|Year : 2016 | Volume
| Issue : 3 | Page : 330-336
A comparative study between terlipressin alone and dobutamine and terlipressin in septic shock patients
Waleed Abdalla MD , F Kamel, Naglaa M Ali, Tarek Shabana
Department of Anesthesia, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||27-Sep-2015|
|Date of Acceptance||26-May-2016|
|Date of Web Publication||31-Aug-2016|
20 Taksem Al-Awkaf, Presidential Palace Street, Al-Sawah, Cairo, 11646
Source of Support: None, Conflict of Interest: None
The use of terlipressin, a long-acting synthetic analog of vasopressin, is associated with reduction in cardiac output and oxygen delivery. The present study was designed to determine whether dobutamine may reverse the terlipressin-induced depression in central venous oxygen saturation (SvO2) in patients with catecholamine-dependent septic shock.
Patients and methods
This clinical trial was conducted in Ain Shams University hospital’s surgical ICU. In total, 90 septic shock patients requiring a continuous infusion of norepinephrine reaching 0.6 µg/kg/min to maintain mean arterial pressure at greater than or equal to 65 mmHg were randomly allocated to three groups be treated as follows: (i): group I, treated with norepinephrine infusion (control); (ii) group II, treated with a single bolus of terlipressin 1 mg, intravenous; (iii) and group III, treated with a single bolus of terlipressin 1 mg, followed by a dobutamine infusion.
The use of terlipressin (with and without dobutamine) resulted in maintaining mean arterial pressure above 65 mmHg with reduction in norepinephrine requirements to 0.2 (0.1) µg/kg/min in group II and 0.15 (0.1) µg/kg/min in group III (P in each <0.001 vs. control at 2, 4, and 6 h). The use of terlipressin alone in group II resulted in a drop in central SvO2 to 58 (3)% (P<0.001 vs. control at 2, 4, and 6 h) and a decrease in heart rate to 105 beat/minute (7) (P vs. control=0.013 at 2 h, 0.001 at 4 h, and 0.01 at 6 h). The addition of dobutamine in group III resulted in an increase in central SvO2 to 70 (3)% (P<0.001 vs. group II at 2, 4, and 6 h).
Administration of terlipressin bolus was effective in increasing mean arterial blood pressure and reducing norepinephrine requirements in catecholamine-dependant septic shock patients. Its use was associated with significant reductions in central SvO2, which was reversed by using dobutamine.
Keywords: dobutamine, norepinephrine, septic shock, terlipressin
|How to cite this article:|
Abdalla W, Kamel F, Ali NM, Shabana T. A comparative study between terlipressin alone and dobutamine and terlipressin in septic shock patients. Ain-Shams J Anaesthesiol 2016;9:330-6
|How to cite this URL:|
Abdalla W, Kamel F, Ali NM, Shabana T. A comparative study between terlipressin alone and dobutamine and terlipressin in septic shock patients. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2022 May 16];9:330-6. Available from: http://www.asja.eg.net/text.asp?2016/9/3/330/189565
| Introduction|| |
Aggressive initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and septic shock is very important; its goals should include elevation of mean arterial pressure (MAP) to be greater than or equal to 65 mmHg. When this is not achieved, use of catecholamines as norepinephrine should be initiated .
Because of adrenergic and postreceptor abnormalities in sepsis, the efficacy of catecholamines gradually decreases over time , necessitating higher doses to counteract arterial hypotension. Excessive concentrations of catecholamines may be associated with major side effects such as tachyarrhythmias or pulmonary hypertension, thereby further impairing the cardiocirculatory functions . Recently, arginine vasopressin and terlipressin have been used as adjunct vasopressors in the treatment of catecholamine-dependent septic shock . Terlipressin has a prolonged duration of action. It is a prodrug and is converted to lysine vasopressin in the circulation after the N-triglycyl residue is cleaved by endothelial peptidases . The effective half-life of terlipressin is 6 h and it elimination half-life is 50 min , and thus it is usually given as an intermittent bolus injection. This may lead to an overshooting increase in systemic vascular resistance and a reduction in cardiac index (CI) ,, thereby compromising the oxygen delivery index and mixed venous oxygen saturation (SvO2). The surviving sepsis campaign recommends a trial of dobutamine infusion up to 20 µg/kg/min to be administered or added to vasopressor in the presence of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP . We hypothesized that dobutamine may reverse the terlipressin-associated depression in global oxygen supply in patients with catecholamine-dependent septic shock.
The aim of this study was to demonstrate the effects of terlipressin on central SvO2 and to compare between the use of terlipressin alone and that of dobutamine in addition to terlipressin to reverse the anticipated reduction in central SvO2 in catecholamine-dependent septic shock patients.
| Patients and methods|| |
After approval by Ain Shams University’s Research Ethical Committee and obtaining a written informed consent from first-degree relatives of the patients, this prospective randomized controlled trial was carried out on 90 adult patients admitted to a mixed medical–surgical ICU and on pharmacologic support in the form of norepinephrine for the treatment of septic shock. Septic shock was diagnosed when patients with sepsis developed hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities including lactic acidosis, oliguria, or an acute alteration in mental state . The study was conducted from February 2012 to January 2013. Patients eligible for the study were included when the norepinephrine dose required to maintain MAP greater than or equal to 65 mmHg reached 0.6 µg/kg/min, despite adequate volume resuscitation [central venous pressure (CVP)=8–12 cmH2O]. Exclusion criteria included pregnancy, sensitivity to dobutamine and/or terlipressin, age less than 18 years, significant valvular heart disease, present or suspected coronary artery disease, present or suspected acute mesenteric ischemia, or peripheral vascular diseases (e.g. Raynaud’s syndrome or related diseases).
All the patients included in the study were managed according to our protocol in ICU. For all patients included in the study, the doses of norepinephrine reached 0.6 µg/kg/min.
Patients were randomly allocated into three equal groups (each group included 30 patients) by using serially numbered opaque envelopes.
Group I patients received norepinephrine (Levophrine; EgyPharma, Nasr City, Cairo, Egypt) infusion only. Group II patients received a single bolus of terlipressin diacetate (Glypressin; FERRING GmbH, Laupheim, Baden-Wurttemberg, Germany) 1 mg, intravenously, in addition to a norepinephrine infusion. Group III patients, following the bolus dose of 1 mg terlipressin diacetate, received dobutamine (Dobutrex, Eli Lilly Company, Indianapolis, Indiana, USA) infusion through a syringe pump through a central venous catheter starting at a rate of 3 µg/kg/min, which was progressively increased to reverse the anticipated depression in central SvO2 produced by terlipressin, and thus maintaining its baseline value.
Systemic hemodynamic measurements (at baseline ‘before starting the study’ and at 2, 4, and 6 h) included MAP through a left radial artery cannula, heart rate (HR) using an ECG for continuous monitoring with automated ST-segment analysis, and CVP through a catheter inserted either in the right internal jugular vein or the right subclavian vein.
Central venous blood samples were taken to determine central SvO2 and arterial blood samples for blood gas analysis, at baseline, 2, 4, and 6 h.
Regional hemodynamic measurements including variables of organ dysfunction and injury (aspartate aminotransferase, alanine transaminase, total bilirubin, international normalized ratio, and troponin I) were analyzed at baseline, 12, and 24 h and arterial lactate at baseline 2, 4, and 6 h.
Norepinephrine requirements: the rate of norepinephrine infusion required to keep MAP at 65 mmHg (at baseline, 2, 4, and 6 h).
Before the study, a power analysis was performed to determine the minimal acceptable number of patients in each group. The minimal number for each group sufficient to detect a 15% decrease in central SvO2 in the terlipressin group was 27 patients, with type I α error of 0.05 and type II β error of 0.1, and the power of the test at 90%; hence, we set the group number at 30 to compensate of possible dropouts.
SPSS statistics (2012, V.210.0; IBM Corp., Armonk, NY, USA) was used for data analysis. Data were expressed as mean (SD) for quantitative parametric measures. Differences between the groups were analyzed using the repeated measure analysis of variance. If statistical significance was reached, comparison between the two independent mean groups for parametric data was done using the unpaired Student t-test. Bonferroni’s correction was carried out whenever applicable. The P of error at 0.05 was considered significant, whereas at 0.01 and 0.001 the P was considered highly significant.
| Results|| |
All groups involved in the study were comparable as regards age and sex [Table 1]. There were no significant differences in systemic hemodynamic variables and norepinephrine doses between the groups at baseline. Highly significant increase in MAP was noticed in groups II and III compared with group I at 2, 4, and 6 h (P<0.001). There was also a highly significant increase in MAP in group III compared with group II at 2 h (P<0.001) [Table 2]. The administration of terlipressin in group II resulted in a decrease in HR compared with norepinephrine group, which was statistically significant at 2 and 6 h (P<0.05) and highly significant at 4 h (P<0.01). The addition of dobutamine in group III did not result in a significant change in HR compared with groups I and II at 2, 4, and 6 h [Table 3]. The administration of terlipressin in group II resulted in a decrease in central SvO2, which was highly significant compared with group I (norepinephrine) at 2, 4, and 6 h (P<0.001). The addition of dobutamine to terlipressin in group III resulted in an increase in central SvO2 compared with group I, which was statistically significant at 4 h (P>0.05) and highly significant at 2 and 6 h (P<0.001) [Table 4] and [Figure 1]. The administration of terlipressin alone in group II and with dobutamine in group III was associated with a statistically significant decrease in the rate of norepinephrine infusion compared with group I at 2, 4, and 6 h (P<0.001) [Table 5] and [Figure 2]. There were no statistically significant differences between the three groups as regards arterial blood gases (partial pressure of oxygen and partial pressure of carbon dioxide), pH, and base excess at baseline, 2, 4, and 6 h or aspartate aminotransferase, alanine transaminase, international normalized ratio, total bilirubin, and troponin I at baseline, 12, and 24 h. Arterial serum lactate levels were comparable between the three groups at baseline. The administration of terlipressin in group II did not result in a statistically significant change in the serum lactate levels compared with group I (norepinephrine) at 2, 4, and 6 h. The addition of dobutamine in group III resulted in a decrease in the serum lactate levels, which was statistically significant compared with group II (P<0.05) and highly significant compared with group I (P<0.001) at 2, 4, and 6 h [Table 6].
|Table 2 Mean arterial blood pressure (mmHg) changes between and within the studied groups|
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|Table 3 Heart rate changes (beats/min) between and within the studied groups|
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|Table 4 Central venous oxygen saturation (%) between and within the studied groups|
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|Figure 1 Central venous oxygen saturation among the three groups at baseline (0 h), 2, 4, and 6 h. *Significance between groups I and II. **Significance between groups I and III. ǂSignificance between groups II and III. Lines denote mean and error bars denote SD.|
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|Figure 2 Norepinephrine requirements (µg/kg/min) among the three groups at baseline (0), 2, 4, and 6 h. *Significance between groups I and II. **Significance between groups I and III. Lines denote mean and error bars denote SD.|
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There were no statistically significant differences between the three groups as regards CVP [Table 7] or urine output (UOP) [Table 8] at 2, 4, and 6 h.
| Discussion|| |
The efficacy of catecholamines in septic shock patients often gradually decreases over time, necessitating incremental doses to counteract arterial hypotension. Exogenous administration of vasopressin may be an effective adjunctive therapy to traditional catecholamines for the management of refractory hypotension during septic shock.
Vasopressin mediates vasoconstriction through V1-receptor activation and mediates its antidiuretic effect through V2 receptors . Small clinical trials have shown terlipressin as having positive effects on several hemodynamic parameters in septic shock patients. When given at a dose of 1–2 mg, terlipressin decreases cardiac output, and oxygen delivery and utilization . Dobutamine is the first-choice inotropic agent for septic patients with low cardiac output. Although dobutamine does not affect the distribution of blood flow, therapy is often aimed at increasing the blood flow to organs, improving global oxygen supply in patients with septic shock .
In the current study, terlipressin was effective in increasing MAP. Since a relatively high bolus dose of terlipressin (1 mg) was administered, MAP exceeded goal values of 70±5 mmHg in some patients. This allowed a significant reduction in norepinephrine requirements. Terlipressin also resulted in a significant decrease in HR.
The results of the current study were in agreement with the first clinical trial to evaluate the efficacy of terlipressin in human septic shock, which was carried by O’Brien et al. . However, this trial was limited by its small sample size (eight patients). Although hemodynamic parameters were obtained, effects on lactate concentrations and oxygen transport indices were not reported.
Fellahi et al.  reported an increase in systemic arterial blood pressure after the administration of terlipressin in two patients with septic shock refractory to catecholamines. The hemodynamic response was immediate, long-acting, dose-dependent, and reversible within a few hours of stopping the drug administration. A further increase in terlipressin dose regimen markedly decreased cardiac performance.
The results of the current study were in agreement with the results of a study carried out to determine the effects of terlipressin on hemodynamics, laboratory parameters, and renal function in 17 patients with septic shock not responsive to high-dose norepinephrine (MAP<55 mmHg) .
Another study compared between terlipressin and norepinephrine on 20 hyperdynamic septic shock patients. Their results agreed with those obtained in the present study to a great extent .
Effects of terlipressin on MAP that were in agreement with the results of the current study have also been reported in clinical scenarios other than septic shock. A study carried by Boccara et al.  compared the effectiveness of terlipressin and norepinephrine for the correction of intraoperative arterial hypotension refractory to ephedrine in 20 patients undergoing carotid endarterectomy, who had received long-term treatment with renin–angiotensin system inhibitors.
Another study reported six cases of postcardiopulmonary bypass refractory vasodilatory hypotension. The cases were treated with terlipressin (1 mg bolus), which led to an elevation of MAP. These effects were associated with a decrease in CI and serum lactate and an increase in UOP .
The TERLIVAP trial compared continuous infusions of vasopressin, terlipressin, or norepinephrine when given as a first-line therapy to catecholamine-naive septic patients. In contrast to our study, they found no difference between the three drugs in elevating MAP and maintaining the CI .
The results of a study carried out to evaluate the effectiveness of terlipressin on patients who developed hypotension after cardiac surgery were different from the results of the current study and the researchers did not recommend this therapy as it proved to be hemodynamically ineffective and was thought to worsen the circulatory situation .
Svoboda et al.  studied the impact of terlipressin on norepinephrine requirements in patients with late advanced septic shock refractory to catecholamines. Their results showed that terlipressin infusion was not effective in reducing norepinephrine consumption or in the mortality of patients.
From the previous studies, it is apparent that terlipressin has a variable neutral to positive effect on UOP. In the current study, there were no statistically significant changes in UOP between the three groups after the administration of terlipressin.
The renal protective effects of terlipressin were demonstrated in a study carried out by Abdullah et al. ; the study concluded that, although terlipressin may not significantly increase UOP, it still provides renal protective effects.
The depression in the CI is a typical characteristic of terlipressin bolus and may be explained by an increase in the left ventricular after load. In the present study, we used central SvO2, measured intermittently through a central venous catheter, as an indicator of tissue perfusion and oxygen extraction.
The results of the current study demonstrated that the administration of terlipressin was associated with a significant reduction in central SvO2; yet, the arterial serum lactate levels remained constant. These effects on central SvO2 were successfully reversed by adding dobutamine, which also resulted in a reduced serum lactate levels owing to improved tissue perfusion.
In the current study, dobutamine doses up to 20 µg/kg/min were needed to reverse the anticipated depression in central SvO2 produced by terlipressin, and thus maintain it at baseline. It has to be taken into consideration that, whereas dobutamine at doses as low as 5 µg/kg/min is usually efficacious in normal participants or in patients with nonseptic heart failure, it may be of poor efficacy in patients with severe septic shock because of impaired signal transduction and downregulation of β-adrenergic receptors. The use of dobutamine was not associated with a significant increase in HR or in troponin levels.
Several early studies have investigated the effects of dobutamine in septic shock patients ,,.
In the current study, reduction in central SvO2 was not associated with significant changes in the serum lactate levels. Thus, although lactate concentrations remained constant, oxygen delivery and utilization also decreased, which could have had negative effects on organ perfusion. A number of studies have suggested that elevated lactate levels may result from cellular metabolic failure rather than from global hypoperfusion in sepsis ,,. In view of the previous evidence, more recent studies stated that an elevated lactate concentration in patients with sepsis is a marker of disease severity and not an indication of anaerobic metabolism. Thus, increasing oxygen delivery to treat a nonexistent oxygen debt may be a harmful undertaking and lactate clearance should not be used as the end-point of resuscitation in patients with sepsis .
| Conclusion|| |
Terlipressin bolus administration is effective in increasing mean arterial blood pressure and reducing norepinephrine requirements in catecholamine-dependant septic shock patients. Use of terlipressin is associated with significant reductions in central SvO2, which can be reversed using dobutamine.
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Conflicts of interest
No potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
| References|| |
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al.
Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637.
Bennett T, Mahajan RP, March JE, Kemp PA, Gardiner SM. Regional and temporal changes in cardiovascular responses to norepinephrine and vasopressin during continuous infusion of lipopolysaccharide in conscious rats. Br J Anaesth 2004;93:400–407.
Luckner G, Dünser MW, Jochberger S, Mayr VD, Wenzel V, Ulmer H et al.
Arginine vasopressin in 316 patients with advanced vasodilatory shock. Crit Care Med 2005;33:2659–2666.
Mitchell SL, Hunter JM. Vasopressin and its antagonists: what are their roles in acute medical care? Br J Anaesth 2007;99:154–158.
Rodriguez-Perez F, Groszmann RJ. Pharmacologic treatment of portal hypertension. Gastroenterol Clin North Am 1992;21:15–40.
Nilsson G, Lindblom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers. Drugs Exp Clin Res 1990;16:307–314.
Westphal M, Bone HG, van Aken H, Sielenkämper AW. Terlipressin for haemodynamic support in septic patients: a double-edged sword? Lancet 2002;360:1250–1251; author reply 1251.
Westphal M, Sielenkämper AW, van Aken H, Stubbe HD, Daudel F, Schepers R et al.
Dopexamine reverses the vasopressin-associated impairment in tissue oxygen supply but decreases systemic blood pressure in ovine endotoxemia. Anesth Analg 2004;99:878–885; table of contents.
Khan ZU, Salzman GA. Management of sepsis: the surviving guidelines for early therapy. Hosp Physician 2007;55:21–30.
Luckner G, Dünser MW, Jochberger S, Mayr VD, Wenzel V, Ulmer H et al.
Arginine vasopressin in 316 patients with advanced vasodilatory shock. Crit Care Med 2005;33:2659–2666.
Pesaturo AB, Jennings HR, Voils SA. Terlipressin: vasopressin analog and novel drug for septic shock. Ann Pharmacother 2006;40:2170–2177.
Beale RJ, Hollenberg SM, Vincent JL, Parrillo JE. Vasopressor and inotropic support in septic shock: an evidenced based review. Crit Care Med 2004;32:455–465.
O’Brien A, Clapp L, Singer M. Terlipressin for norepinephrine-resistant septic shock. Lancet 2002;359:1209–1210.
Fellahi JL, Bénard P, Daccache G, Mourgeon E, Gérard JL. Vasodilatory septic shock refractory to catecholamines: is there a role for terlipressin? Ann Fr Anesth Reanim 2003;22:631–634.
Leone M, Albanèse J, Delmas A, Chaabane W, Garnier F, Martin C. Terlipressin in catecholamine-resistant septic shock patients. Shock 2004;22:314–319.
Albanese J, Leone M, Delmas A, Martin C. Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective randomized study. Crit Care Med 2005;33:1897–1902.
Boccara G, Ouattara A, Godet G, Dufresne E, Bertrand M, Riou B, Coriat P. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology 2003;98:1338–1344.
Noto A, Lentini S, Versaci A, Giardina M, Risitano DC, Messina R, David A. A retrospective analysis of terlipressin in bolus for the management of refractory vasoplegic hypotension after cardiac surgery. Interact Cardiovasc Thorac Surg 2009;9:588–592.
Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Cecchini V et al.
Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study. Crit Care 2009;13:R130.
Kunstyr J, Lincova D, Mourad M, Lips M, Cermak T, Kotulak T et al.
A retrospective analysis of terlipressin infusion in patients with refractory hypotension after cardiac surgery. J Cardiovasc Surg (Torino) 2008;49:381–387.
Svoboda P, Scheer P, Kantorová I, Doubek J, Dudra J, Radvan M, Radvanova J. Terlipressin in the treatment of late phase catecholamine-resistant septic shock. Hepatogastroenterology 2012;59:1043–1047.
Abdullah MH, Saleh SM, Morad WS. Terlipressin vs norepinephrine to counteract intraoperative paracentesis induced refractory hypotension in cirrhotic patients. Egypt J Anesthesiol 2012;28:29–35.
Vincent JL, Roman A, Kahn RJ. Dobutamine administration in septic shock: addition to a standard protocol. Crit Care Med 1990;18:689–693.
Bröking K, Lange M, Morelli A, Ertmer C, Aken HV, Luecke M et al.
Employing dobutamine as a useful agent to reverse the terlipressin-linked impairments in cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep. Shock 2008;29:71–77.
Morelli A, Ertmer C, Lange M, Dünser M, Rehberg S, Van Aken H et al.
Effects of short-term simultaneous infusion of dobutamine and terlipressin in patients with septic shock: the DOBUPRESS study. Br J Anaesth 2008;100:494–503.
Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004;286:686–692.
Auzinger GM, O’Callaghan PG, Harry RA, Wendon JA. Terlipressin in the treatment of catecholamine resistant septic shock. Crit Care 2002;6:131.
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA, Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010;303:739–746.
Marik PE, Bellomo R. Re-thinking resuscitation goals: an alternative point of view! Crit Care 2013;17:458.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]