Table of Contents    
REVIEW ARTICLE
Year : 2018  |  Volume : 9  |  Issue : 2  |  Page : 76-85
 

Terlipressin-Induced ischemic complications: A systematic review of published case reports


1 Department of Pharmacology, PGIMER, Chandigarh, India
2 Department of Gastroenterology, PGIMER, Chandigarh, India

Date of Submission26-Feb-2018
Date of Decision30-Jun-2018
Date of Acceptance05-Jun-2018
Date of Web Publication4-Sep-2018

Correspondence Address:
Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpp.JPP_23_18

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   Abstract 


Terlipressin is used in the management of variceal bleeding and hepatorenal syndrome. Ischemic complications are rare, but serious adverse effects of terlipressin therapy can be fatal. In this context, we reviewed all the published case reports of terlipressin-induced ischemic complications, and data were collected regarding the part of body affected by ischemic complication, latency, geographical variation, different treatment strategies and their outcome, and other relevant information. After an exhaustive search in different databases, 33 published cases were found. The ischemic complications affected virtually every part of the body. Peripheral gangrene was the most common ischemic complication followed by ischemic complications of more proximal parts such as thigh and abdominal wall. Other parts affected were heart, colon, small intestine, scrotum, etc. Most cases were managed conservatively. Although in few cases, other treatment options were also explored, knowledge of this dreaded complication and different management strategies is necessary for early identification of this adverse effect and early management so as to prevent fatality.


Keywords: Gangrene, hepatorenal syndrome, ischemic complication, terlipressin, vericeal bleeding


How to cite this article:
Sarma P, Muktesh G, Singh RS, Mishra A, Singh A, Ruhela RK, Kumar H, Dhaka N, Medhi B. Terlipressin-Induced ischemic complications: A systematic review of published case reports. J Pharmacol Pharmacother 2018;9:76-85

How to cite this URL:
Sarma P, Muktesh G, Singh RS, Mishra A, Singh A, Ruhela RK, Kumar H, Dhaka N, Medhi B. Terlipressin-Induced ischemic complications: A systematic review of published case reports. J Pharmacol Pharmacother [serial online] 2018 [cited 2018 Dec 11];9:76-85. Available from: http://www.jpharmacol.com/text.asp?2018/9/2/76/240553





   Introduction Top


Variceal bleeding and hepatorenal syndrome (HRS) often complicate advanced liver disease. Earlier vasopressin was used for the treatment of HRS and variceal bleeding, but it had moderate efficacy and was associated with high rate of ischemic adverse effects.[1] Terlipressin, introduced in the early 1990s, is a synthetic analog of vasopressin with fewer side effects and longer duration of action.[2] Terlipressin is recommended for the management of both the conditions.[2],[3],[4] Ischemia leading to gangrene is a relatively rare adverse effect of terlipressin. In this context, we reviewed all the published case reports of terlipressin-induced ischemic complications. This is the first review of this kind for evaluation of different terlipressin associated ischemic complications, management strategies, and their outcome.

Search strategy

We used different permutations and combinations of keywords “terlipressin,” “ischemia,” “gangrene,” “necrosis,” “infarction,” “case report,” and “report” for searching different databases such as PubMed, Embase, Google Scholar, and Cochrane database (till July 22, 2016). In addition, we also searched references of the studies of screened articles to extract information about relevant articles.

Study selection

In the first step, titles and abstracts of the articles were reviewed and irrelevant articles were excluded. In the next step, full texts of the selected articles were screened as per inclusion and exclusion criteria.

Inclusion criteria – (a) patients: any age group and both genders, (b) intervention: terlipression, and (c) type of study: case report. Exclusion criteria: articles with an outcome other than ischemic event were excluded from the study.

Data extraction

The first two authors independently extracted the data. In case of any discrepancy, the last and the penultimate authors were consulted and the issue was resolved. In case full article was not available or it was in other language, data were collected from abstract.


   Results Top


Spectrum of ischemic complications and its outcome

Reports of only 33 cases (from 28 published case reports and case series) could be found in literature [Figure 1] and [Table 1]. Ischemic complications affected multiple regions of body including limbs and abdominal wall, heart, gastrointestinal (GI) tract, scrotum, and other miscellaneous body parts (penis, breast, scalp, etc.) The spectrum of ischemic complications are presented in [Table 2]. Out of the 33 cases, 11 cases recovered, death occurred in 17 cases (1 case showed initial improvement but later died due to complications), and information was not available in 5 cases. Patients across all age groups were affected (2 months–79 years). Both males and females were found to be affected.
Figure 1: Flow diagram of case reports included in the review

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Table 1: Data on age range affected and gender-wise distribution of reports

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Table 2: Ischemic complications involving limbs, abdominal wall, and other miscellaneous body parts

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Ischemic complications affecting limbs and abdominal wall

In 61% of the cases, ischemic complications affected different part of limbs and abdominal wall [Table 2] and [Table 3]. [Figure 2] and [Figure 3]a, [Figure 3]b shows the spectrum of gangrene affecting different parts of limbs. Among cases showing ischemic complications of limbs and abdominal wall, 13 cases suffered from gangrene involving distal limbs (5 recovered, 6 died, and information could not be retrieved in 2 cases) and 9 cases involved thigh and abdominal wall (1 recovered, 7 died, and information could not be retrieved in 1 case). One case of finger-sparing upper-limb ischemia was also reported. Latency period for manifestation of complications ranged from 2 to 11 days for ischemia affecting limbs and abdominal wall.
Table 3: Summary of reported cases of ischemic complication of terlipressin

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Figure 2: Terlipressin induced gangrene of both legs

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Figure 3: (a and b) Terlipressin induced gangrene of hand

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Ischemic complications affecting cardiovascular system

Among patients affected by terlipressin-related ischemic complications, 15% had an event which was related to cardiovascular system [Table 3] and [Table 4]. Till now, five reported cases are found in literature. Among the five reports, one report was in French, so data from only four reports were retrieved. Effects of myocardial ischemic complications ranged from ST depression with normal cardiac enzymes to acute ST-elevated myocardial infarction (MI). It affected both males and females (males = 2 and females = 2) and mainly elderly peoples were affected (45–73 years). The latency to ischemia ranged from 20 min to few hours in case of MI. All the cases showed the presence of risk factors for ischemic heart disease. The risk factors present were diabetes, dyslipidemia, coronary artery stenosis, hypothyroidism, hypertension, and smoking. Most cases were managed conservatively with prompt stoppage of terlipressin, moist oxygen inhalation, nitroglycerin infusion, and other medical management strategies. Percutaneous transluminal coronary angioplasty was performed in one case. Among the four cases, three cases survived and one case died. Presence of risk factors such as preexisting coronary artery stenosis, hyperlipidemia, diabetes mellitus, hypertension, and smoking were common among the sufferers from cardiovascular ischemic complications.
Table 4: Reported ischemic complications of heart following terlipressin injection

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Ischemic complications affecting gastrointestinal tract

Nearly 15% of the affected cases reported an adverse event related to ischemia of gastrointestinal tract (GIT) [Table 3] and [Table 5]. Mostly reported cases involved ischemia of small and large intestines. Five cases were related to ischemic complications of colon and small intestine (two recovered, one died, and information could not be retrieved in two cases). One case of ischemia affecting the tongue was also reported (patient died). Latency period for manifestation of ischemic complications of GIT ranged from immediately after bolus to 12 h (after two doses 6 h apart). Presence of risk factors for GI ischemia was noted in one case (complete information was available in two cases), which were concomitant shock, use of other vasopressors, and concomitant coagulopathy. Surgery was the most common mode of therapy for management of the affected cases. Among the affected cases, one case recovered fully, without the need of intestinal resection.
Table 5: Reported ischemic complications of bowel following terlipressin therapy

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Miscellaneous

Five cases of scrotum and one case of penis involvement (all died) were also reported. In one case, ischemic complications affected the breast (completely reversible, latency: few hours). Most commonly, multiple parts of body were affected simultaneously [Table 3].

Other complications such as osteomyelitis, rhabdomyolysis/acute muscle infarction, and necrosis of infusion site were also reported [Table 3].

Geographical distribution of case reports

Data regarding geographical location of adverse drug reactions are shown in [Table 6]. Most of the case reports were from Europe (14 cases) and Asia (13 cases). Only one case was reported from North America (Mexico). No cases have been reported from other continents.
Table 6: Reports as per geographical location

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Diagnosis

In most cases, typical clinical presentation (gangrene in case of limb ischemia) and typical features of ischemic heart disease or pain abdomen were the initial symptoms, which led to secondary investigations for evaluation of the etiology of the ischemic complication. Diagnostic tests were directed by respective symptom domain such as, echocardiography for ischemic complications affecting cardiovascular system, X-ray, abdominal ultrasonography, computed tomography abdomen, and exploratory laparotomy for abdominal symptoms. For ischemic complications affecting limbs, skin biopsy and color Doppler were commonly done to assess the conditions of major vessels and rule out other diagnoses. Among patients with peripheral ischemia, three studies evaluated the blood flow patterns of major vessels by using Doppler. All the three studies reported no sign of obstruction and normal flow in major arteries.[5],[9],[10]

Findings in skin biopsy

Among the cases showing peripheral ischemia, 12 case reports reported skin biopsy findings. The most common features are shown in [Table 7]. Ischemia commonly affected both epidermis and dermis and sometimes subcutaneous tissue. Necrosis and ulceration of dermis and epidermis, subepidermal bullae, vascular congestion in upper dermis, thrombosis of dermal capillaries, and fibrinoid necrosis were the commonly reported features.
Table 7: Peripheral gangrene: Common findings in skin biopsy

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Management of the cases

Most patients were managed conservatively with stoppage of terlipressin, dressing, and management of other concomitant problems [Table 2], [Table 4], and 5]. Among the patients with peripheral gangrene, one patient underwent amputation of three toes.[1] Another patient with forearm and hand involvement (fingers spared) was treated by skin graft.[5]

Use of sildenafil was reported in two cases.[1],[10] In one case, the patient was given both oral sildenafil (50 mg twice daily) and intravenous (IV) alprostidil 10 μg every day.[1] However, the patient developed decreased urine output and the agents were withdrawn. In this patient, maximum ischemia-affected parts recovered, but three toes needed amputation.[1] The other case reported a progressive gradual improvement after initiation of sildenafil.[10]

Management strategies of ischemia affecting heart and GIT are noted in their respective section [Table 3] and [Table 4].


   Discussion Top


Acute variceal bleed is a medical emergency. Management is aimed at controlling the acute hemorrhagic episodes, prevention of rebleeding, and improving morbidity and mortality.[31] Initial management depends on the severity of disease, comorbidities, and availability of endoscopic facility. Pharmacotherapy and endoscopy are the two most common modalities for controlling acute variceal hemorrhage. Pharmacological therapy has an advantage that it requires relatively less expertise than endoscopy and can be initiated as soon as variceal hemorrhage is suspected, even prior to diagnostic endoscopy.[2] Earlier, vasopressin was used for this purpose. Terlipressin is a synthetic analog of vasopressin with longer activity and fewer side effects.[31]

Terlipressin is converted into lysine vasopressin in circulation by endothelial peptidases cleaving the N-triglycyl residue, resulting in “slow release” of vasopressin. This results in prolonged release of vasopressin (half-life of terlipressin is 6 h, whereas that of vasopressin is only 6 min).[14],[32],[33] Arteriolar vasoconstriction induced by lysine vasopressin is primarily mediated by nonselective stimulation of vascular smooth muscle V1 receptors.[13],[34],[35] Vasopressin (and its analogs) also activates V2 receptors on endothelial cells, causing release of von willebrand factor, which enhances platelet aggregation and increases the risk of thrombosis, especially in cases of intense and/or prolonged vasoconstriction.[34]

Ischemic complications are relatively rare adverse effects of terlipressin. Till now, only 33 cases are reported (terlipressin is in use since the early 1990s). Proximal and distal parts of limbs, abdominal wall, heart, bowel, scrotum, penis, and even breast ischemia have been reported. Regarding risk factors associated with terlipressin-induced ischemic complications, various studies mentioned that there was no correlation between the dose of terlipressin administered, length of therapy, and severity of ischemia.[14],[36] Mégarbané et al., 2009, mentioned few possible risk factors, which may be associated with terlipressin-induced ischemic adverse events, which are mode of administration of terlipressin (continuous IV administration), hypervolemia, and prior administration of other pressor agents.[14]

In our review, we found that ischemic complications were more common in persons with risk factors. Common risk factors for the development of ischemic cardiovascular complications were presence of diabetes, preexisting coronary artery stenosis, dyslipidemia, hypertension, and smoking status.[22],[23],[24] Shock, prior use of other vasopressors, and coagulopathy were risk factors associated with the development of ischemic bowel disease.[26]

Anantasit et al. evaluated the risk factors of vasopressin use-associated serious adverse events (SAEs) in patients with septic shock (Vasopressin and Septic Shock Trial cohort). They evaluated vasopressin level among SAE and non-SAE patients and found that SAEs were not dose dependent. It suggests that higher vasopressin level and simple pharmacokinetics were not associated with the occurrence of SAEs. They also evaluated genes related to four vasopressin pathways, namely arginine vasopressin receptor 1A (AVPR1a, 3 SNP), arginine vasopressin receptor 1B (AVPR1b, 5 SNP), leucyl/cystinyl amino peptidase (LNPEP, i.e., 237 SNP), and oxytocin receptor (OXTR, 3 SNP) pathway. It was found that there was a significant association between AA genotype of rs28418396 single-nucleotide polymorphism near the arginine vasopressin receptor 1b gene and SAEs.[35] Mechanism of this association remains unknown and it needs further investigation.[35] The study by Anantasit et al. was done as a part of safety analysis in septic shock patients who received vasopressin. Hence, pharmacogenomics may play a definitive role in predicting and preventing terlipressin-induced SAEs.


   Conclusion Top


Terlipressin is a time-tested drug for the management of vericeal bleeding. Ischemic complications are serious adverse effects of terlipressin therapy. Proper selection of cases with taking into consideration the presence or absence of risk factors may lead to more safe use of the drug. Regarding medical management of the ischemic complications, sildenafil and alprostidil were used in some cases, but we do not have data from any clinical trial regarding this. We need multicentered dedicated studies for evaluation of risk factors of terlipression-induced ischemic complications and associated biomarkers. We reviewed this dreaded complication of terlipressin so that gastroenterologists and physicians become aware of this complication and diagnose it early and thereby prevent further catastrophic events before it turns into a stage of irreversibility.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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