Perioperative Point of Care Coagulation Testing
Background: Conventional laboratory tests of blood coagulation yield only partial diagnostic information. ”Point of care” (POC) devices are increasingly being used at the bedside perioperatively for rapid, detailed testing of hemostatic function and for treatment monitoring in patients with coagulopathies. In this review, we discuss the benefits and limitations of POC coagulation testing—in particular, its effects on the rate of perioperative transfusion of allogeneic blood products, on the frequency of other types of hemostatic treatment, and on the clinical outcome.
Methods: This article is based on a selective review of pertinent literature retrieved by a search in PubMed.
Results: The clinical value of preoperative POC screening for coagulopathies has not yet been examined in a prospective, randomized clinical trial. On the other hand, studies in patients with coagulopathies undergoing (mainly cardiac) surgery have shown that algorithm-based hemostatic treatment based on viscoelastic POC coagulation testing reduces both perioperative blood loss and the rate of transfusion of allogeneic blood products. None of the studies published to date had adequate power to reveal any independent effect of POC coagulation testing on perioperative morbidity or mortality.
Conclusion: Despite certain limitations that must be borne in mind, POC techniques are a valuable means of testing various aspects of hemostasis rapidly and in detail. Their implementation in hemostatic treatment algorithms may reduce both the rate of transfusion of allogeneic blood products and the total cost of treatment for blood loss and coagulopathies. The putative effect of POC testing on perioperative morbidity and mortality has not yet been demonstrated.
Perioperative coagulopathies may necessitate the transfusion of allogeneic blood products and are an independent risk factor for perioperative mortality (1, 2). Coagulopathies usually have multiple causes. Besides disturbances in physiological basic conditions for hemostasis (pH, concentration of ionized calcium, temperature and hematocrit), multifactorial causes for coagulopathy include: (3)
- disturbances of primary hemostasis, e.g., pre-existing or perioperatively acquired disturbances of platelet function;
- abnormalities of blood plasma, e.g., isolated or global clotting-factor deficits;
- complex coagulopathies, e.g., disseminated intravascular coagulation or hyperfibrinolysis.
Blood clotting is conventionally tested with two global tests, the International Normalized Ratio (INR) and the activated partial thromboplastin time (aPTT), along with the platelet count and, in some cases, the fibrinogen concentration. This battery of tests is of limited use for the prediction and detection of perioperative coagulopathies and for the monitoring of their treatment (3, 4). Furthermore, analysis at a standardized temperature of 37° Celsius impedes the detection of coagulopathies induced by hypothermia.
The global tests, aPTT and INR/Quick, reflect only the initial formation of thrombin in plasma and are unaffected by any of the corpuscular elements of the blood. The platelet count is purely quantitative and cannot detect pre-existing, drug-induced, or perioperatively acquired platelet dysfunction. Nor do the conventional coagulation tests convey any information about clot stability over time: they say nothing about fibrinolysis and thus cannot detect hyperfibrinolysis.
In Germany, coagulation test results typically become available 40 to 60 minutes after blood drawing. This turnaround time is so long that the results may not reflect the current state of the coagulation system and lead to inappropriate treatment (5).
The use of bedside tests, also called point of care (POC) tests, may partly compensate for the methodological limitations and diagnostic shortfalls of conventional coagulation testing (6, 7). None of the currently available methods of POC coagulation testing can alone provide an adequate picture of the entire coagulation spectrum; thus, multiple methods must be used together for a comprehensive diagnostic evaluation. Strictly speaking, the simple tests with which the INR and the activated clotting time (ACT) have been measured for decades, involving the use of test strips and small apparatus, actually do meet the definition of POC coagulation testing. This review article, however, will focus on the more complex, viscoelastic whole-blood techniques for the combined analysis of plasma coagulation, clot stability, and fibrinolysis, and on techniques for the analysis of primary hemostasis. These are commonly called POC techniques even though they do not satisfy the classic criteria of laboratory medicine for this designation (including easy measurement of a value, easy interpretation of the measured value, and no handling of reagents by the user). We will discuss the impact of the perioperative use of these techniques on blood loss, the rate of transfusion of allogeneic blood products, the use of clotting-factor concentrates and other hemotherapeutic agents, and the clinical outcome of patients with coagulopathies.
This review article is based on a selective search of the PubMed database for publications on the perioperative use of POC techniques for coagulation testing in patients with coagulopathies. Articles published before 10 September 2011 were sought that contained the keywords “thromboelastometry/-graphy,” “aggregometry,” “point of care coagulation testing,” “blood loss,” and “blood transfusion.” Guidelines and a systematic Cochrane review have also been published on this topic.
Point of care techniques
There are many POC techniques for coagulation testing that can be used in all phases of perioperative patient care. POC techniques can be used preoperatively to screen for coagulopathies (4); in the resuscitation room, the operating room, and the intensive care unit, they are mainly used to detect coagulopathies and to monitor their treatment.
No single POC technique can provide adequate information about all aspects of the complex process of blood clotting. From the pathophysiological point of view, coagulation can be broken down into four components: primary hemostasis, thrombin generation, clot formation/stabilization, and fibrinolysis.
Bedside aggregometric testing of whole-blood samples is used perioperatively mainly to study platelet function (8, 9). In patients with a history of bleeding whose hematocrit is stable (above 30%) and whose platelet count exceeds 100/nL, such tests can be used to screen for disorders of primary hemostasis, e.g., von Willebrand syndrome. The available aggregometric POC tests differ mainly in the agonists that are used to activate platelets in the test cells, such as collagen, adenosine phosphate, epinephrine, arachidonic acid, and thrombin, and in the shearing forces that are generated in the test cells.
Viscoelastic POC techniques are based on thromboelastography, which was described decades ago by Hartert (10). They are used to measure the time until clot formation begins, the dynamics of clot formation, and the solidity and stability of clots over time. They enable parallel measurements to be performed on a single blood sample after clotting has been activated with a variety of agonists. A special advantage of viscoelastic techniques is that they can directly detect hyperfibrinolysis; no conventional coagulation test can do this reliably (7). Rotation thrombelastometry, a type of viscoelastic POC technique, was approved by the United States Food and Drug Administration (FDA) in August 2011 for use as a supplementary diagnostic test of hemostatic function.
A combination of aggregometric and viscoelastic methods yields a far broader diagnostic spectrum than the conventional laboratory testing of blood clotting.
The general advantages and disadvantages of point of care testing
Only a small volume of whole blood (1–5 mL) is needed for POC testing. POC techniques can be used in a wide variety of situations; aside from this, their main advantage is the rapid availability of results. Transporting the blood sample to a laboratory is no longer necessary, nor are the pre-analytical steps that are an obligate part of conventional laboratory testing, including the centrifugation of the specimens and the time-consuming preparation of reagents. POC tests can be carried out by persons without any special training in medical technology and are, as a rule, easy to learn. Most of the results that will have an immediate effect on therapeutic decisions are available within ten minutes of the start of pipetting, even for the more complex viscoelastic techniques (7). POC tests can be carried out in a central laboratory or in the immediate vicinity of the patient in the operating room or intensive care unit (5). Regular equipment maintenance and adherence to prescribed quality-control measures are easier to ensure in a central laboratory setting, which has the further advantage that only a small number of people need to be taught to perform the test. On the other hand, the transport of specimens to a central laboratory can take a long time, and the central laboratory may not be able perform tests outside of regular working hours. POC tests must always be performed under the surveillance of a comprehensive quality-management system.
No single currently available POC coagulation test covers the functioning of the entire hemostatic system. In the perioperative setting, coagulopathy is often multifactorial, and a thorough diagnostic evaluation generally requires the combined use of multiple tests whose findings complement one another. Even such combinations, however, may fail to detect a number of potential causes of perioperative coagulopathy, including the anticoagulant effect of low-molecular-weight heparins, factor Xa inhibitors, direct or indirect thrombin inhibitors, antithrombin, isolated clotting-factor deficiencies, and protein C/S.
The standardized temperature of 37° Celsius at which the viscoelastic and aggregometric tests are carried out hinders the detection of coagulopathies due to hypo- or hyperthermia. Nor can these tests detect coagulopathies caused by abnormalities in the physiological basic conditions for hemostasis, such as an abnormal pH, calcium ion concentration, or hematocrit.
In the absence of prospective, randomized trials, adequate data are not yet available regarding the use of POC techniques to screen for coagulopathies that are already present before surgery, or the predictability of an individual’s risk of bleeding or thrombosis. Pre-existing coagulopathies are usually due to a disorder of primary hemostasis, e.g., iatrogenic platelet dysfunction or a hereditary condition such as von Willebrand syndrome.
When a critically ill patient needs a transfusion urgently because of massive blood loss, there may not be enough time to analyze and document the results of POC testing before the transfusion is given.
The total cost of POC testing (devices, reagents, test tubes, control solutions, maintenance, etc.) exceeds that of conventional coagulation testing. Thorough, combined viscoelastic and aggregometric coagulation testing costs €25 to €35 overall, while a conventional test battery (aPTT, fibrinogen, thrombin time, Quick value, complete blood count) generally costs less than €10. These increased costs, however, may be compensated for by the lower costs of a clinically more rational transfusion regimen and the more efficient use of other hemotherapeutic agents which, it is hoped, will result from the use of POC testing (11, 12). Only a small number of prospective randomized trials of POC coagulation testing have been performed to date on study populations of sufficient size. Multiple such trials have shown that the implementation of viscoelastic techniques in hemotherapeutic algorithms lowers the utilization of blood products, but the algorithm-based use of aggregometric techniques has not yet been adequately studied.
The clinical benefits of point of care testing
Two measures of the usefulness of perioperative coagulation therapy are perioperative blood loss and the rate of transfusion of allogeneic blood products. One or both of these measures were used as primary endpoints in the few prospective, randomized, controlled clinical trials of perioperative POC coagulation testing that have been published to date. The secondary endpoints in these trials included the following:
- changes in laboratory values,
- the overall use of hemostatic therapy,
- the re-thoracotomy rate,
- the frequency of postoperative neurological, respiratory, and renal complications,
- the duration of artificial ventilation,
- the duration of intensive care, and
- postoperative mortality (Table).
POC-associated complications were not reported in any trial.
Eight prospective randomized trials of perioperative POC coagulation testing have been published to date (13–20): six involved POC testing for (mostly) elective cardiac surgery, one for hepatic surgery, and one for thoracic and vascular surgery. As coagulopathies have many causes, the findings of these trials may not apply to other kinds of patients, such as trauma patients.
In only two of these eight trials did the patients in the control group receive coagulation therapy according to a treatment algorithm based on conventional laboratory testing (14, 17). In six trials, the patients who underwent POC testing consumed less fresh-frozen plasma (FFP) than the controls; they had a lower platelet-concentrate (PC) transfusion rate in five trials, and a lower erythrocyte-concentrate transfusion rate in two. More detailed information about the intergroup differences in the rates and quantities of allogeneic blood-product transfusions are found in the Table.
The trial of Nuttal et al. (16) revealed a beneficial effect of POC coagulation testing on postoperative blood loss. This was the only trial that was restricted to patients with coagulopathies. Patients were included in the other seven trials solely on the basis of the type of surgery that they were to undergo (typically, operations with a moderate-to-high risk of bleeding), regardless of their coagulation status. Viscoelastic POC techniques were used in all eight trials; in one, aggregometric testing was performed as well. Thus, these trials cannot easily be compared with one another, in view of the heterogeneity of subjects and of the type, extent, and timing of the POC coagulation tests that were performed.
The findings of the prospective randomized trials listed in the Table do not allow any firm conclusions about the putative economic savings resulting from the use of POC coagulation testing. A number of retrospective studies have compared the costs of hemotherapy before and after the implementation of POC-based hemotherapeutic algorithms (11, 12, 21), albeit with partially conflicting results. These studies varied with respect to
- the hemotherapy algorithms,
- the choice of laboratory tests guiding therapy and the cutoff values used,
- the degree of attention paid to factors besides the physiological basic conditions for hemostasis that can affect blood coagulation, and
- the hemostatic treatment options.
In a study of 1422 patients undergoing elective cardiac surgery, Spalding et al. found that the implementation of POC coagulation testing lowered the cost of allogeneic blood products and other hemotherapeutic agents by about 50% (12). On the other hand, Görlinger et al., in a retrospective study of 3865 cardiac surgical patients, found that the implementation of POC coagulation testing was followed by a 34.3% drop in the cost of allogeneic blood products, but simultaneously by a 104.6% rise in the cost of clotting-factor concentrates. The net cost of hemotherapeutic agents was 6.5% lower (21).
None of these studies considered the so-called secondary costs that might be reduced if patients enjoyed better clinical outcomes as a result of the use of POC coagulation testing. For example, the study of Görlinger et al. revealed a significantly lower frequency of thrombotic/thromboembolic events and unplanned reoperative thoracotomies in the patients treated according to POC-based hemotherapy algorithms (21).
When the findings of the prospective randomized trials and retrospective studies discussed above are considered together, it appears that POC-based coagulation therapy indeed lowers the rate of transfusion of allogeneic blood products overall (mainly by lowering the FFP and PC transfusion rates), but simultaneously increases the use of clotting-factor concentrates (mainly fibrinogen and prothrombin-proconvertin-Stuart factor-antihemophilic factor B [PPSB]). The economic savings from the reduced use of allogeneic blood products may compensate for or outweigh the increased expenditures for clotting-factor concentrates.
The effect on clinical outcomes
In the retrospective study of Görlinger et al., the POC group had fewer postoperative thrombotic/thromboembolic complications than the control group (28 of 1582 patients in the POC group versus 46 of 1441 patients in the group receiving conventional coagulation therapy, p = 0.015) (21). The groups did not differ, however, with respect to perioperative mortality. Data on postoperative mortality are available from five of the prospective randomized trials (13–15, 18, 20)—with differences in the duration of postoperative observation, which ranged from the duration of the hospital stay (20) to three years after surgery (14). No beneficial effect of POC-based coagulation therapy on postoperative mortality was revealed by the individual studies or by a systematic review (22).
It should be pointed out, however, that the studies did not include enough patients to detect a potential benefit with respect to perioperative mortality. Moreover, the study populations were highly inhomogeneous, particularly with respect to the expected risk of perioperative bleeding. Some studies included patients about to undergo elective coronary artery bypass grafting, a procedure with a low risk of bleeding, while others included only patients with a high risk of bleeding or an already diagnosed coagulopathy. Measures of clinical outcome, such as mortality, were not a primary endpoint in any of the studies, not least because improved postoperative mortality (unlike reduced blood loss or transfusion requirement) is not a primary goal of POC coagulation testing.
The German Medical Association’s guidelines for quality assurance in quantitative medical laboratory testing (RiliBÄK-Labor) (23) establish obligatory requirements for quality control that also apply to POC techniques for coagulation testing. Internal quality checks must be performed at regular intervals, generally with quality-control instruments that are supplied by the manufacturers. Moreover, participation in round-robin testing for external quality assurance is also recommended. As whole blood is not very stable over time and therefore cannot be used for round-robin tests, lyophilized plasma is recommended for use as test material in round-robin tests of viscoelastic POC techniques. When lyophilized plasma is used, test results can be profitably compared across centers (24). POC tests of blood coagulation for which an analogous non-POC laboratory test already exists can be externally checked by a comparison of their results with those of the analogous conventional tests.
In the German Medical Association’s cross-sectional guidelines for treatment with blood components and plasma derivatives, it is stated that, aside from fibrinogen measurement, the measurement of D-dimers and/or a thromboelastogram can be a useful means of assessing fibrinogen turnover and fibrinogen formation (e1). A number of guidelines from Germany (e2, e3) and abroad (e4, e5) take a position on viscoelastic POC testing in the perioperative care of patients with coagulopathies. For the most part, recommendations are given concerning the treatment of trauma patients. As there have been only a few prospective randomized trials of POC testing for patients with coagulopathies, these recommendations are necessarily based on evidence of a relatively low level: they are all grade 0 recommendations to the effect that viscoelastic POC techniques can be used for the diagnostic evaluation of a coagulopathy and for the monitoring of treatment for coagulopathy.
Multiple prospective randomized trials have revealed that the algorithm-based use of viscoelastic POC testing of blood coagulation leads to lower perioperative blood loss and a lower rate of transfusion of allogeneic blood products. A systematic Cochrane review did not reveal any effect of the use of POC testing on perioperative morbidity and mortality. POC coagulation testing is faster and more comprehensive than the conventional laboratory tests of blood coagulation in the perioperative setting and enables effective, economical treatment. It thus seems justified to recommend the implementation of POC testing in hemotherapy algorithms that are adapted for use in particular types of patients with specific perioperative coagulation disorders.
Conflict of interest statement
Dr. Weber has received lecture honoraria and reimbursement of travel and accommodation costs from the CSL Behring company.
Prof. Zacharowski has received payment for serving as chairman for scientific symposia sponsored by CSL Behring.
Manuscript submitted on 13 September 2011, revised version accepted on 15 November 2011.
Translated from the original German by Ethan Taub, M.D.
Dr. med. Christian Friedrich Weber
Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie
Klinikum der J. W. Goethe-Universität Frankfurt am Main
60590 Frankfurt am Main, Germany
@For eReferences please refer to:
S3-Leitlinie Polytrauma/Schwerverletzten-Behandlung. 2011; www.awmf.org/uploads/tx_szleitlinien/012–019l_S3_Polytrauma_Schwerverletzten-Behandlung_2011–07_01.pdf
|1.||Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM: Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 2003; 54: 898–905. CrossRef MEDLINE|
|2.||Vivacqua A, Koch CG, Yousuf AM, et al.: Morbidity of bleeding after cardiac surgery: is it blood transfusion, reoperation for bleeding, or both? Ann Thorac Surg 2011; 91: 1780–90. CrossRef MEDLINE|
|3.||Kozek-Langenecker S: Management of massive operative blood loss. Minerva Anestesiol 2007; 73: 401–15. MEDLINE|
|4.||Koscielny J, Ziemer S, Radtke H, et al.: A practical concept for preoperative identification of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004; 10: 195–204. CrossRef MEDLINE|
|5.||Toulon P, Ozier Y, Ankri A, Fleron MH, Leroux G, Samama CM: Point-of-care versus central laboratory coagulation testing during haemorrhagic surgery. A multicenter study. Thromb Haemost 2009; 101: 394–401. MEDLINE|
|6.||Ganter MT, Hofer CK: Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008; 106: 1366–75. CrossRef MEDLINE|
|7.||Calatzis A, Heesen M, Spannagl M: Patientennahe Sofortdiagnostik von Hämostaseveränderungen in der Anästhesie und Intensivmedizin. Anaesthesist 2003; 52: 229–37. CrossRef MEDLINE|
|8.||Jambor C, von Pape KW, Spannagl M, Dietrich W, Giebl A, Weisser H: Multiple electrode whole blood aggregometry, PFA-100, and in vivo bleeding time for the point-of-care assessment of aspirin-induced platelet dysfunction in the preoperative setting. Anesth Analg 2011; 113: 31–9. CrossRef MEDLINE|
|9.||Jambor J, Spannagl M, Zwissler B: Perioperatives Management von Patienten mit Koronarstents bei nichtherzchirurgischen Eingriffen. Anaesthesist 2010; 59: 175–6. CrossRef MEDLINE|
|10.||Hartert H: Die Thrombelastographie, eine Methode zur physikalischen Analyse des Blutgerinnungsvorganges. Z Gesamte Exp Med 1951; 117: 189–203. CrossRef|
|11.||Görlinger K, Dirkmann D, Weber CF, Rahe-Meyer N, Hanke AA: Algorithms for transfusion and coagulation management in massive haemorrhage. Anästh Intensivmed 2011; 52: 145–59.|
|12.||Spalding GJ, Hartrumpf M, Sierig T, Oesberg N, Kirschke CG, Albes JM: Cost reduction of perioperative coagulation management in cardiac surgery: value of „bedside“ thrombelastography (ROTEM). Eur J Cardiothorac Surg 2007; 31: 1052–7. CrossRef MEDLINE|
|13.||Shore-Lesserson L, Manspeizer HE, DePerio M, Francis S, Vela-Cantos F, Ergin MA: Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 1999; 88: 312–9. MEDLINE|
|14.||Wang SC, Shieh JF, Chang KY, et al.: Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. Transplant Proc 2010; 42: 2590–3. CrossRef MEDLINE|
|15.||Royston D, von Kier S: Reduced haemostatic factor transfusion using heparinase-modified thrombelastography during cardiopulmonary bypass. Br J Anaesth 2001; 86: 575–8. CrossRef MEDLINE|
|16.||Nuttall GA, Oliver WC, Santrach PJ, et al.: Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass. Anesthesiology 2001; 94: 773–81. CrossRef MEDLINE|
|17.||Avidan MS, Alcock EL, Da Fonseca J, et al.: Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery. Br J Anaesth 2004; 92: 178–86. CrossRef MEDLINE|
|18.||Ak K, Isbir CS, Tetik S, et al.: Thromboelastography-based transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study. J Card Surg 2009; 24: 404–10. CrossRef MEDLINE|
|19.||Westbrook AJ, Olsen J, Bailey M, Bates J, Scully M, Salamonsen RF: Protocol based on thromboelastograph (TEG) out-performs physician preference using laboratory coagulation tests to guide blood replacement during and after cardiac surgery: a pilot study. Heart Lung Circ 2009; 18: 277–88. CrossRef MEDLINE|
|20.||Girdauskas E, Kempfert J, Kuntze T, et al.: Thromboelastometrically guided transfusion protocol during aortic surgery with circulatory arrest: a prospective, randomized trial. J Thorac Cardiovasc Surg 2010; 140: 1117–24. CrossRef MEDLINE|
|21.||Görlinger K, Dirkmann D, Hanke A, et al.: First line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased blood transfusion in cardiovascular surgery: A retrospective, single-center cohort study. Anesthesiology 2011; 115: 1179–91. MEDLINE|
|22.||Afshari A, Wikkelso A, Brok J, Moller AM, Wetterslev J: Thrombelastography (TEG) or thromboelastometry (ROTEM) to monitor haemotherapy versus usual care in patients with massive transfusion. Cochrane Database Syst Rev 2011; (3): CD007871. MEDLINE|
|23.||Bundesaerztekammer: Richtlinie der Bundesärztekammer zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen. Dtsch Arztebl 2007; 105(7): A 341–55. VOLLTEXT|
|24.||Dick A, Schwaiger M, Jambor C: Evaluation von Ringversuchsproben zur externen Qualitätssicherung viskoelastischer Messungen – Eine Pilotstudie. Hamostaseologie 2010; 30: 91–5. MEDLINE|
|e1.||Bundesärztekammer: Querschnitts-Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten. 2008, Köln: Deutscher Ärzte-Verlag. 4. Auflage, Kapitel 220.127.116.11.|
|e2.||Fries D, Innerhofer P, Perger P, Gutl M, Heil S, Hofmann N, et al.: Gerinnungsmanagement bei traumatisch bedingter Massivblutung – Empfehlungen der Arbeitsgruppe für perioperative Gerinnung der OGARI. Anasthesiol Intensivmed Notfallmed Schmerzther 2010; 45: 552–61.|
|e3.||Deutsche Gesellschaft für Unfallchirurgie (federführend): |
S3-Leitlinie Polytrauma/Schwerverletzten-Behandlung. 2011; www.awmf.org/uploads/tx_szleitlinien/012–019l_S3_Polytrauma_Schwerverletzten-Behandlung_2011–07_01.pdf
|e4.||Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al.: Management of bleeding following major trauma: an updated European guideline. Crit Care 2010; 14: R52. MEDLINE|
|e5.||Lier H, Bottiger BW, Hinkelbein J, Krep H, Bernhard M: Coagulation management in multiple trauma: a systematic review. Intensive Care Med 2011; 37: 572–82. CrossRef MEDLINE|