Volume therapy in trauma and neurotrauma

Best Practice & Research Clinical Anaesthesiology 28 (2014) 285e296

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Volume therapy in trauma and neurotrauma M.F.M. James, MBChB, PhD, FRCA, FFA(SA), Emeritus Professor * Department of Anaesthesia, University of Cape Town, Anzio Road, Observatory, Cape Town, Western Cape 7925, South Africa

Keywords: trauma fluid therapy blood transfusion resuscitation crystalloids colloids

Volume therapy in trauma should be directed at the restitution of disordered physiology including volume replacement to reestablishment of tissue perfusion, correction of coagulation deficits and avoidance of fluid overload. Recent literature has emphasised the importance of damage control resuscitation, focussing on the restoration of normal coagulation through increased use of blood products including fresh frozen plasma, platelets and cryoprecipitate. However, once these targets have been met, and in patients not in need of damage control resuscitation, clear fluid volume replacement remains essential. Such volume therapy should include a balance of crystalloids and colloids. Pre-hospital resuscitation should be limited to that required to sustain a palpable radial artery and adequate mentation. Neurotrauma patients require special consideration in both pre-hospital and in-hospital management. © 2014 Elsevier Ltd. All rights reserved.

Trauma of various kinds is the leading cause of death in people under the age of 40 years, worldwide. The top priority in fluid resuscitation in the traumatised patient is the control of haemorrhage and the replacement of lost circulating volume with appropriate fluid therapy [1].

* Tel.: þ27 (0) 21 531 8295. E-mail addresses: [email protected], [email protected].

http://dx.doi.org/10.1016/j.bpa.2014.06.005 1521-6896/© 2014 Elsevier Ltd. All rights reserved.

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Physiological consequences of trauma Circulatory adaptation Physical injury initiates a stress response aimed at directing blood flow and supply of basic nutrients to the so-called “fight or flight organs” e the heart, lungs, skeletal muscle and the brain e at the expense of a reduction in perfusion of the rest of the body. Redistribution of intra-renal blood flow, secretion of aldosterone and antidiuretic hormone result in sodium retention, minimal urine volume and retention of water in excess of sodium. The consequences are a reduction in urine volume, an increase in the urine concentration and a reduction in the concentration of plasma sodium with loss of potassium. Where these adaptive mechanisms fail to maintain adequate tissue perfusion in the face of trauma and volume loss, dire metabolic consequences ensue, resulting in tissue ischaemia and the metabolic consequences of cellular hypoxia. Even more deleterious is the global release of cytokines in response to injury. These substances are primarily designed for the mediation of local inflammatory responses, but with extensive injury, widespread release of cytokines predisposes to the development of systemic inflammation and endothelial damage. Endothelial glycocalyx The endothelial glycocalyx is essential for the functioning of infused fluids and damage to this surface layer may reduce or even eliminate the benefits of colloidal infusions. In trauma, the glycocalyx is readily damaged and shedding of the components of this layer occurs early and in proportion to the degree of injury [2]. Jacob and Chappell review the role of the glycocalyx elsewhere in this edition of Best Practice & Research: Clinical Anaesthesiology. Coagulopathy in trauma The physiology of coagulation is significantly disturbed in trauma as well as by resuscitation strategies. Trauma induced coagulopathy (TIC) has long been considered to be a secondary event related to consumption of coagulation factors and dilution of those factors by aggressive fluid administration, together with hypothermia and acidosis. When it occurs, it is a significant predictor of mortality [3] with an incidence ranging between 10 and 34% [4]. However, more recently it has been suggested that trauma itself induces a significant derangement of the clotting process. Consumptive coagulopathy has been advocated as a major mechanism for the development of TIC and has been associated with adverse outcomes including prolonged intensive care stay and multiple organ dysfunction syndromes [5]. A more recent alternative concept has been advocated suggesting that damage to the endothelial glycocalyx results in excess of production of activated protein C that not only inhibits normal thrombin activation of the coagulation cascade but also inhibits plasminogen activator inhibitor, resulting in enhanced fibrinolysis [4,6,7]. Severe tissue hypoxaemia and endothelial damage have also been postulated as drivers of the coagulopathic state [8]. In a recent study of TIC, two cohorts of moderately injured patients were studied, divided into those with and without early TIC (ETIC). Both cohorts showed increased thrombin activation with fibrin generation and increased fibrinolysis, but the ETIC group had received greater volumes of crystalloid prior to admission to hospital and these authors concluded that decreasing the amount of pre-hospital crystalloid administration together with early administration of coagulation factors may prevent the development of TIC [9]. The key message is that, through a variety of mechanisms, coagulation pathways are disrupted in severe trauma and attention to these disruptions is essential if improved survival is to be attained. Ideally, the presence of coagulopathy should be established prior to embarking on aggressive coagulation resuscitation unless it is obvious from the outset that the patient will require massive transfusion. Recent research has emphasised the value of point-of-care (POC) testing of coagulation such as thrombelastography (TEG® Coagulation Analyzer, Haemoscope Corporation, Niles, IL, USA) and thrombelastometry (ROTEM® Whole Blood Haemostasis Analyser, Pentapharm GmbH, Munich, Germany) to provide rapid assessment of clot formation [10]. Numerous reports attest to the potential

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value of these technologies, but further evidence is required before they can be considered the standard of care [11e13]. Neural tissue injury Neurological injury represents a specific form of trauma with its own considerations. Damage suffered at the time of injury is largely irreversible, but substantial secondary insults frequently occur that are largely treatable or avoidable. Such secondary injuries can have serious implications for the long-term outcome of injured patients. Cerebral ischaemia and inflammatory mediators result in neuronal and astrocytic swelling which, together with vasogenic oedema, contribute to brain oedema [14]. These secondary insults are influenced by changes in cerebral blood flow (hypo- and hyperperfusion), impairment of cerebrovascular autoregulation, cerebral metabolic dysfunction and inadequate cerebral oxygenation. Furthermore, excitotoxic cell damage and inflammation may lead to apoptotic and necrotic cell death [14]. The damaged brain is particularly sensitive to changes in plasma osmotic pressure and the management of neural injury requires an appreciation of the constituents of resuscitation fluids and their possible effects on osmotic swelling of neural tissues. Spinal cord trauma raises additional complications in the form of spinal shock resulting in hypotension disproportionate to the volume of fluid lost. There is also emerging evidence that high-level spinal-cord injury (above T6) may result in disordered cerebral blood flow regulation [15]. The early management phase following cerebral trauma aims to achieve haemodynamic stability and limit secondary insults (e.g. hypotension, hypoxia) prior to definitive management. [16,17] Principles of volume therapy The objective of volume therapy in trauma is the restoration of tissue perfusion through the replacement of lost volume and the components of shed blood. However, both the volume and content of intravenous solutions have been highly controversial over the last hundred years and remain so today. History The advent of the First World War led to substantial advances in blood transfusion for trauma victims. The earlier discovery of sodium citrate as an anticoagulant allowed for the storage of whole blood that could be prepared in advance and held in reserve for the management of casualties, a practice that has been hailed as perhaps the most important medical advance of the war [18]. Only Group O blood was used as it had already been recognised as the “universal donor” [19]. The use of gelatin to replace lost plasma was also advocated by Robertson [19] and the efficacy of this colloid in haemorrhagic shock was supported by Hogan [20]. Similar practices using saline, colloid and whole blood were adopted in the Second World War, but by this time albumin and freeze-dried plasma were available to expand the pool of blood-based volume therapy. Following the Second World War, a paradigm shift occurred in trauma resuscitation with greater emphasis on resuscitation of the extracellular fluid space. This philosophy, initiated by Wiggers [21], was subsequently supported by Dillon [22] and Shires [23] and advocated the administration of a 3:1 ratio of crystalloid to shed blood. This ratio became widely used for resuscitation into the 21st-century despite a lack of evidence for its validity in the clinical situation. Although survival from the initial injury improved and the incidence of acute renal failure diminished, these strategies led to the emergence of pulmonary fluid overload and the Acute Respiratory Distress Syndrome (ARDS) [24]. In parallel with these high-crystalloid strategies, logistical issues led to the almost universal adoption of component therapy instead of whole blood, although there is a lack of evidence demonstrating that such an approach is equivalent, let alone superior to a whole blood strategy [25]. These high-volume crystalloid strategies have been widely criticised recently as increasing complications [26,27]. Surgical studies in the 21st Century demonstrated a significant reduction in perioperative complication rates, particularly those related to gut function, following the introduction of more conservative crystalloid administration strategies [28,29]. Clear evidence of the dangers of highvolume crystalloid resuscitation in trauma patients emanated from a study of supra-normal oxygen

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delivery in an attempt to improve outcome. To achieve these targets, large volumes of crystalloid were required (>13L in the first 24 h) and this resulted in increased occurrence of abdominal compartment syndrome, multiple organ failure and death compared to a standard resuscitation group who received in the order of 7L [30]. Timing of resuscitation Timing of resuscitation is also controversial. During the First World War, it was found that soldiers treated appropriately within 1 h of being wounded sustained a mortality of 10%, whereas those who had treatment rendered 8 h post-injury had mortality rates as high as 75%, thus defining the ‘‘Golden Hour’’ concept [31]. However, at the same time, Cannon and Fraser called for the limited use of fluids and blood during haemorrhage, indicating that “Injection of a fluid that will increase blood pressure has dangers in itself. Haemorrhage in a case of shock may not have occurred to a marked degree because the blood pressure has been too low and the flow too scant to overcome the obstacle offered by a clot. If the pressure is raised before the surgeon is ready to check any bleeding that may take place, blood that is sorely needed may be lost” [32]. These authors also stated as follows: “When a patient must wait for a considerable period, elevation of his systolic blood pressure to approximately 85 mm Hg is all that is necessary and when profuse internal bleeding is present, it is wasteful of time and blood to attempt to get the patient's blood pressure up to normal.” This principle has recently been revisited. In 1994, Bickell et al. performed a randomised trial of 598 patients with penetrating torso injuries who presented with a prehospital systolic arterial pressure (SBP)  90 mmHg. An immediate resuscitation group received standard fluid therapy during hospital transfer whereas the delayed-resuscitation group received no fluid until they arrived in the operating room. The authors reported a small but significant 8% reduction in mortality in the delayed group, but this was confined to patients with cardiac injuries [33]. A subsequent trial randomised patients in haemorrhagic shock to one of 2 protocols: SBP > 100 mmHg (conventional) or a target SBP of 70 mmHg. Overall survival was virtually identical between the two groups, which these authors attributed to better in-hospital management [34]. These evolving ideas and strategies have resulted in the concept of damage control procedures, involving both damage control surgery and damage control resuscitation (DCR). The two concepts are inextricably linked. Current concepts of early resuscitation, particularly for penetrating trauma, involve a coordinated sequence starting with the pre-hospital phase with rapid hospital transport, hypotensive resuscitation for uncontrolled haemorrhage and maintenance of baseline tissue energy delivery [35]. Pre-hospital resuscitation The use of pre-hospital fluid resuscitation is controversial. In a large retrospective study, with rapid hospital transit times, initial SBP affected mortality, but fluid infusion had no influence [36]. An extensive review of 776,734 patients extracted from the TRAUMA Data Bank concluded that patients who received pre-hospital intravenous cannulation had an increased mortality [37]. However, this finding was widely criticised, predominantly on the basis that a causal relationship could not be established from the data available [38,39]. By contrast, a prospective study using data from 10 Level 1 trauma centres found that patients receiving limited pre-hospital intravenous fluid (up to 700 mL) had a decreased hospital mortality compared to those who received no fluid [40]. A retrospective review of the German Trauma Registry examined data from 948 matched pairs in which one group received <1500 mL prior to hospital admission and the other received greater than this resuscitation volume. The difference in shock on arrival at the hospital was not different between the groups but the highvolume group required significantly more blood and blood products and had a reduced ability to coagulate. Mortality was increased in the high-volume group [41]. The same group showed a similar trend in children that was not statistically significant. [42] Cotton et al. concluded that there was insufficient evidence for or against the insertion of an IV cannula in the pre-hospital setting, but that attempted placement should not delay hospital transfer. Their consensus was that volume resuscitation should be limited to small boluses of fluid and that consideration might be given to hypertonic solutions, but there was insufficient evidence for a firm recommendation [43]. Given the lack of definitive evidence, the current status of pre-hospital resuscitation appears to favour hypotensive resuscitation with low volumes of crystalloid prior to, and

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during hospital transfer targeting the presence of the radial artery pulse and adequate mentation. Various SBP targets between 70 and 90 mmHg have been proposed but lack definitive evidence. The situation for head injured patients is less clear, but generally higher SBP targets are advocated for patients with neurotrauma. Current recommendations are unclear as to an acceptable approach for the patient with combined non-cranial and neurological injuries. While driving SBP to “normal” levels with large volume crystalloid infusions is clearly not appropriate, definitive data on the target SBP for hypotensive resuscitation are lacking especially where trauma is complicated by head injury [44]. Harris et al. [45] concluded that minimising secondary brain injury through optimal supportive care was critical to improving outcome in neurotrauma [45]. However, the definition of what is optimal remains unclear and definitive evidence regarding hypotensive resuscitation remains elusive [46]. In-hospital resuscitation Modern concepts of in-hospital care have the same goal as limited-volume pre-hospital resuscitation to minimise blood loss. Consequently, the concept of DCR together with damage control surgery has aimed at minimising further blood loss through surgical procedures directed at haemorrhagic control and resuscitation strategies aimed at optimising coagulation. In many ways, this has seen a return to the concepts of the First World War resuscitation strategies with early use of blood coupled with mechanical control of bleeding. Early damage control surgery to control further haemorrhage is coupled with DCR that targets patients likely to develop coagulopathy. Damage control surgery for severely injured patients is a process in which the initial operation is abbreviated after control of bleeding and contamination to allow on-going resuscitation in the intensive-care unit [47] while DCR is the overall guiding concept to emerge from the recent military experience [6,48]. DCR advocates provision of coagulation factors, rapid control of surgical bleeding, prevention of acidosis, hypocalcaemia and hypothermia, and limitation of excessive crystalloid use to decrease haemodilution [49]. The correction of hypocalcaemia has more to do with cardiac performance than coagulation as it has been shown that coagulation is unaffected until ionised calcium is < 0.55 mmol/L [50]. Recent military experience has argued strongly in favour of attempting to recreate whole blood through the administration of packed red blood cells (RBCs), fresh frozen plasma (FFP) and platelets in a 1:1:1 unit ratio from the outset of resuscitation. In severely injured patients requiring massive transfusion there is good evidence to suggest that this may contribute to a reduction in haemorrhagic mortality. Borgman et al., using a retrospective chart review of 246 patients requiring massive transfusion (defined as 10 units RBCs in 24 h) in a combat support hospital, divided the casualties into low FFP:RBC ratios (1:8) medium (1:2.5) and high (1:1.4). In these groups, overall mortality rates were 65%, 34% and 19% (p < 0.001) [51]. However, this was followed by a prospective study of 806 consecutive civilian trauma patients of whom 250 received both RBCs and FFP. Analysis by stepwise regression controlling for significant variables found that the FFP:RBC ratio did not predict intensive care unit days, hospital days or mortality in patients requiring massive transfusion [52]. Riskin and colleagues studied 40 patients before and 37 patients after the introduction of a massive transfusion protocol (MTP) and found a reduction in mortality despite the fact that the FFP:RBC ratio was unchanged at 1:1.8. They concluded that early availability of blood and blood products appeared to decrease mortality significantly [53]. Several other authors have supported the concept of a high FFP:RBC ratio (<1:2) [54e56]. However, in patients where there was no demonstrable coagulation defect there was no evidence of benefit from a high ratio and concern was expressed that the higher costs and risks associated with inappropriate administration of FFP required further study [57]. Furthermore, in patients who did not require massive transfusion, plasma administration was associated with a substantial increase in complications, particularly ARDS, with no improvement in survival [58]. It has also been noted that time-based analysis found no association between the FFP:RBC ratio and survival, suggesting that survival bias may have influenced earlier results [59]. The importance of mechanical control of haemorrhage is emphasised by a recent publication showing that, despite aggressive haemostatic resuscitation, ROTEM parameters and lactate clearance did not improve until haemorrhage control was achieved [60]. It is crucial to remember that FFP is relatively deficient in fibrinogen, with a concentration of around 1 g/L compared to the normal value of 1.5e3.0 g/L. In cases of severe fibrinogen deficiency, fibrinogen concentrates (where available) or cryoprecipitate seem to be better options as they can restore fibrinogen levels more effectively. The role of fibrinogen concentrate has been the subject of a recent commentary [61].

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Non-blood resuscitation Whilst haemostatic resuscitation appears to be of value in the management of patients requiring massive transfusions, it must be recognised that this represents the minority of trauma patients. Only 25% of trauma patients actually receive blood transfusions and between 2 and 3% of the civilian casualties and 7e8% of military casualties require massive transfusion [62]. Thus, it is inappropriate to commence haemostatic resuscitation in all patients until it is obvious that massive transfusion will be required or the presence of coagulopathy has been established. For the majority of trauma patients, volume resuscitation should be based on standard principles using non-blood products as the primary resuscitating fluid. Blood and blood products should be administered against fixed endpoints, usually a Hb of 7e9 g/dL or the presence of coagulopathy on laboratory or POC tests. Similarly, once the Hb deficit and coagulation problems have been resolved, on-going resuscitation should probably not be primarily with blood products. Crystalloid solutions The clearest evidence to emerge from trauma resuscitation data in the last 10 years is that crystalloid overload is uniformly harmful and should be avoided. Unless there are obvious sources of ECF losses crystalloid administration should not greatly exceed the maximum daily crystalloid load of approximately 2 L per day in the average adult. Crystalloid remains the most widely used initial resuscitation fluid, but small volume resuscitation in the pre-hospital phase should be limited to 250 mL boluses and should not exceed 1 L in total volume. Once in hospital, resuscitation should focus on blood components including RBCs, coagulation factors as required and limited crystalloid administration. Progressive crystalloid resuscitation in hospital patients correlated with adverse outcomes other than mortality including an increased incidence of ARDS, multiorgan failure and compartment syndromes [63]. In a retrospective survey of 3137 patients in the emergency department administration of crystalloid in excess of 1.5 L was an independent risk factor for mortality, especially in elderly patients [64]. The composition of the individual crystalloid solutions is important and this will be dealt with elsewhere in this publication. However, some comments are relevant. Since acidosis contributes to impaired coagulation, the use of 0.9% saline must be carefully considered in trauma. Ringer's lactate is substantially hypo-osmolar, and its use may well contribute to worsening cerebral oedema in neurotrauma although there is little conclusive evidence of this in humans. Nevertheless, it is generally recommended that Ringer's lactate should not be used in resuscitation of head injured patients. The solution also contains a substantial calcium concentration, ranging between 1.8 and 2.4 mmol/L all as ionised calcium. This creates potential problems if it is mixed with citrated solutions containing clotting factors including whole blood, FFP or cryoprecipitate. Better balanced solutions such as Plasmalyte A (also known as Plasmalyte 148) have been shown to produce less acid-base disturbances with better preservation of renal cortical tissue perfusion in trauma resuscitation than saline. [65] Colloid solutions There is a variety of colloid solutions available, including various albumin preparations and the semi-synthetic colloids: gelatin, dextran and hydroxyethyl starch (HES). Although there is a substantial volume of literature on the crystalloid-colloid debate, the nature of trauma and the difficulties in conducting appropriate randomised, controlled trials in this area have meant that the quality of evidence is poor and there are few well-conducted trials demonstrating the relative advantages of each type of fluid. Several meta-analyses have failed to demonstrate any benefit of colloid solutions over crystalloid resuscitation in critically ill patients [66,67], but most of the literature is based on postresuscitation intensive care studies in sepsis and seldom includes properly conducted randomised trials in trauma. Recent evidence on the place of colloids in trauma has been reviewed [68]. Albumin Albumin has been widely advocated for trauma resuscitation. However, it is extremely expensive and prone to the same supply problems as other human-derived blood products. No clear evidence of

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benefit or harm has been shown for the use of albumin in trauma, with the possible exception of head injury as discussed below. Gelatins The gelatins are the oldest synthetic colloids available, and are derived from the degradation of bovine collagen. There are two types of gelatins available, the urea-linked form typified by Haemaccel® and the succinylated form as typified by Gelofusin®. Gelatins have a negative charge that enhances intravascular retention, despite the molecular weight of only 30e35 kDa. They have a short lived plasma volume expansion lasting for 1e3 h [69]. The gelatins are fully cleared from the body through the kidney. The gelatins exert little effect on coagulation. Although they may impair clot strength, mainly on a dilution basis, only minor coagulation disturbances are recognised and no volume limitation applies. The main adverse effect attributable to the gelatins is that of anaphylaxis. The risk is significantly greater for the urea-linked gelatins than the fluid gelatins, but both appear to have a higher risk of allergic reactions than other colloids [70]. Dextrans The dextrans have numerous adverse effects. Dextran 40 10% is substantially hyperoncotic and may lead to hyperosmotic renal failure. Rarely, adverse reactions including the dextran syndrome and anaphylaxis may occur. Recent research has suggested that the combination of hypertonic saline and dextran may have advantages in resuscitation, particularly in patients with brain injury [71,72]. However, the problems that the dextrans pose with cross matching together with the risk of anaphylaxis have led to these products being seldom used in trauma resuscitation. Hydroxyethyl starch (HES) Of the semi-synthetic colloids, HES has been by far the most widely investigated. A variety of different HES products exists, with considerable differences in their pharmacological properties. HES solutions are classified according to the in vitro molecular weight (MW) and molar substitution (MS). The current classification is as follows: Molar substitution ratio classification: MS

Generic name

Commercial products

0.7 0.6 0.5 0.4

Hetastarch Hexastarch Pentastarch Tetrastarch

Hespan®, Plasmasteril®, Hextend® Elohes® HAES-Steril®, Pentaspan®, Hemohes® Voluven®, Venofundin®, Tetraspan®

There has been considerable criticism of HES recently in the light of 3 “pragmatic” critical care studies that have been associated with harm, notably renal complications. The first of these studies used a hyperoncotic 10% HES in doses well in excess of those recommended by the manufacturer and showed a dose-related incidence of renal injury [73]. The second study (CHEST) comparing HES and saline found no difference in mortality over nearly 7000 subjects. Although the HES group received more renal replacement therapy (RRT), the RIFLE criteria favoured the HES [74]. The third (6S) study found an increased incidence of RRT in septic patients in the HES (potato starch) group together with an increased 90-day mortality [75]. All of these studies enrolled patients after primary resuscitation and are not pertinent to the consideration of acute trauma resuscitation. By contrast a recent study in which colloid was compared to crystalloid for initial resuscitation found a 90-day mortality signal in favour of colloid, with the predominant colloid being HES 130/0.4 [76]. Two systematic reviews of the use of HES 130/0.4 in perioperative medicine found no evidence of renal injury or increased mortality in this group of patients [77,78]. A retrospective study of 1714 patients admitted to a level 1 trauma centre examined the outcomes in patients who did, or did not receive a colloid (Hextend®) as part of the resuscitation strategy. Compared to the crystalloid-only standard of care treatment, the overall mortality analysed by

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univariate analysis was significantly lower in the colloid-treated patients (5.2% v 8.9%, p ¼ 0.0035), particularly in penetrating trauma. Coagulation measures, urine output and renal function were similar between the groups, but there were more early deaths in the standard of care group, which introduces the possibility of selection bias. Controlling for early deaths with multivariate analysis showed similar trends, but the data no longer reached statistical significance [79]. A recent study comparing DCR in combination with either HES (Hextend®) or crystalloid demonstrated a reduction in mortality (7.1% v 39.3%) when colloid was used in conjunction with high ratio DCR compared to any volume of crystalloid. This study also demonstrated an apparent “dose-response” of crystalloid, with decreased survival associated with increased use of crystalloid [80]. The first randomised, double-blind controlled trial of crystalloid (0.9% saline) versus isotonic colloid (HES 130/0.4 in saline) in trauma resuscitation has recently been published. In this study of 109 patients, blunt and penetrating trauma were randomised separately. In penetrating trauma (n ¼ 67), the HES group showed faster lactate clearance over the first four hours of resuscitation and acid base balance and lactate levels were significantly better on Day 1. The HES group had a zero incidence of renal injury (RIFLE criteria) compared to 16% in patients treated with saline p ¼ 0.019). Maximum SOFA scores were significantly lower in the HES group. Substantially less colloid was required than crystalloid and the use of blood and blood products was similar. The blunt trauma analysis was severely hampered by the fact that patients in the blunt HES group were much more severely injured (median ISS 29.5 vs. 18; P < 0.01). There was no significant difference in the use of study fluid between groups but the HES group required significantly more blood and blood products. Outcomes were similar in both blunt trauma groups in terms of renal function and organ recovery, with no differences in mortality [81]. Neurotrauma The issue of neurotrauma remains poorly resolved. In the pre-hospital phase, it is generally accepted that, in the absence of active bleeding, more aggressive resuscitation may be appropriate than in other forms of trauma. Where there is a conflict of interests in a bleeding patient who also has suffered neurological injury, the situation is much less clear, but most authorities would recommend a higher SBP (>100 mmHg) in the pre-hospital phase [44]. Once the patient is in hospital, similar principles apply, with DCR being appropriate in patients requiring massive transfusion. Aggressive management including resuscitation with blood products and hyperosmolar therapy in gunshot wounds of the brain was associated with significant improvements in survival in a recent report [82]. In less seriously bleeding patients, fluid resuscitation volumes should probably be minimised and there is an argument in favour of hypertonic solutions, although these have not been shown to be beneficial. In the SAFE study [83] albumin was associated with a worse outcome in head injured patients, probably on the basis of increased intracranial pressure [84,85]. However, the albumin used in this study was substantially hypo-osmolar with an osmolality of around 260 mosm/L [86]. Other studies of the use of HES or albumin in head injured patients have not demonstrated similar increases in intracranial pressure [87]. Recent animal and human studies suggest a benefit for albumin over Ringer's lactate in head injury [88]. A retrospective study of 93 patients with severe traumatic brain injury investigated the impact of a resuscitation protocol that incorporated the use of albumin. These authors reported an early achievement of negative fluid balance in these patients with well-maintained plasma albumin concentrations. Over the first 10 days for which the patients were studied, colloids constituted 40e60% of the total fluids given daily and fluid balance was assisted by the use of furosemide. Mortality at 28 days and 18 months was 11% and 14% respectively [89]. The authors contrast this with the SAFE study where mortality was substantially higher, but these comparisons should be viewed with caution as the resuscitation strategies, particularly the management of intracranial pressure may well have been different between the two studies. However, a reappraisal of the use of albumin in brain injury has recently been advocated [90]. Burns There have been several recent papers examining the use of fluids in patients suffering burns. A pilot study of hyperoncotic 10% HES 200/0.5, was abandoned prematurely as the hyperoncotic starch was associated with an apparent increase in mortality [91]. These data underline the view that the use of

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hyperoncotic colloids as acute resuscitation solutions is problematic. However, a number of other studies and reviews suggest that the role of colloids in the resuscitation of patients suffering burns is being reexamined [68]. A recent review of this topic commented that, while crystalloids have been the mainstay of resuscitation for the better part of four decades, there has been a progressive but as yet unexplained recent trend toward provision of resuscitation volumes well in excess of those predicted by the various formulae (“fluid creep”). This increased fluid load has been associated with numerous oedema-related complications. This review emphasizes that, in burns involving >25% body surface area, capillary permeability is increased, not only in the damaged tissue, but also in non-burnt areas. It was proposed that correction of fluid creep will likely include tighter control of titration, re-emergence of colloids and hypertonic salt solutions, with possibly the use of adjunctive markers of resuscitation other than urinary output [92]. Another review concluded that starch colloids may limit burn oedema by ameliorating capillary leak and that improved endpoints for resuscitation may help to minimize the problems of over-resuscitation [93]. A further retrospective review examined the effect of adding albumin to the resuscitation fluid strategy on fluid input/output (I/O) ratios. The administration of albumin rapidly reduced hourly fluid requirements, restored normal I/O ratios and ameliorated fluid creep [94]. A study in paediatric burns confirmed these findings showing that the use of albumin restored a normal I/O ratio in paediatric patients, adding further weight to the inclusion of colloid in burns resuscitation strategies [95]. Conclusions In recent years there has been a marked shift in the concepts governing trauma resuscitation, with modern views startlingly resembling the initial findings in the First World War. In patients with severe trauma requiring massive transfusions (<10% of all trauma patients) aggressive damage-control resuscitation and surgery carry the prospect of reducing mortality particularly amongst battle casualties with penetrating injuries. The use of high FFP:RBC unit ratios (>1:2) has been widely recommended. In the civilian population, these data are less conclusive, but the principles are probably still valid when limited to massive transfusion or clearly coagulopathic patients. Pre-hospital resuscitation now focuses on minimal fluid interventions with low volumes of crystalloid as the first line fluid approach. Once the patient reaches hospital, more aggressive fluid resuscitation strategies may be appropriate. In patients not requiring massive transfusion, substantial portions of the resuscitation volume should be administered with clear fluids. No more than 2 L of such fluid should be given as crystalloid, preferably as a balanced solution that is isotonic with plasma. The role of colloid in penetrating trauma seems to be beneficial, but there is insufficient data at present to make evidencebased recommendations in blunt trauma.

Practice points  Damage control resuscitation is the principal consideration for volume therapy and should involve appropriate volume therapy and management of bleeding.  Pre-hospital resuscitation should be limited and aimed at establishment of a palpable radial pulse and maintenance of mentation. In neurotrauma higher arterial pressure may be necessary.  Coagulation management is essential and should include a consideration of a high FFP:RBC ratio in patients needing massive transfusion (>10 units RBC) or who show coagulopathy.  Patients not requiring massive transfusion should be resuscitated with clear fluids with an appropriate balance of crystalloid and colloid. Excessive use of FFP in such patients may be harmful.  Crystalloid overload must be avoided.  There is no evidence that resuscitation with colloids, including HES, is harmful and there is reasonable evidence of benefit especially in penetrating trauma.

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Research agenda  Further research is needed to establish the best form of damage control resuscitation including the place of coagulation support in the form of fibrinogen concentrate and tranexamic acid.  Which patients benefit from a high FFP:RBC ratio needs to be better defined.  The place of colloid resuscitation in blunt trauma needs further exploration.  The optimal volume management of neurotrauma patients who also have non-cranial trauma needs to be established.

Acknowledgement Acknowledgement/Conflict of interest statement: Prof James has received honoraria for lectures from various fluid companies including Fresenius Kabi, BBraun and Baxter. The FIRST trial was supported by an unrestricted educational grant to the University of Cape Town from Fresenius Kabi.

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