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American Journal of Emergency Medicine (2010) 28, 540.e1–540.e6

Case Report

Terlipressin-induced severe left and right ventriculardysfunction in patient presented with uppergastrointestinal bleeding: case report andliterature review

Abstract

Terlipressin is an analog of vasopressin that is effectivelyused for the management of gastrointestinal (GI) bleeding.We report a 52-year-old man presented with upper GIbleeding and was treated with intravenous (IV) injection ofterlipressin that resulted in severe left and right ventriculardysfunction and severe peripheral ischemia. We discuss theunderlying mechanisms of terlipressin-related acute cardio-vascular effects and review the literature.

Fig. 1 Esophagogastroduodenoscopy reveals previously eradicated esovarices/gastropathy.

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Terlipressin is an analog of vasopressin that provideslonger duration of action in the treatment of upper GI bleedingwithout deleterious cardiac effects as compared with vasopres-sin [1-6]. Herein, we report on the cardiovascular complicationsthat have been encountered after terlipressin use in a patientwith upper GI bleeding and review the literature.

A 52-year-old man presented to the accident andemergency department with epigastric discomfort, giddiness,and passing blackish stool for 1 day. The patient was knownto have type 2 diabetes mellitus for 2 years, hypothyroidism,and cryptogenic liver cirrhosis with esophageal varices. Onexamination, he was conscious and alert but in distress andlooked pale. Vital signs revealed the following: temperatureof 37.0°C, pulse rate of 100 beats/min, blood pressure of130/70 mm Hg, and respiratory rate 14/min. Abdominal

phageal varices and severe portal gastropathy with ooze from gastric

Fig. 2 Cardiac complications after terlipressin injection in the form of supraventricular tachycardia (upper panel) and pulmonary edema(lower panel).

540.e2 Case Report

examination showed only tender epigastrium; chest wasclear on auscultation. Cardiac and neurologic examinationswere unremarkable.

Laboratory investigations reveal the following: red bloodcells, 4.1 × 106 μL; white blood cells, 6.5 × 103/μl; platelet,115 × 103; hemoglobin, 9.3 and 8.4 gm/L; hematocrit, 29%;mean corpuscular volume, 70 fl; albumin, 34 g/L;, totalbilirubin, 23 μmol/L; bicarbonate, 20 mmol/L; osmolality,269 Os/kg; pancreatic amylase, 34 μ/L; serum glutamic-pyruvic transaminase, 24 μ/L; international normalized ratio,1.0; ammonia, 23 μmol/L; serum glutamic-oxaloacetictransaminase, 24 μ/L;, lactic acid, 6.2 mmol/L; blood culturein aerobic and anaerobic samples, negative; alkalinephosphatase, 162 μ/L; serial troponin T (reference range,b0.1 ng/mL), b0.01, 0.06, 0.14, 1.60, 4.16, and 2.6; serialcreatine kinase MB (reference range, b5 ng/mL), 2.27, 5.95,71.8, 291, 109, and 54; serum glucose, 7.5 mmol/L; ureanitrogen, 3.7 mmol/L: creatinine, 146 μmol/L; potassium,3.8 mmol/L; sodium, 140 mmol/L; and erythrocyte sedi-mentation rate, 59 mm/1 h.

The patient underwent esophagogastroduodenoscopy thatrevealed previously eradicated esophageal varices, severe

portal gastropathy with ooze from gastric varices/gastro-pathy (Fig. 1). Patient started on terlipressin acetate IVbolus (4 mg stat then 2 mg IV every 6 hours) for 2 days.Few hours after starting terlipressin, patient developedpalpitation and was found to have supraventricular tachy-cardia that responded to 3 IV boluses of adenosine (Fig. 2).On the second day, there was no evidence of activebleeding; however, the patient went into acute pulmonaryedema (Fig. 2) and shock that required mechanicalventilation, dopamine, and then noradrenaline infusion,and terlipressin was stopped. Electrocardiogram showed nosignificant changes (Fig. 3) but with elevated serial cardiacmarkers. Transthoracic echocardiogram revealed diffuseglobal left and right ventricular hypokinesia, severe leftventricle dysfunction with ejection fraction of 18%, rightventricle enlargement, right ventricular systolic pressure 32mm Hg, normal valves, and normal pericardium. On thethird day of admission, the patient started to have signs ofperipheral ischemia that started in the upper and lower limbsand then progressed to develop dry gangrene of the distalphalanges of the right and left fingers and all toes of the leftand right foot (Fig. 4).

Fig. 3 Non–ST-elevation myocardial infarction (upper panel for 12-lead electrocardiography) and normal left and right coronary arterialsystems (lower panel for coronary angiogram).

540.e3Case Report

Three days later, the patient improved hemodynami-cally and was successfully disconnected from themechanical ventilator and inotropic support. Echocardio-gram was repeated 2 weeks later and showed completenormalization of the ventricular function with ejectionfraction of 52%. Subsequently, coronary angiogramshowed patent epicardial left and right coronary arterialsystems (Fig. 3).

This is the first case report describing the associationbetween IV terlipressin and severe cardiac complications inthe form of supraventricular tachycardia, non–ST-elevationmyocardial infarction, severe myocardial dysfunction, andcardiogenic shock in patient with upper GI bleeding. Thesecomplications preceded severe bilateral upper and lowerlimbs ischemia. We assume that severe coronary spasminvolving the left and right coronary arterial systems is theunderlying cause of the severe, reversible left and rightventricular dysfunction. Subsequent coronary angiogramrevealed patent coronary arteries. This case report demon-strated serious regional and systemic vasoconstrictiveeffects of terlipressin that resulted in gangrenous changesin all limbs; the severity and distribution of peripheralischemia were not described previously. Terlipressin is a

synthetic analog of vasopressin that rapidly metabolized tolysine-vasopressin by endopeptidases and provides longerduration of smooth muscle constriction as compared withvasopressin [6]. Intravenous injection of terlipressin hasbeen successfully used in treatment of acute upper GIhemorrhage [1,6]. Despite vasopressin/terlipressin wide-spread use, there is considerable uncertainty regarding theadverse cardiac effects of each [4]. Although, there are noenough data to compare the coronary vasopressor effects ofterlipressin and vasopressin, and the pharmacokinetics ofboth drugs are difficult to compare, reports claimed thatterlipressin is safer than vasopressin from the cardiovascularpoint of view [3,5-8].

Vasopressin effects are mediated through at least 5receptors (V1R, V2R, V3R, OTR, and P2R). V1R isresponsible for increased vascular tone, whereas OTRmediates vasodilation. Therefore, vasopressin/terlipressinis able to cause either vasoconstriction or vasodilationdepending on the distribution of V1R versus OTR [4].Terlipressin-induced cardiac effects are significantly lesspronounced than those observed by vasopressin and, likevasopressin, are essentially mediated but with higheraffinity via V1R vasopressin receptors. Although terli-

Fig. 4 Severe peripheral ischemic changes in the upper and lower limbs after 2 days of terlipressin injection.

540.e4 Case Report

pressin-induced coronary vasopressor effects occurredonly in supratherapeutic concentrations, they were pow-erful enough to provoke ischemic adverse effects [3].Vasopressin has controversial and dose-dependent effectson both cardiac contractility and coronary arterial tone.The effect on the coronary vascular bed is intensified byendothelial dysfunction [5,9]. Our patient is expected tohave 2 risk factors of endothelial dysfunction, that is,diabetes mellitus and hypothyroidism [10,11]. Medel et al[1] reported a case of myocardial ischemia occurringsimultaneously with an episode of severe hypertensionafter terlipressin use. The investigators hypothesized thatcoronary artery spasm and/or an acute increase of leftventricular afterload was likely induced by terlipressin.Vasopressin has also some thrombotic effects by releasingfactor von Willebrand and activating tissue plasminogenactivator inhibitor [1].

The inotropic effects of vasopressin are also debat-able, and the effects seem to depend on the dose usedand the model studied [5]. The net effect of vasopressin

on the myocardium in an intact preparation depends alsoon the relative balance of its effects on coronaryperfusion pressure, coronary vascular tone, and anydirect effects on the myocardial contractility [5]. Onthe contrary, an observational study [12] demonstratedthat low-dose vasopressin improved myocardial perfor-mance in patients with postcardiotomy shock. Whenstudied at high doses in GI bleeding, deleterious effectsof vasopressin on myocardial performance were reportedincluding coronary vasospasm [4,13,14]. Vasopressinmay also impair indices of ventricular contraction andrelaxation without overt global ischemia [15]. Experi-mentally, low-dose vasopressin infusion had no signifi-cant cardiovascular effect in normal heart, whereas afterischemic injury to the myocardium, vasopressin exerted astrong negative inotropic effect, resulting in a significantdecline in cardiac ejection fraction [3,4]. Ischemic injury,by decreasing OTR expression in the heart, may result invasopressin-inducing vasoconstriction and myocardialdysfunction [4].

540.e5Case Report

Moreover, vasopressin has been found to block KATP

channels in the vascular endothelium and may contribute tosudden vasospasm in the coronary circulation [16,17].Increased membrane excitability as a result of vasopressinacting to close KATP channels could increase the risk ofarrhythmia. In our case, terlipressin-induced supraventriculartachycardia, which was not reported previously, may be relatedto the higher doses of terlipressin (4 mg, then 2 mg).Intravenous treatment with terlipressin for recurrent GI bleedinghas been reported to induce ventricular tachycardia with orwithout prolonged QT interval and torsade de pointes [18,19].

Recurrent pulmonary edema have been described withrepeated administration of vasopressin in patients presentedwith GI bleeding after either systemic or local administrationof vasopressin [20,21]. Previous data reported several drugsthat induced coronary artery spasm and resulted inmyocardial infarction (ST- or non–ST-elevation), pulmonaryedema, and/or cardiogenic shock [22-24]. To our knowledge,the current report is the third case demonstrating theoccurrence of myocardial infarction during terlipressininjection; however, in comparison to the previous cases,this is the first non–ST-elevation myocardial infarction caseafter terlipressin [20,25].

In summary, during treatment of GI bleeding, terlipressin-induced serious cardiovascular complications secondary tointense coronary spasm should be expected at higherterlipressin dose. Therefore, low-doses and premedicationof coronary vasodilators are recommended particularly inpatients who are at high risk of endothelial dysfunction.However, this speculation needs further investigation.

Abdul-Naser Elzouki MBchB, MSc, PhD, MDDepartment of Internal Medicine

Hamad General HospitalDoha, Qatar

Ayman El-Menyar MBchB, MScDepartment of Cardiology

Hamad General Hospital, HMCDoha, Qatar

Weill Cornell Medical SchoolClinical Medicine

Doha, QatarE-mail address: elmenyar@yahoo.com

Emad Ahmed MBchB, MDDepartment of Cardiology

Hamad General Hospital, HMCDoha, Qatar

Mohammed E. Elbadri MBchBYahia Z. Imam MBchB

Department of Internal MedicineHamad General Hospital

Doha, Qatar

Bahlul A. Gurbanna MRCPDepartment of Cardiology

Hamad General Hospital, HMCDoha, Qatar

doi:10.1016/j.ajem.2009.08.012

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