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Hemorrhagic Shock NEJM - 024729
Hemorrhagic Shock NEJM - 024729
Review Article
Hemorrhagic Shock
Jeremy W. Cannon, M.D.
H
From the Division of Traumatology, Sur- emorrhagic shock is a form of hypovolemic shock in which
gical Critical Care, and Emergency Sur- severe blood loss leads to inadequate oxygen delivery at the cellular level.
gery, Department of Surgery, Perelman
School of Medicine, University of Penn- If hemorrhage continues unchecked, death quickly follows. The causes of
sylvania, Philadelphia, and the F. Edward hemorrhage resulting in shock vary widely and include trauma, maternal hemor-
Hebert School of Medicine, Uniformed rhage, gastrointestinal hemorrhage, perioperative hemorrhage, and rupture of an
Services University, Bethesda, MD. Ad-
dress reprint requests to Dr. Cannon at aneurysm.1-4
the Division of Traumatology, Surgical Death from hemorrhage represents a substantial global problem, with more
Critical Care, and Emergency Surgery, than 60,000 deaths per year in the United States and an estimated 1.9 million
51 N. 39th St., Medical Office Bldg. 120,
Philadelphia, PA 19104, or at jeremy deaths per year worldwide, 1.5 million of which result from physical trauma.5
.cannon@uphs.upenn.edu. Because trauma affects a disproportionate number of young people, these 1.5 mil-
N Engl J Med 2018;378:370-9. lion deaths result in nearly 75 million years of life lost (Table 1). Furthermore,
DOI: 10.1056/NEJMra1705649 those who survive the initial hemorrhagic insult have poor functional outcomes
Copyright © 2018 Massachusetts Medical Society. and significantly increased long-term mortality.3,8 This article summarizes recent
advances in our knowledge of the pathobiology of hemorrhagic shock and details
new approaches to treatment for these critically ill patients.
Pathobiol o gy
Understanding the host response to severe hemorrhage has taken more than a
century.9 Early theories that hemorrhagic shock resulted from nervous system
dysfunction or a toxin released from ischemic tissues were ultimately disproved,
giving way to the accepted view that blood loss causes inadequate oxygen delivery
and activates a number of homeostatic mechanisms designed to preserve perfusion
to vital organs. Only now is the complexity of these events at the cellular, tissue,
and whole-organism levels becoming clear, along with the relative contributions
of hemorrhage-induced hypoperfusion and tissue injury from physical trauma
(Fig. 1).
At the cellular level, hemorrhagic shock results when oxygen delivery is insuf-
ficient to meet oxygen demand for aerobic metabolism.10 In this delivery-dependent
state, cells transition to anaerobic metabolism. Lactic acid, inorganic phosphates,
and oxygen radicals start to accumulate as a result of the mounting oxygen debt.11
Release of damage-associated molecular patterns (known as DAMPs or alarmins),
including mitochondrial DNA and formyl peptides, incites a systemic inflamma-
tory response.12 As ATP supplies dwindle, cellular homeostasis ultimately fails,
and cell death ensues through necrosis from membrane rupture, apoptosis, or
necroptosis.
At the tissue level, hypovolemia and vasoconstriction cause hypoperfusion and
end-organ damage in the kidneys, liver, intestine, and skeletal muscle, which can
lead to multiorgan failure in survivors. In extreme hemorrhage with exsanguina-
tion, pulselessness results in hypoperfusion of the brain and myocardium, leading to
cerebral anoxia and fatal arrhythmias within minutes.13 Hemorrhage also induces
Table 1. Estimated Hemorrhage-Related Deaths per Year and Years of Life Lost in the United States and Worldwide,
According to the Cause of Hemorrhage.
Deaths from
Cause of Hemorrhage Hemorrhage* U.S. Cases of Hemorrhage Global Cases of Hemorrhage
percent
Abdominal aortic aneurysm 100 9,988† 65,273‡ 191,700§ 2,881,760¶
Maternal disorder 23§ 138‖ 7,572** 69,690‖ 4,298,240**
Peptic ulcer disease 60†† 1,860‖ 38,597** 141,000‖ 3,903,600**
Trauma 30‡‡ 49,440‖ 1,931,786** 1,481,700‖ 74,568,000**
Total 61,426 2,043,228 1,884,090 85,651,600
* This column lists the best estimates of deaths from hemorrhage as a percentage of all deaths from the given diagno-
sis (e.g., all deaths from abdominal aortic aneurysm are ultimately related to hemorrhage).
† Information is from Leading Causes of Death Reports, 1981–2015, Centers for Disease Control and Prevention, 2017
(https://webappa.cdc.gov/sasweb/ncipc/leadcause.html).
‡ Data are from Years of Potential Life Lost (YPLL) Reports, 1999–2015, Centers for Disease Control and Prevention, 2017
(https://webappa.cdc.gov/sasweb/ncipc/ypll10.html).
§ Data are from Lozano et al.5
¶ Data are from Global Health Data Exchange, 2016 (http://ghdx.healthdata.org/gbd-results-tool).
‖ Data are from Global Health Estimates 2015: Global Deaths by Cause, Age, Sex, by Country and by Region, 2000–2015.
World Health Organization, 2016 (www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html).
** Data are from Global Health Estimates 2015: Disease Burden by Cause, Age, Sex, by Country and Region, 2000–2015.
World Health Organization, 2016 (www.who.int/healthinfo/global_burden_disease/estimates/en/index2.html).
†† Information is from Christensen et al.6
‡‡ Information is from Kauvar et al.7
profound changes in the vascular endothelium agulopathy in patients with active bleeding.23
throughout the body.14 At the site of hemor- Overzealous resuscitation with crystalloid dilutes
rhage, the endothelium and blood act synergisti- the oxygen-carrying capacity and clotting factor
cally to promote thrombus formation. However, concentrations. Infusion of cold fluids exacer-
the mounting oxygen debt and the catechola bates the heat lost from hemorrhage, depleted
mine surge eventually induce a so-called endo- energy stores, and environmental exposure and
theliopathy through systemic shedding of the leads to decreased function of the enzymes in the
protective glycocalyx barrier.15 clotting cascade.24 Finally, overadministration of
With hemorrhage and shock, both adaptive acidic crystalloid solutions worsens the acidosis
and maladaptive changes occur in the blood. At caused by hypoperfusion and further impairs the
the site of hemorrhage, the clotting cascade and function of clotting factors, resulting in a “bloody
platelets are activated, forming a hemostatic vicious cycle” of coagulopathy, hypothermia, and
plug.16 Remote from the site of hemorrhage, fi- acidosis (Fig. 1).25
brinolytic activity increases, presumably to pre- New insights into the genetic response to
vent microvascular thrombosis.17 However, excess severe injury and hemorrhage have been gleaned
plasmin activity and autoheparinization from from the Inflammation and the Host Response
glycocalyx shedding can result in pathologic to Injury research program.26 Historically, the
hyperfibrinolysis and diffuse coagulopathy.14,17,18 prevailing view was that a patient’s initial re-
Conversely, nearly half of patients with trauma sponse to severe injury and shock was a robust,
have a hypercoagulable phenotype of fibrinolysis innate systemic inflammatory response syndrome
shutdown.18 Depleted platelet numbers, decreased (SIRS), which was followed by relative immuno-
platelet margination due to anemia, and reduced suppression, termed compensatory antiinflam-
platelet activity also contribute to coagulopathy matory response syndrome (CARS), and then
and increased mortality.19-22 eventual recovery. If there were any complica-
Iatrogenic factors can further exacerbate co- tions, the cycle would reset with another SIRS,
Hypothermia
Sites of Hemorrhage
Lung
laceration Chest-wall
injury
Solid-organ
Upper
injury
GI tract
Ruptured
aneurysm
Dialysis
access
Lower
GI tract
Ectopic
pregnancy
Pelvic
Injured fracture
vessels
Endothelial Conversion
activation of fibrinogen
Glycocalyx to fibrin
shedding
Neutrophil
activation
Platelet
Endothelial activation
Permeability
activation
Vasoconstriction
0 Bleeding Event 1 2 3 4
applied proximal to any bleeding wounds in the subtle. In most patients, robust compensatory
extremities. mechanisms render hypotension an insensitive
indicator of shock until more than 30% of the
Evaluation of Patients with Severe patient’s blood volume has been lost (Table 2).
Hemorrhage More subtle clinical cues indicative of shock in-
Signs and symptoms of hemorrhagic shock, es- clude anxiety, tachypnea, a weak peripheral pulse,
pecially from occult sources of bleeding, are often and cool extremities with pale or mottled skin.
Promising technologies that may help clinicians tion, since they can fluctuate wildly.24,48 Finally,
more quickly identify patients in shock include coagulopathy should be identified and ongoing
the compensatory reserve index43 and portable blood-product resuscitation should be guided by
incident dark-field microscopy to assess micro- measuring clot-formation kinetics with the use of
vascular beds in real time.44 viscoelastic testing such as thromboelastography
During the initial evaluation, potential sources or rotational thromboelastometry.49 Taken togeth-
of hemorrhage should be identified. Examples er, these laboratory measures will indicate the
include hematemesis or hematochezia, copious severity of shock, the need for mobilizing blood
vaginal bleeding, and a known history of an bank resources, and the presence and type of
abdominal aortic aneurysm. In patients with coagulopathy.
trauma, bleeding from sources in the extremities Although computed tomographic (CT) imaging
is obvious before the onset of shock, but these is now ubiquitous in the emergency evaluation of
sites may no longer be bleeding after severe critically ill patients, it should be performed only
hemorrhage. Also, the proximal thighs and the if the source of bleeding remains uncertain and
retroperitoneum can hold a large volume of blood the patient’s condition has been stabilized with
that may not be readily apparent on the initial initial resuscitation. Often, in cases of severe
assessment. Intracavitary sources of bleeding in hemorrhage, the patient is better served by rapid
patients with trauma include the chest, abdomen, interventions that are both diagnostic and thera-
and pelvis. Rapid evaluation of these cavities peutic, such as operative exploration, angiography
with chest and pelvic radiographs and focused with embolization, or gastrointestinal endoscopy.
assessment with sonography for trauma (FAST)
can indicate potential sites of bleeding.45 Ultra- Resuscitation
sonography can also be used in patients without Successful resuscitation requires aggressive mea-
trauma to identify occult sources of bleeding sures to prevent the accumulation of further
such as a ruptured abdominal aortic aneurysm, oxygen debt and to repay the existing oxygen
uterine bleeding, or a ruptured ectopic preg- debt by stanching all sources of hemorrhage and
nancy, and echocardiography can be used to restoring the intravascular volume as quickly as
assess cardiac filling and contractility.46 possible.10 In patients with trauma, the com-
Laboratory measures of cellular hypoperfusion panion concepts of damage-control surgery50
include base deficit and lactate values obtained and damage-control resuscitation51,52 achieve these
from blood gas analysis. Other useful laboratory objectives. Similarly, patients with severe hemor-
values in a patient with severe bleeding include rhage from causes other than trauma benefit
hemoglobin and the international normalized from rapid localization and control of hemor-
ratio, which can be used to predict the need for rhage paired with blood-product resuscitation.
a massive transfusion.47 The platelet count and When the patient arrives at the hospital, the
fibrinogen levels should be measured and nor- priorities for management of bleeding include
malized. Electrolytes, including potassium and restoration of intravascular volume and rapid
calcium, should be measured early and often control of hemorrhage as part of the damage-
during the course of blood-product resuscita- control resuscitation paradigm (Table 3). Strate-
appropriate use of these medications in patients with acute gastrointestinal bleeding, endoscopy
with acute bleeding. At present, my hemostatic should be performed within 24 hours after pre-
adjunct of choice is tranexamic acid, administered sentation; adherence to this recommendation
when the massive-transfusion protocol is activat- may, at least in part, explain the decreasing mor-
ed. Vasopressin supplementation is another ther- tality associated with gastrointestinal bleeding
apy that may reduce blood-product and fluid re- in recent years.70,71
quirements in patients with hemorrhagic shock.61
Resuscitation End Points
Achieving Definitive Hemostasis After the initial course of resuscitation and defini-
All patients with severe bleeding require timely, tive hemostasis, the patient should be assessed for
definitive hemostasis to ensure survival (Fig. 2). evidence of ongoing hemorrhage, unpaid oxygen
A prolonged time to hemostasis has been linked debt, anemia, coagulopathy, electrolyte derange-
to increased blood-transfusion requirements, in- ments, and other sequelae of over- or under-resus-
creased mortality, or both for patients with pelvic citation (Fig. 2).72 Bedside echocardiography can
fractures,62 ruptured abdominal aortic aneurysm,63 be used by critical care physicians to assess intra-
or gastrointestinal bleeding.64 Patients with acute vascular volume and cardiac function. Thrombo-
torso hemorrhage due to trauma should remain elastography or rotational thromboelastography
in the emergency department less than 10 min- can be used to identify coagulation abnormali-
utes for initial diagnosis and resuscitation in ties that require further correction.49 Symptom-
order to mitigate the risk of death.65 Patients atic anemia should also be corrected to normalize
with hemorrhage in an extremity and a con- intravascular volume and to repay any residual
firmed need for tourniquet application should be oxygen debt. Values approaching the normal
quickly moved to the operating room for vascu- range for lactate and base excess indicate that
lar exploration. For patients with multicavity the patient is being resuscitated appropriately
torso hemorrhage, it is important to identify the and that ongoing bleeding is unlikely.
cavity with the most severe bleeding at the out-
set, since initial surgical exploration of a body F u t ur e Dir ec t ions
cavity with less severe bleeding increases the
risk of death.66 Diagnostic adjuncts such as tube A systematic and comprehensive focus on hem-
thoracostomy and FAST help ensure proper opera- orrhage and injury research by the Department
tive sequencing for such patients, whose condi- of Defense has led to many of the advances de-
tion is too unstable for CT. Patients with purely tailed above28,73; however, gaps in both knowl-
abdominal or pelvic bleeding from any source edge and capability remain.74 Efforts to reduce the
may benefit from endovascular occlusion of the number of potentially preventable deaths from
aorta as a temporizing measure to slow hemor- hemorrhage must combine preventive measures75
rhage.67 This approach, termed resuscitative endo- with an all-out, multidisciplinary focus on early
vascular balloon occlusion of the aorta (REBOA), control of hemorrhage33 and a reduced time to
lowers the perfusion pressure to distal sites of definitive hemostasis.76 New approaches to early
severe hemorrhage, increases afterload, and re- hemorrhage control are in development, includ-
distributes the remaining blood volume prefer- ing partial REBOA, which extends the safe oc-
entially to the heart and brain. REBOA reduces clusion time while reducing the risk of distal
intraoperative mortality among patients with ischemia.77 Both type O whole blood and freeze-
ruptured abdominal aortic aneurysm68 and is dried plasma are also being investigated for early
being evaluated in two prospective studies for resuscitation of patients with bleeding from
patients with trauma (Aortic Occlusion for Re- trauma.78,79
suscitation in Trauma and Acute Care Surgery
[www.aast.org/Research/MultiInstitutionalStudies C onclusions
.aspx] and the Effectiveness and Cost-Effective-
ness of REBOA for Trauma [Current Controlled Hemorrhagic shock is a major cause of death
Trials number, ISRCTN16184981]).69 REBOA has and disability both in the United States and
also been used for severe gastrointestinal bleed- globally. Through an improved understanding of
ing and peripartum hemorrhage.67 For patients the pathobiology of hemorrhage and an emphasis
on rapid achievement of definitive hemostasis, The opinions expressed in this document are solely those of
the author and do not represent an endorsement by or the views
starting with prehospital care, survival of pa- of the U.S. Air Force, the Department of Defense, or the U.S.
tients with massive bleeding and recovery from government.
hemorrhagic shock are now possible. However, Dr. Cannon reports receiving simulation equipment from
Prytime Medical. No other potential conflict of interest relevant
much work remains to be done in the areas of to this article was reported.
primary prevention, early recognition, resuscitation Disclosure forms provided by the author are available with the
options, and rapid hemostasis to increase the full text of this article at NEJM.org.
I thank Colonel Kevin Chung, M.D., and Mark Seamon, M.D.,
likelihood of recovery and reduce the burden of for their insightful comments on an earlier version of the manu-
hemorrhagic shock to zero. script.
References
1. Mannucci PM, Levi M. Prevention and Arrest from Trauma clinical trial. J Trauma the Glue Grant experience. J Trauma Acute
treatment of major blood loss. N Engl J Acute Care Surg 2017;83:803-9. Care Surg 2015;78:671-86.
Med 2007;356:2301-11. 14. White NJ, Ward KR, Pati S, Stran- 27. Tisherman SA, Schmicker RH, Brasel
2. Hunt BJ. Bleeding and coagulopathies denes G, Cap AP. Hemorrhagic blood fail- KJ, et al. Detailed description of all deaths
in critical care. N Engl J Med 2014;370: ure: oxygen debt, coagulopathy, and endo- in both the shock and traumatic brain in-
847-59. thelial damage. J Trauma Acute Care Surg jury hypertonic saline trials of the Resus-
3. Halmin M, Chiesa F, Vasan SK, et al. 2017;82:Suppl 1:S41-S49. citation Outcomes Consortium. Ann Surg
Epidemiology of massive transfusion: a bi- 15. Johansson PI, Henriksen HH, Stens- 2015;261:586-90.
national study from Sweden and Denmark. balle J, et al. Traumatic endotheliopathy: 28. National Academies of Sciences, Engi-
Crit Care Med 2016;44:468-77. a prospective observational study of 424 neering, and Medicine. A national trauma
4. Ruseckaite R, McQuilten ZK, Oldroyd severely injured patients. Ann Surg 2017; care system:integrating military and civil-
JC, et al. Descriptive characteristics and 265:597-603. ian trauma systems to achieve zero pre-
in-hospital mortality of critically bleeding 16. Hoffman M, Cichon LJH. Practical co- ventable deaths after injury. Washington,
patients requiring massive transfusion: agulation for the blood banker. Transfu- DC:National Academies Press, 2016.
results from the Australian and New Zea- sion 2013;53:1594-602. 29. Schroll R, Smith A, McSwain NE Jr,
land Massive Transfusion Registry. Vox 17. Chang R, Cardenas JC, Wade CE, Hol- et al. A multi-institutional analysis of pre-
Sang 2017;112:240-8. comb JB. Advances in the understanding hospital tourniquet use. J Trauma Acute
5. Lozano R, Naghavi M, Foreman K, of trauma-induced coagulopathy. Blood Care Surg 2015;79:10-4.
et al. Global and regional mortality from 2016;128:1043-9. 30. Kragh JF Jr, Walters TJ, Baer DG, et al.
235 causes of death for 20 age groups in 18. Moore HB, Moore EE, Liras IN, et al. Survival with emergency tourniquet use
1990 and 2010: a systematic analysis for Acute fibrinolysis shutdown after injury to stop bleeding in major limb trauma.
the Global Burden of Disease Study 2010. occurs frequently and increases mortality: Ann Surg 2009;249:1-7.
Lancet 2012;380:2095-128. a multicenter evaluation of 2,540 severely 31. American College of Surgeons Stop
6. Christensen S, Riis A, Nørgaard M, injured patients. J Am Coll Surg 2016;222: the Bleed campaign. 2017 (http://www
Sørensen HT, Thomsen RW. Short-term 347-55. .bleedingcontrol.org/).
mortality after perforated or bleeding pep- 19. Brown LM, Call MS, Margaret Knud- 32. Singletary EM, Charlton NP, Epstein
tic ulcer among elderly patients: a popula- son M, et al. A normal platelet count may JL, et al. Part 15: first aid: 2015 American
tion-based cohort study. BMC Geriatr 2007; not be enough: the impact of admission Heart Association and American Red Cross
7:8. platelet count on mortality and transfu- guidelines update for first aid. Circulation
7. Kauvar DS, Lefering R, Wade CE. Im- sion in severely injured trauma patients. 2015;132:Suppl 2:S574-S589.
pact of hemorrhage on trauma outcome: J Trauma 2011;71:Suppl 3:S337-S342. 33. Bulger EM, Snyder D, Schoelles K, et al.
an overview of epidemiology, clinical pre- 20. Kutcher ME, Redick BJ, McCreery RC, An evidence-based prehospital guideline
sentations, and therapeutic considerations. et al. Characterization of platelet dysfunc- for external hemorrhage control: Ameri-
J Trauma 2006;60:S3-11. tion after trauma. J Trauma Acute Care can College of Surgeons Committee on
8. Mitra B, Gabbe BJ, Kaukonen K-M, Surg 2012;73:13-9. Trauma. Prehosp Emerg Care 2014; 18:
Olaussen A, Cooper DJ, Cameron PA. Long- 21. Wohlauer MV, Moore EE, Thomas S, 163-73.
term outcomes of patients receiving a et al. Early platelet dysfunction: an unrec- 34. Achneck HE, Sileshi B, Jamiolkowski
massive transfusion after trauma. Shock ognized role in the acute coagulopathy of RM, Albala DM, Shapiro ML, Lawson JH.
2014;42:307-12. trauma. J Am Coll Surg 2012;214:739-46. A comprehensive review of topical hemo-
9. Maier RV. Scudder oration on trauma: 22. Spann AP, Campbell JE, Fitzgibbon static agents: efficacy and recommenda-
a century of evolution in trauma resusci- SR, et al. The effect of hematocrit on tions for use. Ann Surg 2010;251:217-28.
tation. J Am Coll Surg 2014;219:335-45. platelet adhesion: experiments and simu- 35. Bickell WH, Wall MJ Jr, Pepe PE, et al.
10. Barbee RW, Reynolds PS, Ward KR. lations. Biophys J 2016;111:577-88. Immediate versus delayed fluid resuscita-
Assessing shock resuscitation strategies 23. Maegele M, Schöchl H, Cohen MJ. An tion for hypotensive patients with pene-
by oxygen debt repayment. Shock 2010; update on the coagulopathy of trauma. trating torso injuries. N Engl J Med 1994;
33:113-22. Shock 2014;41:Suppl 1:21-5. 331:1105-9.
11. Chaudry IH. Cellular mechanisms in 24. Sihler KC, Napolitano LM. Complica- 36. Bulger EM, May S, Kerby JD, et al.
shock and ischemia and their correction. tions of massive transfusion. Chest 2010; Out-of-hospital hypertonic resuscitation
Am J Physiol 1983;245:R117-R134. 137:209-20. after traumatic hypovolemic shock: a ran-
12. Zhang Q, Raoof M, Chen Y, et al. Cir- 25. Cosgriff N, Moore EE, Sauaia A, Kenny- domized, placebo controlled trial. Ann
culating mitochondrial DAMPs cause in- Moynihan M, Burch JM, Galloway B. Pre- Surg 2011;253:431-41.
flammatory responses to injury. Nature dicting life-threatening coagulopathy in the 37. Roberts I, Blackhall K, Alderson P,
2010;464:104-7. massively transfused trauma patient: hypo- Bunn F, Schierhout G. Human albumin
13. Tisherman SA, Alam HB, Rhee PM, thermia and acidoses revisited. J Trauma solution for resuscitation and volume ex-
et al. Development of the Emergency Pres- 1997;42:857-61. pansion in critically ill patients. Cochrane
ervation and Resuscitation for Cardiac 26. Tompkins RG. Genomics of injury: Database Syst Rev 2011;11:CD001208.
38. Shackelford SA, Del Junco DJ, Powell- BA, et al. Damage control resuscitation: shot wounds to the torso: the golden 10
Dunford N, et al. Association of prehos- the new face of damage control. J Trauma minutes. J Trauma Acute Care Surg 2016;
pital blood product transfusion during 2010;69:976-90. 81:685-91.
medical evacuation of combat casualties 52. Cannon JW, Khan MA, Raja AS, et al. 66. Hirshberg A, Wall MJ Jr, Allen MK,
in Afghanistan with acute and 30-day Damage control resuscitation in patients Mattox KL. Double jeopardy: thoracoab-
survival. JAMA 2017;318:1581-91. with severe traumatic hemorrhage: a prac- dominal injuries requiring surgical in-
39. Cotton BA, Jerome R, Collier BR, et al. tice management guideline from the East- tervention in both chest and abdomen.
Guidelines for prehospital fluid resuscita- ern Association for the Surgery of Trauma. J Trauma 1995;39:225-9.
tion in the injured patient. J Trauma 2009; J Trauma Acute Care Surg 2017;82:605-17. 67. Morrison JJ, Galgon RE, Jansen JO,
67:389-402. 53. Spinella PC, Cap AP. Whole blood: Cannon JW, Rasmussen TE, Eliason JL.
40. Kotwal RS, Howard JT, Orman JA, back to the future. Curr Opin Hematol A systematic review of the use of resusci-
et al. The effect of a golden hour policy on 2016;23:536-42. tative endovascular balloon occlusion of
the morbidity and mortality of combat 54. Meyer DE, Vincent LE, Fox EE, et al. the aorta in the management of hemor-
casualties. JAMA Surg 2016;151:15-24. Every minute counts: time to delivery of rhagic shock. J Trauma Acute Care Surg
41. Wandling MW, Nathens AB, Shapiro initial massive transfusion cooler and its 2016;80:324-34.
MB, Haut ER. Police transport versus impact on mortality. J Trauma Acute Care 68. Raux M, Marzelle J, Kobeiter H, et al.
ground EMS: a trauma system-level evalu- Surg 2017;83:19-24. Endovascular balloon occlusion is associ-
ation of prehospital care policies and 55. Holcomb JB, del Junco DJ, Fox EE, et al. ated with reduced intraoperative mortality
their effect on clinical outcomes. J Trau- The Prospective, Observational, Multicen of unstable patients with ruptured abdom-
ma Acute Care Surg 2016;81:931-5. ter, Major Trauma Transfusion (PROMMTT) inal aortic aneurysm but fails to improve
42. American College of Surgeons Com- study: comparative effectiveness of a time- other outcomes. J Vasc Surg 2015;61:304-8.
mittee on Trauma. Advanced Trauma Life varying treatment with competing risks. 69. DuBose JJ, Scalea TM, Brenner M, et al.
Support (ATLS) student course manual. JAMA Surg 2013;148:127-36. The AAST prospective Aortic Occlusion
9th ed. Chicago:American College of Sur- 56. Holcomb JB, Tilley BC, Baraniuk S, for Resuscitation in Trauma and Acute
geons, 2012:69. et al. Transfusion of plasma, platelets, and Care Surgery (AORTA) registry: data on
43. Nadler R, Convertino VA, Gendler S, red blood cells in a 1:1:1 vs a 1:1:2 ratio contemporary utilization and outcomes of
et al. The value of noninvasive measure- and mortality in patients with severe aortic occlusion and resuscitative balloon
ment of the compensatory reserve index in trauma: the PROPPR randomized clinical occlusion of the aorta (REBOA). J Trauma
monitoring and triage of patients experi- trial. JAMA 2015;313:471-82. Acute Care Surg 2016;81:409-19.
encing minimal blood loss. Shock 2014; 57. Etchill EW, Myers SP, McDaniel LM, 70. Laine L. Upper gastrointestinal bleed-
42:93-8. et al. Should all massively transfused pa- ing due to a peptic ulcer. N Engl J Med
44. Hutchings S, Naumann DN, Harris T, tients be treated equally? An analysis of 2016;374:2367-76.
Wendon J, Midwinter MJ. Observational massive transfusion ratios in the nontrau- 71. Gralnek IM, Neeman Z, Strate LL.
study of the effects of traumatic injury, ma setting. Crit Care Med 2017;45:1311-6. Acute lower gastrointestinal bleeding.
haemorrhagic shock and resuscitation 58. Spahn DR, Bouillon B, Cerny V, et al. N Engl J Med 2017;376:1054-63.
on the microcirculation: a protocol for the Management of bleeding and coagulopa- 72. Carson JL, Triulzi DJ, Ness PM. Indi-
MICROSHOCK study. BMJ Open 2016;6: thy following major trauma: an updated cations for and adverse effects of red-cell
e010893. European guideline. Crit Care 2013;17:R76. transfusion. N Engl J Med 2017;377:1261-
45. Rozycki GS, Ballard RB, Feliciano DV, 59. Shafi S, Collinsworth AW, Richter KM, 72.
Schmidt JA, Pennington SD. Surgeon- et al. Bundles of care for resuscitation 73. Rasmussen TE, Kellermann AL. War-
performed ultrasound for the assessment from hemorrhagic shock and severe brain time lessons — shaping a national trauma
of truncal injuries: lessons learned from injury in trauma patients — translating action plan. N Engl J Med 2016;375:1612-5.
1540 patients. Ann Surg 1998;228:557-67. knowledge into practice. J Trauma Acute 74. Jenkins DH, Rappold JF, Badloe JF, et al.
46. Shokoohi H, Boniface KS, Pourmand A, Care Surg 2016;81:780-94. Trauma hemostasis and oxygenation re-
et al. Bedside ultrasound reduces diagnos- 60. Schöchl H, Schlimp CJ. Trauma bleed- search position paper on remote damage
tic uncertainty and guides resuscitation in ing management: the concept of goal- control resuscitation: definitions, current
patients with undifferentiated hypotension. directed primary care. Anesth Analg 2014; practice, and knowledge gaps. Shock 2014;
Crit Care Med 2015;43:2562-9. 119:1064-73. 41:Suppl 1:3-12.
47. Callcut RA, Cotton BA, Muskat P, et al. 61. Cohn SM, McCarthy J, Stewart RM, 75. Norton R, Kobusingye O. Injuries.
Defining when to initiate massive trans- Jonas RB, Dent DL, Michalek JE. Impact N Engl J Med 2013;368:1723-30.
fusion: a validation study of individual mas- of low-dose vasopressin on trauma out- 76. Champion HR, Lombardo LV, Wade
sive transfusion triggers in PROMMTT come: prospective randomized study. CE, Kalin EJ, Lawnick MM, Holcomb JB.
patients. J Trauma Acute Care Surg 2013; World J Surg 2011;35:430-9. Time and place of death from automobile
74:59-65. 62. Tesoriero RB, Bruns BR, Narayan M, crashes: research endpoint implications.
48. MacKay EJ, Stubna MD, Holena DN, et et al. Angiographic embolization for hem- J Trauma Acute Care Surg 2016;81:420-6.
al. Abnormal calcium levels during trauma orrhage following pelvic fracture: is it 77. Russo RM, Neff LP, Lamb CM, et al.
resuscitation are associated with increased “time” for a paradigm shift? J Trauma Partial resuscitative endovascular balloon
mortality, increased blood product use, Acute Care Surg 2017;82:18-26. occlusion of the aorta in swine model of
and greater hospital resource consump- 63. Salhab M, Farmer J, Osman I. Impact hemorrhagic shock. J Am Coll Surg 2016;
tion: a pilot investigation. Anesth Analg of delay on survival in patients with rup- 223:359-68.
2017;125:895-901. tured abdominal aortic aneurysm. Vascu- 78. Yazer MH, Jackson B, Sperry JL, Alar-
49. Gonzalez E, Moore EE, Moore HB, et al. lar 2006;14:38-42. con L, Triulzi DJ, Murdock AD. Initial safety
Goal-directed hemostatic resuscitation of 64. Laine L, Laursen SB, Dalton HR, Ngu and feasibility of cold-stored uncross-
trauma-induced coagulopathy: a pragmat- JH, Schultz M, Stanley AJ. Relationship of matched whole blood transfusion in civil-
ic randomized clinical trial comparing a time to presentation after onset of upper ian trauma patients. J Trauma Acute Care
viscoelastic assay to conventional coagu- GI bleeding with patient characteristics Surg 2016;81:21-6.
lation assays. Ann Surg 2016;263:1051-9. and outcomes: a prospective study. Gastro- 79. Pusateri AE, Given MB, Schreiber MA,
50. Chovanes J, Cannon JW, Nunez TC. intest Endosc 2017;86:1028-37. et al. Dried plasma: state of the science and
The evolution of damage control surgery. 65. Meizoso JP, Ray JJ, Karcutskie CA IV, recent developments. Transfusion 2016;56:
Surg Clin North Am 2012;92:859-75. et al. Effect of time to operation on mor- Suppl 2:S128-S139.
51. Duchesne JC, McSwain NE Jr, Cotton tality for hypotensive patients with gun- Copyright © 2018 Massachusetts Medical Society.