]. Later, several cases were reported and described the association of TCM with alcohol withdrawal [16—20]. To the best of our knowledge, the only case of TCM associated with delirium tremens was reported by Agu et al. [21] but our case is the first to recognize this association in the context of liver cirrhosis. Recently,
a retrospective national cohort of TCM patients with alcoholism [4] observed that the frequency of TCM in alcohol withdrawal (0.023%) and delirium tremens (0.059%) was significantly higher than that of TCM with alcoholism alone (0.016%). After adjustment, the odds of coexisting TCM was 1.53 [95% CI: 1.03—2.29] times higher in alcohol withdrawal and 4.38 [95% CI: 2.91—6.59] in delirium tremens compared to alcoholism [4]. In previous cases report, TCM was associated with acute liver failure [22] or decompensated cirrhosis [23] independently of the occurrence of AWS and delirium tremens suggesting that a pathophysiologic hyperadrenergic state associated with liver failure could induce the occurrence of TCM [24]. In another case report, TCM was probably the direct consequence of intravenous epinephrine administration to maintain adequate mean arterial pressure in a patient suffering from acute liver failure associated with hepatic encephalopathy [25]. Anyway, these putative mechanisms associated with stressful events may have herein acted synergistically and favored the occurrence of TCM. In summary, clinicians should be alerted to the possibility of TCM when managing cirrhotic patients presenting with delirium tremens and signs of ventricular dysfunction or acute respiratory distress syndrome. Importantly, the diagnosis of TCM should be made only when the other usual causes of respiratory distress or ventricular dysfunction have been ruled out. Furthermore, we underline the importance of providing adequate sedation to reduce the intense adrenergic surge and, hopefully, to prevent complications like TCM.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Angeli TR, Du P, Midgley D, Paskaranandavadivel N, Sathar S, Lahr C, et al. Acute slow wave responses to high-frequency gastric electrical stimulation in patients with gastroparesis defined by high-resolution mapping. Neuromodulation J Int Neuromodulation Soc 2016;19:864—71, http://dx.doi.org/10. 1111/ner.12454. [2] Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, et al. Management of alcohol withdrawal delirium: an evidence-based practice guideline. Arch Intern Med 2004;164:1405—12, http://dx.doi.org/10.1001/ archinte.164.13.1405. [3] Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy 1996;16:49—57. [4] Joy PS, Kumar G. Delirium tremens is a risk factor for Takotsubo cardiomyopathy. Int J Cardiol 2015;191:185—6, http://dx.doi.org/10.1016/j.ijcard.2015.04.251. [5] Cuculi F, Kobza R, Ehmann T, Erne P. ECG changes amongst patients with alcohol withdrawal seizures and delirium tremens. Swiss Med Wkly 2006;136:223—7 [https://doi.org/2006/13/smw-11319]. [6] Monte R, Rabu˜ nal R, Casariego E, López-Agreda H, Mateos A, Pértega S. Analysis of the factors determining survival of alcoholic withdrawal syndrome patients in a general hospital. Alcohol Alcohol 2010;45:151—8, http://dx.doi.org/ 10.1093/alcalc/agp087.
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient [7] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408—17, http://dx.doi.org/10.1016/j.ahj.2007.11.008. [8] Akashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 2008;118:2754—62, http://dx.doi.org/10. 1161/CIRCULATIONAHA.108.767012. [9] Kurowski V, Kaiser A, von Hof K, Killermann DP, Mayer B, Hartmann F, et al. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132:809—16, http://dx.doi.org/10.1378/chest.07-0608. [10] Fazio G, Pizzuto C, Barbaro G, Sutera L, Incalcaterra E, Evola G, et al. Chronic pharmacological treatment in takotsubo cardiomyopathy. Int J Cardiol 2008;127:121—3, http://dx.doi.org/10.1016/j.ijcard.2007.04.013. [11] Ghadri JR, Cammann VL, Jurisic S, Seifert B, Napp LC, Diekmann J, et al. A novel clinical score (InterTAK Diagnostic Score) to differentiate takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry. Eur J Heart Fail 2017;19:1036—42, http://dx.doi.org/ 10.1002/ejhf.683. [12] Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539—48, http://dx.doi.org/10.1056/NEJMoa043046. [13] Lyon AR, Rees PSC, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy–a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008;5:22—9, http://dx.doi.org/10.1038/ncpcardio1066. [14] Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O’Gara P, et al. High levels of circulating epinephrine trigger apical cardiodepression in a 2-adrenergic receptor/Gidependent manner: a new model of Takotsubo cardiomyopathy. Circulation 2012;126:697—706, http://dx.doi.org/10.1161/ CIRCULATIONAHA.112.111591. [15] Suzuki K, Osada N, Akasi YJ, Suzuki N, Sakakibara M, Miyake F, et al. An atypical case of ‘‘Takotsubo cardiomyopathy’’ during alcohol withdrawal: abnormality in the transient left
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
5
ventricular wall motion and a remarkable elevation in the ST segment. Intern Med Tokyo Jpn 2004;43:300—5. Stout BJ, Hoshide R, Vincent DS. Takotsubo cardiomyopathy in the setting of acute alcohol withdrawal. Hawaii J Med Public Health 2012;71:193—4. Mitchell SA, Crone RA. Takotsubo cardiomyopathy: a case report. J Am Soc Echocardiogr Off 2006;19:1190, http://dx.doi.org/10.1016/j.echo.2006.04.032 [e9-10]. Yazdan-Ashoori P, Nichols R, Baranchuk A. Tako-tsubo cardiomyopathy precipitated by alcohol withdrawal. Cardiol J 2012;19:81—5. Alexandre J, Benouda L, Champ-Rigot L, Labombarda F. Takotsubo cardiomyopathy triggered by alcohol withdrawal. Drug Alcohol Rev 2011;30:434—7, http://dx.doi.org/10.1111/j. 1465-3362.2011.00289.x. Omar HR, Abdelmalak HD, Komorova I, Helal E, Camporesi EM. Alcohol withdrawal-induced Takotsubo. Intern Emerg Med 2012;7(Suppl 2):S107—8, http://dx.doi.org/10. 1007/s11739-012-0766-0. Agu CC, Bakhit A, Basunia M, Bhattarai B, Oke V, Salhan D, et al. Takotsubo cardiomyopathy precipitated by delirium tremens. J Community Hosp Intern Med Perspect 2015;5:29704, http://dx. doi.org/10.3402/jchimp.v5.29704. Jophlin LL, Koch DG. Takotsubo cardiomyopathy following acute liver failure. Hepatology 2015;61:1430—1, http://dx.doi.org/10.1002/hep.27247. Al Juboori A, Gautam S, Kaur S. Diagnostic dilemma of Takotsubo cardiomyopathy in the setting of decompensated cirrhosis. J Clin Gastroenterol 2016;50:896, http://dx.doi.org/ 10.1097/MCG.0000000000000586. Ytrebø LM, Sen S, Rose C, Davies NA, Nedredal GI, Fuskevaag O-M, et al. Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis. Scand J Gastroenterol 2006;41:1350—60, http://dx.doi.org/10. 1080/00365520600714527. Seemann A, Demars N, Manzo-Silberman S, Cariou A, Fichet J. An unusual trigger for a neurogenic left ventricular dysfunction: Tako-Tsubo syndrome associated with hepatic encephalopathy. Liver Int 2011;31:585—6, http://dx.doi. org/10.1111/j.1478-3231.2010.02429.x.
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2019) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT
Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report Abdellah Hedjoudje a, Jean-Paul Cervoni a,∗, Cyrille Patry b, Marion Chatot c, Morgan Faivre a, Thierry Thévenot a a
Service d’hépatologie, CHRU Jean-Minjoz, Besanc¸on, France Service de réanimation médicale, CHRU Jean-Minjoz, Besanc¸on, France c Service de cardiologie, CHRU Jean-Minjoz, Besanc¸on, France b
KEYWORDS Takotsubo cardiomyopathy; Transient apical ballooning; Stress-induced cardiomyopathy; Alcohol withdrawal; Delirium tremens; Autonomic Hyperactivity; liver cirrhosis; case report.
Summary A 64-year-old cirrhotic woman was admitted for alcoholic hepatitis associated with renal failure. Subsequently, she displayed symptoms of alcohol withdrawal progressing to delirium tremens. During hospitalization, she developed acute respiratory distress. The electrocardiogram showed diffuse anteroseptal ST elevation. Transthoracic echocardiography revealed systolic left ventricular apical balloon-like dilation, hypokinesis of the left ventricular mid- and apical segments, and a left ventricular ejection fraction of 30%. Coronary angiography was normal and led to the diagnosis of Takotsubo cardiomyopathy. This report describes a singular case of Takotsubo cardiomyopathy precipitated by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure. © 2019 Published by Elsevier Masson SAS.
Introduction Takotsubo cardiomyopathy (TCM) is a reversible cardiomyopathy frequently precipitated by acute emotional or
Abbreviations: AWS, alcohol withdrawal syndrome; CI, confidence interval; TCM, Takotsubo cardiomyopathy; ULN, upper limit of normal. ∗ Corresponding author at: Hepatology department, Besanc ¸on Uni¸on-cedex, 25030, versity Hospital, 3, rue Alexandre Fleming, Besanc France. E-mail address: [email protected] (J.-P. Cervoni).
physical stressors through excessive catecholamine release [1]. Both alcohol withdrawal (and subsequent development of delirium tremens) and liver failure are associated with a hyperadrenergic state predisposing to cardiovascular complications. We report herein the case of a 64-year-old woman presenting a TCM triggered synergistically by alcohol withdrawal and acute-on-chronic liver failure.
Case report A 64-year-old woman was admitted to our Hepatology intensive care unit after being diagnosed with Child-Pugh C10
https://doi.org/10.1016/j.clinre.2019.11.010 2210-7401/© 2019 Published by Elsevier Masson SAS.
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
2
A. Hedjoudje et al.
liver cirrhosis complicated by acute kidney failure and likely acute alcoholic hepatitis. Her past medical history included liver cirrhosis diagnosed two months previously, and breast adenocarcinoma treated in 1993 by surgery. She was a smoker with a history of 38 pack-years, and had a history of alcohol abuse, with self-reported consumption of 80 g of wine per day. On admission, vital signs were as follows: temperature 36.5 ◦ C, pulse 71 beats per minute, respiratory rate 16 breaths per minute, blood pressure 125/85 mmHg, and peripheral capillary oxygen saturation was 96% in room air. Physical examination revealed jaundice, and spider angiomas on the trunk, but there was no clinical sign of hepatic encephalopathy, no ascites or peripheral edema. Cardiopulmonary and neurological physical examinations were considered normal. Digital rectal exam found no blood. Laboratory test results were as follows: total bilirubin 6 mg/dL, aspartate aminotransferase (AST) 182 IU/mL (5.3 × ULN), alanine aminotransferase (ALT) 65 IU/mL (1.2 × ULN), international normalized ratio (INR) 1.53, white blood cells 6.5 109 /L, platelets 250 × 109 /L, hemoglobin 10 g/dL, creatinine 3.2 mg/dL, blood urea nitrogen 65.5 mg/dL, natremia 131 mmol/L, kalemia 3.3 mmol/L and C-reactive protein 36.7 mg/L. Electrocardiogram and chest X-ray on admission were normal. In addition, the abdominal ultrasound found morphologic features suggestive of liver cirrhosis with no ascites, no lesion suggestive of hepatocellular carcinoma and no urinary tract obstruction. After three days of sobriety, the patient developed alcohol withdrawal syndrome (AWS) with delirium tremens. She was managed using standard practices, including use of oral benzodiazepines and fluid balance. On day five, she developed acute respiratory distress with chest wall retraction and paradoxical breathing. Her vital signs were as follows: temperature 37 ◦ C, pulse 140 beats per minute, respiratory rate 25 breaths per minute, blood pressure 125/85 mmHg, and oxygen saturation 92% with 10 L/min of oxygen. The Glasgow score was 15/15. The patient did not report chest pain, chest discomfort, or palpitations. Chest X-ray found alveolar edema (Fig. 1). ECG revealed sinus tachycardia with antero-apical ST-segment elevation (Fig. 2). Serum electrolyte values (sodium, potassium, phosphorus and magnesium) were normal and kidney function was improved (serum creatinine level was 0.75 mg/dL). Arterial blood gases with 8L/min of oxygen revealed pH = 7.47, pO2 = 7.4 kPa, pCO2 = 3.43 kPa, lactates = 3.40 mmol/L; troponin I was found to be elevated at 3.96 ng/mL (normal range below 0.016), and decreased progressively thereafter (3.66 and 0.66 ng/mL respectively 6 and 24 hours later). Brain Natriuretic Peptide was elevated at 1393 ng/L (normal range; 0—100). The patient was subsequently transferred to the critical care unit. Bedside echocardiography showed left ventricular dilatation with apical ballooning on systole, hypokinesis of the left ventricular mid-segments and apex, a left ventricular ejection fraction of 30% and normal pulmonary artery pressures. Left ventriculogram during systole showed apical ballooning suggestive of TCM (Fig. 3) and cardiac catheterization further confirmed the characteristic pattern of apical ballooning in the absence of coronary atherosclerosis and no significant lesions of the coronary arteries (Fig. 4). Three days later, another echocardiography showed
Figure 1 Chest X-ray at admission and at day 5. Chest X-ray at day 5 during respiratory distress showing alveolar oedema.
normal systolic function without wall motion abnormalities. The diagnosis of TCM was retained, and supportive therapy was initiated. The respiratory distress syndrome was successfully treated with nasal high-flow therapy (OptiflowTM system), which delivered a fraction of inspired oxygen of 40% with a flow rate up to 50 L/min. Respiratory symptoms promptly improved after one-hour session associated with diuretics. Thereafter, oxygen supply was gradually reduced and was removed seven hours later. The electrocardiogram returned to normal 8 hours after the admission in the critical care unit. The patient remained confused with auditory and visual hallucinations, but he was no longer agitated and did not display other cardiac or renal complications. He returned to our hepatology intensive care unit two days later, and blood cultures remained negative and no infection occurred until the end of its hospital stay.
Discussion This case highlights the risk of TCM in the context of liver cirrhosis with acute-on-chronic liver failure associated with delirium tremens. The diagnosis of TCM is clinically challenging and can be made only after ruling out several other possible causes of respiratory distress in a cirrhotic patient with delirium tremens. First, patients with cirrhosis may develop progressive impairment of circulatory and cardiac function during the course of their illness, independently of alcohol cardiotoxicity, termed ‘‘cirrhotic cardiomyopathy’’ (CCM). This term denotes a condition of infra-clinical, chronic cardiac dysfunction in a patient with established cirrhosis, characterized by a blunted contractile response to stress (pharmacological, surgical or inflammatory) and altered diastolic relaxation in the absence of any other cardiac disease [1]. Second, respiratory depression is a common side effect of high dose benzodiazepine treatment. The primary initial pharmacologic therapy for AWS involves gammaaminobutyric acid receptor inhibition, most often achieved
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient
3
Figure 2 12-lead electrocardiogram at day 6. This electrocardiogram shows ST-segment elevation at derivations V3, V4, V5, and T-wave inversion at V6.
Figure 3 Left ventriculogram during diastole (A) and systole (B). These figures show the characteristic apical ballooning suggestive of Takotsubo cardiomyopathy.
Figure 4
Coronary angiogram. Coronary angiogram shows no obstruction of the coronary arteries.
with intermittent administration of benzodiazepines, to replace the neurodepressant activity of alcohol [2]. The decreased hepatic clearance of drugs observed in cirrhotic patients can result in drug accumulation, which may potentially increase hazardous side effects, such as over-sedation and respiratory depression in an already debilitated patient [3]. Third, excessive hydration may lead to respiratory distress syndrome due to iatrogenic pulmonary edema. Fourth, electrolyte imbalance (such as hypokalemia or hypomagnesemia) are common in AWS, and can increase the risk of acute coronary syndrome [4]. Electrophysiological alterations, such as prolongation of the QT interval, are observed in up to 63% of patients with AWS [5]. Other arrhythmogenic
events reported include torsade de pointes, sustained ventricular tachycardia, atrial fibrillation and supraventricular tachycardia [4]. Finally, in case of respiratory failure with sepsis, a diagnosis of pneumonia should be considered, since it is a frequent complication that accounts for the majority of deaths [6]. In our case, TCM was diagnosed by the absence of coronary artery disease and the presence of characteristic transient left ventricular apical ballooning. While no consensus on the diagnostic criteria for TCM exists, the most widely accepted diagnostic criteria have been proposed by the Mayo Clinic [7]. Their suggested diagnostic criteria are the presence of all of the following features, which were all present in our patient:
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
4
A. Hedjoudje et al.
transient hypokinesis, akinesis or dyskinesis in the left ventricular mid segments with or without apical involvement; regional wall motion abnormalities that extend beyond that expected from a single epicardial vascular distribution; and frequently, but not always, a stressful trigger: • the absence of obstructive coronary artery disease or angiographic evidence of acute plaque rupture; • new ECG abnormalities (ST-segment elevation and/or Twave inversion); • the absence of pheochromocytoma and myocarditis or other reason for left ventricular dysfunction. TCM is becoming an increasingly recognized clinical disorder first reported in 1990 in the Japanese population [8]. It remains an under-diagnosed condition that may account for 1% to 2% of all cases of suspected acute myocardial infarction [9]. Clinically, patients display signs and symptoms that often mimic acute coronary syndrome, such as chest pain, dyspnea, occasional syncope and abnormal ECG findings. Most often, the diagnosis is made after exclusion of other cardiac disease, and in the presence of normal cardiac catheterization. Treatment is only supportive since no definitive benefit was yielded from pharmacologic therapy [10]. Recently, a novel clinical score has been developed to help distinguish between TCM and acute coronary syndrome [11]. The physiopathology of TCM is not yet fully elucidated. However, the most likely hypothesis remains catecholamine cardiotoxicity. In more than 85% of cases, TCM is provoked by either a physically or emotionally stressful event that precedes the onset of symptoms, leading to overproduction of endogenous catecholamine [12]. It has been found that catecholamine surges exert positive inotropic and lusitropic effects on cardiomyocytes. Catecholamine-mediated stimulation of myocardial 1- and 2- adrenergic receptors induces coupling with intracellular stimulatory G protein (Gs) and subsequent activation of adenylyl cyclase, which increase cyclic adenosine monophosphate (cAMP), which secondarily activates protein kinase A. This in turn stimulates several downstream intracellular targets resulting in a positive inotropic response [13] . At supraphysiological levels, catecholamines have a negative inotropic effect due to a switch in the 2-adrenergic receptors coupling from Gs protein to Gi protein signaling in the ventricular myocardium, a mechanism known as ‘‘biased agonism’’ or ‘‘stimulus trafficking’’. Consequently, the 2-adrenergic receptors-Gi signaling predominantly located at the apex can then cause direct myocyte injury, leading to acute myocardial stunning and transient hypokinesis[14]. This effect appears to be greatest at the apex, where -adrenergic receptors are most predominant, with an apical—basal gradient of -adrenergic receptor leading to the typical ampulla-shaped cardiomyopathy. This hyperadrenergic status is well established in AWS. The first association of TCM with AWS was described in 2004 by Suzuki et al. [15]. Later, several cases were reported and described the association of TCM with alcohol withdrawal [16—20]. To the best of our knowledge, the only case of TCM associated with delirium tremens was reported by Agu et al. [21] but our case is the first to recognize this association in the context of liver cirrhosis. Recently,
a retrospective national cohort of TCM patients with alcoholism [4] observed that the frequency of TCM in alcohol withdrawal (0.023%) and delirium tremens (0.059%) was significantly higher than that of TCM with alcoholism alone (0.016%). After adjustment, the odds of coexisting TCM was 1.53 [95% CI: 1.03—2.29] times higher in alcohol withdrawal and 4.38 [95% CI: 2.91—6.59] in delirium tremens compared to alcoholism [4]. In previous cases report, TCM was associated with acute liver failure [22] or decompensated cirrhosis [23] independently of the occurrence of AWS and delirium tremens suggesting that a pathophysiologic hyperadrenergic state associated with liver failure could induce the occurrence of TCM [24]. In another case report, TCM was probably the direct consequence of intravenous epinephrine administration to maintain adequate mean arterial pressure in a patient suffering from acute liver failure associated with hepatic encephalopathy [25]. Anyway, these putative mechanisms associated with stressful events may have herein acted synergistically and favored the occurrence of TCM. In summary, clinicians should be alerted to the possibility of TCM when managing cirrhotic patients presenting with delirium tremens and signs of ventricular dysfunction or acute respiratory distress syndrome. Importantly, the diagnosis of TCM should be made only when the other usual causes of respiratory distress or ventricular dysfunction have been ruled out. Furthermore, we underline the importance of providing adequate sedation to reduce the intense adrenergic surge and, hopefully, to prevent complications like TCM.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Angeli TR, Du P, Midgley D, Paskaranandavadivel N, Sathar S, Lahr C, et al. Acute slow wave responses to high-frequency gastric electrical stimulation in patients with gastroparesis defined by high-resolution mapping. Neuromodulation J Int Neuromodulation Soc 2016;19:864—71, http://dx.doi.org/10. 1111/ner.12454. [2] Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, et al. Management of alcohol withdrawal delirium: an evidence-based practice guideline. Arch Intern Med 2004;164:1405—12, http://dx.doi.org/10.1001/ archinte.164.13.1405. [3] Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy 1996;16:49—57. [4] Joy PS, Kumar G. Delirium tremens is a risk factor for Takotsubo cardiomyopathy. Int J Cardiol 2015;191:185—6, http://dx.doi.org/10.1016/j.ijcard.2015.04.251. [5] Cuculi F, Kobza R, Ehmann T, Erne P. ECG changes amongst patients with alcohol withdrawal seizures and delirium tremens. Swiss Med Wkly 2006;136:223—7 [https://doi.org/2006/13/smw-11319]. [6] Monte R, Rabu˜ nal R, Casariego E, López-Agreda H, Mateos A, Pértega S. Analysis of the factors determining survival of alcoholic withdrawal syndrome patients in a general hospital. Alcohol Alcohol 2010;45:151—8, http://dx.doi.org/ 10.1093/alcalc/agp087.
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010
+Model CLINRE-1354; No. of Pages 5
ARTICLE IN PRESS
Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient [7] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408—17, http://dx.doi.org/10.1016/j.ahj.2007.11.008. [8] Akashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 2008;118:2754—62, http://dx.doi.org/10. 1161/CIRCULATIONAHA.108.767012. [9] Kurowski V, Kaiser A, von Hof K, Killermann DP, Mayer B, Hartmann F, et al. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132:809—16, http://dx.doi.org/10.1378/chest.07-0608. [10] Fazio G, Pizzuto C, Barbaro G, Sutera L, Incalcaterra E, Evola G, et al. Chronic pharmacological treatment in takotsubo cardiomyopathy. Int J Cardiol 2008;127:121—3, http://dx.doi.org/10.1016/j.ijcard.2007.04.013. [11] Ghadri JR, Cammann VL, Jurisic S, Seifert B, Napp LC, Diekmann J, et al. A novel clinical score (InterTAK Diagnostic Score) to differentiate takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry. Eur J Heart Fail 2017;19:1036—42, http://dx.doi.org/ 10.1002/ejhf.683. [12] Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539—48, http://dx.doi.org/10.1056/NEJMoa043046. [13] Lyon AR, Rees PSC, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy–a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008;5:22—9, http://dx.doi.org/10.1038/ncpcardio1066. [14] Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O’Gara P, et al. High levels of circulating epinephrine trigger apical cardiodepression in a 2-adrenergic receptor/Gidependent manner: a new model of Takotsubo cardiomyopathy. Circulation 2012;126:697—706, http://dx.doi.org/10.1161/ CIRCULATIONAHA.112.111591. [15] Suzuki K, Osada N, Akasi YJ, Suzuki N, Sakakibara M, Miyake F, et al. An atypical case of ‘‘Takotsubo cardiomyopathy’’ during alcohol withdrawal: abnormality in the transient left
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
5
ventricular wall motion and a remarkable elevation in the ST segment. Intern Med Tokyo Jpn 2004;43:300—5. Stout BJ, Hoshide R, Vincent DS. Takotsubo cardiomyopathy in the setting of acute alcohol withdrawal. Hawaii J Med Public Health 2012;71:193—4. Mitchell SA, Crone RA. Takotsubo cardiomyopathy: a case report. J Am Soc Echocardiogr Off 2006;19:1190, http://dx.doi.org/10.1016/j.echo.2006.04.032 [e9-10]. Yazdan-Ashoori P, Nichols R, Baranchuk A. Tako-tsubo cardiomyopathy precipitated by alcohol withdrawal. Cardiol J 2012;19:81—5. Alexandre J, Benouda L, Champ-Rigot L, Labombarda F. Takotsubo cardiomyopathy triggered by alcohol withdrawal. Drug Alcohol Rev 2011;30:434—7, http://dx.doi.org/10.1111/j. 1465-3362.2011.00289.x. Omar HR, Abdelmalak HD, Komorova I, Helal E, Camporesi EM. Alcohol withdrawal-induced Takotsubo. Intern Emerg Med 2012;7(Suppl 2):S107—8, http://dx.doi.org/10. 1007/s11739-012-0766-0. Agu CC, Bakhit A, Basunia M, Bhattarai B, Oke V, Salhan D, et al. Takotsubo cardiomyopathy precipitated by delirium tremens. J Community Hosp Intern Med Perspect 2015;5:29704, http://dx. doi.org/10.3402/jchimp.v5.29704. Jophlin LL, Koch DG. Takotsubo cardiomyopathy following acute liver failure. Hepatology 2015;61:1430—1, http://dx.doi.org/10.1002/hep.27247. Al Juboori A, Gautam S, Kaur S. Diagnostic dilemma of Takotsubo cardiomyopathy in the setting of decompensated cirrhosis. J Clin Gastroenterol 2016;50:896, http://dx.doi.org/ 10.1097/MCG.0000000000000586. Ytrebø LM, Sen S, Rose C, Davies NA, Nedredal GI, Fuskevaag O-M, et al. Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis. Scand J Gastroenterol 2006;41:1350—60, http://dx.doi.org/10. 1080/00365520600714527. Seemann A, Demars N, Manzo-Silberman S, Cariou A, Fichet J. An unusual trigger for a neurogenic left ventricular dysfunction: Tako-Tsubo syndrome associated with hepatic encephalopathy. Liver Int 2011;31:585—6, http://dx.doi. org/10.1111/j.1478-3231.2010.02429.x.
Please cite this article in press as: Hedjoudje A, et al. Takotsubo cardiomyopathy triggered by delirium tremens in a cirrhotic patient with acute-on-chronic liver failure: A case report. Clin Res Hepatol Gastroenterol (2019), https://doi.org/10.1016/j.clinre.2019.11.010