The Journal of Emergency Medicine, Vol. -, No. -, pp. 110, 2013 Copyright 2013 Published by Elsevier Inc.

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http://dx.doi.org/10.1016/j.jemermed.2012.11.025

Trauma Reports

MASSIVE TRANSFUSION IN TRAUMATIC SHOCK

Jonathan Elmer, MD,* Susan R. Wilcox, MD, and Ali S. Raja, MD, MBA, MPH*
*Department of Emergency Medicine, Brigham and Womens Hospital, Boston, Massachusetts, Department of Emergency Medicine, and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts Reprint Address: Ali S. Raja, MD, MBA, MPH, Department of Emergency Medicine, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115

, AbstractBackground: Hemorrhage after trauma is a common cause of death in the United States and globally. The primary goals when managing traumatic shock are the restoration of oxygen delivery to end organs, maintenance of circulatory volume, and prevention of ongoing bleeding through source control and correction of coagulopathy. Achieving these goals may require massive transfusion of blood products. Although use of blood products may be lifesaving, dose-related adverse effects are well described. Discussion: Complications of massive transfusion include interdependent derangements such as coagulopathy, hypothermia, acidosis, and electrolyte abnormalities, as well as infectious and immunomodulatory phenomena. This article explores the pathogenesis, implications, prevention, and treatment of these complications through the use of massive transfusion protocols. Particular attention is given to the optimal ratio of blood products transfused in large volume resuscitation and prevention of secondary coagulopathy. Conclusions: Observational data indicate that the development and use of a massive transfusion protocol may reduce the morbidity and mortality associated with large-volume resuscitation of patients with hemorrhagic shock. Such protocols should include a pre-dened ratio of packed red blood cells, fresh frozen plasma, and platelets transfused; most commonly, the ratio used is 1:1:1. Additionally, such protocols should monitor for and correct hypothermia, hypobrinogenemia, and electrolyte disturbances such as hypocalcemia and hyperkalemia. 2013 Elsevier Inc. , Keywordshemorrhage; coagulopathy; massive transfusion; resuscitation; trauma

CASE PRESENTATION An 84-year-old woman was transferred to our facility from another Emergency Department (ED) for further management of traumatic retroperitoneal hemorrhage. Per the patient, she had tripped while walking to the bathroom and had fallen down six steps. Upon Emergency Medical Services arrival, her initial blood pressure (BP) was 77/51 mm Hg, and she received 1 L of normal saline during transport. Her past medical history included hypertension, hyperlipidemia, and paroxysmal atrial brillation, for which she took diltiazem, carvedilol, rosuvastatin, and warfarin. She was hemodynamically stable at the initial hospital, and underwent tomography scan of the head, neck chest, abdomen, and pelvis. Her only identied injury was a large retroperitoneal hematoma that tracked anteriorly into the abdominal mesentery (Figure 1). Her initial laboratory assessments were notable for a hematocrit of 29.1%, an international normalized ratio (INR) of 2.4, and a serum calcium of 9.8 mg/dL. Before arrival at our facility, she received 2 units of packed red blood cells (PRBCs), 4 units of fresh frozen plasma (FFP), 10 units of intravenous vitamin K, and 3 L of normal saline. On arrival to our ED, the patient complained only of right ank pain. Initial evaluation revealed an alert, elderly woman who was awake and mentating well. Her temperature was 35.78 C (96.4 F), her heart rate was 77 beats/min, and her blood pressure was 144/77 mm Hg.

RECEIVED: 12 March 2012; FINAL SUBMISSION RECEIVED: 3 July 2012; ACCEPTED: 5 November 2012
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BACKGROUND Approximately 5 to 6 million people die globally from trauma each year, and trauma is the leading cause of death of Americans under 35 years of age (13). In industrialized nations, hemorrhage accounts for 30 40% of these fatalities (46). The primary goals when managing traumatic hemorrhage are the restoration of oxygen delivery to end organs, maintenance of circulatory volume, and prevention of ongoing bleeding through control of the source of hemorrhage and correction of coagulopathy (7). Prehospital providers and emergency physicians frequently begin resuscitation with 0.9% (normal) saline due to its ready availability. However, the disadvantages of crystalloids such as saline and lactated Ringers solution for the management of hemorrhagic shock are well known (8). Although it supports circulatory volume, crystalloid infusion leads to dilutional anemia and coagulopathy. Furthermore, its use activates inammatory cascades, leads to cellular swelling, acidosis, metabolic dysfunction, and apoptosis, leading to interstitial edema and organ dysfunction (9). These effects may ultimately be associated with increased mortality (10). These ndings mostly derive from studies of patients receiving large-volume infusions of crystalloid (typically $ 1.5L), and it is not known if there is a doseresponse relationship or a threshold below which crystalloid infusion is safer (8,9). However, current recommendations from the American College of Surgeons, other national trauma organizations, and expert opinion, are to avoid large-volume resuscitation with crystalloids, and instead favor early transfusion of blood products (8,11,12). Although use of blood products may be lifesaving, dose-related adverse effects are well described (13,14). Massive transfusion is traditionally dened as the transfusion of at least 10 units of PRBCs within 24 h and occurs in 13% of civilian traumas (15,16). In patients receiving massive transfusion, mortality rates are as high as 5070%, due in part to the overall injury severity in this patient population (17,18). However, massive transfusion is itself a non-physiologic state and leads to many complications (19). These include interdependent derangements such as coagulopathy, hypothermia, acidosis, and electrolyte abnormalities, as well as infectious and immunomodulatory phenomena, which may lead to multi-system organ dysfunction. With the exception of blood-borne infections, all of these complications are seen in the acute setting by emergency providers, and each can be life-threatening in its own right. To be effective, preventive measures must be implemented early in a patients course, when providers anticipate that the patient may require massive

Figure 1. Computed tomography scan of the abdomen and pelvis demonstrating a large retroperitoneal hematoma tracking into the mesentery (arrows), shown in the transverse (A) and coronal (B) planes.

Physical examination was signicant for an 8 cm 10 cm ecchymosis on the right ank, mild right-sided abdominal tenderness without peritoneal ndings, and cool extremities. Initial laboratory testing demonstrated a hemoglobin of 8.3 mg/dL, an INR of 1.7, a serum calcium of 8.6 mg/dL, and a base decit of 6.3 mmol/L. The trauma surgical service was consulted after initial evaluation and admitted her to their service. In light of her hemodynamic stability, their initial plans were for volume resuscitation, supportive care, and observation in the surgical intensive care unit. Her anticoagulation was further reversed with 2 additional units of FFP, and she received 2 additional units of PRBCs. A radial arterial line was placed for close BP monitoring, and a subclavian venous introducer sheath was placed.

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transfusion, rather than after a patient has been massively transfused. By mitigating the impact of these complications, prehospital providers and emergency physicians at both small hospitals and referral centers play an integral role in modifying the overall trajectory of a patients hospital course. DISCUSSION Coagulopathy after massive transfusion is multifactorial. Growing data support the existence of a primary acute coagulopathy after trauma. This phenomenon develops quickly after the initial injury, is detectable by measurement of routine coagulation studies such as prothrombin or partial thromboplastin time, and is identied in 2530% of trauma patients on presentation to the ED (2023). The mechanism of this acute coagulopathy is not fully understood. Tissue hypoperfusion increases endothelial thrombomodulin expression, which leads to activation of the anticoagulant Protein C (24). Furthermore, trauma causes local tissue factor generation leading to disseminated intravascular coagulopathy and hyperbrinolysis (25). This intrinsic coagulopathy is worsened by a secondary coagulopathy caused by massive transfusion. Consumption of clotting factors and platelets and dilution with infused crystalloids and PRBCs are major contributors to this secondary coagulopathy (20). Hypothermia is common among trauma patients, and infusion of cold uids (including blood products) is the primary driver of heat loss after trauma (26). Each 1 C drop in temperature is associated with a 10% drop in clotting factor activity, and temperatures below 33 C are associated with a >50% reduction in normal factor activity (27,28). Signicant platelet dysfunction is also observed below 34 C (27). Acidosis resulting from systemic hypoperfusion and lactatemia further compounds the coagulopathy caused by hypothermia (26). Transfused blood products themselves worsen this acidosis, as the pH of PRBCs decreases from 7.4 to 6.9 almost immediately after banking and falls as low as 6.7 after 3 weeks, whereas lactate concentrations increase 15-fold (29). Clotting factor activity is 5090% lower at a pH of 7.0, compared to a pH of 7.4 (30). Together, this acidosis and hypothermia lead to the so-called bloody vicious cycle of worsening hemorrhage and transfusion requirements (31). It is important for clinical providers to recognize that routine laboratory tests such as the prothrombin time or activated partial thromboplastin time do not correctly quantify coagulopathy in trauma patients because they are conducted under standard laboratory conditions (20,32,33). Thromboelastography (TEG) more accurately measures

intrinsic coagulopathy, and is available as a point-of-care test in some settings (3436). TEG evaluates the viscoelastic properties of whole blood, and may be used to quantify brinogen levels, platelet function, brinolysis, and thrombin generation (37). The assay measures the degree to which a gyrating aliquot of whole blood oscillates a pin suspended in the blood, a reection of clot rmness (37). Application of TEG in operative and trauma settings reduces transfusion requirements and blood loss (3842). Unfortunately, such testing is not yet widely available in the ED setting. Prevention of Coagulopathy Prevention of coagulopathy during massive transfusion can minimize ongoing blood loss from injuries or during operative interventions. Clinicians must be vigilant to maintain normothermia, prevent the worsening acidosis that results from systemic hypoperfusion, and avoid excessive infusion of crystalloids. As hypothermia is associated with increased morbidity and mortality in trauma patients, if a large volume of uids is infused, these uids must be warmed; direct warming of the patient may also be benecial (4345). Although simple, these interventions may be lifesaving, and should be implemented before the development of coagulopathy in any patient in whom providers anticipate the need for ongoing transfusions. Additionally, care must be taken to prevent the dilutional coagulopathy that follows the transfusion of crystalloid or PRBCs in the absence of plasma and platelets. Historically, the use of FFP in massive transfusion was avoided, in part due to early recognition of the inammatory sequelae of its use (see Discussion below) (15). However, growing evidence favors transfusion of a high ratio of FFP to PRBCs to correct the acute coagulopathy of trauma and prevent dilutional coagulopathy and worsening hemorrhage. The optimal ratio of FFP to PRBCs to maximize survival is not known. Although randomized trials are lacking, a growing body of observational data lend support to transfusion of FFP and PRBCs in a ratio between 1:1 and 1:2 units (4653). Studies supporting these ratios are primarily retrospective, and either compare patient outcomes before and after implementation of a massive transfusion protocol (MTP) or compare the subgroups of patients who received high and low ratios of FFP:PRBCs (4651,53). One prospective observational study has also been conducted, with similar results (52). The optimal ratio of units of platelets to PRBCs transfused is less well dened, but is likely also close to 1:1, a recommendation based on similar observational studies (50,54,55). Finally, a high ratio of transfused brinogen to PRBCs has been associated with improved outcomes

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(21,56). Although each unit of FFP contains approximately 0.5 g of brin, trauma and massive transfusion may still lead to consumptive and dilutional hypobrinogenemia, even when aggressive ratios of FFP to PRBCs are transfused (57,58). Coagulopathy worsens when serum brinogen levels fall below 100 mg/dL (59,60). Therefore, in ongoing massive transfusion, brinogen levels must be monitored, and some centers utilize pooled cryoprecipitate to correct hypobrinogenemia (20,21). It is important to note that a transfusion ratio of 1:1:1 does not result in a solution that is physiologically similar to whole blood. Instead, it yields an approximate hematocrit of 29%, a platelet count of 85 K/uL, and approximately 60% of normal clotting activity (19). Therefore, although this predened ratio is a useful initial guide, ongoing resuscitation requires serial monitoring of blood cell counts and coagulation indices and correction of abnormalities to prevent worsening physiologic derangements caused by dilutional coagulopathy. Additionally, although prompt initiation of FFP transfusion may improve outcomes for patients who require massive transfusion, there are no data to support routine early transfusion of FFP for non-coagulopathic patients who do not require massive transfusion. Two recent studies found no improvement in mortality and signicantly increased complications, including development of the acute respiratory distress syndrome (ARDS), when patients who did not require massive transfusion were given FFP (61,62). This effect was seen in patients receiving any FFP, and the risk of ARDS was 12 times higher in the subgroup of patients receiving > 6 units of FFP compared to those who did not receive FFP. The risk of complications increased with each unit of FFP transfused and when the ratio was >1:2 units of FFP to PRBC. Therefore, principles of coagulopathy prevention with early FFP transfusion should be applied only to patients who are anticipated to require over 10 units of PRBC in the rst 24 h. Further Emergency Department Course Approximately 2 h after her arrival to our hospital, our patient complained of an acute increase in her abdominal pain, and became minimally responsive. Her arterial line-measured BP was noted to have rapidly decreased to the 40s/20s mm Hg. The surgical team was notied, and plans were made to take the patient emergently to the operating room for exploratory laparotomy. While awaiting transfer to the operating room, she received 7 additional units of PRBCs, 4 additional units of FFP, and one platelet-apheresis product (approximately 6 units of single-donor platelets). She required low-dose norepinephrine infusion for additional hemo-

dynamic support, and received 2 g intravenous calcium gluconate empirically for presumed hypocalcemia. An arterial blood gas sent on arrival to the operating room demonstrated a pH of 7.20, ionized calcium of 0.58 mmol/L, hemoglobin of 8.2 g/dL, and a base decit of 12.7 mmol/L. Electrolyte Derangement The most clinically signicant electrolyte disturbances observed in massive transfusion are hypocalcemia and hyperkalemia. The current storage medium for PRBCs and FFP includes approximately 3 g of citrate, which is added as an anticoagulant and binds ionized calcium (6365). Although the liver can clear this dose of citrate in approximately 5 min under optimal conditions, hepatic clearance may be impaired by hypothermia and pre-existing liver disease, and be overwhelmed by the rapid infusion of blood products (19,66). Hypocalcemia due to citrate chelation may be further worsened by dilution. Calcium is necessary for clotting factor activity, myocardial contraction, and vasomotor tone, and ionized hypocalcemia below a level of 0.8 mmol/L to 0.9 mmol/L leads to coagulopathy and impaired cardiovascular function (26). Although no consensus guidelines exist, our practice is to check ionized calcium levels every 12 h during large-volume transfusions. Additionally, at our institution, 2 g of intravenous calcium gluconate for every 24 units of PRBCs infused is often administered empirically to prevent development of severe hypocalcemia, although this has not been evaluated in clinical trials. Fluctuations in serum potassium may also be seen during massive transfusion. As PRBCs are stored, the concentration of extracellular potassium increases 5- to 10-fold (29,67). Although mild hyperkalemia related to transfusion is generally well tolerated, patients with renal insufciency or crush injuries may be particularly vulnerable to cardiac dysrhythmias during rapid transfusion (67). Importantly, hypokalemia may also follow massive transfusion, and occurs via dilution with potassium-poor solutions such as crystalloid and FFP, intracellular shifts of potassium as transfused PRBCs become metabolically active, and alkalosis secondary to citrate metabolism to bicarbonate (19). Infection and Immunomodulation Although uncommon in the United States, the risk of transmission of blood-borne viral and parasitic infections persists and is more common in the developing world. This risk includes transmission of human immunodeciency virus, hepatitis B and C, cytomegalovirus, parvovirus B19, dengue, malaria, and lariasis (6871).

Massive Transfusion in Traumatic Shock

Figure 2. Outline of massive transfusion protocol and ongoing patient evaluation. INR = international normalized ratio; H/H = hemoglobin and hematocrit; PRBC = packed red blood cell; FFP = fresh frozen plasma.

Bacterial contamination of stored blood, particularly with ferrophilic organisms such as Yersinia, is also a concern (72). These risks are directly proportional to the volume of blood products infused. In addition to direct infectious risks, transfusion of blood products is profoundly immunomodulatory, leading to both systemic inammation and immunosuppression. Transfusion of older PRBCs is associated with increased organ failure and infection rates after trauma, cardiac surgery, and critical illness (7377). Donor leukocytes transfused along with red blood cells, soluble inammatory mediators from donor plasma, and accumulation of proinammatory lipid debris in stored PRBCs are all thought to contribute to these phenomena (78,79). Additional manifestations of this immunomodulation include minor effects such as febrile non-hemolytic transfusion reactions, which are attributed to activation of donor leukocytes and accumulation of interleukin-1 in stored PRBCs (8082). A more serious complication,

transfusion-related acute lung injury (TRALI), occurs after approximately 1 in 5000 units of PRBCs transfused, with an associated mortality of 58% (8386). TRALI develops within 6 h after transfusion, most commonly within the rst 12 h, and is typically characterized by the rapid onset of respiratory distress, hypoxemia, and fever (87). TRALI is clinically indistinguishable from the ARDS that may develop in response to other inammatory stimuli in critically ill populations, although its development may be more rapid. All of these complications are even more common after transfusion of FFP or platelet concentrates, likely due to the higher concentrations of inammatory cytokines in these products compared to those in PRBCs (52,86,88,89). Although it is difcult for clinicians to directly prevent infectious or inammatory sequelae of blood transfusion, all of these adverse effects are dose related. Therefore, blood products must be transfused judiciously, and excessive transfusion should be avoided.

J. Elmer et al.

Pharmacologic Therapy Lysine analogues such as aminocaproic acid and tranexamic acid inhibit brinolysis. These medications have been used in major surgery to reduce bleeding and the need for perioperative transfusion. A recent randomized, multi-center, placebo-controlled trial of 20,211 hemorrhaging trauma patients found that tranexamic acid reduces all-cause mortality as well as mortality from bleeding without an increased risk of vascular occlusive events (90). A subgroup analysis found that the risk of death due to all causes and the risk of death due to bleeding both signicantly decreased when tranexamic acid was administered within 3 h of injury (91). The results of this trial have been controversial, given that tranexamic acid was not associated with fewer transfusions and the mechanism of mortality reduction is unclear. However, as the patients in the trial did not have an increased rate of adverse events from vascular occlusions, the risks of early administration seem minimal. Additionally, tranexamic acid is an inexpensive, cost-effective medication (92). Given the time-sensitive nature of this intervention, anti-brinolytic treatment should be considered in the ED for any patient who may require massive transfusion. Prothrombin complex concentrates (PCCs) were initially developed for reversal of warfarin-mediated anticoagulation and contain concentrated levels of vitamin K-dependent clotting factors (93). They offer several advantages over FFP in that they are easily stored, may be rapidly administered in a lower volume, and are not blood type specic (93). PCCs have been proposed as an alternative to FFP to prevent coagulopathy associated with massive transfusion, and animal models suggest that it may be effective (9496). However, data in humans are lacking and PCCs should not yet be considered standard of care in massive transfusion. Recombinant activated factor VII (rVIIa) offers similar advantages to PCCs in the treatment of coagulopathy associated with trauma and massive transfusion. One randomized, controlled trial of rVIIa in trauma patients found no reduction in morbidity or mortality in patients receiving rVIIa, although fewer patients who received the study drug went on to require massive transfusion (97). A subsequent large phase II trial of rVIIa administration in trauma patients found an increased risk of myocardial infarction in patients receiving rVIIa (98). Thus, we do not currently recommend use of rVIIa in the treatment of traumatic hemorrhage or as part of an MTP. Massive Transfusion Protocols Protocolized care can reduce variability and improve patient outcomes in complex environments (99). Massive

transfusion is no exception, and current consensus guidelines favor the development and use of an MTP with predetermined ratios of blood products designed to prevent the complications associated with unbalanced transfusions discussed above (100). In theory, such protocols improve patient outcomes and reduce resource utilization when compared to standard care by encouraging the early and aggressive use of FFP and platelet transfusion to supplement PRBC transfusion. Additionally, such protocols emphasize close collaboration between the laboratory, blood bank, and hemorrhaging patients care team to ensure the timely delivery of blood products, incorporate serial monitoring of coagulation parameters, ionized calcium and pH, and prompt correction of physiologic derangements (21). MTPs have been shown to reduce organ failure, blood component use, cost, and mortality in multiple single-center observational studies when comparing patient outcomes before and after implementation of an MTP (46,101104). However, although the use of MTPs has face validity and is supported by these data, randomized trials are currently lacking. Consensus criteria for selecting appropriate patients in whom to initiate an MTP are also lacking. Most studies either include patients for whom the treating physicians anticipate the need for transfusion of >10 units of PRBCs, or do not explicitly state inclusion criteria (46,101104). Several studies have dened clinical predictors that identify patients at risk of requiring massive transfusion (Table 1) (105108). These generally include anemia, hypotension, tachycardia, metabolic acidosis, and high-risk injuries such as pelvic or long-bone fractures. Each clinical prediction score (Table 1) has similar receiver operating characteristics (area under the curve 0.84), although vary in their complexity (108). However, these scores have not been demonstrated to be superior to clinical judgment, and it is not known whether their application improves patient outcomes. Similarly, the optimal resuscitation end points for patients undergoing massive transfusion are unknown. There are strong animal data, and some human data, that support permissive moderate hypotension to slow ongoing blood loss and promote hemostasis in patients with ongoing hemorrhage. This is counterbalanced by the need to maintain end-organ perfusion, most importantly cerebral perfusion. Even a single episode of hypotension is associated with increased mortality in patients with traumatic brain injury (TBI) (109). Therefore, in patients without evidence of TBI, we recommend maintaining a systolic BP of 90 mm Hg and targeting a hemoglobin level of 79 mg/dL, rather than attempting to restore normotension (110).

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Table 1. Clinical Prediction Tools to Predict Patients Who Will Require Massive Transfusion after Trauma Characteristic Blood pressure Heart rate FAST examination Mechanism Demographics Laboratory tests ABC Score (109) SBP # 90 mm Hg HR $ 120 beats/min Positive FAST examination Penetrating mechanism TASH Score (107) SBP (categorical) HR > 120 beats/min Positive FAST examination Complex long bone or pelvic fracture Male gender Hemoglobin (categorical) Base excess (categorical)

McLaughlin Score (106) SBP < 110 mm Hg HR > 105 beats/min Hematocrit < 32% pH < 7.25

ABC = assessment of blood consumption; TASH = trauma-associated severe hemorrhage; SBP = systolic blood pressure; HR = heart rate; FAST = focused assessment with sonography for trauma.

Case Conclusion Exploratory laparotomy was performed on our patient with evacuation of intra-abdominal and retroperitoneal hematomas. A lacerated mesenteric vein was identied as the primary source of bleeding. The abdomen was packed and left open. Intraoperatively, the patient lost an estimated 5 L of blood and was transfused 15 units of PRBCs, 10 units of FFP, 12 units of platelets, 1 L of her own whole blood via a cell saver, and received 3 g calcium chloride. She was transferred to the surgical intensive care unit, where she was noted to have diffuse medical oozing from her incision and persistent hemodynamic instability with escalating vasopressor requirements. A family meeting was held, and per the familys wishes, the patients goals of care were transitioned to comfort measures only. She died approximately 15 h after arrival to our hospital. CONCLUSIONS Traumatic shock requiring massive transfusion is a highly morbid state. Acute trauma leads to coagulopathy, which may be worsened by consumption and dilution of clotting factors, hypothermia, and acidosis. In addition, blood products are immunomodulatory, and may induce multi-system organ dysfunction. The development and use of an MTP may reduce the morbidity and mortality associated with massive transfusion, and, if used, should be applied as soon as clinicians anticipate the need for transfusion of >10 units of PRBCs or > 40% blood volume loss. This determination may be made clinically, or based on one of several clinical prediction tools (Table 1). Such protocols should include a predened ratio of PRBCs, FFP, and platelets transfused; most commonly, the ratio used is 1:1:1. Additionally, such protocols should monitor for and correct hypothermia, hypobrinogenemia, and electrolyte disturbances such as hypocalcemia and hyperkalemia. The stepwise transfusion algorithm described in Figure 2 outlines one potential protocol that incorporates ongoing patient evaluation. In patients without TBI, we recommend

maintaining a systolic blood pressure of 90 mm Hg and targeting a hemoglobin level of 79 mg/dL, rather than attempting to restore normotension. Implementation of such a protocol requires signicant coordination and multidisciplinary collaboration between emergency medicine, trauma surgery, the blood bank, the operating room, and the intensive care units.

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