Vasopressin, not octreotide, may be beneficial in the treatment of hepatorenal syndrome: a retrospective study

Tyree H. Kiser1, Douglas N. Fish1, Marilee D. Obritsch1, Rose Jung1, Robert MacLaren1 and Chirag R. Parikh2

1 Department of Clinical Pharmacy, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO and 2 Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA

Correspondence and offprint requests to: Chirag Parikh, MD PhD, 950 Campbell Ave, Mail box 151B, Building 35A, Room 219, West Haven, CT 06516, USA. Email: chirag.parikh{at}yale.edu



   Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Hepatorenal syndrome (HRS) is a severe complication of cirrhosis and is associated with high mortality. Ornipressin and terlipressin are effective in treatment of HRS, but are not available in the USA. The efficacy of vasopressin (AVP) and octreotide (OCT) infusions, commonly utilized in the USA, in the treatment of HRS is unknown. This study aims to evaluate the effects of AVP and OCT on renal function, systemic haemodynamics and clinical outcomes in HRS.

Methods. This observational study evaluated patients receiving AVP or OCT therapy for HRS from January 2000 to December 2003. Recovery from HRS was defined as a decrease in the serum creatinine (SCr) to a value ≤1.5 mg/dl.

Results. Forty-three patients were identified: eight received AVP, 16 received OCT and 19 received both AVP and OCT. Patients who received AVP alone or in combination with OCT had significantly greater recovery rates than those receiving OCT monotherapy (42 vs 38 vs 0%, respectively, P = 0.01). The average time to response in serum creatinine (SCr) was 7± 2 days. The mean AVP doses were 0.23±0.19 U/min in patients demonstrating clinical response. Therapy with AVP was an independent predictor of recovery (odds ratio 6.4, 95% confidence interval 1.3–31.8). Patients who responded to therapy had significantly lower mortality (23 vs 67%, P = 0.008) and higher rates of liver transplantation (23 vs 0%, P = 0.005). No adverse effects related to AVP therapy were observed.

Conclusion. When compared with OCT, HRS patients treated with AVP had significantly higher recovery rates, improved survival and were more likely to receive a liver transplant.

Keywords: acute renal failure; cirrhosis; dopamine; mortality; recovery; response



   Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Hepatorenal syndrome (HRS) is a progressive renal dysfunction associated with advanced cirrhosis of the liver and portal hypertension. HRS may occur in up to 40% of patients with cirrhosis and ascites within 5 years of diagnosis [1]. Rapidly progressive HRS (type I) is associated with ~95% mortality in untreated patients within the first 30 days of onset, while the more slowly progressive HRS (type II) has a marginally better prognosis [1]. Patients with renal failure at the time of liver transplantation have poorer outcomes compared with patients without renal failure [2]. Reversal of HRS facilitates liver transplantation and helps improve long-term survival after liver transplantation in patients with liver cirrhosis [3].

Patients with HRS have significant splanchnic arterial vasodilation causing severe arterial underfilling in the systemic circulation [4]. Decreased blood flow and oxygen delivery to the kidney stimulates the activation of compensatory pathways including the renin–angiotensin–aldosterone system (RAAS), the sympathetic nervous system and non-osmotic vasopressin release. Decreased arterial blood volume leads to marked vasoconstriction of the renal arterioles, reduced renal perfusion and glomerular filtration rate (GFR), and ultimately HRS [4,5]. Because no anatomical damage is demonstrated in the kidney, HRS is potentially controllable with agents that improve renal perfusion and GFR. Vasopressin analogues, such as ornipressin, terlipressin and synthetic lysine vasopressin, have shown moderate success in improving renal function in patients with HRS [6–11]. However, the only definitive treatment for HRS is liver transplantation.

Vasopressin analogues cause vasoconstriction of the splanchnic circulation, improve effective arterial blood volume, attenuate activation of the RAAS and sympathetic nervous system, and thereby increase renal perfusion and GFR [8]. Ornipressin is a non-selective V1 receptor agonist that is a potent vasoconstrictor, but is associated with ischaemic side effects in up to 33% of patients [6,7]. Terlipressin, which has a lower incidence of ischaemic complications in comparison with ornipressin, is approved in most European countries for oesophageal varicele bleedings and shows promise in the treatment of HRS [8,10].

Although ornipressin and terlipressin have shown potential in the treatment of HRS, neither of these agents are available in many countries including the USA. Vasopressin and octreotide also cause splanchnic vasoconstriction and are frequently used by US physicians in the management of HRS. However, these agents have not been studied systematically to determine their clinical efficacy or their effect on clinical outcomes in patients with HRS. The purpose of this study was to evaluate the safety, clinical efficacy and patient outcomes associated with the use of vasopressin and octreotide in the management of HRS.



   Methods
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 Methods
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Study design
This study was a retrospective cohort design and included patients who were admitted to the University of Colorado Hospital between January 1, 2000 and December 31, 2003. Patients were included in this study if they had a diagnosis of HRS and received continuous vasopressin or octreotide infusions for the management of HRS.

Patients’ charts were identified by cross-referencing pharmacy billing codes for vasopressin and octreotide with ICD-9 codes for hepatorenal syndrome (572.4), cirrhosis and end-stage liver disease (571.0–572.8). Diagnosis of HRS was confirmed by the criteria set by the International Ascites Club [4] and the renal consultation note when available. Patients were excluded if they were <18 years of age or their medical records were incomplete or unavailable for review.

The following variables, if available, were collected for every patient: demographics (age, gender, race, weight), co-morbid conditions, Child–Pugh and APACHE II scores at initiation of vasopressin or octreotide therapy, length of intensive care unit (ICU) and hospital stays, need for mechanical ventilation, use of albumin, need for renal replacement therapy (RRT) and mode of RRT (continuous vs intermittent). Daily laboratory measurements including selected serum and urine chemistries were also recorded. Urinalysis results and ultrasound evaluation of kidney function were collected. Duration and dose of concomitant medications along with vasopressin and octreotide therapy were recorded. Haemodynamic parameters including systolic, diastolic and mean arterial pressure (MAP), and heart rate (HR) were collected every 8 h. Fluid intake and urine output (UOP) were collected every 8 h. Data were collected until hospital discharge, liver transplantation or death. The reliability of the data collection process was confirmed by comparing data independently collected by three investigators (T.K., D.F. and C.P.) on 20% of randomly selected charts. The kappa statistic was >0.8, demonstrating an excellent reliability for the abstracted variables between the three observers.

The primary outcome for this study was clinical response to vasopressin or octreotide therapy. Definition of response was consistent with criteria from Ortega et al. [10]. Complete response was defined as a decrease of serum creatinine (SCr) to a value ≤1.5 mg/dl. The ability to discontinue RRT was needed for complete response in patients who required RRT for their HRS. Partial response was defined as a 50% decrease in SCr to a value >1.5 mg/dl for patients who did not require RRT. Secondary outcomes included changes in haemodynamic parameters (MAP and HR), mortality, length of ICU and hospital stay, and UOP. Response in UOP was defined as an increase in UOP to >1 l/day or >400 ml/day if the patient was oliguric at baseline. An analysis of responders (complete and partial responders) vs non-responders to therapy was conducted to evaluate the outcomes of mortality, length of ICU and hospital stay, liver transplantation, MAP, need for RRT and time on RRT. Any documented adverse events potentially associated with vasopressin or octreotide therapy were collected to assess the safety of therapy. Daily serum lactate levels were specifically recorded to assess for intestinal ischaemia that may be associated with vasopressin or octreotide therapy.

Statistical analysis
Categorical data were compared using the Fisher's exact test or {chi}2 test where appropriate. Means of the continuous variables were compared using the unpaired t-test with Welch correction or analysis of variance (ANOVA) with Tukey's test where appropriate. Survival curves were generated by the Kaplan–Meier method and compared with the log rank test. Multivariate analysis to evaluate significant predictors for recovery of renal function in HRS patients was performed by stepwise logistic regression. All variables that had a P-value <0.25 on univariate analysis were considered for multivariate analysis. All tests were two-tailed and a P-value <0.05 was considered significant. Data are reported as the mean±SD unless stated otherwise. The statistical analysis were performed with SAS software version 8.0 (SAS Institute, Cary, NC), InStat 3.06 (GraphPad Software, Inc. San Diego, CA) and GraphPad Prism 4 (GraphPad Software, Inc. San Diego, CA).

Study conduct
The investigational review board of the University of Colorado Health Sciences Center approved the protocol prior to data collection. Patient consent was not required and a Health Insurance Portability and Accountability Act waiver was obtained.



   Results
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 Abstract
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 Methods
 Results
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Patients
We identified 54 patients with HRS who received octreotide or vasopressin therapy between January 1, 2000 and December 31, 2003. Eleven of the 54 patients who met the inclusion criteria were excluded due to incomplete or inaccessible medical records. A total of 43 patients were therefore evaluated in the present study; demographic and clinical characteristics are summarized in Table 1. All patients met the following three International Ascites Club criteria [4] for diagnosis of HRS: chronic or acute liver disease with advanced hepatic failure and portal hypertension; serum creatinine >1.5 mg/dl; and no sustained improvement in renal function following diuretic withdrawal and expansion of plasma volume. All patients had proteinuria <500 mg/dl and 14% of patients had red blood cells >5/high-power field present in their urine. Twenty-eight (out of 28) patients had no ultrasonographic evidence of obstructive uropathy or hydronephrosis. No patients were receiving nephrotoxic drugs at study entry, and none were receiving vasopressor support.


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Table 1. Demographics and clinical parameters in all patients on day of starting vasopressin or octreotide therapy

 
Based on treatment, patients were divided into three groups: vasopressin plus octreotide (n = 19), octreotide monotherapy (n = 16) or vasopressin monotherapy (n = 8). The demographic and clinical characteristics of these three groups are shown in Table 2. A total of 34 patients (80%) were in the ICU at entry into the study. The treatment groups were overall very similar, with some exceptions. Patients treated with vasopressin monotherapy had higher mean APACHE II scores (P = 0.047) and higher rates of mechanical ventilation at baseline (P = 0.04). Patients receiving octreotide monotherapy were more likely to have type II HRS rather than type I HRS (P = 0.01) and received fewer consultations from the renal service (P = 0.01). Patients who received vasopressin therapy were more often in the ICU or intermediate care unit compared with octreotide monotherapy patients who were more often treated on general medicine floors (P = 0.08). This difference is partially explained by the restriction of vasopressin infusions to the ICU or intermediate care areas of the hospital.


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Table 2. Demographics and clinical parameters on the day of starting vasopressin or octreotide therapy

 
Response to therapy
Complete response to therapy was observed in 11 patients (26%), partial response in two patients (5%), and no response was seen in 30 patients (69%). Forty-two percent of patients who received vasopressin therapy in conjunction with octreotide (eight of 19) and 38% of those who received vasopressin monotherapy (three of eight) demonstrated a clinical response (Table 3). These were significantly higher in comparison with 0% in the octreotide monotherapy group (P = 0.01). Two patients (12.5%) in the octreotide monotherapy group had a partial response. For comparison of responders vs non-responders, the two partial responders were combined with the 11 complete responders. Mean time to response in SCr after initiation of therapy was 7±2 days (range 5–11). Time to response in UOP was 3.2±2.1 days (range 1–9). No significant difference in time to response was observed between any treatment groups. Dosing and duration of vasopressin, octreotide and dopamine are shown in Table 4. The mean vasopressin dose in the group of responders was 0.23±0.19 U/min (dosing range 0.01–0.8 U/min) and 0.14±0.14 U/min (dosing range 0.01–0.45 U/min) for non-responders (P = 0.19). One of five (20%) patients responded to vasopressin at a dose ≤0.04 U/min, three of six (50%) patients responded at a dose of >0.04 to 0.1 U/min, and seven of 16 (44%) patients responded at a dose of >0.1 U/min (P = 0.45). Mean octreotide doses were 50±3 and 65±67 µg/h for responders and non-responders, respectively (P = 0.28). Renal dose dopamine was utilized concomitantly in seven (50%) responders and 11 (40%) non-responders (P = 0.33), with similar doses used in responders and non-responders (P = 0.18). Albumin use was not different between responders and non-responders (P = 0.16).


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Table 3. Outcomes by treatment group

 

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Table 4. Dosing and duration of vasopressin, octreotide, dopamine and albumin therapy: change in MAP, SCr and UOP from start of therapy

 
Changes in MAP, SCr and UOP from baseline are shown in Table 4. The absolute increase in MAP was 10±13 mmHg for responders and 6±13 mmHg for non-responders, respectively (P = 0.61). The percentage reduction in SCr in patients not on RRT was 62±9% for responders. The mean increase in UOP was 624±360 ml/day for responders and 231±465 ml/day for non-responders (P = 0.01).

Clinical outcomes for responders vs non-responders are demonstrated in Table 5. Although the length of ICU stay was not significantly different (P = 0.12), total hospital length of stay was significantly longer for responders (P = 0.01). Significantly more patients in the responder group received a liver transplantation (P = 0.005), and in-hospital mortality was significantly lower in the responder group (three of 13, 23%) than in the non-responder group (20 of 30, 67%) (P = 0.008). Kaplan–Meier survival curves demonstrated a significant difference in mortality between responders and non-responders (Figure 1). The 28 day mortality hazard ratio for non-responders was 4.0 [95% confidence interval (CI) 1.3–8.1] fold when compared with responders.


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Table 5. Outcomes of responders vs non-responders

 


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Fig. 1. Twenty-eight day survival curves for responders vs non-responders. The difference in survival becomes significant at day 7 of therapy. The responders group includes 11 complete responders and two partial responders.

 
Renal replacement therapy was utilized in five patients in the responder group and 15 non-responders (P = 0.53) (Table 5). Time to initiation of RRT from start of therapy was 135±109 h for responders and 61±95 h for non-responders (P = 0.16). Recorded fluid removal every 8 h was not different between responders (757±368 ml) and non-responders (1236±928 ml) (P = 0.28). Fluid intake every 8 h was also not different between responders and non-responders: 868±821 and 879±952 ml, respectively (P = 0.97).

Predictive factors of response
The following variables were included in the multivariate analysis: vasopressin therapy, octreotide therapy, type I vs type II HRS, APACHE II score, renal consult and MAP. In the multivariate analysis, only vasopressin therapy was found to be a statistically significant predictor of complete response. Patients who received vasopressin as either monotherapy or with octreotide were 6.4 (95% CI 1.3–31.8) times more likely to have responded than those who received octreotide monotherapy. Although not a significant predictor of renal function recovery, patients with an increase in MAP ≥10 mmHg from baseline had a trend towards increased response [odds ratio (OR) 3.8, 95% CI 0.95–15.5].

Adverse reactions
One patient experienced diarrhoea that was attributable to octreotide. No adverse effects were reported with vasopressin therapy. Overall, lactate concentrations trended downward from baseline 8±8 to 3.7±4.2 mg/dl in all patients. The decreasing trend in lactate concentrations provides some reassurance that treatment with splanchnic vasoconstrictors was not worsening intestinal ischaemia.



   Discussion
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 Methods
 Results
 Discussion
 References
 
The results of this study indicate that vasopressin has a higher likelihood of response in the treatment of HRS compared with octreotide (OR 6.4). Patients treated with vasopressin had a 41% complete response rate compared with octreotide monotherapy that had a complete response rate of 0%. This response with vasopressin is higher than response rates reported with dopamine monotherapy (0%), octreotide (16%) and midodrine (<10%); however, it is much lower than some studies with transjugular intrahepatic portosystemic shunt (TIPS; 81–86%), terlipressin (77%) or ornipressin (57%) [6–8,10–16].

The effective dose of vasopressin that should be recommended for the treatment of HRS is not known. The mean vasopressin dose of 0.23 U/min utilized in responders is significantly higher than doses used in other critically ill populations (e.g. treatment of septic shock ≤0.04 U/min). Ischaemic skin lesions have been reported with vasopressin in norepinephrine-resistant patients with vasodilatory shock [17]. Cardiac arrest, ischaemic/mottled digits and extremities, myocardial infarction and hyponatraemia have been associated with vasopressin doses ≥0.04 U/min in the treatment of vasodilatory shock [18]. A recent study in pigs showed heterogeneous vasoconstriction and mesenteric ischaemia with vasopressin infusions ≥0.04 U/min [19]. No adverse reactions were reported in our patients; however, the retrospective design of this study severely limits the ability to assess for adverse effects not documented in the medical chart. There was a decreasing trend in lactate concentrations in the vasopressin-treated patients, which may indicate that HRS patients tolerate higher doses of vasopressin without suffering ischaemic effects. In stating this, extreme caution and careful monitoring of serum lactate levels and extremities for ischaemia should be utilized in patients receiving doses >0.1 U/min.

The titration of vasopressin was left to individual prescribers in this study; however, a common trend in patients involved titrating the dose to achieve a 10 mmHg increase in MAP from baseline or MAP >70 mmHg. An observation of MAP in this study showed no difference between complete responders (72±13 mmHg), partial responders (82±14 mmHg) and non-responders (71±13 mmHg) while on therapy (P = 0.52). Vasopressin-treated patients showed a larger increase in MAP from baseline compared with octreotide patients (61 to 72 mmHg vs from 71 to 74 mmHg). This is most probably due to vasopressin's more potent splanchnic vasoconstriction that may allow for increased perfusion and response rates. In the multivariate analysis, a trend towards increased response was seen in patients who had a MAP increase of at least 10 mmHg from baseline (OR 3.8).

Octreotide monotherapy has demonstrated little benefit in the treatment of HRS in the present study. Similarly, Pomier-Layrargues and colleagues showed no effect of octreotide infusions on the mesenteric artery resistance index, renal haemodynamics or renal function in HRS patients [16]. Octreotide's splanchnic vasoconstriction is partially mediated by inhibition of glucagon synthesis and suggested direct effects on the vascular smooth muscle. Octreotide is considered a potent splanchnic vasoconstrictor; however, it has not demonstrated a significant effect on splanchnic or hepatic blood flow in patients with cirrhosis [20]. A continuous 50 µg/h infusion is utilized at many institutions for the treatment of varicele bleeding. This regimen failed to show significant haemodynamic effects or improvement of renal function in the present study. It is likely that higher doses of octreotide could increase its vasoconstrictive effects, but future studies are needed. Octreotide should be utilized as an adjunctive agent for the treatment of HRS in situations that may provide added benefit: vasopressin-treated HRS patients with bleeding oesophageal varices or out-patient regimens combining albumin, midodrine and subcutaneous octreotide therapy.

Previously published studies have discussed the role of albumin in combination with vasopressin analogues for the treatment of HRS [6–8,10]. It is likely that albumin may improve renal perfusion by increasing circulatory volume; however, only one study offers some proof that albumin is required for the beneficial effects of vasopressin analogues [10]. All 43 patients in this study received albumin before and during vasopressin or octreotide therapy. No significant differences between responders and non-responders could be found in dose or duration of albumin therapy.

Time to complete response to therapy of 5–9 days was similar to previous studies [11]. Patients who did not respond to therapy continued to display worsening renal dysfunction. If patients have not shown any response to vasopressin therapy at day 10, it is unlikely that the patient will respond and other treatment avenues should be explored.

There are some limitations that need to be considered while interpreting the results of this study. As this was an observational study, there was little control over the variables abstracted. Also, there was variability in the treatment regimens as they were designed on an individual basis by several different practitioners. The observational study design did not allow for inferences to be made regarding vasopressin and/or octreotide initiation, titration or discontinuation. Albumin or crystalloid use was also at the discretion of the prescriber. All patients receiving vasopressin were treated in an ICU setting. Interventions provided in the ICU setting, but not on the general medical ward, could improve patient prognosis. Accurate diagnosis of HRS is difficult and it is possible that some cases of HRS had superimposed acute tubular necrosis. To minimize this, the diagnosis of HRS was established in congruence with the International Ascites Club [4] criteria and obtained from the renal specialty consultation note rather than the note of the admitting physician. Three of the five major International Ascites Club criteria for the diagnosis of HRS were met in all patients; however, due to the retrospective design, data on the possibility of ongoing bacterial infections, gastrointestinal and renal fluid losses, and ultrasonographic evidence of obstructive uropathy or parenchymal renal disease were not available in every patient. There is a small possibility that some cases of HRS may have been missed, because of lack of diagnosis or reporting of this condition. Eleven patients with a HRS diagnosis had to be excluded due to incomplete or unobtainable medical records. Also, it is likely that there is under-reporting of adverse effects due to poor documentation in the medical chart.

Summary
This study suggests that vasopressin is an effective agent for treating patients with HRS. Vasopressin appears safe even at moderate to high doses in patients with HRS; however, careful monitoring is necessary. Octreotide monotherapy is associated with a poor response rate. Significantly higher doses of vasopressin are needed and response in SCr occurs 5–9 days into therapy. Response in UOP is faster at 2–4 days. Mortality is decreased in patients who respond to therapy compared with patients who do not respond. The conclusions drawn from this study should ideally be verified by a prospective randomized study. Future studies with vasopressin are needed to determine the optimal dosing strategies and identify which patients are most likely to benefit from therapy.



   Acknowledgments
 
C.R.P. was supported by grant K23- DK064689 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 24. 1.05
Accepted in revised form: 3. 5.05





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