Is spontaneous bacterial peritonitis an inducer of vasopressin analogue side-effects? A case report

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Digestive and Liver Disease 35 (2003) 503–506 www.elsevier.com / locate / dld

Brief Clinical Observation

Is spontaneous bacterial peritonitis an inducer of vasopressin analogue side-effects? A case report F. Vaccaro*, A. Giorgi, O. Riggio, A. De Santis, A. Laviano, F. Rossi-Fanelli Department of Clinical Medicine, University of Rome ‘ La Sapienza’, Viale dell’ Universita` 37, 00185 Rome, Italy Received 21 February 2002; accepted 18 July 2002

Abstract In recent years, the use of vasopressin analogues in the treatment of hepatorenal syndrome has become an effective therapeutic strategy leading to improved survival and often allowing the completion of liver transplantation. Terlipressin, in particular, has proven to be safe and effective. Due to the limited number of patients treated so far, it is, however, difficult to draw any definite conclusions on the optimal dosage and on the occurrence of side-effects in these patients. The case is reported of an ascitic cirrhotic patient who developed spontaneous bacterial peritonitis followed by a type-I hepatorenal syndrome. Treatment with terlipressin boluses (0.5 mg / 4 h) associated with albumin infusion was then started. The course of the disease was monitored by clinical and laboratory means. After 10 boluses of terlipressin, rectorrhagia and severe ischaemic complications involving the skin of the abdomen, lower limbs, scrotus, and penis, occurred. These ischaemic complications improved after terlipressin withdrawal, while renal failure evolved leading to the patient’s death. This case report shows that, in patients with type-I hepatorenal syndrome, the use of terlipressin, even at low dosages, may induce life-threatening ischaemic complications and, moreover, suggests that the recent occurrence of spontaneous bacterial peritonitis, even if properly treated, may significantly increase the risk of major ischaemic complications.  2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Science Ltd. All rights reserved. Keywords: Ascites; Hepato-renal syndrome; Liver cirrhosis; Spontaneous bacterial peritonitis; Terlipressin

1. Introduction Hepatorenal syndrome (HRS) is a severe complication of liver failure occurring in 18% of cirrhotic patients with ascites [1]. HRS is classified clinically as type I and type II: the former is characterised by a rapidly evolving renal failure, while a slow impairment of the renal function is the hallmark of type-II HRS [2]. The prognosis of HRS is poor [1] and survival of patients, on a waiting list for liver transplantation, is often too short, particularly after the onset of type-I HRS. During the last decade, a better understanding of the pathogenesis of ascites and its related syndromes prompted the development of new and promising therapeutic strategies. The peripheral arterial vasodilation hypothesis, proposed to explain renal dysfunction in cirrhosis, prompted the use of vasoconstrictors in association with plasma volume expansion in the treatment of HRS [3]. Ornipressin, a non-selective agonist of V1 vas*Corresponding author. Tel.: 139-6-4997-2028; fax: 139-6-4440-806. E-mail address: [email protected] (F. Vaccaro).

opressin receptors with a marked vasoconstrictor effect, has proven to be efficacious in the treatment of HRS but its use is limited by the high incidence (33%) of severe side-effects, which include ischaemic colitis, ischaemic ulcers of the tongue, and ventricular arrhythmias [4,5]. A more promising vasoconstrictor agent is terlipressin, another non-selective V1 agonist with a similar vasoconstrictor effect but a lower incidence of ischaemic complications [6]. The clinical results obtained so far suggest that terlipressin associated with albumin infusion safely reverses HRS in a large proportion of patients [7–12]. In these reports, two cases of severe ischaemic complications, one involving the skin of the scrotus [10] and the other the myocardium [12], have been described. The case is reported here of a cirrhotic patient with spontaneous bacterial peritonitis (SBP) complicated by the development of type-I HRS, in whom treatment with terlipressin had to be withdrawn due to onset of lifethreatening ischaemic side-effects, the peculiarity of which was the simultaneous involvement of various organs. It is tempting to hypothesise that this unusual side-effect of

1590-8658 / 03 / $30  2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016 / S1590-8658(03)00225-1

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terlipressin might have occurred as a consequence of the ongoing infection due to the presence of SBP.

2. Case report In March 2001, a 73-year-old caucasian male was admitted to our department on account of progressive abdominal swelling, body weight gain, and oliguria persisting after 1 week of aggressive diuretic treatment (furosemide 150 mg / day, spironolactone 400 mg / day). At the age of 50, the patient was diagnosed with alcoholic hepatitis. He then abstained from drinking and no relevant health problems were reported during the following years. In October 2000, a progressive abdominal swelling associated with jaundice, increasing weakness, and fatigue developed. The patient was hospitalised and a diagnosis of alcoholic cirrhosis with ascites was made. After discharge, the patient was regularly followed-up and treated with standard diuretic treatment (daily furosemide1spironolactone). Upon admission in our department, the patient was in poor clinical condition with massive ascites, jaundice, and dyspnoea. The abdomen was palpable but slightly painful in all quadrants; peristalsis and fever (38 8C) were present, blood pressure was 100 / 70 mmHg and heart rate 80 bpm. Diuretic treatment was withdrawn, and an evacuative paracentesis (4 l) was performed with a simultaneous infusion of albumin (40 g). Normal saline (1.5 l) was also infused to expand plasma volume. The microscopic examination of ascites showed 2290 granulocytes / mm 3 . Laboratory tests revealed: erythrosedimentation rate (ESR) 40 mm / h; haemoglobin (Hb) 10.4 g / dl; white blood cells (WBC) 4410 / mm 3 (N 77%); platelets 82 000 / mm 3 ; plasma creatinine 1.7 mg / dl; creatinine clearance 40 ml / min; plasma sodium 127 mEq / l; plasma potassium 4.7 mEq / l; urinary sodium 8 mEq / l; total bilirubin. 3.8 mg / ml; indirect bilirubin 1.8 mg / ml; AST 43 IU; g-glutamyltransferase (g-GT) 113 IU; alkaline phosphatase 845 IU; partial thromboplastin time (PTT) ratio 1.05; INR 1.62; fibrinogen 272 mg / dl; total protein 7 g / dl; plasma albumin 3.6 g / dl. Urinary sediment was normal and proteinuria was absent. A chest X-ray was negative, while abdominal ultrasonography revealed massive ascites, hepato-splenomegaly, and incomplete portal vein thrombosis likely of recent onset. Antibiotic therapy (cefotaxime 2 g bid i.v.) was, therefore, associated with daily infusions of 20 g of albumin to expand the plasma volume. Two days later the fever disappeared. On the fourth day after admission, urinary outflow decreased to 150 ml / day, serum creatinine increased to 3.1 mg / dl, and creatinine clearance and serum sodium decreased to 23 ml / min and 119.4 mEq / l, respectively. Urinary sediment, proteinuria and renal ultrasound were repeated and no signs of organic renal disease were found.

Terlipressin i.v. was then instituted at a cumulative dose of 3 mg / day given in six 0.5-mg boluses. Daily infusion of 20 g albumin was also maintained. On the fifth day, after five terlipressin boluses, urinary outflow was 350 ml / day, serum creatinine was 3.3 mg / dl, serum sodium was 126 mEq / l, and blood pressure was 120 / 70 mmHg. The patient presented with peripheral cool cyanosis and abdominal discomfort in the lower quadrants. Abdominal palpation was not associated with a defensive reaction and peristalsis was present. On the following day, after 10 terlipressin boluses, abdominal discomfort worsened to pain, and rectorrhagia occurred. Large and merging purpuric lesions, both irregular and circular in outline, appeared on the skin of the abdomen, thighs, scrotus, and penis, rapidly becoming necrotising on the scrotus and penis. Terlipressin was withdrawn and coagulation tests were immediately screened for disseminated intravascular coagulation (DIC). Laboratory tests revealed reduced AT III (25%), slightly increased D-dimers (442 mg / dl) and impaired international normalised ratio (INR) (3.14) and activated partial thromboplastin time (aPTT) ratios (1.86). Diagnosis of DIC, however, was not confirmed since the platelet count (101 000 / mm 3 ) and plasma fibrinogen (434 mg / dl) had both increased when compared with values on admission. After terlipressin withdrawal, abdominal pain improved and disappeared, while the purpuric lesions did not disseminate further. However, blood pressure decreased to 90 / 60 mmHg, urinary outflow decreased to below 200 ml / day, and the patient died on the seventh day. It was concluded that terlipressin infusion had likely induced acute ischaemic colitis and cutaneous scattered haemorrhagic infarctions.

3. Discussion This case report deals with a cirrhotic patient with refractory ascites and SBP, complicated by the development of type-I HRS even in the presence of adequate therapy (antibiotics, diuretic withdrawal, and plasma expansion). The attempt to treat and possibly reverse HRS using terlipressin was based on the existing evidence of its effectiveness and safety. Following an exhaustive search through the literature, we found 60 cases of HRS treated with terlipressin [7–12], in most of these patients this drug was given at an initial dose of 0.5 mg / 4 h. An analysis of these reports for side-effects revealed one case of a severe, yet limited, cutaneous ischaemic complication (scrotal necrosis) [10] and one case of myocardial ischaemia [12]. The low incidence (5%) of severe ischaemic complications reported in a population of 1258 cirrhotic patients receiving terlipressin at a higher dose (8–12 mg / day) for the management of variceal bleeding [6] was further evidence of its safety. The number of HRS patients treated with

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terlipressin is, at present, limited and too few to draw any conclusion on the incidence of ischaemic complications associated with administration of this drug. However, the clinical importance of our case is based on its rapid occurrence, life-threatening severity, and widespread ischaemic complications. Furthermore, in our patient, the complications occurred while the patient was on terlipressin infusion at a relatively low dosage, which is in apparent contrast with the likely dose-dependency of ischaemic side-effects. To understand the dramatic hypersensitivity to terlipressin presented by our patient, we focused our attention on the SBP, which preceded the occurrence of HRS. SBP is among the most frequent causes of type-I HRS [13]. Evidence exists showing that peritoneal macrophages from ascitic cirrhotic patients developing SBP are activated and overproduce nitric oxide (NO) [14,15]. It has been postulated that the overproduction of ascites NO which occurs in SBP patients (also referred to as high-output NO metabolic pathway) may accentuate the arteriolar vasodilation in the splanchnic territory, already dilated due to the advanced liver failure [13–17]. This creates a favourable haemodynamic situation, which may promote the occurrence of HRS [13,15,17]. It should also be stressed that overproduction of NO in SBP patients, induced by bacterial endotoxins and inflammatory cytokines, is long-lasting and persists even after SBP resolution. Addressing this issue, Jimenez et al. measured ascites and plasma NO in patients with cirrhosis and ascites without peritonitis and in patients with resolved or unresolved SBP [15]. They found increased NO concentrations in those patients with unresolved or antibiotic-resolved SBP when compared with patients without peritonitis. More interestingly, higher plasma and ascites levels were found in patients with fully resolved SBP [15]. The lack of association between the NO production and the clinical course of SBP is not surprising. It is, in fact, well known that, after immunological or inflammatory challenges, the inducible form of NO synthase (NOS II) is widely expressed in many cell types and generates large amounts of NO over periods even longer than 4 days [14,18–20]. Scharte et al. studied the effect of terlipressin in an animal model of hyperdynamic septic shock, characterised by vascular hyporeactivity to endogenous catecholamines secondary to an overproduction of NO [21–23]. These authors demonstrated a more profound vasopressive effect of terlipressin in hyperdynamic endotoxaemia compared with the nonseptic state [24]. Considering that terlipressin inhibits Larginine-dependent NO synthesis [25], Scharte et al. hypothesised that terlipressin hypersensitivity in hyperdynamic endotoxaemia, also reported in small-case studies on patients with hyperdynamic septic shock [26], might be due to a restored vascular responsiveness to norepinephrine by inhibition of NO overproduction [24]. In summary, cirrhotic patients with SBP present a peculiar haemodynamic scenario, which predisposes to

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type-I HRS, characterised by a hyperdynamic circulation and a hyperactivation of endogenous vasoconstrictor systems, and, possibly, favours the early development of severe vasopressin analogue side-effects. To support this hypothesis, it would be useful to ascertain whether cirrhotic patients treated so far with vasopressin analogues had SBP-related type-I HRS. Unfortunately, such an analysis would be difficult based on data currently available in the literature. Considering this likely growing use of terlipressin in the treatment of HRS, it would be useful that studies on the effectiveness and safety of terlipressin include the measurement of NO concentrations, both at baseline and during terlipressin treatment. However, since NO evaluation is still an expensive and time-consuming procedure, at least investigations on the presence of SBP or its recent occurrence should be mandatory. While awaiting definitive data on the safety and effectiveness of terlipressin, it would be advisable to start the infusion at a lower dose in these patients with SBP-related HRS. However, the hypothesis that bacterial infection and NO overproduction may be the cause of terlipressin-induced ischaemia is only an hypothesis and more evidence is necessary before this can be demonstrated. Indeed, other factors, such as the age of the patient, genetic predisposition and arterial patency, as well as individual differences in drug disposal, may influence the effects of vasopressin analogues. Moreover, it has been shown that the responsiveness of the vasodilated arterial vascular bed may be restored in patients with HRS also by inhibiting the release of glucagon and that as an alternative to terlipressin, the association of midodrine and octreotide is effective and safe in cirrhotic patients with HRS [27]. Albeit, the possibility that the latter association might be safer than terlipressin in patients with HRS after SBP deserves further investigation. Another point that deserves attention is the possibility that the patient described in the present report was affected by SBP-induced renal failure and not by type-I HRS. In fact, the absence of ongoing bacterial infection is among the major criteria for the diagnosis of HRS [2]. This criterion is in some way under defined and is a common opinion that many cases of HRS are, indeed, due to precipitating factors, the most important being bacterial infections and, particularly, SBP [13]. In our patient, the diagnosis of type-I HRS was based on the exclusion of organic renal disease, however, although the fever promptly disappeared after antibiotic treatment, the absence of bacterial infection cannot be excluded. Even the fact that an infection was the precipitating factor in this case of functional renal failure may be important. In conclusion, it is tempting to suggest that when functional renal failure develops in a cirrhotic patient, a search for a precipitating event, especially a bacterial infection, is mandatory [28]. If present, the first approach in the management of the renal failure (whether SBP-induced renal failure or SBP-induced HRS) is treatment of the infection, while the use of terlipressin or other vasoconstrictors deserves caution.

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Conflict of interest statement None declared.

List of abbreviations aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; HRS, hepato-renal syndrome; PTT, partial thromboplastin time; SBP, spontaneous bacterial peritonitis.

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