Rossaint et al. Critical Care 2010, 14:R52 Page 2 of 29http://ccforum.com/content/14/2/R52state, it may be appropriate to reassess some data from or ethical reasons. The formulation and grading of thethe past, and with time new research will doubtless lead recommendations presented here are therefore weightedto a better understanding of the risks and benefits of to reflect both this reality and the current state-of-different therapeutic approaches applied to this group of the-art.patients. In 2007, we published a European guideline for the Materials and methodsmanagement of bleeding following major trauma that These recommendations were formulated and gradedincluded recommendations for specific interventions to according the Grading of Recommendations Assess-identify and control bleeding sources using surgical, ment, Development and Evaluation (GRADE) hierarchyphysiological and pharmacological strategies . The of evidence [14-16] summarised in Table 1. Comprehen-guideline was developed by a multidisciplinary group of sive computer database literature searches were per-European experts, including designated representatives formed using the indexed online databases MEDLINE/from relevant professional societies, to guide the clini- PubMed and the Cochrane Library. Lists of cited litera-cian in the early phases of treatment. Here we present ture within relevant articles were also screened. The pri-an updated version of the guideline that incorporates a mary intention of the review was to identify prospectiverenewed critical survey of the evidence published during randomised controlled trials (RCTs) and non-RCTs,the intervening three years and a consideration of existing systematic reviews and guidelines. In thechanges in clinical practice that have taken place based absence of such evidence, case-control studies, observa-on technologies that have become more widely available tional studies and case reports were considered.and pharmacological agents that have entered or left the Boolean operators and Medical Subject Headingmarket. Although the level of scientific evidence has (MeSH) thesaurus keywords were applied as a standar-improved in some areas, other areas remain devoid of dised use of language to unify differences in terminologyhigh-level evidence, which may never exist for practical into single concepts. Appropriate MeSH headings andTable 1 Grading of recommendations from Guyatt and colleagues Grade of Clarity of risk/benefit Quality of supporting evidence Implicationsrecommendation1AStrong Benefits clearly outweigh risk and RCTs without important limitations or Strong recommendation, canrecommendation, burdens, or vice versa overwhelming evidence from observational apply to most patients in mosthigh-quality evidence studies circumstances without reservation1BStrong Benefits clearly outweigh risk and RCTs with important limitations (inconsistent Strong recommendation, canrecommendation, burdens, or vice versa results, methodological flaws, indirect or apply to most patients in mostmoderate-quality imprecise) or exceptionally strong evidence from circumstances without reservationevidence observational studies1CStrong Benefits clearly outweigh risk and Observational studies or case series Strong recommendation but mayrecommendation, burdens, or vice versa change when higher qualitylow-quality or very evidence becomes availablelow-quality evidence2AWeak Benefits closely balanced with risks RCTs without important limitations or Weak recommendation, bestrecommendation, and burden overwhelming evidence from observational action may differ depending onhigh-quality evidence studies circumstances or patient or societal values2BWeak Benefits closely balanced with risks RCTs with important limitations (inconsistent Weak recommendation, bestrecommendation, and burden results, methodological flaws, indirect or action may differ depending onmoderate-quality imprecise) or exceptionally strong evidence from circumstances or patient orevidence observational studies societal values2CWeak Uncertainty in the estimates of Observational studies or case series Very weak recommendation; otherrecommendation, benefits, risks, and burden; benefits, alternatives may be equallyLow-quality or very risk and burden may be closely reasonablelow-quality evidence balancedReprinted with permission from the American College of Chest Physicians.RCTs, randomised controlled trials.
Rossaint et al. Critical Care 2010, 14:R52 Page 3 of 29http://ccforum.com/content/14/2/R52subheadings for each question were selected and modi- updated document was approved by the endorsing orga-fied based on search results. The scientific questions nisations between October 2009 and January 2010. Anposed that led to each recommendation and the MeSH updated version of the guideline is anticipated in dueheadings applied to each search are listed in Additional time.file 1. Searches were limited to English language In the GRADE system for assessing each recommenda-abstracts and human studies, and gender and age were tion, the letter attached to the grade of recommendationnot limited. The time period was limited to the past reflects the degree of literature support for the recom-three years for questions addressed in the 2007 version mendation, whereas the number indicates the level ofof the guideline, but no time-period limits were imposed support for the recommendation assigned by the com-on new searches. Original publications were evaluated mittee of experts. Recommendations are grouped byfor abstracts that were deemed relevant. Original publi- category and somewhat chronologically in the treatmentcations were graded according to the levels of evidence decision-making process, but not by priority or hierarchy.developed by the Oxford Centre for Evidence-BasedMedicine (Oxford, Oxfordshire, UK) . Results The selection of the scientific enquiries to be I. Initial resuscitation and prevention of further bleedingaddressed in the guideline, screening and grading of the Minimal elapsed timeliterature to be included and formulation of specific Recommendation 1 We recommend that the timerecommendations were performed by members of the elapsed between injury and operation be minimised forTask Force for Advanced Bleeding Care in Trauma, a patients in need of urgent surgical bleeding controlmultidisciplinary, pan-European group of experts with (Grade 1A).specialties in surgery, anaesthesia, emergency medicine, Rationale Trauma patients in need of emergency sur-intensive care medicine and haematology. The core gery for ongoing haemorrhage have increased survival ifgroup was formed in 2004 to produce educational mate- the elapsed time between the traumatic injury andrial on the care of the bleeding trauma patient , on admission to the operating theatre is minimised. Morewhich an update (in 2006) and subsequent review article than 50% of all trauma patients with a fatal outcome diewere based . The task force consisted of the core within 24 hours of injury . Despite a lack of evidencegroup, additional experts in haematology and guideline from prospective RCTs, well-designed retrospective stu-development, and representatives of relevant European dies provide evidence for early surgical intervention inprofessional societies, including the European Society of patients with traumatic haemorrhagic shock [21-23].Anaesthesiology, the European Society of Intensive Care In addition, studies that analyse trauma systems indir-Medicine, the European Shock Society, the European ectly emphasise the importance of minimising the timeSociety of Trauma and Emergency Surgery and the Eur- between admission and surgical bleeding control inopean Society for Emergency Medicine. The European patients with traumatic haemorrhagic shock [24,25]. AtHematology Association declined the invitation to desig- present, the evidence base for the impact of the imple-nate a representative to join the task force. mentation of the Advanced Trauma Life Support As part of the guideline development process that led (ATLS) protocol on patient outcome is very poor,to the 2007 guideline, task force members participated because the available literature focuses primarily on thein a workshop on the critical appraisal of medical litera- effectiveness of ATLS as an educational tool . Futureture. The nominal group process for the updated guide- studies are needed to define the impact of the ATLSline included several remote (telephone and web-based) program within trauma systems at the hospital andmeetings and one face-to-face meeting supplemented by health system level in terms of controlled before-and-several Delphi rounds . The guideline development after implementation designed to assess post-injurygroup participated in a web conference in March 2009 mortality as the primary outcome parameter.to define the scientific questions to be addressed in the Tourniquet useguideline. Selection, screening and grading of the litera- Recommendation 2 We recommend adjunct tourniquetture and formulation of recommendations were accom- use to stop life-threatening bleeding from open extre-plished in subcommittee groups consisting of at least mity injuries in the pre-surgical setting (Grade 1C).three members via electronic or telephone communica- Rationale Much discussion has been generated recentlytion. After distribution of the recommendations to the regarding the use of tourniquets for acute external hae-entire group, a face-to-face meeting of the task force morrhage control. Pressure bandages rather than tourni-was held in June 2009 with the aim of reaching a con- quets should be applied in the case of minor bleedingsensus on the draft recommendations from each sub- from open wounds in extremity injuries. When uncon-committee. After final refinement of the rationale for trolled arterial bleeding occurs from mangled extremityeach recommendation and the complete manuscript, the injuries, including penetrating or blast injuries or
Rossaint et al. Critical Care 2010, 14:R52 Page 4 of 29http://ccforum.com/content/14/2/R52traumatic amputations, a tourniquet represents a simple systems, and the patient’s physiological presentation andand efficient method to acutely control haemorrhage response to resuscitation should further guide the deci-[27-31]. Several publications from military settings sion to initiate early surgical bleeding control as out-report the effectiveness of tourniquets in this specific lined in the ATLS protocol [34-37]. Table 2 summarisessetting [27-30]. A study of volunteers showed that any estimated blood loss based on intitial presentation.tourniquet device presently on the market works effi- Table 3 characterises the three types of response tociently . The study also showed that ‘pressure point initial fluid resuscitation, whereby the transient respon-control’ was ineffective because collateral circulation ders and the non-responders are candidates for immedi-was observed within seconds. Tourniquet-induced pain ate surgical bleeding control.was not an important consideration. Ventilation Tourniquets should be left in place until surgical con- Recommendation 4 We recommend initial normoventi-trol of bleeding is achieved [28,30]; however, this time- lation of trauma patients if there are no signs of immi-span should be kept as short as possible. Improper or nent cerebral herniation (Grade 1C).prolonged placement of a tourniquet can lead to com- Rationale Ventilation can affect the outcome of severeplications such as nerve paralysis and limb ischaemia trauma patients. There is a tendency for rescue person-. Some publications suggest a maximum time of nel to hyperventilate patients during resuscitationapplication of two hours . Reports from military set- [38,39], and hyperventilated trauma patients appear totings report cases in which tourniquets have remained have increased mortality when compared with non-in place for up to six hours with survival of the extre- hyperventilated patients .mity . A high percentage of severely injured patients with ongoing bleeding have traumatic brain injury (TBI).II. Diagnosis and monitoring of bleeding Relevant experimental and clinical data have shown thatInitial assessment routine hyperventilation is an important contributor toRecommendation 3 We recommend that the physician adverse outcomes in patients with head injuries; how-clinically assess the extent of traumatic haemorrhage ever, the effect of hyperventilation on outcome inusing a combination of mechanism of injury, patient patients with severe trauma but no TBI is still a matterphysiology, anatomical injury pattern and the patient’s of debate. A low partial pressure of arterial carbon diox-response to initial resuscitation (Grade 1C). ide on admission to the emergency room is associatedRationale The mechanism of injury represents an with a worse outcome in trauma patients with TBIimportant screening tool to identify patients at risk for [40-43].significant traumatic haemorrhage. For example, the There are several potential mechanisms for theAmerican College of Surgeons defined a threshold of adverse effects of hyperventilation and hypocapnia,6 m (20 ft) as a ‘critical falling height’ associated with including increased vasoconstriction with decreased cer-major injuries . Further critical mechanisms include ebral blood flow and impaired tissue perfusion. In theblunt versus penetrating trauma, high-energy decelera- setting of absolute or relative hypovolaemia, an excessivetion impact, low-velocity versus high-velocity gunshot ventilation rate of positive-pressure ventilation mayinjuries, etc. The mechanism of injury in conjunction further compromise venous return and produce hypo-with injury severity, as defined by trauma scoring tension and even cardiovascular collapse [41,42]. It hasTable 2 American College of Surgeons Advanced Trauma Life Support (ATLS) classification of blood loss based oninitial patient presentation Class I Class II Class III Class IVBlood loss* (ml) Up to750 750-1500 1500-2000 >2000Blood loss (% blood volume) Up to 15% 15%-30% 30%-40% >40%Pulse rate <100 100-120 120-140 >140Blood pressure Normal Normal Decreased DecreasedPulse pressure (mmHg) Normal or increased Decreased Decreased DecreasedRespiratory rate 14-20 20-30 30-40 >35Urine output (ml/h) >30 20-30 5-15 NegligibleCentral nervous system/mental status Slightly anxious Mildly anxious Anxious, confused Confused, lethargicFluid replacement Crystalloid Crystalloid Crystalloid and blood Crystalloid and bloodTable reprinted with permission from the American College of Surgeons .*for a 70 kg male.
Rossaint et al. Critical Care 2010, 14:R52 Page 5 of 29http://ccforum.com/content/14/2/R52Table 3 American College of Surgeons Advanced Trauma Life Support (ATLS) responses to initial fluid resuscitation* Rapid response Transient response Minimal or no responseVital signs Return to normal Transient improvement, recurrence Remain abnormal of decreased blood pressure and increased heart rateEstimated blood loss Minimal (10%-20%) Moderate and ongoing (20%-40%) Severe (>40%)Need for more crystalloid Low High HighNeed for blood Low Moderate to high ImmediateBlood preparation Type and crossmatch Type-specific Emergency blood releaseNeed for operative intervention Possibly Likely Highly likelyEarly presence of surgeon Yes Yes Yes* 2000 ml of isotonic solution in adults; 20 ml/kg bolus of Ringer’s lactate in children.Table reprinted with permission from the American College of Surgeons .also been shown that cerebral tissue lactic acidosis combined with signs of severe hypovolaemic shock spe-occurs almost immediately after induction of hypocapnia cifically require early surgical bleeding control. Thisin children and adults with TBI and haemorrhagic shock observation is also true but to a lesser extent for. In addition, even a modest level of hypocapnia abdominal stab wounds . Data on injuries caused by(<27 mmHg) may result in neuronal depolarisation with penetrating metal fragments from explosives or gunshotglutamate release and extension of the primary injury wounds in the Vietnam War confirm the need for earlyvia apoptosis . surgical control when patients present in shock . In Ventilation with low tidal volume is recommended in blunt trauma, the mechanism of injury can determine topatients with acute lung injury. In patients with normal a certain extent whether the patient in haemorrhagiclung function, the evidence is scarce, but some obser- shock will be a candidate for surgical bleeding control.vational studies show that the use of a high tidal Only a few studies address the relation between thevolume is an important risk factor for the development mechanism of injury and the risk of bleeding, and noneof lung injury [46,47]. The injurious effect of high tidal of these publications is a randomised prospective trial ofvolume may be initiated very early. Randomised studies high evidence . We have found no objective datademonstrate that short-time ventilation (<five hours) describing the relation between the risk of bleeding andwith high tidal volume (12 ml/kg) without positive the mechanism of injury of skeletal fractures in generalend-expiratory pressure (PEEP) may promote pulmon- or of long-bone fractures in particular.ary inflammation and alveolar coagulation in patients Traffic accidents are the leading cause of pelvic injury.with normal lung function . Although more studies Motor vehicle crashes cause approximately 60% of pelvicare needed, the early use of protective ventilation with fractures followed by falls from great heights (23%).low tidal volume and moderate PEEP is recommended, Most of the remainder result from motorbike collisionsparticularly in bleeding trauma patients at risk of acute and vehicle-pedestrian accidents [53,54]. There is a cor-lung injury. relation between ‘unstable’ pelvic fractures and intra-Immediate intervention abdominal injuries [53,55]. An association betweenRecommendation 5 We recommend that patients pre- major pelvic fractures and severe head injuries, conco-senting with haemorrhagic shock and an identified mitant thoracic, abdominal, urological and skeletal inju-source of bleeding undergo an immediate bleeding con- ries is also well described . High-energy injuriestrol procedure unless initial resuscitation measures are produce greater damage to both the pelvis and organs.successful (Grade 1B). Patients with high-energy injuries require more transfu-Rationale The source of bleeding may be immediately sion units, and more than 75% have associated head,obvious, and penetrating injuries are more likely to thorax, abdominal or genitourinary injuries . It isrequire surgical bleeding control. In a retrospective well documented that ‘unstable’ pelvic fractures arestudy of 106 abdominal vascular injuries, all 41 patients associated with massive haemorrhage [55,57], and hae-arriving in shock following gunshot wounds were candi- morrhage is the leading cause of death in patients withdates for rapid transfer to the operating theatre for sur- major pelvic fractures.gical bleeding control . A similar observation in a Further investigationstudy of 271 patients undergoing immediate laparotomy Recommendation 6 We recommend that patients pre-for gunshot wounds indicates that these wounds senting with haemorrhagic shock and an unidentified
Rossaint et al. Critical Care 2010, 14:R52 Page 6 of 29http://ccforum.com/content/14/2/R52source of bleeding undergo immediate further investiga- Huber-Wagner and colleagues  also showed the ben-tion (Grade 1B). efit of integration of the whole-body CT into earlyRationale A patient in haemorrhagic shock with an uni- trauma care. CT diagnosis significantly increases thedentified source of bleeding should undergo immediate probability of survival in patients with polytrauma.further assessment of the chest, abdominal cavity and Whole-body CT as a standard diagnostic tool during thepelvic ring, which represent the major sources of acute earliest resuscitation phase for polytraumatised patientsblood loss in trauma. Aside from a clinical examination, provides the added benefit of identifying head and chestX-rays of chest and pelvis in conjunction with focused injuries and other bleeding sources in patients with mul-abdominal sonography for trauma (FAST)  or diag- tiple injuries.nostic peritoneal lavage (DPL)  are recommended Some authors have shown the benefit of contrastdiagnostic modalities during the primary survey medium enhanced CT scanning. Anderson and collea-[37,60,61]. In selected centres, readily available com- gues [82,83] found high accuracy in the evaluation ofputed tomography (CT) scanners  may replace con- splenic injuries resulting from trauma after administra-ventional radiographic imaging techniques during the tion of intravenous contrast material. Delayed phase CTprimary survey. may be used to detect active bleeding in solid organs.Imaging Fang and colleagues  demonstrated that the poolingRecommendation 7 We recommend early imaging of contrast material within the peritoneal cavity in blunt(FAST or CT) for the detection of free fluid in patients liver injuries indicates active and massive bleeding.with suspected torso trauma (Grade 1B). Patients with this finding showed rapid deterioration ofRecommendation 8 We recommend that patients with haemodynamic status and most of them required emer-significant free intra-abdominal fluid and haemodynamic gent surgery. Intraparenchymal pooling of contrastinstability undergo urgent intervention (Grade 1A). material with an unruptured liver capsule often indicatesRecommendation 9 We recommend further assessment a self-limited haemorrhage, and these patients respondusing CT for haemodynamically stable patients who are well to non-operative treatment.either suspected of having torso bleeding or have a Compared with MSCT, all traditional techniques ofhigh-risk mechanism of injury (Grade 1B). diagnostic and imaging evaluation are associated withRationale Blunt abdominal trauma represents a major some limitations. The diagnostic accuracy, safety anddiagnostic challenge and an important source of internal effectiveness of immediate MSCT are dependent onbleeding. FAST has been established as a rapid and sophisticated pre-hospital treatment by trained andnon-invasive diagnostic approach for the detection of experienced emergency personnel and short transporta-intra-abdominal free fluid in the emergency room tion times [85,86]. If an MSCT is not available in the[63-65]. Large prospective observational studies deter- emergency room, the realisation of CT scanning impliesmined a high specificity and accuracy but low sensitivity transportation of the patient to the CT room, and there-of initial FAST examination for detecting intra-abdom- fore the clinician must evaluate the implications andinal injuries in adults and children [66-72]. Liu and col- potential risks and benefits of the procedure. Duringleagues  found a high sensitivity, specificity and transport, all vital signs should be closely monitored andaccuracy of initial FAST examination for the detection resuscitation measures continued. For those patients inof haemoperitoneum. Although CT scans and DPL were whom haemodynamic stability is questionable, imagingshown to be more sensitive than sonography for the techniques such as ultrasound and chest and pelvicdetection of haemoperitoneum, these diagnostic modal- radiography may be useful. Peritoneal lavage is rarelyities are more time-consuming (CT and DPL) and inva- indicated if ultrasound or CT is available . Transfersive (DPL) . times to and from all forms of diagnostic imaging need The role of CT scanning of acute trauma patients is to be considered carefully in any patient who is haemo-well documented [74-81], and in recent years imaging dynamically unstable. In addition to the initial clinicalfor trauma patients has migrated towards multi-slice CT assessment, near patient testing results, including full(MSCT). The integration of modern MSCT scanners in blood count, haematocrit (Hct), blood gases and lactate,the emergency room area allows the immediate assess- should be readily available under ideal circumstances.ment of trauma victims following admission [76,77]. Hypotensive patients (systolic blood pressure belowUsing modern MSCT scanners, total whole-body scan- 90 mmHg) presenting with free intra-abdominal fluidning time may be reduced to less than 30 seconds. In a according to FAST or CT are potential candidates forretrospective study comparing 370 patients in two early surgery if they cannot be stabilised by initiatedgroups, Weninger and colleagues  showed that faster fluid resuscitation [88-90]. A retrospective study bydiagnosis using MSCT led to shorter emergency room Rozycki and colleagues  of 1540 patients (1227and operating room time and shorter ICU stays . blunt, 313 penetrating trauma) assessed with FAST as
Rossaint et al. Critical Care 2010, 14:R52 Page 7 of 29http://ccforum.com/content/14/2/R52an early diagnostic tool showed that the ultrasound This study showed that changes in lactate concentra-examination had a sensitivity and specificity close to tions provide an early and objective evaluation of a100% when the patients were hypotensive. patient’s response to therapy and suggested that A number of patients who present with free intra- repeated lactate determinations represent a reliableabdominal fluid according to FAST can safely undergo prognostic index for patients with circulatory shockfurther investigation with MSCT. Under normal circum- . Abramson and colleagues  performed a pro-stances, adult patients need to be haemodynamically spective observational study in patients with multiplestable when MSCT is performed outside of the emer- trauma to evaluate the correlation between lactate clear-gency room . Haemodynamically stable patients with ance and survival. All patients in whom lactate levelsa high risk mechanism of injury, such as high-energy returned to the normal range (≤2 mmol/l) withintrauma or even low-energy injuries in the elderly popu- 24 hours survived. Survival decreased to 77.8% if nor-lation, should be scanned after FAST for additional inju- malisation occurred within 48 hours and to 13.6% inries using MSCT. As CT scanners are integrated in those patients in whom lactate levels were elevatedresuscitation units, whole-body CT diagnosis may above 2 mmol/l for more than 48 hours . Thesereplace FAST as a diagnostic method. findings were confirmed in a study by Manikis and col-Haematocrit leagues  who showed that the initial lactate levelsRecommendation 10 We do not recommend the use of were higher in non-survivors after major trauma, andsingle Hct measurements as an isolated laboratory mar- that the prolonged time for normalisation of lactateker for bleeding (Grade 1B). levels of more than 24 hours was associated with theRationale Hct assays are part of the basic diagnostic development of post-traumatic organ failure .work up for trauma patients. The diagnostic value of Similar to the predictive value of lactate levels, thethe Hct for detecting trauma patients with severe injury initial base deficit has been established as a potent inde-and occult bleeding sources has been a topic of debate pendent predictor of mortality in patients with trau-in the past decade [92-94]. A major limit of the diagnos- matic hemorrhagic shock . Davis and colleaguestic value of Hct is the confounding influence of resusci-  stratified the extent of base deficit into three cate-tative measures on the Hct due to administration of gories, mild (-3 to -5 mEq/l), moderate (-6 to -9 mEq/l)intravenous fluids and red cell concentrates [94-97]. and severe (<-10 mEq/l), and established a significantA retrospective study of 524 trauma patients determined correlation between the admission base deficit anda low sensitivity (0.5) of the initial Hct on admission for transfusion requirements within the first 24 hours anddetecting those patients with traumatic haemorrhage the risk of post-traumatic organ failure or death .requiring surgical intervention . Two prospective The same group of authors showed that the base deficitobservational diagnostic studies determined the sensitiv- is a better prognostic marker of death than the pH inity of serial Hct measurements for detecting patients arterial blood gas analyses . Furthermore, the basewith severe injury [92,93]. Decreasing serial Hct mea- deficit was shown to represent a highly sensitive markersurements may reflect continued bleeding, but the for the extent of post-traumatic shock and mortality,patient with significant bleeding may maintain his or both in adult and paediatric patients [109,110].her serial Hct. In contrast to the data on lactate levels in haemorrha-Serum lactate and base deficit gic shock, reliable large-scale prospective studies on theRecommendation 11 We recommend both serum lac- correlation between base deficit and outcome are stilltate and base deficit measurements as sensitive tests to lacking. Although both the base deficit and serum lac-estimate and monitor the extent of bleeding and shock tate levels are well correlated with shock and resuscita-(Grade 1B). tion, these two parameters do not strictly correlate withRationale Serum lactate has been used as a diagnostic each other in severely injured patients . Therefore,parameter and prognostic marker of haemorrhagic the independent assessment of both parameters isshock since the 1960s . The amount of lactate pro- recommended for the evaluation of shock in traumaduced by anaerobic glycolysis is an indirect marker of patients [99,101,111,112]. Composite scores that assessoxygen debt, tissue hypoperfusion and the severity of the likelihood of massive transfusion and include basehaemorrhagic shock [99-102]. Similarly, base deficit deficit and other clinical parameters have been devel-values derived from arterial blood gas analysis provide oped but require further validation [112,113]. Callawayan indirect estimation of global tissue acidosis due to and colleagues  performed a seven-year retrospec-impaired perfusion [99,101]. tive analysis of a prospective trauma registry from a Vincent and colleagues  showed the value of level I trauma centre to determine predictors of mortal-serial lactate measurements for predicting survival in a ity in elderly patients 65 years or older who sustainedprospective study in patients with circulatory shock. blunt trauma and presented with a normal initial
Rossaint et al. Critical Care 2010, 14:R52 Page 8 of 29http://ccforum.com/content/14/2/R52systolic blood pressure (≥90 mmHg). The odds ratio for outcomes. There is insufficient evidence at present todeath was increased more than four-fold in those support the utility of thrombelastometry in the detectionpatients who had either elevated serum lactate levels of post-traumatic coagulopathy. More research isabove 4 mmol/l or a base deficit below -6 mEq/l, required in this area, and in the meantime physicianscompared with patients with normal lactate levels should make their own judgement when developing(<2.5 mmol/l) or a base excess (>0 mEq/l). Paladino and local policies.colleagues  assessed the prognostic value of a com- It is theoretically possible that the pattern of change inbination of abnormal vital signs (heart rate >100 beats/ measures of coagulation such as D-dimers may help tomin or a systolic blood pressure <90 mmHg) in con- identify patients with ongoing bleeding. However, therejunction with serum lactate and base deficit for identify- are no publications relevant to this question, so tradi-ing trauma patients with major injuries, using cut-off tional methods of detection for ongoing bleeding, suchvalues for lactate at more than 2.2 mmol/l and base def- as serial clinical evaluation of radiology (ultrasound, CTicit at less than -2.0 mEq/l, respectively. The authors or angiography) should be used.found that the addition of the metabolic parameters tothe vital signs increased the sensitivity for identifying III. Rapid control of bleedingmajor injury from 40.9% to 76.4%, implying that the Pelvic ring closure and stabilisationaddition of lactate and base deficit to triage vital signs Recommendation 13 We recommend that patients withincreases the ability to distinguish major from minor pelvic ring disruption in haemorrhagic shock undergoinjury. immediate pelvic ring closure and stabilisation (GradeCoagulation monitoring 1B).Recommendation 12 We recommend that routine prac- Packing, embolisation and surgerytice to detect post-traumatic coagulopathy include the Recommendation 14 We recommend that patients withmeasurement of international normalised ratio (INR), ongoing haemodynamic instability despite adequate pel-activated partial thromboplastin time (APTT), fibrinogen vic ring stabilisation receive early preperitoneal packing,and platelets. INR and APTT alone should not be used angiographic embolisation and/or surgical bleeding con-to guide haemostatic therapy (Grade 1C). We suggest trol (Grade 1B).that thrombelastometry also be performed to assist in Rationale The mortality rate of patients with severecharacterising the coagulopathy and in guiding haemo- pelvic ring disruptions and haemodynamic instabilitystatic therapy (Grade 2C). remains unacceptably high [119-122]. The early detec-Rationale Little evidence supports a recommendation tion of these injuries and initial efforts to reduce disrup-for the best haemostatic monitoring tool(s). Standard tion and stabilise the pelvis as well as containingmonitoring comprises INR, APTT, platelets and fibrino- bleeding is therefore crucial. Markers of pelvic haemor-gen, although there is little direct evidence for the effi- rhage include anterior-posterior and vertical shearcacy of these measures. Increasing emphasis focuses on deformations, CT ‘blush’ (active arterial extravasation),the importance of fibrinogen and platelet measurements. bladder compression pressure, pelvic haematoma It is often assumed that the conventional coagulation volumes of more than 500 ml evident by CT andscreens (INR and APTT) monitor coagulation; however, ongoing haemodynamic instability despite adequate frac-these tests monitor only the initiation phase of blood ture stabilisation [123-125].coagulation and represent only the first 4% of thrombin The initial therapy of pelvic fractures includes controlproduction . It is therefore possible that the con- of venous and/or cancellous bone bleeding by pelvic clo-ventional coagulation screen appears normal, while the sure. Some institutions use primarily external fixators tooverall state of blood coagulation is abnormal. There- control haemorrhage from pelvic fractures [124,125] butfore, a more complete monitoring of blood coagulation pelvic closure may also be achieved using a bed sheet,and fibrinolysis, such as thrombelastometry, may facili- pelvic binder or a pelvic C-clamp [126-128]. In additiontate more accurate targeting of therapy. Case series to the pelvic closure, fracture stabilisation and the tam-using thrombelastometry to assess trauma patients have ponade effect of the haematoma, pre, extra or retroperi-been published. One study applied thrombelastometry toneal packing will reduce or stop the venous bleedingto 23 patients, but without a comparative standard [122,129-131]. Preperitoneal packing decreases the need. Another study found a poor correlation between for pelvic embolisation and may be performed simulta-thrombelastometry and conventional coagulation para- neously or soon after initial pelvic stabilisationmeters . Johansson  implemented a haemostatic [122,129,131]. The technique can be combined with aresuscitation regime (early platelets and fresh frozen consecutive laparotomy if deemed necessary [122,129].plasma (FFP)) guided using thrombelastometry in This may decrease the high mortality rate observed ina before-and-after study which showed improved patients with major pelvic injuries who underwent
Rossaint et al. Critical Care 2010, 14:R52 Page 9 of 29http://ccforum.com/content/14/2/R52laparotomy as the primary intervention. As a conse- injury, a need for time-consuming procedures or conco-quence, it was recommended that non-therapeutic lapar- mitant major injury outside the abdomen (Grade 1C).otomy should be avoided . Rationale The severely injured patient arriving to the Angiography and embolisation is currently accepted as hospital with continuous bleeding or deep haemorrhagica highly effective means with which to control arterial shock generally has a poor chance of survival unlessbleeding that cannot be controlled by fracture stabilisa- early control of bleeding, proper resuscitation and bloodtion [122-126,131-140]. The presence of sacroiliac joint transfusion are achieved. This is particularly true fordisruption, female gender and duration of hypotension patients who present with uncontrolled bleeding due tocan reliably predict patients who would benefit from the multiple penetrating injuries or patients with multipleprocedure . Controversy exists about the indica- injuries and unstable pelvic fractures with ongoingtions and optimal timing of angiography in haemodyna- bleeding from fracture sites and retroperitoneal vessels.mically unstable patients . Institutional differences The common denominator in these patients is thein the capacity to perform timely angiography and exhaustion of physiological reserves with resulting pro-embolisation may explain the different treatment algo- found acidosis, hypothermia and coagulopathy, alsorithms suggested by many authors [119-122,125,129, known as the ‘bloody vicious cycle’. In 1983, Stone and131,132,140]. Nevertheless, the general consensus is that colleagues described the techniques of abbreviated lapar-a multidisciplinary approach to these severe injuries is otomy, packing to control haemorrhage and of deferredrequired. definitive surgical repair until coagulation has beenEarly bleeding control established . Since then, a number of authors haveRecommendation 15 We recommend that early bleed- described the beneficial results of this concept, nowing control of the abdomen be achieved using packing, called ‘damage control’ [50,54,121,134,151,156-158].direct surgical bleeding control and the use of local hae- Damage control surgery of the abdomen consists ofmostatic procedures. In the exsanguinating patient, aor- three components: the first component is an abbreviatedtic cross-clamping may be employed as an adjunct resuscitative laparotomy for control of bleeding, the res-(Grade 1C). titution of blood flow where necessary and the controlRationale Abdominal resuscitative packing is an early of contamination. This should be achieved as rapidly aspart of the post-traumatic laparotomy to identify major possible without spending unnecessary time on tradi-injuries and sources of haemorrhage [141,142]. If bleed- tional organ repairs that can be deferred to a latering cannot be controlled using packing and conventional phase. The abdomen is packed and temporary abdom-surgical techniques when the patient is in extremis or inal closure is performed. The second component iswhen proximal vascular control is deemed necessary intensive care treatment, focused on core re-warming,before opening the abdomen, aortic cross clamping may correction of the acid-base imbalance and coagulopathybe employed as an adjunct to reduce bleeding and redis- as well as optimising the ventilation and the haemody-tribute blood flow to the heart and brain [143-145]. namic status. The third component is the definitive sur-When blood losses are important, when surgical mea- gical repair that is performed only when targetsures are unsuccessful and/or when the patient is cold, parameters have been achieved [159-162]. Although theacidotic and coagulopathic, definitive packing may also concept of ‘damage control’ intuitively makes sense, nobe the first surgical step within the concept of damage RCTs exist to support it. Retrospective studies supportcontrol [146-155]. Packing aims to compress liver rup- the concept showing reduced morbidity and mortalitytures or exert direct pressure on the sources of bleeding rates in selective populations [50,151,157,161].[141,142,146-150,152-154]. The definitive packing of the The same ‘damage control’ principles have beenabdomen may allow further attempts to achieve total applied to orthopaedic injuries in severely injuredhaemostasis through angiography and/or correction of patients [134,163-166]. Scalea was the first to coin thecoagulopathy . The removal of packs should prefer- term ‘damage control orthopaedics’ . Relevant frac-ably be performed only after 48 hours to lower the risk tures are primarily stabilised with external fixatorsof rebleeding [152,153]. rather than primary definitive osteosynthesis [134,163].Damage control surgery The less traumatic and shorter duration of the surgicalRecommendation 16 We recommend that damage con- procedure aims to reduce the secondary trauma load.trol surgery be employed in the severely injured patient Definitive osteosynthesis surgery can be performed afterpresenting with deep haemorrhagic shock, signs of 4 to 14 days when the patient has recovered sufficiently.ongoing bleeding and coagulopathy. Additional factors Retrospective clinical studies and prospective cohort stu-that should trigger a damage control approach are dies seem to support the concept of damage controlhypothermia, acidosis, inaccessible major anatomical [134,163-165]. The only available randomised study
Rossaint et al. Critical Care 2010, 14:R52 Page 10 of 29http://ccforum.com/content/14/2/R52shows an advantage for this strategy in ‘borderline’ and diatoms and microporous polysaccharide haemo-patients . spheres produced from potato starch. The mechanism ofLocal haemostatic measures action is complex and depends on the purity or combina-Recommendation 17 We recommend the use of topical tion with other substances such as cellulose or fibrin.haemostatic agents in combination with other surgical A number of different products are currently availablemeasures or with packing for venous or moderate arterial and have been shown to be efficient for external use.bleeding associated with parenchymal injuries (Grade 1B). An observational study showed that haemorrhage controlRationale A wide range of local haemostatic agents are was achieved using an N-acetylglucosamine-based ban-currently available for use as adjuncts to traditional dage applied to 10 patients with severe hepatic andsurgical techniques to obtain haemorrhage control. abdominal injuries, acidosis and clinical coagulopathyThese topical agents can be particularly useful when .access to the bleeding area is difficult. Local haemo- vi) The inorganic haemostatics based on minerals suchstatic agents include collagen, gelatin or cellulose- as zeolite or smectite have been used and studied mainlybased products, fibrin and synthetic glues or adhesives on external bleeding [167,168].that can be used for both external and internal bleed-ing while polysaccharide-based and inorganic haemo- IV. Tissue oxygenation, fluid and hypothermiastatics are still mainly used and approved for external Volume replacementbleeding. The use of topical haemostatic agents should Recommendation 18 We recommend a target systolicconsider several factors such as the type of surgical blood pressure of 80 to 100 mmHg until major bleedingprocedure, cost, severity of bleeding, coagulation status has been stopped in the initial phase following traumaand each agent’s specific characteristics. Some of these without brain injury (Grade 1C).agents should be avoided when autotransfusion is Rationale In order to maintain tissue oxygenation, tra-used and several other contraindications need to be ditional treatment of trauma patients uses early andconsidered [167,168]. The capacity of each agent to aggressive fluid administration to restore blood volume.control bleeding was initially studied in animals but This approach may, however, increase the hydrostaticincreasing experience from humans is now available pressure on the wound, cause a dislodgement of blood[167-180]. clots, a dilution of coagulation factors and undesirable The different types of local haemostatics are briefly cooling of the patient. The concept of low-volume fluidpresented according to their basis and haemostatic resuscitation, so-called ‘permissive hypotension’, avoidscapacity: the adverse effects of early aggressive resuscitation while i) Collagen-based agents trigger platelet aggregation maintaining a level of tissue perfusion that, althoughresulting in clot formation when in contact with a lower than normal, is adequate for short periods .bleeding surface. They are often combined with a pro- A controlled hypotensive fluid resuscitation should aimcoagulant substance such as thrombin to enhance the to achieve a mean arterial pressure of 65 mmHg orhaemostatic effect. A positive haemostatic effect has more . Its general effectiveness remains to be con-been shown in several human studies [169-172]. firmed in RCTs; however, studies have demonstrated ii) Gelatin-based products can be used alone or in increased survival when a low volume fluid resuscitationcombination with a procoagulant substance . Swel- concept was used in penetrating trauma [182,183]. Inling of the gelatin in contact with blood reduces the contrast, no significant difference in survival was foundblood flow and, in combination with a thrombin-based in patients with blunt trauma . One study con-component, enhances haemostasis. A similar or superior cluded that mortality was higher after on-site resuscita-haemostatic effect has been observed compared with tion compared with in-hospital resuscitation . Itcollagen-based agents [173-175]. seems that greater increases in blood pressure are toler- iii) The effect of cellulose-based haemostatic agents on ated without exacerbating haemorrhage when they arebleeding has been less well studied and only case reports achieved gradually and with a significant delay followingthat support their use are available. the initial injury . All the same, a recent Cochrane iv) Fibrin and synthetic glues or adhesives have both systematic review concluded that there is no evidencehaemostatic and sealant properties and their significant from RCTs for or against early or larger volume intrave-effect on haemostasis have been shown in several nous fluids to treat uncontrolled haemorrhage .human RCTs involving vascular, bone, skin and visceral However, a recent retrospective analysis demonstratedsurgery [176-178]. that aggressive resuscitation techniques, often initiated v) Polysaccharide-based haemostatics can be divided in the prehospital setting, appear to increase the likeli-into two broad categories : N-acetyl-glucosamine- hood that patients with severe extremity injuries developcontaining glycosaminoglycans purified from microalgae secondary abdominal compartment syndrome (ACS)
Rossaint et al. Critical Care 2010, 14:R52 Page 11 of 29http://ccforum.com/content/14/2/R52. In this study, early, large-volume crystalloid therapy strategies, limited quality of analysed studies,administration was the greatest predictor of secondary mortality not always being the primary outcome, andACS. Moreover, a retrospective analysis of the German different, often short, observation periods. It is thereforeTrauma Registry database including 17,200 multiply difficult to reach a definitive conclusion as to the advan-injured patients showed that the incidence of coagulopa- tage of one type of resuscitation fluid over the other.thy increased with increasing volume of intravenous The Saline versus Albumin Fluid Evaluation study com-fluids administered pre-clinically. Coagulopathy was pared 4% albumin with 0.9% sodium chloride in 6997observed in more than 40% of patients with more than ICU patients and showed that albumin administration2000 ml, in more than 50% with more than 3000 ml, was not associated with worse outcomes; however, thereand in more than 70% with more than 4000 ml adminis- was a trend towards higher mortality in the braintered . trauma subgroup that received albumin (P = 0.06) . The low-volume approach is contraindicated in TBI Promising results have been obtained with hypertonicand spinal injuries, because an adequate perfusion pres- solutions. Recently, a double-blind, RCT in 209 patientssure is crucial to ensure tissue oxygenation of the with blunt traumatic injuries analysed the effect of theinjured central nervous system. In addition, the concept treatment with 250 ml of 7.5% hypertonic saline and 6%of permissive hypotension should be carefully consid- dextran 70 compared with lactated Ringer solution onered in the elderly patient and may be contraindicated if organ failure. The intent-to-treat analysis demonstratedthe patient suffers from chronic arterial hypertension. no significant difference in organ failure and in acute A recent analysis from an ongoing multi-centre pro- respiratory disress syndrome (ARDS)-free survival. How-spective cohort study suggests that the early use of vaso- ever, there was improved ARDS-free survival in the sub-pressors for haemodynamic support after haemorrhagic set (19% of the population) requiring 10 U or more ofshock in comparison to aggressive volume resuscitation packed red blood cells (RBCs) . One study showedmay be deleterious and should be used cautiously . that the use of hypertonic saline was associated withHowever, this study has several limitations: the study is lower intracranial pressure than with normal saline ina secondary analysis of a prospective cohort study, and brain-injured patients  and a meta-analysis compar-was not designed to answer the specific hypothesis ing hypertonic saline dextran with normal saline fortested. Thus, it is not possible to separate vasopressor resuscitation in hypotension from penetrating torsofrom the early management of trauma patients. In addi- injuries showed improved survival in the hypertonic sal-tion, although the use of a vasopressor helps to rapidly ine dextran group when surgery was required .restore arterial pressure, it should not be viewed as a A clinical trial with brain injury patients found thatsubstitute for fluid resuscitation and the target blood hypertonic saline reduced intracranial pressure morepressure must be respected. effectively than dextran solution with 20% mannitolFluid therapy when compared in equimolar dosing . However,Recommendation 19 We recommend that crystalloids Cooper and colleagues found almost no difference inbe applied initially to treat the bleeding trauma patient neurological function six months after TBI in patients(Grade 1B). We suggest that hypertonic solutions also who had received pre-hospital hypertonic saline resusci-be considered during initial treatment (Grade 2B). We tation compared with conventional fluid . In con-suggest that the addition of colloids be considered clusion, the evidence suggests that hypertonic salinewithin the prescribed limits for each solution in haemo- solutions are safe, and will improve haemodynamicsdynamically unstable patients (Grade 2C). during hypovolaemic resuscitation. The evidence forRationale It is still unclear what type of fluid should be increased survival with use of hypertonic saline solutionsemployed in the initial treatment of the bleeding trauma is inconclusive. It is possible that certain subgroupspatient. Although several meta-analyses have shown an might benefit from hypertonic saline solutions, butincreased risk of death in patients treated with colloids further research is required .compared with patients treated with crystalloids Normothermia[190-194] and three of these studies showed that the Recommendation 20 We recommend early applicationeffect was particularly significant in a trauma subgroup of measures to reduce heat loss and warm the hypother-[190,193,194], a more recent meta-analysis showed no mic patient in order to achieve and maintain nor-difference in mortality between colloids and crystalloids mothermia (Grade 1C).. If colloids are used, modern hydroxyethyl starch Rationale Hypothermia, defined as a core body tem-or gelatin solutions should be used because the risk:ben- perature below 35°C, is associated with acidosis, hypo-efit ratio of dextran is disadvantageous. Problems in tension and coagulopathy in severely injured patients. Inevaluating and comparing the use of different resuscita- a retrospective study with 122 patients, hypothermiation fluids include the heterogeneity of populations and was an ominous clinical sign, accompanied by high
Rossaint et al. Critical Care 2010, 14:R52 Page 12 of 29http://ccforum.com/content/14/2/R52mortality and blood loss . The profound clinical arrested. If mild hypothermia is applied in TBI, coolingeffects of hypothermia ultimately lead to higher morbid- should take place within the first three hours followingity and mortality, and hypothermic patients require injury, preferably using selective brain cooling by cool-more blood products . ing the head and neck, be maintained for at least Hypothermia is associated with an increased risk of 48 hours , rewarming should last 24 hours and thesevere bleeding, and hypothermia in trauma patients cerebral perfusion pressure should be maintained aboverepresents an independent risk factor for bleeding and 50 mmHg (systolic blood pressure ≥70 mmHg). Patientsdeath . The effects of hypothermia include altered most likely to benefit from hypothermia are those withplatelet function, impaired coagulation factor function a GCS at admission between 4 and 7 . Possible(a 1°C drop in temperature is associated with a 10% side effects are hypotension, hypovolaemia, electrolytedrop in function), enzyme inhibition and fibrinolysis disorders, insulin resistance and reduced insulin secre-[206,207]. Body temperatures below 34°C compromise tion and increased risk of infection . Further stu-blood coagulation, but this has only been observed dies are warranted to investigate the postulated benefitwhen coagulation tests (prothrombin time (PT) and of hypothermia in TBI taking these important factorsAPTT) are carried out at the low temperatures seen in into account.patients with hypothermia, and not when assessed at37°C as is routine practice for such tests. Steps to pre- V. Management of bleeding and coagulationvent hypothermia and the risk of hypothermia-induced Erythrocytescoagulopathy include removing wet clothing, covering Recommendation 21 We recommend a target haemo-the patient to avoid additional heat loss, increasing the globin (Hb) of 7 to 9 g/dl (Grade 1C).ambient temperature, forced air warming, warm fluid Rationale Erythrocytes contribute to haemostasis bytherapy and, in extreme cases, extracorporeal re-warm- influencing the biochemical and functional responsive-ing devices [208,209]. ness of activated platelets via the rheological effect on Animal and human studies of controlled hypothermia platelet margination and by supporting thrombin gen-in haemorrhage have shown some positive results com- eration ; however, the optimal Hct or Hb concen-pared with normothermia [210,211]. Contradictory tration required to sustain haemostasis in massivelyresults have been observed in meta-analyses that examine bleeding patients is unclear. Further investigations intomortality and neurological outcomes associated with the role of the Hb concentration on haemostasis in mas-mild hypothermia in patients with TBI, possibly due to sively transfused patients are therefore warranted.the different exclusion and inclusion criteria for the stu- The effects of the Hct on blood coagulation have notdies used for the analysis [212-214]. The speed of induc- been fully elucidated . An acute reduction of thetion and duration of hypothermia, which may be very Hct results in an increase in the bleeding time [223,224]important factors that influence the benefit associated with restoration upon re-transfusion . This maywith this treatment. It has been shown that five days of relate to the presence of the enzyme elastase on the sur-long-term cooling is more efficacious than two days of face of RBC membranes, which may activate coagulationshort-term cooling when mild hypothermia is used to factor IX [225,226]. However, a moderate reduction ofcontrol refractory intracranial hypertension in adults the Hct does not increase blood loss from a standardwith severe TBI . Obviously, the time span of spleen injury , and an isolated in vitro reduction ofhypothermia is crucial, because a recent prospective RCT the Hct did not compromise blood coagulation asin 225 children with severe TBI showed that hypothermic assessed by thrombelastometry .therapy initiated within 8 hours after injury and contin- No prospective RCT has compared restrictive and liberalued for 24 hours did not improve the neurological out- transfusion regimens in trauma, but 203 trauma patientscome and may increase mortality . Furthermore, the from the Transfusion Requirements in Critical Care trialmode of inducing cerebral hypothermia induction may  were re-analysed . A restrictive transfusion regi-influence its effectiveness. In a RCT comparing non-inva- men (Hb transfusion trigger <7.0 g/dl) resulted in fewersive selective brain cooling (33 to 35°C) in 66 patients transfusions as compared with the liberal transfusion regi-with severe TBI and mild systemic hypothermia (rectal men (Hb transfusion trigger <10 g/dl) and appeared to betemperature 33 to 35°C) and a control group not exposed safe. However, no statistically significant benefit in termsto hypothermia, natural rewarming began after three of multiple organ failure or post-traumatic infections wasdays. Mean intracranial pressure 24, 48 or 72 hours after observed. It should be emphasised that this study wasinjury was significantly lower in the selective brain cool- neither designed nor powered to answer these questionsing group than in the control group . with precision. In addition, it cannot be ruled out that the Prolonged hypothermia may be considered in patients number of RBC units transfused merely reflects the sever-with isolated head trauma after haemorrhage has been ity of injury. Nevertheless, RBC transfusions have been
Rossaint et al. Critical Care 2010, 14:R52 Page 13 of 29http://ccforum.com/content/14/2/R52shown in multiple studies to be associated with increased and persistent coagulopathy at ICU entry has beenmortality [230-234], lung injury [234-236], increased infec- shown to be associated with a increased mortality .tion rates [237,238] and renal failure in trauma victims Therefore, early aggressive treatment is likely to improve. This ill effect may be particularly important with the outcome of severely injured patients . However,RBC transfusions stored for more than 14 days . there are also studies in which no survival benefit could Despite the lack of high-level scientific evidence for a be shown [247,250].specific Hb transfusion trigger in patients with TBI, Calciumthese patients are currently transfused in many centres Recommendation 23 We recommend that ionised cal-to achieve an Hb of approximately 10 g/dl . This cium levels be monitored during massive transfusionmight be justified by the recent finding that increasing (Grade 1C). We suggest that calcium chloride be admi-the Hb from 8.7 to 10.2 g/dl improved local cerebral nistered during massive transfusion if ionised calciumoxygenation in 75% of patients . In another preli- levels are low or electrocardiographic changes suggestminary study in patients with TBI, one to two RBC hypocalcaemia (Grade 2C).transfusions at a Hb of approximately 9 g/dl transiently Rationale Calcium in the extracellular plasma exists(three to six hours) increased cerebral oxygenation, either in a free ionised state (45%) or bound to proteinsagain in approximately 75% of patients [240,241]. A sto- and other molecules in a biologically inactive staterage time of more than 19 days precluded this effect (55%). The normal concentration of the ionised form. In another recent study, cerebral tissue oxygena- ranges from 1.1 to 1.3 mmol/l and is influenced by thetion, on average, did not increase due to an increase in pH. A 0.1 unit increase in pH decreases the ionised cal-Hb from 8.2 to 10.1 g/dl . Nevertheless, the authors cium concentration by approximately 0.05 mmol/l .came to the conclusion based on multivariable statistical The availability of ionised calcium is essential for themodels that the changes in cerebral oxygenation corre- timely formation and stabilisation of fibrin polymerisa-lated significantly with Hb concentration . This tion sites, and a decrease in cytosolic calcium concentra-conclusion, however, was questioned in the accompany- tion precipitates a decrease in all platelet-relateding editorial . activities . In addition, contractility of the heart In an initial outcome study the lowest Hct was corre- and systemic vascular resistance are compromised atlated with adverse neurological outcome and RBC trans- low ionised calcium levels. Combining beneficial cardio-fusions were also found to be an independent factor vascular and coagulation effects, the level for ionisedpredicting adverse neurological outcome . Interest- calcium concentration should therefore be maintainedingly, the number of days with a Hct below 30% was above 0.9 mmol/l .found to be correlated with an improved neurological Early hypocalcaemia following traumatic injury showsoutcome . In a more recent outcome study in 1150 a significant correlation with the amount of infused col-patients with TBI, RBC transfusions were found to be loids, but not with crystalloids, and may be attributableassociated with a two-fold increased mortality and a to colloid-induced haemodilution . Also, hypocal-three-fold increased complication rate . Therefore, caemia develops during massive transfusion as a resultpatients with severe TBI should not have an Hb transfu- of the citrate employed as an anticoagulant in bloodsion threshold different than that of other critically ill products. Citrate exerts its anticoagulant activity bypatients. binding ionised calcium, and hypocalcaemia is mostCoagulation support common in association with FFP and platelet transfu-Recommendation 22 We recommend that monitoring sion because these products contain high citrate concen-and measures to support coagulation be initiated as trations. Citrate undergoes rapid hepatic metabolism,early as possible (Grade 1C). and hypocalcaemia is generally transient during standardRationale Major trauma results not only in bleeding transfusion procedures. Citrate metabolism may be dra-from anatomical sites but also frequently in coagulopa- matically impaired by hypoperfusion states, hypothermiathy, which is associated with a several-fold increase in and in patients with hepatic insufficiency .mortality [3,5,8,9,245]. This early coagulopathy of Fresh frozen plasmatrauma is mainly found in patients with hypoperfusion Recommendation 24 We recommend early treatment(base deficit >6 mE/l) [8,245] and is characterised by an with thawed FFP in patients with massive bleedingup-regulation of endothelial thrombomodulin, which (Grade 1B). The initial recommended dose is 10 toforms complexes with thrombin . 15 ml/kg. Further doses will depend on coagulation Early monitoring of coagulation is essential to detect monitoring and the amount of other blood productstrauma-induced coagulopathy and to define the main administered (Grade 1C).causes, including hyperfibrinolysis [10,117]. Early thera- Rationale The clinical efficacy of FFP is largely unpro-peutic intervention does improve coagulation tests  ven . Nevertheless, most guidelines recommend the
Rossaint et al. Critical Care 2010, 14:R52 Page 14 of 29http://ccforum.com/content/14/2/R52use of FFP either in massive bleeding or in significant consideration only patients alive upon ICU admission,bleeding complicated by coagulopathy (PT or APTT and another defined massive transfusion as 10 units ormore than 1.5 times control) [7,254,255]. Patients trea- more prior to ICU admission. One report  definedted with oral anticoagulants (vitamin K antagonists) pre- massive transfusion as more than 10 units over 6 hours.sent a particular challenge, and FFP is recommended Two of the studies are based on data collected in a only when prothrombin complex concentrate combat setting, while the other eight were performed(PCC) is not available . The most frequently based on data collected at civilian trauma centres. Therecommended dose is 10 to 15 ml/kg [254,255], and majority of the studies are single centre; one study isfurther doses may be required . As with all pro- multi-centre  and one is a retrospective analysis ofducts derived from human blood, the risks associated the German Trauma Registry .with FFP treatment include circulatory overload, ABO Seven studies showed better outcomes using a highincompatibility, transmission of infectious diseases FFP:RBC ratio [3,261-266] and two did not [250,267].(including prion diseases), mild allergic reactions and One study may be classified as indeterminate because atransfusion-related acute lung injury [254,257,258]. FFP high FFP:RBC ratio (average 1:2) was associated with aand platelet concentrates appear to be the most fre- better survival than a low ratio (average 1:4), but thequently implicated blood products in transfusion-related survival curve was U-shaped, with the lowest mortalityacute lung injury [257-260]. Although the formal link at a 1:2 to 1:3 ratio . The two combat studiesbetween the administration of FFP, control of bleeding showed better outcomes using a high ratio [265,266].and an eventual improvement in the outcome of bleed- Early empirical infusion of FFP may increase the fre-ing patients is lacking, most experts would agree that quency of delayed traumatic intracerebral haematomaFFP treatment is beneficial in patients with massive and the mortality in patients with severe head injurybleeding or significant bleeding complicated by . Most of the studies calculate FFP:RBC ratio atcoagulopathy. 24 hours after admission. When Snyder and colleagues There are very few well-designed studies that explore  used the FFP:RBC ratio at 24 hours as a fixedmassive transfusion strategy. The need for massive value, patients who received a higher ratio had signifi-transfusion is relatively rare, occurring in less than 2% cantly better outcomes, but if the timing of componentof civilian trauma patients, but higher (7%) in the mili- product transfusion was taken into account, the differ-tary setting. Massive transfusion management has been ence was no longer statistically significant.based on the concept that coagulopathy associated with These combat data are retrospective, refer to young,severe trauma was primarily consumptive due to the previously healthy male patients with penetrating inju-dilution of blood clotting factors and the consumption ries and may be confounded to some extent by treat-of haemostasis factors at the site of injury. ment biases. Because FFP requires a significant amount FFP was recommended when PT or APTT was 1.5 of time before it is thawed and available for transfusiontimes normal or after 10 RBC units had been transfused. and many trauma deaths occur soon after hospitalMany massive transfusion protocols stipulated one unit admission, patients who die early may receive RBC unitsof FFP for every four units of RBCs. In recent years, ret- but die before FFP therapy has begun. These cases mayrospective data from the US Army combat support hospi- therefore be included in the low ratio group even if atals have shown an association between survival and a 1:1 strategy was intended. One further ground for criti-higher ratio of transfused FFP and RBC units. These data cism of many of these studies is that the number ofshow that casualties who received FFP and RBCs at a RBCs units transfused is an indicator of severity ofratio of 1:4 or lower, had a three-fold higher mortality injury that cannot be completely adjusted for by regres-than those who received a massive transfusion with a 2:3 sion analysis. All of these limitations must be kept inratio. These data have induced many civilian trauma cen- mind when analysing the available recent literature andtres to modify their transfusion approach to incorporate emphasises the need for prospective trials.the early use of thawed FFP in ratios approaching 1:1. Platelets Ten relevant studies addressing FFP:RBC ratio have Recommendation 25 We recommend that platelets bebeen identified, all of which were retrospective studies, administered to maintain a platelet count above 50 ×although some are based on data collected prospectively 109/l (Grade 1C). We suggest maintenance of a plateletfor other reasons. None of the studies were clinical count above 100 × 10 9 /l in patients with multipleRCTs. The majority of the authors used massive transfu- trauma who are severely bleeding or have TBI (Gradesion (10 RBC units within 24 hours) as the entry criter- 2C). We suggest an initial dose of four to eight plateletion; however, to limit bias due to FFP unavailability, concentrates or one aphaeresis pack (Grade 2C).one study  excluded patients who died within the Rationale In medical conditions leading to thrombocy-first 30 minutes. One of the studies  took into topaenia, haemorrhage does not often occur until the
Rossaint et al. Critical Care 2010, 14:R52 Page 15 of 29http://ccforum.com/content/14/2/R52platelet count falls below 50 × 109/l, and platelet func- local collection practice, and physicians should be cogni-tion decreases exponentially below this point [269-272]. sant of the doses provided locally. A pool of four toThere is no direct evidence to support a particular pla- eight platelet concentrates or a single-donor aphaeresistelet transfusion threshold in the trauma patient. A con- unit is usually sufficient to provide haemostasis in asensus development conference sponsored by the thrombocytopaenic, bleeding patient. If required, theNational Institutes of Health (NIH; Bethesda, MD, USA) dose of platelets (× 109) can be calculated in more detailin 1986 determined that bleeding is unlikely to be from the desired platelet increment, the patient’s bloodcaused by thrombocytopaenia at platelet counts of 50 × volume in litres (estimated by multiplying the patient’s109/l or greater and agreed that platelet transfusion is body surface area by 2.5, or 70 ml/kg in an adult), and aappropriate to prevent or control bleeding associated correction factor of 0.67 to allow for pooling of approxi-with deficiencies in platelet number or function mately 33% of transfused platelets in the spleen.[273,274]. The NIH consensus did not consider trauma, Fibrinogen and cryoprecipitatebut it seems reasonable to recommend that a platelet Recommendation 26 We recommend treatment withcount of at least 50 × 10 9 /l be maintained following fibrinogen concentrate or cryoprecipitate if significantinjury. bleeding is accompanied by thrombelastometric signs of a An argument can be made for maintaining a higher functional fibrinogen deficit or a plasma fibrinogen level oflevel of platelets, perhaps up to 100 × 109/l, following less than 1.5 to 2.0 g/l (Grade 1C). We suggest an initialinjury. If a patient has increased fibrin degradation pro- fibrinogen concentrate dose of 3 to 4 g or 50 mg/kg ofducts due to disseminated intravascular coagulation cryoprecipitate, which is approximately equivalent to 15 toand/or hyperfibrinolysis, this will interfere with platelet 20 units in a 70 kg adult. Repeat doses may be guided byfunction and a higher threshold of 75 × 109/l has been thrombelastometric monitoring and laboratory assessmentsuggested by consensus groups [275,276]. Moreover, of fibrinogen levels (Grade 2C).platelet-rich concentrate is an autologous concentration Rationale The formation of fibrin is a key step inof platelets and growth factors (e.g. transforming growth blood coagulation [222,279], and hypofibrinogenemia isfactor-beta, vascular endothelial growth factor and plate- a usual component of complex coagulopathies asso-let-derived growth factor), and due to the increased con- ciated with massive bleeding. Coagulopathic civiliancentration and release of these factors, platelet-rich trauma patients had a fibrinogen concentration ofconcentrates could potentially enhance bone and soft 0.9 g/l (interquartile ratio (IQR) 0.5 to 1.5 g/l) in con-tissue healing . Transfusion threshold levels of up junction with a maximum clot firmness of 6 mm (IQRto 100 × 10 9 /l have been suggested for treatment of 0 to 9 mm) using thrombelastometry, whereas onlysevere brain injury and massive haemorrhage, but the 2.5% of healthy volunteers had a maximum clot firm-evidence for the higher threshold is weak [275,276]. One ness of 7 mm or less . In trauma patients, a maxi-group showed that trauma patients receiving platelets mum clot firmness of 7 mm was associated with aand RBCs at a ratio of 1:5 or greater had a lower 30-day fibrinogen level of approximately 2 g/l . Duringmortality when compared with those with who received massive blood loss replacement, fibrinogen may be theless than this ratio (38% vs. 61%, P = 0.001) . first coagulation factor to decrease critically .Another study of massively transfused trauma patients During postpartum haemorrhage, fibrinogen plasmahas pointed to an early aggressive correction of coagulo- concentration is the only coagulation parameter inde-pathy with platelet transfusion as a possible contributing pendently associated with progress toward severefactor to good outcome . In this retrospective bleeding, with a level less than 2 g/l having a positivecohort study, survivors received one platelet transfusion predictive value of 100% . Blood loss and bloodfor every 7.7 units of blood transfused whereas nonsur- transfusion needs were also found to inversely corre-vivors received only one platelet transfusion for every late with preoperative fibrinogen levels in coronary11.9 units of blood transfused (P = 0.03). artery bypass graft surgery . When platelet transfusion was introduced in the During serious perioperative bleeding, fibrinogen1950s, no clinical trials were employed to assess the uti- treatment (2 g, range 1 to 5 g) was associated with ality of platelet therapy compared with placebo, and such reduction in allogeneic blood product transfusion .trials today might be considered unethical. The appro- The fibrinogen concentration before treatment waspriate dose of platelets is therefore uncertain. Platelet 1.4 g/l (IQR 1.0 to 1.8 g/l) rising to 2.4 g/l (IQR 2.1 toconcentrate produced from a unit of whole blood con- 2.6 g/l) after fibrinogen substitution . An observa-tains 7.5 × 1010 platelets on average and should increase tional study suggests that fibrinogen substitution canthe platelet count by 5 to 10 × 109/l in a 70 kg recipient. improve survival in combat-related trauma . AnAphaeresis platelet concentrates generally contain RCT in patients undergoing radical cystectomy withapproximately 3 to 6 × 10 11 platelets, depending on excessive blood loss has shown that postoperative blood