Arginine Vasopressin Supplementation in Early Traumatic Shock | Emergency Medicine | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Effect of Low-Dose Supplementation of Arginine Vasopressin on Need for Blood Product Transfusions in Patients With Trauma and Hemorrhagic ShockA Randomized Clinical Trial

Educational Objective To determine the effect of low-dose vasopressin (AVP) administration on the need for blood transfusion in a select injured population with hemorrhagic shock.
1 Credit CME
Key Points

Question  Does low-dose arginine vasopressin supplementation decrease the need for blood product transfusions in patients with trauma and hemorrhagic shock?

Findings  In this randomized clinical trial of 100 adult trauma patients in hemorrhagic shock, arginine vasopressin supplementation significantly decreased the volume of blood products given in the first 48 hours by a median of 1.4 L without increasing complications.

Meaning  Including low-dose arginine vasopressin supplementation when resuscitating trauma patients in hemorrhagic shock may safely decrease the need for blood products.

Abstract

Importance  Current therapies for traumatic blood loss focus on hemorrhage control and blood volume replacement. Severe hemorrhagic shock, however, is associated with a state of arginine vasopressin (AVP) deficiency, and supplementation of this hormone may decrease the need for blood products in resuscitation.

Objective  To determine whether low-dose supplementation of AVP in patients with trauma (hereinafter referred to as trauma patients) and with hemorrhagic shock decreases their need for transfused blood products during resuscitation.

Design, Setting, and Participants  This randomized, double-blind placebo-controlled clinical trial included adult trauma patients (aged 18-65 years) who received at least 6 U of any blood product within 12 hours of injury at a single urban level 1 trauma center from May 1, 2013, through May 31, 2017. Exclusion criteria consisted of prehospital cardiopulmonary resuscitation, emergency department thoracotomy, corticosteroid use, chronic renal insufficiency, coronary artery disease, traumatic brain injury requiring any neurosurgical intervention, pregnancy, prisoner status, or AVP administration before enrollment. Data were analyzed from May 1, 2013, through May 31, 2017, using intention to treat and per protocol.

Interventions  After administration of an AVP bolus (4 U) or placebo, participants received AVP (≤0.04 U/min) or placebo for 48 hours to maintain a mean arterial blood pressure of at least 65 mm Hg.

Main Outcomes  The primary outcome was total volume of blood product transfused. Secondary end points included total volume of crystalloid transfused, vasopressor requirements, secondary complications, and 30-day mortality.

Results  One hundred patients underwent randomization (49 to the AVP group and 51 to the placebo group). Patients were primarily young (median age, 27 years [interquartile range {IQR}, 22-25 years]) and male (n = 93) with penetrating trauma (n = 79). Cohort characteristics before randomization were well balanced. At 48 hours, patients who received AVP required significantly less blood products (median, 1.4 [IQR, 0.5-2.6] vs 2.9 [IQR, 1.1-4.8] L; P = .01) but did not differ in requirements for crystalloids (median, 9.9 [IQR, 7.9-13.0] vs 11.0 [8.9-15.0] L; P = .22) or vasopressors (median, 400 [IQR, 0-5900] vs 1400 [IQR, 200-7600] equivalent units; P = .22). Although the groups had similar rates of mortality (6 of 49 [12%] vs 6 of 51 [12%]; P = .94) and total complications (24 of 44 [55%] vs 30 of 47 [64%]; P = .37), the AVP group had less deep venous thrombosis (5 of 44 [11%] vs 16 of 47 [34%]; P = .02).

Conclusions and Relevance  Low-dose AVP during the resuscitation of trauma patients in hemorrhagic shock decreases blood product requirements. Additional research is necessary to determine whether including AVP improves morbidity or mortality.

Trial Registration  ClinicalTrials.gov identifier: NCT01611935

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: May 26, 2019.

Corresponding Author: Carrie A. Sims, MD, PhD, Division of Traumatology, Surgical Critical Care, and Emergency Surgery, Department of Surgery, University of Pennsylvania, 51 N 39th St, Medical Office Building, Ste 120, Philadelphia, PA 19104 (carrie.sims@uphs.upenn.edu).

Published Online: August 28, 2019. doi:10.1001/jamasurg.2019.2884

Author Contributions: Dr Sims and Ms Zimmerman had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sims, Grill, Reilly.

Acquisition, analysis, or interpretation of data: Sims, Holena, Kim, Pascual, Smith, Martin, Seamon, Shiroff, Raza, Kaplan, Grill, Zimmerman, Mason, Abella.

Drafting of the manuscript: Sims, Grill, Zimmerman, Abella.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Raza, Zimmerman.

Obtained funding: Sims.

Administrative, technical, or material support: Sims, Holena, Pascual, Smith, Martin, Seamon, Raza, Kaplan, Grill, Mason, Abella, Reilly.

Supervision: Sims, Martin.

Conflict of Interest Disclosures: Dr Sims reported receiving grants from the National Trauma Institute/Department of Defense during the conduct of the study. Dr Seamon reported receiving personal fees from Wolters Kluwer outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by award NTI-TRA-09-062 from the National Trauma Institute and prime award W81XWH-10-0924 from the Department of the Army (Dr Sims).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The US Army Medical Research Acquisition Activity, 820 Chandler St, Fort Detrick, MD 21702, is the awarding and administering acquisition office. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of the Army or the National Trauma Institute.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Joy Steele, RN, served as the Clinical Research Coordinator for this study. Myra Rodriguez, BA, provided administrative assistance, regulatory support, and coordination with the US Food and Drug Administration and the institutional review board of the University of Pennsylvania. Both were paid employees at the University of Pennsylvania.

References
1.
Heron  M.  Deaths: Leading Causes for 2016.  Natl Vital Stat Rep. 2018;67(6):1-77.PubMedGoogle Scholar
2.
Tisherman  SA, Schmicker  RH, Brasel  KJ,  et al.  Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium.  Ann Surg. 2015;261(3):586-590. doi:10.1097/SLA.0000000000000837PubMedGoogle ScholarCrossref
3.
Cotton  BA, Guy  JS, Morris  JA  Jr, Abumrad  NN.  The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies.  Shock. 2006;26(2):115-121. doi:10.1097/01.shk.0000209564.84822.f2PubMedGoogle ScholarCrossref
4.
Sihler  KC, Napolitano  LM.  Complications of massive transfusion.  Chest. 2010;137(1):209-220. doi:10.1378/chest.09-0252PubMedGoogle ScholarCrossref
5.
Gearhart  MM, Luchette  FA, Proctor  MC,  et al.  The risk assessment profile score identifies trauma patients at risk for deep vein thrombosis.  Surgery. 2000;128(4):631-640. doi:10.1067/msy.2000.108224PubMedGoogle ScholarCrossref
6.
Landry  DW, Oliver  JA.  The pathogenesis of vasodilatory shock.  N Engl J Med. 2001;345(8):588-595. doi:10.1056/NEJMra002709PubMedGoogle ScholarCrossref
7.
Landry  DW, Levin  HR, Gallant  EM,  et al.  Vasopressin deficiency contributes to the vasodilation of septic shock.  Circulation. 1997;95(5):1122-1125. doi:10.1161/01.CIR.95.5.1122PubMedGoogle ScholarCrossref
8.
Landry  DW, Levin  HR, Gallant  EM,  et al.  Vasopressin pressor hypersensitivity in vasodilatory septic shock.  Crit Care Med. 1997;25(8):1279-1282. doi:10.1097/00003246-199708000-00012PubMedGoogle ScholarCrossref
9.
Altura  BM.  Evidence that endogenous vasopressin plays a protective role in circulatory shock: role for reticuloendothelial system using Brattleboro rats.  Experientia. 1980;36(9):1080-1082. doi:10.1007/BF01965981PubMedGoogle ScholarCrossref
10.
Errington  ML, Rocha e Silva  M  Jr.  Vasopressin clearance and secretion during haemorrhage in normal dogs and in dogs with experimental diabetes insipidus.  J Physiol. 1972;227(2):395-418. doi:10.1113/jphysiol.1972.sp010039PubMedGoogle ScholarCrossref
11.
Oliver  JA, Landry  DW.  Endogenous and exogenous vasopressin in shock.  Curr Opin Crit Care. 2007;13(4):376-382. doi:10.1097/MCC.0b013e3282435e16PubMedGoogle ScholarCrossref
12.
Morales  D, Madigan  J, Cullinane  S,  et al.  Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock.  Circulation. 1999;100(3):226-229. doi:10.1161/01.CIR.100.3.226PubMedGoogle ScholarCrossref
13.
Sims  CA, Guan  Y, Bergey  M,  et al.  Arginine vasopressin, copeptin, and the development of relative AVP deficiency in hemorrhagic shock.  Am J Surg. 2017;214(4):589-595. doi:10.1016/j.amjsurg.2017.06.015PubMedGoogle ScholarCrossref
14.
Cohn  SM, DeRosa  M, McCarthy  J,  et al.  Characterizing vasopressin and other vasoactive mediators released during resuscitation of trauma patients.  J Trauma Acute Care Surg. 2013;75(4):620-628. doi:10.1097/TA.0b013e31829eff31PubMedGoogle ScholarCrossref
15.
Voelckel  WG, Raedler  C, Wenzel  V,  et al.  Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs.  Crit Care Med. 2003;31(4):1160-1165. doi:10.1097/01.CCM.0000060014.75282.69PubMedGoogle ScholarCrossref
16.
Möhring  J, Glänzer  K, Maciel  JA  Jr,  et al.  Greatly enhanced pressor response to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension.  J Cardiovasc Pharmacol. 1980;2(4):367-376. doi:10.1097/00005344-198007000-00004PubMedGoogle ScholarCrossref
17.
Colucci  G, Stutz  M, Rochat  S,  et al.  The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects.  Blood. 2014;123(12):1905-1916. doi:10.1182/blood-2013-04-497123PubMedGoogle ScholarCrossref
18.
Stadlbauer  KH, Wagner-Berger  HG, Raedler  C,  et al.  Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs.  Anesthesiology. 2003;98(3):699-704. doi:10.1097/00000542-200303000-00018PubMedGoogle ScholarCrossref
19.
Cohn  SM, McCarthy  J, Stewart  RM, Jonas  RB, Dent  DL, Michalek  JE.  Impact of low-dose vasopressin on trauma outcome: prospective randomized study.  World J Surg. 2011;35(2):430-439. doi:10.1007/s00268-010-0875-8PubMedGoogle ScholarCrossref
20.
Collier  B, Dossett  L, Mann  M,  et al.  Vasopressin use is associated with death in acute trauma patients with shock.  J Crit Care. 2010;25(1):173.e9-173.e14. doi:10.1016/j.jcrc.2009.05.003PubMedGoogle ScholarCrossref
21.
Sims  CA, Isserman  JA, Holena  D,  et al.  Exception from informed consent for emergency research: consulting the trauma community.  J Trauma Acute Care Surg. 2013;74(1):157-165. doi:10.1097/TA.0b013e318278908aPubMedGoogle ScholarCrossref
22.
Brown  SM, Lanspa  MJ, Jones  JP,  et al.  Survival after shock requiring high-dose vasopressor therapy.  Chest. 2013;143(3):664-671. doi:10.1378/chest.12-1106PubMedGoogle ScholarCrossref
23.
Pennsylvania Outcomes and Performance Improvement Measurement System (POPIMS) Operations Manual. Pennsylvania Trauma Systems Foundation. 2015. http://ptsf.org/upload/POPIMS_Manual_2015_Final.pdf. Accessed May 1, 2017.
24.
Bolland  K, Whitehead  J.  Formal approaches to safety monitoring of clinical trials in life-threatening conditions.  Stat Med. 2000;19(21):2899-2917. doi:10.1002/1097-0258(20001115)19:21<2899::AID-SIM597>3.0.CO;2-OPubMedGoogle ScholarCrossref
25.
Austin  PC.  Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples.  Stat Med. 2009;28(25):3083-3107. doi:10.1002/sim.3697PubMedGoogle ScholarCrossref
26.
McNutt  LA, Wu  C, Xue  X, Hafner  JP.  Estimating the relative risk in cohort studies and clinical trials of common outcomes.  Am J Epidemiol. 2003;157(10):940-943. doi:10.1093/aje/kwg074PubMedGoogle ScholarCrossref
27.
Al-Refaie  WB, Parsons  HM, Markin  A, Abrams  J, Habermann  EB.  Blood transfusion and cancer surgery outcomes: a continued reason for concern.  Surgery. 2012;152(3):344-354. doi:10.1016/j.surg.2012.06.008PubMedGoogle ScholarCrossref
28.
Glance  LG, Dick  AW, Mukamel  DB,  et al.  Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery.  Anesthesiology. 2011;114(2):283-292. doi:10.1097/ALN.0b013e3182054d06PubMedGoogle ScholarCrossref
29.
Turan  A, Yang  D, Bonilla  A,  et al.  Morbidity and mortality after massive transfusion in patients undergoing non-cardiac surgery.  Can J Anaesth. 2013;60(8):761-770. doi:10.1007/s12630-013-9937-3PubMedGoogle ScholarCrossref
30.
Holmes  CL, Landry  DW, Granton  JT.  Science review: vasopressin and the cardiovascular system part 2: clinical physiology.  Crit Care. 2004;8(1):15-23. doi:10.1186/cc2338PubMedGoogle ScholarCrossref
31.
Williams  TD, Da Costa  D, Mathias  CJ, Bannister  R, Lightman  SL.  Pressor effect of arginine vasopressin in progressive autonomic failure.  Clin Sci (Lond). 1986;71(2):173-178. doi:10.1042/cs0710173PubMedGoogle ScholarCrossref
32.
Rudichenko  VM, Beierwaltes  WH.  Arginine vasopressin–induced renal vasodilation mediated by nitric oxide.  J Vasc Res. 1995;32(2):100-105. doi:10.1159/000159082PubMedGoogle ScholarCrossref
33.
Edwards  RM, Trizna  W, Kinter  LB.  Renal microvascular effects of vasopressin and vasopressin antagonists.  Am J Physiol. 1989;256(2, pt 2):F274-F278.PubMedGoogle Scholar
34.
Kaufmann  JE, Vischer  UM.  Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP).  J Thromb Haemost. 2003;1(4):682-689. doi:10.1046/j.1538-7836.2003.00190.xPubMedGoogle ScholarCrossref
35.
Pecci  A, Balduini  CL.  Desmopressin and super platelets.  Blood. 2014;123(12):1779-1780. doi:10.1182/blood-2014-01-551242PubMedGoogle ScholarCrossref
36.
Barrett  LK, Singer  M, Clapp  LH.  Vasopressin: mechanisms of action on the vasculature in health and in septic shock.  Crit Care Med. 2007;35(1):33-40. doi:10.1097/01.CCM.0000251127.45385.CDPubMedGoogle ScholarCrossref
37.
Haas  T, Voelckel  WG, Wiedermann  F, Wenzel  V, Lindner  KH.  Successful resuscitation of a traumatic cardiac arrest victim in hemorrhagic shock with vasopressin: a case report and brief review of the literature.  J Trauma. 2004;57(1):177-179. doi:10.1097/01.TA.0000044357.25191.1BPubMedGoogle ScholarCrossref
38.
American College of Surgeons.  Advanced Trauma Life Support 10th Edition Student Course Manual. Chicago, IL: American College of Surgeons; 2018.
39.
Sperry  JL, Minei  JP, Frankel  HL,  et al.  Early use of vasopressors after injury: caution before constriction.  J Trauma. 2008;64(1):9-14. doi:10.1097/TA.0b013e31815dd029PubMedGoogle ScholarCrossref
40.
Marik  PE, Corwin  HL.  Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature.  Crit Care Med. 2008;36(9):2667-2674. doi:10.1097/CCM.0b013e3181844677PubMedGoogle ScholarCrossref
41.
Boutin  A, Moore  L, Lauzier  F,  et al.  Transfusion of red blood cells in patients with traumatic brain injuries admitted to Canadian trauma health centres: a multicentre cohort study.  BMJ Open. 2017;7(3):e014472. doi:10.1136/bmjopen-2016-014472PubMedGoogle Scholar
42.
Spinella  PC, Perkins  JG, Grathwohl  KW,  et al.  Effect of plasma and red blood cell transfusions on survival in patients with combat related traumatic injuries.  J Trauma. 2008;64(2)(suppl):S69-S77. doi:10.1097/TA.0b013e318160ba2fPubMedGoogle ScholarCrossref
43.
Watson  GA, Sperry  JL, Rosengart  MR,  et al; Inflammation and Host Response to Injury Investigators.  Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome.  J Trauma. 2009;67(2):221-227. doi:10.1097/TA.0b013e3181ad5957PubMedGoogle ScholarCrossref
44.
Goel  R, Patel  EU, Cushing  MM,  et al.  Association of perioperative red blood cell transfusions with venous thromboembolism in a North American registry.  JAMA Surg. 2018;153(9):826-833. doi:10.1001/jamasurg.2018.1565PubMedGoogle ScholarCrossref
45.
Dhillon  NK, Smith  EJT, Ko  A,  et al.  The risk factors of venous thromboembolism in massively transfused patients.  J Surg Res. 2018;222:115-121. doi:10.1016/j.jss.2017.09.038PubMedGoogle ScholarCrossref
46.
Karcutskie  CA, Meizoso  JP, Ray  JJ,  et al.  Association of mechanism of injury with risk for venous thromboembolism after trauma.  JAMA Surg. 2017;152(1):35-40. doi:10.1001/jamasurg.2016.3116PubMedGoogle ScholarCrossref
47.
Douros  A, Jobski  K, Kollhorst  B, Schink  T, Garbe  E.  Risk of venous thromboembolism in cancer patients treated with epoetins or blood transfusions.  Br J Clin Pharmacol. 2016;82(3):839-848. doi:10.1111/bcp.13019PubMedGoogle ScholarCrossref
48.
Xenos  ES, Vargas  HD, Davenport  DL.  Association of blood transfusion and venous thromboembolism after colorectal cancer resection.  Thromb Res. 2012;129(5):568-572. doi:10.1016/j.thromres.2011.07.047PubMedGoogle ScholarCrossref
49.
Russell  JA, Walley  KR.  Vasopressin and its immune effects in septic shock.  J Innate Immun. 2010;2(5):446-460. doi:10.1159/000318531PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close