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A Century of Arginine Vasopressin Research Leading to New Therapeutic Strategies

Dünser, Martin W. M.D.*; Lindner, Karl H. M.D.†; Wenzel, Volker M.D., M.Sc.†

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DRS. Oliver and Schäfer1 reported more than 100 yr ago that extracts of the pituitary gland had potent vasopressor effects, and this action was restricted to extracts from the posterior pituitary lobe.2 Having been known only as vasopressin for the first 20 yr after its detection, its strong antidiuretic effects and beneficial actions in diabetes insipidus resulted in the renaming of vasopressin as antidiuretic hormone.3 In 1951, the specific peptide fraction of posterior pituitary preparations attributed to the antidiuretic action was isolated.4 The first complete synthetic preparation of the hormone by Vincent du Vigneaud et al.5 was accomplished in 1954. These researchers received the Nobel Prize for their work 1 yr later. Until approximately 15 yr ago, vasopressin was used to treat polyuria in patients with diabetes insipidus6 and to reduce blood loss in patients with gastrointestinal bleeding.7 There was interest in vasopressin as a pro-peristaltic drug during the 1970s and 1980s,8 but this soon diminished because of the drug's unpredictable effects.9 The beneficial effects of vasopressin in shock patients was originally described in 1957 as a brief report,10 but it was only in the 1990s that vasopressin was used clinically for the potent vasopressor effects it was originally described for almost 100 yr ago.
Stimulated by reports in patients with cardiac arrest11 and vasodilatory septic shock,12 the clinical use of arginine vasopressin (AVP) and its analogs as vasopressor drugs has increased substantially during the past 15 yr. In this issue of Anesthesiology, Drs. Treschan and Peters give a comprehensive overview of clinical strategies for which AVP has already been successfully applied.13 AVP has also been used as a supplementary vasopressor in patients with cardiogenic shock,14 cardiocirculatory failure after successful cardiopulmonary resuscitation (Viktoria Mayr, M.D., Resident, Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria, verbal personal communication, May 26, 2006), drug intoxication,15,16 and during surgery of carcinoid tumors.17 Because an anesthesiologist may face any of these pathophysiologic states, it is of paramount importance to be familiar with the physiologic and pharmacologic characteristics of AVP and its analogs.
Despite numerous reports and small studies describing the successful and potentially lifesaving effects of AVP in cardiovascular shock states seemingly incompatible with survival, the concept of AVP as a “magic bullet” must be avoided, and AVP should be used only at recommended dosages for indications that have been defined through clinical investigations. Before introducing AVP into standard treatment protocols, the results of major clinical outcome studies must be awaited. However, the difficulties of proving significant survival benefits of a rescue therapy in multicenter trials is readily apparent. Furthermore, for some indications, e.g., anaphylactic shock or drug intoxications, it is unlikely that large clinical studies can ever be performed. It should also be remembered that it is unlikely that a drug used in diseases where the disturbance of homeostasis is as complex as in cardiac arrest, severe shock states, or multiple organ dysfunction syndrome will be free of side effects. The first overview of significant side effects of a supplementary AVP infusion in patients with advanced vasodilatory shock has recently been presented,18 but results of major studies are needed to assess the risk-to-benefit ratio of AVP in critically ill patients.
Currently, three multicenter trials evaluating the effects of AVP in cardiac arrest, septic shock, and uncontrolled hemorrhagic shock are being performed. The Vasopressin and Septic Shock Trial, a multicenter, triple-blind, randomized controlled study in intensive care units across Canada and Australia, examines the effectiveness of AVP (0.03 U/min) as a supplementary vasopressor on 28-day and 90-day survival in patients with septic shock. Finalization of patient randomization is expected soon, but initial promising results of the interim analysis have been reported. The hypothesis being tested is that compared with norepinephrine treatment alone, supplementary infusion of low-dose AVP (0.03 U/min) would increase 28-day survival from 40% to 50%. In France, an investigation studying the combination of AVP and epinephrine versus epinephrine alone during prehospital cardiopulmonary resuscitation is under way; 2000 patients have already been enrolled, and first results are expected in late 2006. In summer 2006, our study group will initiate a multicenter trial in Europe to analyze the effects of AVP in prehospital trauma patients with uncontrolled hemorrhagic shock who do not respond to standard treatment.19
Since its discovery more than 100 yr ago, AVP is increasingly acknowledged as a valuable adjunct vasopressor in catecholamine-resistant shock states. AVP is an excellent example of how an orphan drug can be developed to improve the treatment of our patients.
Martin W. Dünser, M.D.,*
Karl H. Lindner, M.D.,†
Volker Wenzel, M.D., M.Sc.,†
*Department of Intensive Care Medicine, University Hospital Bern, Switzerland. †Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Austria. volker.wenzel@uibk.ac.at
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References

1. Oliver GS, Schäfer EA: On the physiological action of extracts of pituitary body and certain other glandular organs. J Physiol (London) 1895;18: 277–9

2. Howell W: The physiological effects of the hypophysis cerebri and infundibular body. J Exp Med 1898;3: 248–58

3. Velden RVD: Die Nierenwirkung von Hypophysenextrakten beim Menschen. Berl Klin Wochenschr 1913; 50:2083–6

4. Turner RA, Pierce JG, Du Vigneaud V: The purification and the amino acid content of vasopressin preparation. J Biol Chem 1951; 191:21–8

5. Du Vigneaud V, Gash DT, Katsoyannis PG: A synthetic preparation possessing biological properties associated with arginine-vasopressin. J Am Chem Soc 1954; 76:4751–2

6. Czako L, Mezei G, Laszlo FA: Treatment of diabetes insipidus with 1-deamino-8-d-arginine vasopressin. Acta Med Acad Sci Hung 1975; 32:75–84

7. Kehne S, Hughes FA, Gompertz ML: The use of surgical pituitrin in the control of esophageal varix bleeding. Surgery 1956; 39:917–25

8. Gothlin J: Vasopressin in the elimination of intestinal gas. Acta Radiol Diagn (Stockh) 1972; 12:100–12

9. Voderholzer WA, Klauser AG, Muhldorfer BE, Fiedler F, Müller-Lissner SA: The influence of arginine-vasopressin on stool output and gastrointestinal transit time in healthy volunteers. Z Gastroenterol 1995; 33:189–92

10. Wislicki L: Hypotension after neo-synephrine infusion treated by pitressin. Acta Med Orient 1957; 16:174–7

11. Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG: Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 1997; 349:535–7

12. Landry DW, Levin HR, Gallant EM, Seo S, D'Alessandro D, Oz MZ, Oliver JA: Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997;25: 1279–82

13. Treschan TA, Peters J: The vasopressin system: Physiology and clinical strategies. Anesthesiology 2006; 105:599–612

14. Jolly S, Newton G, Horlick E, Seidelin PH, Ross HJ, Husain M, Dzavik V: Effect of vasopressin on hemodynamics in patients with refractory cardiogenic shock complicating acute myocardial infarction. Am J Cardiol 2005; 96:1617–20

15. Leone M, Charvet A, Delmas A, Albanese J, Martin C, Boyle WA: Terlipressin: A new therapeutic for calcium-channel blocker overdose. J Crit Care 2005; 20:114–5

16. McNamee JJ, Trainor D, Michalek P: Terlipressin for refractory hypotension following angiotensin-II receptor antagonist overdose. Anaesthesia 2006; 61:408–9

17. Veall GRQ, Peacocdk JE, Bax NDS, Reilly CS: Review of the anaesthetic management of 21 patients undergoing laparotomy for carcinoid syndrome. Br J Anaesth 1994; 72:335–41

18. Luckner G, Dünser MW, Jochberger S, Mayr VD, Wenzel V, Ulmer H, Schmid S, Knotzer H, Pajk W, Hasibeder W, Mayr AJ, Friesenecker BE: Arginine vasopressin in 316 patients with advanced vasodilatory shock. Crit Care Med 2005; 33:2659–66

19. Krismer AC, Wenzel V, Voelckel W, Innerhofer P, Stadlbauer KH, Haas T, Pavlic M, Sparr HJ, Lindner KH, Königsrainer A: Employing vasopressin as an adjunct vasopressor in uncontrolled traumatic hemorrhagic shock: Three cases and a brief analysis of the literature. Anaesthesist 2005; 54:220–4

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