TRAUMA III

Trauma III

The next generation in shock resuscitation

Frederick A Moore, Bruce A McKinley, Ernest E Moore Resuscitation of the severely injured patient who presents in shock has improved greatly, following focused wartime experience and insight from laboratory and clinical studies. Further benefit is probable from technologies that are being brought into clinical use, especially hypertonic saline dextran, haemoglobin-based oxygen carriers, less invasive early monitors, and medical informatics. These technologies could improve the potential of prehospital and early hospital care to pre-empt or more rapidly reverse hypoxaemia, hypovolaemia, and onset of shock. Damage control surgery and definitive interventional radiology will probably combine with more real-time detection and intervention for hypothermia, coagulopathy, and acidosis, to avoid extreme pathophysiology and the bloody vicious cycle. Although now widely practised as standard of care in the USA and Europe, shock resuscitation strategies involving haemoglobin replacement and fluid volume loading to regain tissue perfusion and oxygenation vary between trauma centres. One of the difficulties is the scarcity of published evidence for or against seemingly basic intervention strategies, such as early or largevolume fluid loading. Standardised protocols for resuscitation, representing the best and most current knowledge of the clinical process, could be devised and widely implemented as interactive computerised applications among trauma centres in the USA and Europe. Prevention of injury is preferable and feasible, but early care of the severely injured patient and modulation of exaggerated systemic inflammatory response due to transfusion and other complications of traditional strategies will probably provide the next generation of improvements in shock resuscitation. Advances in shock resuscitation have occurred during military conflict because of concentrated experience with patients. With other clashes around the world that will probably involve both military personnel and civilians, what further advances should we expect in the next several years? Shock resuscitation is an obligatory intervention that with refinement has changed the epidemiology of deaths from trauma (table 1). During World War I, as a result of the wound toxin hypothesis, no preoperative resuscitation was administered and many soldiers died. In World War II and the Korean conflict, due to the misconception over haemoconcentration, colloid was administered and eventually banked blood resuscitation became standard care. Early survival improved, but many casualties later died of acute renal failure. During the Vietnam conflict, with the recognition that the extracellular fluid space had to be repleted, large volume isotonic crystalloid solutions replaced colloids for initial shock resuscitation. Mortality rates and the incidence of acute renal failure decreased but adult respiratory distress syndrome emerged as a major source of morbidity and mortality. Through the 1970s and early 1980s, intensive care units (ICUs) were developed, where advanced technology and improved care allowed patients with single organ failure to survive for long periods. Patients no longer died of acute renal failure or adult respiratory distress syndrome, but developed multiple organ failure, which, at that time, was usually fatal. From the mid-1980s to the present, regional trauma systems have been implemented, in which the most severely injured patients are rapidly triaged to high volume, level 1 trauma centres where rapid intervention and
Lancet 2004; 363: 198896
Department of Surgery, University of TexasHouston Medical School, Houston, TX, USA (Prof F A Moore MD, B A McKinley PhD); and Department of Surgery, University of ColoradoDenver Health Medical Center, Denver, CO USA (Prof E E Moore MD) Correspondence to: Dr Frederick A Moore, Department of Surgery, University of TexasHouston Medical School, 6431 Fannin Street, Suite 4264, Houston, TX 77030, USA (e-mail: Frederick.A.Moore@uth.tmc.edu)

Era World War I World War II, Korean war Vietnam war

Focus Wound toxins Intravascular repletion

Resuscitation None Colloids, blood

Outcome Early death Early survival ARF death Early survival ARF ARDS death ARF ARDS ? MOF MOF deaths

Intravascular Crystalloids, and extracellular banked blood fluid repletion ICUs, organ PA catheters, failure, metabolic endpoints of support resuscitation Trauma centres, trauma systems

1970s80s

Mid-1980s to present

Rapid triage, Early survival damage control, ARDS/MOF shock and ARDS/MOF deaths trauma ICUs

ARF=acute renal failure. ARDS=adult respiratory distress syndrome. MOF=multiple organ failure.

Table 1: Improvements in resuscitation and the changing epidemiology of trauma deaths over time

prompt definitive care are given.1 Consequently, the epidemiology of death from trauma has changed.2 Rates of early hospital death from blood-loss have been reduced with the introduction of damage control surgery. For example, damage control laparotomy is well established in the initial surgical care of patients with severe torso injury, and consistent results have been achieved in the USA and Europe.3 These patients, however, remain at high risk of multiple organ failure.4 Although mortality rate from multiple organ failure is decreasing, it remains the major cause of prolonged ICU stays. As we learn more about the relations between the initial traumatic shock insult, the obligatory resuscitation, and the dysfunctional inflammatory response that causes multiple organ failure, some

Search strategy
For this review we drew on a continuously updated collection of references on shock resuscitation, maintained at the Trauma Research Center, University of Texas-Houston Medical School, supplemented by a PubMed search using the keywords shock, trauma, and resuscitation.

1988

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disconcerting observations indicate that our fundamental approach to resuscitation needs to be reassessed.510 The purpose of this report is to briefly review traditional resuscitation, discuss its inherent flaws in view of our current understanding of the pathogenesis of multiple organ failure, and identify alternative methods of fluid resuscitation, haemorrhage control, and monitoring techniques that could be used in the near future to improve outcome.

Traditional resuscitation
Crystalloid versus colloid debate Since the early 1940s, when restoration of circulatory blood volume was embraced as pivotal in shock resuscitation, controversy has existed as to which fluid to use for this purpose.11 A review article from that era concluded that saline and glucose solutions were unsuitable because they were quickly lost from the intravascular space. Plasma and serum were considered the best substitutes for whole bloodand in some cases, better than blood itself.12 This was the resuscitation strategy used in World War II. Isotonic crystalloids became the standard of care in the late 1960s based on the laboratory work of Moyer, Shires, Moss, and others,1315 which showed that: (1) large-volume resuscitation with isotonic crystalloids provided the best survival; (2) extracellular fluid was redistributed during shock into both the intravascular and intracellular spaces; (3) optimal resuscitation corrected this extracellular fluid deficit, required infusion of isotonic crystalloid fluid, and shed blood in a ratio of three volumes of crystalloid to one of blood; and (4) in severe shock, this ratio increased up to eight to one. Isotonic crystalloid fluids were used in the Vietnam conflict. For various reasons, mortality and acute renal failure decreased, but a new entity called shock lung emerged. This complication was soon described in civilian publications as adult respiratory distress syndrome, and was shown to be the major source of morbidity and mortality in the ICU. The pathogenesis was not known, but controversy existed over whether adult respiratory distress syndrome was an iatrogenic complication of resuscitation with crystalloids.16,17 Beginning in the mid1970s, prospective randomised controlled trials were done to compare crystalloids with colloids in resuscitation, with pulmonary dysfunction as the primary endpoint.1820 Results conflicted because of shortcomings in study design, which included small numbers of patients, heterogeneous populations, and different resuscitation endpoints and sodium loads, and difficulty in defining pulmonary dysfunction. These data have been assessed by meta-analysis,19,20 and no difference in the incidence of pulmonary dysfunction has been found. However, when mortality is used as the endpoint and the data are subgrouped, the use of crystalloids in trauma patients is associated with improved survival. Although these data are not definitive, this finding does lend support to the current common use of crystalloids in US trauma centres. The type of crystalloid fluid used in resuscitation engenders less controversy. Normal saline and lactated Ringers are the two balanced salt solutions that are commonly used. Although important theoretical differences favour lactated Ringers, laboratory investigators have had difficulty demonstrating substantial differences in outcome.21,22 Results of one study showed that the two solutions were equivalent in moderate haemorrhagic shock, but that with massive haemorrhage normal saline was associated with greater physiological derangement and greater mortality rate, compared with Ringers.23

Transfusion trigger Banked red blood cells have been widely available since World War II, but the indications for administration continue to be debated. Animals with haemorrhagic shock show improved survival with haemoglobin concentration maintained in the range 120130 g/L.24,25 Animal models of isovolaemic haemodilution suggest that the optimum haemoglobin concentration for maintaining systemic oxygen delivery (DO2) is 100 g/L, but in healthy human volunteers isovolaemic haemodilution is tolerated at concentrations as low as 50 g/L.26 Until recently, clinical studies in critically ill patients concluded that 100 g/L haemoglobin was optimum for shock resuscitation,27 but more recent consensus panels have judged that a lower concentration is adequate. The American Society of Anesthesiology recommends maintaining haemoglobin at greater than 60 g/L, whereas the National Institutes of Health recommends a concentration of greater than 70 g/L.28,29 A prospective randomised controlled trial has shown that ICU patients randomised to restrictive blood transfusions (transfuse if haemoglobin concentration <70 g/L and maintain between 70 and 90 g/L) did as well and possibly better than patients who were liberally transfused (transfuse if <100 g/L and maintain between 100 and 120 g/L).30 This study was done in a select group of euvolaemic patients. Malone and colleagues report blood transfusion as a risk factor, independent of shock severity, for poor outcome in patients with trauma.31 Short-term improvement in survival is believed to be due to reduction of the adverse immunological consequences of transfusion of banked red blood cells. The concept of transfusion-related immunosuppression dates from the early 1970s with the observation that greater pretransplant transfusion was associated with improved renal allograft survival.32 Subsequently, perioperative transfusion was associated with cell-mediated immunosuppression, tumour recurrence, and postoperative infections.3336 The capacity of banked red blood cells to provoke neutrophil cytotoxicity is a key mechanism in multiple organ failure.5,37 In epidemiological studies, early transfusion has been shown to be a strong independent risk factor for multiple organ failure.4,8 Focused clinical studies have shown that severely injured patients at high risk of multiple organ failure have circulating neutrophils that are primed for cytotoxicity within the first 6 h after injury, increased expression of adhesion receptors, activation of p38 mitogen-activated protein kinase, and delayed apoptosis.6,38,39 The precise mechanisms linking red blood cell transfusion and neutrophil priming remain to be established, but it is generally believed that passenger leucocytes accompanying red blood cells in storage are important in the generation of proinflammatory agents and progressively increase from 14 to 42 days of storage.4042 Some investigators have implicated cytokines (tumour necrosis factor , interleukin 1, interleukin 6, interleukin 8), but our focus has been on proinflammatory lipids presumably generated from the degradation of the red blood cell membrane.4345 Although pre-storage leucoreduction of red blood cells decreases the generation of cytokines, this process does not eliminate neutrophil priming.46 Another emerging concern regarding stored cells is that substantial shape changes and impaired deformability occur by the second week of storage and progress during further preservation.47 The effects of decreased deformability on microcirculation have been documented experimentally, and include impaired tissue access and entrapment resulting in microvascular obstruction.48 These findings might account for the observation that blood transfusion failed to improve

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oxygen consumption in critically ill and injured patients and, in one study, seemed to induce splanchnic ischaemia.49,50 Endpoints of resuscitation Initial care Initial care of severely injured patients presenting in shock is prioritised to ensure survival (ie, advanced trauma life support), and empiric volume loading is an emphasised early intervention.1 The response of blood pressure and heart rate to volume loading defines stability. For patients who do not respond appropriately, diagnostic testing is focused on identifying sources of uncontrolled haemorrhage, which need prompt attention in the operating room or interventional radiology suite. Controversy exists as to whether blood pressure and heart rate should be restored to normal at this point.51,52 One recent prospective trial in penetrating torso trauma showed worse survival in patients who were volume loaded before definitive vascular control was obtained in the operating room, although subgroup analysis showed this effect to be significant only in those with pericardial tamponade.53 Whether this finding applies to patients with blunt trauma is not clear.53,54 Furthermore, 20% of patients with major torso trauma will have a serious concomitant closed head injury and, if the patient is under-resuscitated, decreased cerebral perfusion pressure can result in devastating secondary brain injury.55 Fortunately, in most patients, there is time to obtain additional information. Measurement of arterial blood gases with base deficit determination indicates the severity of shock, and serial haemoglobin measurements assess ongoing bleeding. Additional monitoring should include central venous pressure (via central venous line), urine output rate (via Foley catheter), and arterial haemoglobin oxygen saturation (via pulse oximetry). The current goal is to return blood pressure and heart rate to normal, and establish urine output while maintaining central venous pressure in a moderate range (815 mm Hg). Oxygen delivery and optimisation Once operating room and interventional radiology procedures are complete, severely injured patients are transferred to the ICU where attention is focused on optimising resuscitation. The use of pulmonary artery catheters is controversial, but most trauma centres in the USA use them in most patients with evidence of ongoing haemorrhagic shock.56 Prospective studies in the 1980s showed that high-risk surgical patients had improved survival when subjected to resuscitation protocols aimed at optimising DO257 These findings gave rise to the hypothesis that unrecognised flow-dependent oxygen consumption (VO2) was an important cause of multiple organ failure and could be eliminated by maximising DO2. Although the physiological argument and epidemiological data supporting this concept are enticing, investigators have failed in several prospective randomised trials to document consistent outcome advantages, and one multicentre European study concluded that maximising DO2 is harmful.5860 These disparate results could be due to a number of confounding variables, including different inclusion criteria, variable timing of the intervention, and different types of intervention. The original studies were designed to optimise DO2 before a major operative insult and to maintain DO2 perioperatively. Studies in nonsurgical ICUs were primarily done in patients with established sepsis, septic shock, or adult respiratory distress syndrome. At the time of enrolment, these patients already had organ failure, and prolonged

resuscitation with high dose inotrope and vasopressor agents might well have been harmful. On the other hand, earlier intervention with less aggressive interventions remain an attractive approach in patients with major torso trauma. High risk trauma patients can have unrecognised early myocardial dysfunction, which is greatly improved by volume loading. The primary goal of shock resuscitation is the establishment of adequate DO2. The definition of adequate, however, remains controversial. The three primary determinants are arterial haemoglobin concentration, oxygen saturation, and cardiac output. In acute shock, high oxygen saturation is easily maintained by increasing the fraction of inspired oxygen concentration (FIO2), and haemoglobin concentration is maintained by liberal blood transfusion, but cardiac output is more difficult to manipulate and monitor. Continuous cardiac output monitoring by pulmonary artery catheter thermodilution technology is the standard of care. Traditionally, thermodilution has been used to measure cardiac output because it was more convenient than alternative indicator dilution methods (direct Fick, dye dilution). The process has become even more convenient with the introduction of continuous cardiac output technology, which has proven to be as accurate as the bolus technique and provides a real-time response to resuscitation. Less invasive techniques of measuring cardiac output include transthoracic electrical bioimpedance, transoesophageal echocardiography, Doppler ultrasound, combined indicator dilution, and arterial pressure waveform analysis and analysis of carbon dioxide rebreathing. These technologies continue to be refined and have replaced thermodilution in some ICUs, but unfortunately have not been systematically tested in trauma resuscitation. The pulmonary artery catheter also provides essential information about preload assessment (ie, pulmonary artery capillary wedge pressure, or, more recently, right ventricular end diastolic volume index). To optimise cardiac output, preload often needs to be pushed to relatively high pressures and, if this does not work, vasoactive drugs need to be administered. How far to increase DO2 is a clinical dilemma. Driving DO2 until VO2 reaches a plateau makes sense intuitively, but is not clinically practical. Cardiac output has substantial variability and since both DO2 and VO2 are derived from cardiac output, it is virtually impossible to obtain a stable plateau. Shoemaker and colleagues57 have simplified this dilemma. In an analysis of the physiological response in survivors and non-survivors, they showed that a DO2 index of greater than 600 mL/min per m2 was associated with survival. They then showed in prospective trials that patients maintained at such a DO2 index had improved survival. Most other investigators have not succeeded in reproducing these results. Our current experience is that a DO2 index of greater than 500 mL/min per m2 obtains a similar response with less need for volume loading and blood transfusions.61 An alternative is to maintain increased DO2 until lactate concentration returns to normal. In our experience VO2 fails to increase, despite increased DO2, in a substantial subset of patients, and lactate concentration remains persistently increased. This finding probably represents a defect in mitochondrial function in peripheral tissues, and these patients often develop multiple organ failure.7 Conceptually, this response is similar to that of resuscitating patients with advanced septic shock. Early volume loading has been shown to be beneficial, but aggressive resuscitation in the later stages does not improve outcome and a persistently increased lactate is highly

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predictive of death. An alternative explanation is that high lactate concentration occurs following severe insults because excessive mobilised substrates cannot be processed through the Krebs cycle.62,63 As a result, there is a build up of intracellular pyruvate that is converted to lactate, which then exits the cell and is taken back to the liver to be converted into glucose (the Cori cycle). Thus, a high lactate concentration at the end of resuscitation simply reflects a more severe stress response.

observation that blood transfusions contain proinflammatory mediators that both prime and activate neutrophils.4045

The next generation

Fluid resuscitation Crystalloid versus colloid debate revisited Unfortunately, the prospective randomised controlled trials comparing crystalloid and colloid resuscitation were done in the 1970s and 1980s, before the recognition of abdominal compartment syndrome as an important clinical entity. Additionally, albumin was the principal colloid used, but other types of colloid (starches and gelatins) are available. Because of their higher molecular weights, these colloids are confined to the intravascular space and their infusion results in more efficient plasma volume expansion. In severe haemorrhagic shock, however, the permeability of capillary membranes increases, allowing colloids to enter the interstitial space, which can then worsen oedema and impair tissue oxygenation. The theory that these highmolecular-weight agents plug capillary leaks that occur during neutrophil-mediated organ injury has not been established.70,71 Furthermore, Lucas and colleagues72,73 propose that resuscitation with albumin induces renal failure and even impairs pulmonary function. Similarly, hetastarch has been shown to induce renal dysfunction in patients with septic shock and in recipients of kidneys from brain-dead donors.7476 Hetastarch also has a limited role in massive resuscitation because it causes a coagulopathy and hyperchloraemic acidosis due to its high chloride content. A new hydroxyethyl starch preparation (Hextend) purportedly does not cause these adverse effects, but has not been studied in massive resuscitation.77 We share the belief that colloids might reduce the incidence of abdominal compartment syndrome, but this possible benefit must be weighed against the potentially detrimental effects of colloids already reported. Additionally, alternative crystalloid solutions are being developed that not only expand the intravascular space and replete the extracellular fluid, but also have anti-inflammatory properties (eg, Ringers ethyl pyruvate).78 Hypertonic saline A provocative report by Velasco and colleagues in 198079 spurred research interest in hypertonic saline. Smallvolume hypertonic saline was shown to be as effective as large-volume crystalloids in expanding plasma volume and enhancing cardiac output in haemorrhagic shock in animals.80 Furthermore, hypertonic saline increased perfusion of the microcirculation, presumably by selective arteriolar vasodilation and by decreasing swelling of red blood cells and of the endothelium.81 This improved microcirculation, however, could lead to increased bleeding. Consequently, hypertonic saline was tested in animal models of uncontrolled haemorrhagic shock and was shown to increase bleeding, but mortality was modeldependent and the best survival was obtained when saline was given with high-volume crystalloids.82,83 Additionally, the resuscitative effectiveness of hypertonic saline was found to be enhanced by combination with dextran (hypertonic saline dextran [HSD])84 In view of the small volume needed to achieve these effects, there was great interest in the use of these fluids in resuscitation in the field for both military and civilian use. From the late 1980s through the early 1990s, several trials were done. Individually, these trials found survival outcome to be inconsistently improved, but did document that a bolus of hypertonic saline or HSD was safe.85,86 Meta-analysis of these data suggests that hypertonic saline is no better than

Why change resuscitation?

Over the last decade, epidemiological studies of patients with torso trauma have revealed several disturbing observations that have led us to conclude that fundamental changes in current resuscitation strategies are needed. Although now widely practised as standard of care in the US and Europe, shock resuscitation strategies involving haemoglobin replacement and fluid volume loading to regain tissue perfusion and oxygenation are quite variable among trauma centres, and published evidence for or against seemingly basic intervention strategies (eg, early or large volume fluid loading6466) is scant. First, the clinical trajectory of patients who develop multiple organ failure is set early in the resuscitation process (ie, within 6 h of injury).5,9 Many patients at high risk require emergency surgery or interventional radiology, and arrive in the ICU after this time window.9 Although resuscitation efforts in the ICU can clearly modify the subsequent clinical course, even highly refined and individually tailored resuscitation cannot reverse the dysfunctional response that has already occurred.10 To substantially reduce the incidence of multiple organ failure, interventions before ICU admission will need to be modified. Unfortunately, this will need to be accomplished in chaotic clinical situations such as damage control surgery, and in environments not traditionally focused on monitoring resuscitation. Second, although initial crystalloid volume loading is valuable in defining haemodynamic stability, to continue this process in the face of ongoing haemorrhage promotes further bleeding, haemodilutes the patient, and sets the stage for the so-called bloody vicious cycle of hypothermia, acidosis, and coagulopathy.10 This syndrome is particularly problematic in patients with blunt trauma, who often have sources of bleeding that are not amenable to direct control. Failure to resuscitate these patients will, however, ultimately lead to irreversible shock. Third, although crystalloid resuscitation is efficacious in most patients, it produces problematic tissue oedema in patients who arrive in severe shock. These patients typically need massive fluid resuscitation to maintain intravascular volume and many develop the abdominal compartment syndrome, which seems to be a second hit for multiple organ failure.10,67 Patients with severe torso trauma who are admitted with shock and an associated severe closed head injury are in a precarious situation. Under-resuscitation decreases cerebral perfusion pressure, which causes secondary brain injury. Excessive crystalloid administration promotes cerebral oedema, which increases intracranial pressure and further decreases cerebral perfusion pressure. Fourth, shock initiates dysfunctional inflammation that causes multiple organ failure. Resuscitation is an obligatory intervention to decrease the severity of the shock insult, but the current strategy is not directed at modulating inflammationin fact, it may worsen it. Laboratory studies show that lactated Ringers solution activates neutrophils.68,69 Even more disturbing is the

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Carrier Haemolysates

Developments 1933Bovine haemolysates into dogs/cats: preservation of neurological function, maintenance of oxygen consumption95 1949Human haemolysates into patients: transport oxygen, observed pressor effect96 1951Human filtered haemolysates into humans: renal dysfunction97 1967Human Hb tetramer into dogs: no renal dysfunction98 1978Human Hb tetramer into humans: renal toxicity, hypertension, abdominal pain99 1993Human modified Hb into animals: improved survival as low-volume resuscitation agent, but concern about systemic and pulmonary vasoconstriction100 1999Human modified Hb into trauma patients: increased mortality101

Modified haemolysates Tetrameric Hb

Modified tetrameric Hb

Polymerised Hb 1984 Human glutaraldehyde polymerised Hb102 1989Bovine glutaraldehyde polymerised Hb103 2000Human o-raffinose polymerised Hb104
Hb=haemoglobin.

Table 2: History of haemoglobin-based oxygen carriers

standard of care isotonic crystalloid fluids, but that HSD might be better.87 Subgroup analysis showed that patients who presented with shock and concomitant severe closed head injury benefited most from HSD.88 This observation was consistent with laboratory data showing that, compared with isotonic crystalloid, hypertonic saline or HSD increases cerebral perfusion pressure, decreases intracranial pressure, and decreases brain oedema, in combined head injury and haemorrhagic shock.89 This finding has led some authorities to recommend that hypertonic saline should replace mannitol in the management of intracranial hypertension in patients with severe closed head injury.90,91 The argument in favour of hypertonic saline is even more compelling with the recent recognition that hypertonic saline resuscitation markedly decreases the inflammatory response (specifically neutrophil cytotoxicity) in animal models of haemorrhagic shock, ischaemia and reperfusion, and sepsis.9294 Blood substitutes Another potential avenue to decrease the need for massive crystalloid administration could be earlier administration of bloodspecifically, packed red blood cells. For reasons described earlier, the Advanced Trauma Life Support guidelines recommendation to initiate resuscitation of class IV haemorrhagic shock with lactated Ringers may not be optimal. However, the present limited supply of stored blood and potential adverse effects make the option of earlier administration of packed red blood cells (or other blood components) logistically impractical and probably harmful. Haemoglobin-based oxygen carriers for trauma resuscitation may provide a workable compromise, and their development has an interesting history (table 2). The most clinically successful of these carriers are polymerised haemoglobin solutions.105 Interest in haemoglobin-based oxygen carriers dates from the 1933 report of Amberson and colleagues95 who showed that haemolysates could transport oxygen in mammals. Unfortunately, when infused into humans, these solutions had excessively toxic effectsvasoconstriction, acute renal failure, and abdominal painwhich were attributed to stromal contamination.96 The next generation of carrier solutions were stroma-free, but toxicity persisted and was attributed to instability of the haemoglobin tetramer, which spontaneously dissociates into dimers and monomers. One formulation of stabilised tetramer, diaspirin cross-linked

haemoglobin, was authorised for a phase III study in trauma patients.101 This product, however, failed and the trial was prematurely stopped due to unexpectedly high mortality in the treatment group (24 of 52 [46%] vs eight of 46 [17%]). Although this event was judged a major setback for clinical implementation of haemoglobin-based oxygen carriers, the product used was a solution of diaspirin cross linked haemglobin, which had previously been shown to markedly increase pulmonary and systemic vascular resistance in animals. Tetrameric haemoglobin extravasates from the vascular space, binds nitric oxide within the vessel wall and, thereby, results in unopposed vasoconstriction. This issue was addressed in another product by polymerising the haemoglobin tetramer.102 The additional benefit of these larger moieties is that they exert less colloid osmotic activity and therefore a higher dose can be administered. A further limitation of earlier haemoglobinbased oxygen carriers was that, because of the loss of 2,3 diphosphoglycerate, oxygen affinity was greatly increased (normal P50 of 26 mm Hg decreased to 12 mm Hg). This problem was addressed by pyroxidilation of the haemoglobin tetramer, which increased P50 to 29 mm Hg. One such polymerised haemoglobin solution has been tested extensively in phase I and phase II trials in patients with trauma and has been shown to be safe and effective.106108 A phase III pre-hospital trial is underway. Haemorrhage control The combination of hypothermia, coagulopathy, and acidosis is a syndrome that accelerates its effects in a cycle that is rapidly fatal unless interrupted.109 In addition to rewarming, coagulation factor replacement or enhanced haemostasis via intravenous infusion of procoagulants or antifibrinolytics might have a role in recalcitrant coagulopathy. Recombinant activated factor VII (rFVIIa) is an attractive candidate. When administered, it ostensibly binds only to exposed subendothelial tissue factor. This complex then activates the extrinsic clotting system at the injury site without causing systemic hypercoagulability. rFVIIa is approved in many countries for treatment of bleeding in haemophilia patients with inhibitors. In various animal models, rFVIIa has been shown to be an effective procoagulant adjunct for haemorrhage control.110,111 In these models, rFVIIa does not activate the systemic clotting system or cause diffuse microthrombosis. Case reports document variable effectiveness of rFVIIa in patients with acquired coagulopathy including trauma, cirrhosis, gastrointestinal bleeding, bone-marrow transplant, and heart-valve replacement.112,113 No adverse effects have been attributed to administration of the drug. However, patients with major torso trauma who survive massive resuscitation are at high risk of multiple organ failure, and the potential that rFVIIa might contribute to its pathogenesis is an unresolved concern. Informatics and monitoring technology Over the past decade, damage-control surgical techniques, presumptive embolisation by interventional radiology, and refined ICU resuscitation have saved many lives. To further improve outcome, future efforts need to be directed at better control of pre-ICU resuscitation. The first challenge will be to accurately identify high-risk bleeding patients in the field so that their early resuscitation can be optimised and novel treatments tested. Since the early 1970s, there has been a great interest in developing trauma centre triage instruments, such as the Glasgow coma score, trauma score, and revised trauma score. By necessity, these scores were designed to be easy to calculate to reduce distraction of pre-hospital staff from

1992

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TRAUMA III

Monitor Pulmonary artery catheter* Bedside Hb*

Variable CCO, CVP, PAP, PAWP, SmvO2 (SVRI) Blood Hb concentration

Manufacturer/supplier Edwards Lifesciences (Irvine, USA), Abbott Critical Care (Morgan Hill, USA) HemoCue AB (Angelholm, Sweden) Cardiodynamics International (San Diego, USA)

Placement PA via right heart N/A

Sensor technology

Advantages; disadvantages

Catheter tip thermistor, Standard of care for haemodynamic foil heater element; instability; invasive, ICU placement fibre-optic hemoximetry procedure Disposable reagent cuvette, optical read Easy, accurate; quality control check to verify calibration needed before use (nurse time, material storage)

Impedance CCO cardiography (thoracic bioimpedance)* Central venous oximetry* ScvO2, CVP

Chest, neck adhesive electrodes SVC via CV Skin surface (shoulder, chest) Shoulder (deltoid)

AC microcurrent Noninvasive CCO, HR; imprecision with injection, measurement tachycardia

Edwards Lifesciences Radiometer AG (Copenhagen, Denmark) Hutchinson Technology (Minneapolis, USA)

Fibre-optic hemoximetry Less invasive than PAC; CO needed if non-resolving haemodynamic instability Polarographic PO2 electrode, skin surface heater, thermistor Fibre-optic skin surface probe, NIR light source Non-invasive blood gas, continuous; nurse intensive (calibration time, site maintenance) Non-invasive tissue SO2, continuous; efficacy for diagnosis of shock unproven in clinical trial

Transcutaneous PtcO2 blood gas, PO2* Near infrared spectrometry* Tissue gas* StO2

PtO2, PtCO2, pHt Diametrics Medical (Minneapolis, USA) PslCO2 PgCO2 CapnoProbe, Nellcor (Pleasanton, USA) Tonocap, Datex Ohmeda (Helsinki, Finland)

Subcutaneous, Fibre-optic optode Low invasiveness, continuous tissue gas, skeletal (fluorescent, absorption pH; efficacy for diagnosis of shock unproven muscle indicator chemistry) in clinical trial Sublingual Nasogastric tube Fibre-optic optode CO2 gas analysis Non-invasive; single measurement per sensor (not continuous) Combined PCO2 monitor and nasogastric tube, continuous; non-specific (PgCO2 increasewith severe hypotension, peritoneal hypertension)

Gastrointestinal tract mucosal PCO2*

CCO=continuous cardiac output. CVP=central venous pressure. PAP=pulmonary artery pressure. PAWP=pulmonary artery wedge pressure. SmvO2=mixed venous Hb O2 saturation. SVRI=systemic vascular resistance index. Hb=haemoglobin. ScvO2=central venous Hb oxygen saturation. PtcO2=transcutaneous O2. StO2=subcutaneous tissue O2 saturation. PtO2, PtCO2, pHt=tissue (interstitial fluid) PO2, PCO2, pH. PslCO2=sublingual mucosa PCO2. PgCO2=gastric mucosa PCO2. PA=pulmonary artery. N/A=not applicable. SVC=superior vena cava. NIR=near infrared spectroscopy. HR=heart rate. PAC=pulmonary artery catheter. CO=cardiac output. SO2=O2 saturation. *Commercially available. Frequently used, or with US Food and Drug Administration clearance for indication of shock, or both.

Table 3: Pre-ICU resuscitation monitors

providing vital care. With advanced informatics technology, monitored variables can now be automatically obtained and assessed for trend responses to initial interventions.114 This information, combined with demographics and injury description, has the potential to accurately identify patients who are actively bleeding and at high risk early, before arrival in hospital. The second challenge will be to monitor the early resuscitation of bleeding patients in environments not traditionally equipped for advanced monitoringie, from the field to the emergency department to the interventional radiology suite. The ideal monitor for these environments would be one that senses an essential variable, provides accurate, stable, and continuous measurement and trend analysis, and, furthermore, is easily used, easily understood, noninvasive, small in size and transportable. Some potential monitors are described in table 3. For resuscitation in the field, a simple monitor of the adequacy of tissue perfusion is needed. This should be done in an easily accessible tissue that undergoes disproportionate vasoconstriction during shock, such as skin, subcutaneous fat, muscle, and oral mucosa. If perfusion in this tissue can be normalised with resuscitation, then perfusion in other tissues will be adequate. Near infrared spectroscopy is a method that can quantitatively monitor oxygen saturation of haemoglobin in skeletal muscle and subcutaneous tissue (StO2), and that can function as an index of tissue perfusion. In a recent study, we used this method to monitor StO2 over the deltoid region during active shock resuscitation and found that StO2 correlated closely with DO2.115 Near infrared spectroscopy also has the potential to simultaneously monitor the aa3 redox state, which reflects mitochondrial oxygen consumption.7 Another alternative is placement of very small probes, electrodes, or fibre-optic sensors for PO2, PCO2, and pH directly into the tissue of interest for

continuous monitoring.116,117 We have shown the pH of skeletal muscle to be a variable indicative of metabolic status that is useful to track resuscitation.115 A third possibility is a commercially available fibre-optic sensor of sublingual carbon dioxide.118 This monitor is based on the principle that hypoperfusion leads to increased PCO2 in tissue (interstitial fluid). Once a patient has arrived in the emergency department, more complex monitoring is feasible. Of the available technology, monitoring of transcutaneous O2 (PtcO2) has been shown to be valuable in shock resuscitation.119121 This is a time-honoured monitoring technique in neonatal ICUs and, in stable patients, PtcO2 correlates well with PaO2.122124 If PtcO2 decreases below normal, then either PaO2 has decreased (poor oxygenation) or cardiac output has decreased (poor perfusion). These two alternatives can be differentiated easily by obtaining an arterial blood gas analysis. Limitations of PtcO2 monitoring in the emergency department include a calibration time of roughly 10 min and instability with patient movement. Another more invasive alternative is to place a central venous line in the superior vena cava to monitor central venous haemoglobin oxygen saturation (ScvO2). The same fibre-optic reflective spectroscopy technology that is used to measure mixed venous haemoglobin O2 saturation (SmvO2) in pulmonary artery catheters has been incorporated into a standard central venous catheter. Although ScvO2 is not the same as SmvO2, the principle that these variables reflect the balance between DO2 and VO2 is familiar to most clinicians. This technology is known to provide an accurate, stable measurement, and a trial in which ScvO2 was used as the endpoint in resuscitation of patients with septic shock in the emergency department has shown improved survival compared with routine care.125 Because un-

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recognised myocardial dysfunction is a substantial problem after major trauma, a monitor of cardiac output in the emergency department would be valuable. Transthoracic electrical bioimpedance best meets the specifications for pre-ICU monitoring.126 Early bioimpedance systems provided continuous cardiac output measurements that correlated well with discrete measurements made by pulmonary artery catheter thermodilution in stable patients, but did not perform well in critically ill patients, especially those who were tachycardic. Newer bioimpedance technology has been used to successfully direct trauma resuscitation in the emergency department.127 The third and perhaps the most difficult challenge in controlling pre-ICU resuscitation is the early identification of patients who are unresponsive to treatment, and implementation of alternative interventions to alter their poor clinical trajectory before it becomes irreversible. Here again, informatics technology will be invaluable. The intensity of data from physiological monitors, laboratory analyses, radiological imaging, life-support devices, and ongoing physical examinations can overwhelm the bedside clinician, especially those with less expertise. Hospital wide electronic medical records are being implemented in most medical centres.128 The ability to rapidly transmit, record, recall, and review represents a tremendous advance in patient care. The association of measurements and observations with specific template care processes ie, decision support protocolsis the next step, and has been done successfully for care processes in the ICU, including fluid and electrolyte management, mechanical ventilation, and diagnosis and treatment of nosocomial infections.129,130 We have developed and implemented a bedside computerised shock resuscitation protocol in our ICU.61 This standardised process has improved our ability to direct and monitor an aspect of care that is often controversial, variable among patients, and confusing to bedside personnel. With ongoing review and analysis, we have been able to identify interventions that work best and can now accurately predict, at admission to ICU, whether a patient will or will not respond, so that alternative strategies can be employed. This standardised, rule-based, data-driven approach is being extended to the very early clinical course in the emergency department at our institution using mobile workstation and wireless technology to facilitate communication. Further extension of communication with field rescue personnel is currently the subject of military and civilian study in the USA, with implementation of computer, wireless, and satellite technologies, including video, voice, text, and data.131 The developments described in the present report may improve the ability of prehospital and early hospital care to pre-empt or more rapidly reverse hypoxaemia, hypovolaemia and onset of shock. Such advances are of particular interest for the initial management in the field of military or civilian casualties of combat.132,133 Prevention of the first hit is preferable and feasible,134 but prehospital care of severely injured patients135 and modulation of exaggerated systemic inflammatory response due to transfusion and other second hit complications of traditional strategies will probably provide the next generation of improvements in shock resuscitation.
Conflict of interest statement
None declared.

References
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Acknowledgments
The authors are funded by grants P50-GM4922, P50 GM38529, and U54 GM62119.

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