REVIEW ARTICLE
Hemorrhagic shock Donald S. Gann, MD and William R. Drucker, MD
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ore than 600 articles on shock have been published in the Journal of Trauma during its initial 50 years. This review has been guided by studies that advanced understanding of mechanisms, provided clarification of controversies, or introduced challenging concepts worthy of further study. Clearly some exceptional articles in the Journal of Trauma were overlooked, and for this, the authors apologize. Some citations from other journals have been included when their omission would have compromised the perspective of history and possibly confused the reader. We have come to appreciate the growth and development of the Journal and welcome the opportunity to share our findings. The word shock entered our lexicon almost by accident, following at least 18 centuries of descriptions of the body’s reaction to wounds with massive blood loss. Some historians claim that Celsus (AD 20)1 provided the first written description of a condition following a penetrating wound of the heart, ‘‘The pulse fades away, the color is extremely pallid, cold and malodorous sweats break out of the body as if the body has been wetted by dew, the extremities become cold and death quickly follows.’’ Other colorful descriptions appeared until the word shock was coined in a publication in 1743 by LeDran,2 a French military surgeon, in his Treatise or Reflections on Gunshot Wounds describing (in French) ‘‘The bullet-thrown from the gunpowder acquires such rapid force that the whole animal participates in the jarring (shock and agitation).’’ From that time, shock became a word to describe a large number of probably unrelated conditions ranging from massive hemorrhage to the modern posttraumatic shock disorder. These and many other intermediate conditions have found their way into the Journal of Trauma but do not allow any synoptic description. In this brief review, we limit ourselves to circulatory shock caused primarily by hemorrhage associated with trauma, with some references to septic, cardiogenic, or dehydration shock.
States and Sir Henry Dale in Great Britain.4 They thought that the toxin was the recently defined substance histamine. Numerous articles supported this hypothesis. This notion was discarded when it was determined that histamine produced local reactions that were not seen in shock and failed to mimic shock in other ways. As other vasoactive amines were identified, one after another became a candidate as the ‘‘shock toxin,’’ without success. In the late 1920s and 1930s, Blalock5 developed an alternative hypothesis that shock is the direct result of loss of fluid from the bloodstream, culminating in peripheral vascular failure, that is, persisting poor peripheral perfusion. He showed that the fluid accumulating in tissues after injury contained all the components of plasma and that a sudden injury, with fluid accumulation at the injured site, could produce shock rapidly and did not require postulating a toxin. Nonetheless, many workers continued the search, without success. In part, the reluctance to abandon the search for a toxin resulted from the work of Moon and Kennedy,6 who showed that whereas in small hemorrhage, there was consistent hemodilution, in shock (with large hemorrhage), there was no dilution and even hemoconcentration. The tide of opinion gradually flowed to favor Blalock’s hypothesis, and fluid therapy became the principal therapy for circulatory shock.
SHOCK TOXIN
1. Volume therapy. It is not widely appreciated that in their review, Artz and Fitts8 noted a frequent need to give additional salt water as well as blood in treating volume deficiency after hemorrhage. This concept was soon to be highlighted by the seminal work of Shires9 on supplemental saline therapy in the resuscitation of persisting hemorrhagic shock. 2. Ventilation. Kinney and Wells10 criticized the then current immediate therapeutic attention to the many problems associated with trauma without regard to the patient’s ventilation. Their writing established a new objective: therapy in all injured patients should look beyond blood pressure to assure provision and maintenance of effective tissue gas exchange. 3. ‘‘Irreversible shock.’’ Lansing et al.11 advocated the use of vasoactive drugs to increase perfusion pressure of vital
Serious scientific study of the pathogenesis of circulatory shock did not start until the beginning of the 20th century, facilitated by the emergence of biologic chemistry. Most of the physiologists of this period joined in the hypothesis that shock involves the appearance of a toxin released into the circulation in response to the initial injury. The search was led by two distinguished physiologists, Walter Cannon3 in the United Submitted: March 19, 2013, Revised: July 2, 2013, Accepted: July 8, 2013. From the Departments of Surgery and Physiology (D.S.G., W.R.D.), R Adams Cowley Shock Trauma Center, University of Maryland, Baltimore, Maryland; and Department of Surgery (D.S.G., W.R.D.), University of Vermont, Burlington, Vermont. Corresponding author: Donald S. Gann, MD, 1127 Greenspring Valley Rd, Lutherville, MD, 21093; email: [email protected]. DOI: 10.1097/TA.0b013e3182a686ed
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SYMPOSIUM ON SHOCK (1962) In 1962, during the second year of its publication, the Journal of Trauma held a symposium on shock chaired by Fraser Gurd.7 He selected four ‘‘areas of greatest difficulty for those charged with the intelligent care of severely injured patients.’’ The goal of the symposium was to stimulate thought about a subject and to ‘‘provide considered practical advice as to therapy.’’ This dual philosophical construct, academic and pragmatic, has endured 50 years of studies of shock presented in the Journal of Trauma. The areas were as follows:
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organs with due observance of the primary need for restoration of circulatory volume. Nickerson and Gourzis12 advanced an opposing pharmacologic view by their advocacy of blocking an ultimately disadvantageous vasoconstriction. 4. Sepsis. MacLean13 cited numerous studies that indicate bacteria assume an important detrimental role when hypovolemic shock is prolonged. His analysis anticipated recent work distinguishing sepsis from infection, identifying the cytokines, bacterial translocation, and multiple-organ failure.
STUDIES OF SHOCK PATHOPHYSIOLOGY Shock Model Advances in understanding the physiology of hemorrhagic shock led to interest in developing a shock model more analogous to human shock than the widely used Wiggers model.14,15 Dissatisfaction with the Wiggers’ model also led to the search for an anesthetic agent less likely to impose its own constraints on metabolism. Comparison by Drucker et al.16 of cyclopropane with halothane for the management of patients injured by trauma moved to favor halothane for studies of shock. Current experimental and clinical work leans toward induction and maintenance with isoflurane, a halothane derivative. The physiologic signs of anesthesia are dispelled within 5 minutes. Nevertheless, concern with results induced by the anesthetic agent remains challenging.
METABOLIC ALTERATIONS The metabolic alterations during hemorrhagic shock have been believed to serve a teleologic goal, that is, to maintain energy homeostasis. Claude Bernard17 discovered in 1877 that hemorrhage stimulates liver glycogen to provide glucose, the ubiquitous body fuel. The experiences of the World War II stimulated investigators to seek better understanding of shock pathophysiology. Cuthbertson18 characterized the metabolic changes produced by injury by dividing them into an early ‘‘ebb’’ phase with reduced consumption of oxygen and heat production, followed by a ‘‘flow’’ phase characterized by increased consumption of energy and oxygen and a rising body temperature. When the injury or blood loss was fatal, death was preceded by a period, termed by Stoner19,20 necrobiosis, characterized by continuing decrease in heat production and reduced consumption of oxygen. Most of the early in-depth studies of metabolic alterations during hypovolemic shock published in the Journal drew on studies by Engle.21 These studies demonstrated that the hypoxia of shock impaired the use of energy, while simultaneously, the neurohumoral defense of homeostasis created a hypermetabolic state that increased glucose uptake for consumption by muscles.22 Failure of exogenous glucose to suppress gluconeogenesis suggested a link among gluconeogenesis and the hypermetabolism, intolerance for glucose, and increased production of urea in hypovolemic patients.23 If shock persisted, the glycogen store became depleted, and glucose was maintained by hormonally driven gluconeogenesis.24 Ultimately, the process failed, and hypoglycemia replaced hyperglycemia. The finding by Pearce and Drucker25 that glucose infusion during persisting hemorrhagic shock prolonged survival suggested that it can serve as an energy substrate in defense of homeostasis. The finding that
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glucose is a major factor in moving fluid from cells to facilitate blood volume restitution and thus cardiovascular stabilization as well as the finding that glucose uptake into cells is inhibited by the hormonal response to injury led Gann and Foster26 to the alternative explanation that this nonmetabolic role of glucose is the critical factor.
VOLUME RESTORATION Rapid expansion of depleted circulatory volume is the primary means for overcoming the distortion of energy metabolism in hypovolemic shock. Dahn et al.27 found depressed insulin production in trauma and sepsis. Clemens et al.28 found insulin resistance instead. Baue et al.29 found that both erythrocyte-free and colloidal solutions improved the metabolic indices of oxidative metabolism, but their use produced an ‘‘obligatory’’ increase in cardiac output, cardiac work, and peripheral flow resulting from rapid dilution of the hematocrit. Drucker et al.30 found that circulatory volume has greater influence on protecting energy metabolism than on the mass of circulating erythrocytes. However, slow return of lost volume was not protective. Acute reduction of circulating volume less than 25% required urgent attention, whereas the hematocrit could be diluted more than 50% before a critical shortage of red blood cells became evident. For many years, the rapid refill of plasma volume following hemorrhage was ascribed to the osmotic action across the capillary by hyperglycemia produced by hypovolemic shock. There is no transcapillary osmotic gradient, so this must be incorrect. However, osmolality increases after hemorrhage, and this is a dominant factor (discussed later). Friedman et al.31 found that fed animals had better plasma refill and longer survival times. Chadwick et al.32 discovered that if the starved rats were well hydrated, they could achieve 80% of the plasma refill found in well-fed animals. Survival times were similar in the two groups. Expansion of extracellular volume by hydration can substitute for osmotically driven movement of water into that space. Haller et al.33 found that cardiac output was a reliable method to study the influence of controlled reduction of blood flow on oxidative metabolism and catecholamines response. Halmagyi et al.34 found no correlation between the levels of glucagon or epinephrine and the development of hyperglycemia during shock. Consistent with Blalock’s observation that blood pressure is an inadequate guide to the state of the circulation in incipient shock, Halmagyi et al. also found no relation between the concentration of blood glucose during hypovolemia and either the hemodynamic alterations or the plasma level of insulin. Gann’s laboratory focused attention on the mechanisms restoring blood volume after hemorrhage. There are two phases. The first, initiated by a fall in capillary hydrostatic pressure, stops when the sum of capillary hydrostatic and oncotic pressures equals the sum of interstitial hydrostatic and oncotic pressures. The second phase is mediated by movement of albumin, with interstitial fluid, into capillaries in response to a rise in interstitial pressure. This rise is driven by an increase in extracellular glucose that generates an osmotic gradient across cell membranes. Glucose is derived from hepatic glycogen by action of the counterregulatory hormones,26 including increased cortisol,
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glucagon, catecholamines, vasopressin, and angiotensin II, and inhibited insulin release. Blockade of any of these hormones prevents complete restitution of blood volume. The most important factor is the increased cortisol, without which restitution of blood volume fails completely.35 If hepatic glycogen is inadequate, other molecules will be substituted, primarily glycolytic products such as lactate and pyruvate.36 Complete restitution of blood volume is required for complete restoration of cardiovascular variables such as cardiac output.37,38 For hemorrhages up to 25% of initial blood volume, restoration is complete within 48 hours. If the hemorrhage exceeds 26%, restitution of blood volume fails.39 This is the same level at which Shires40 found the threshold for decreased transmembrane potential. Subsequently, Shires’ laboratory reported that this phenomenon, observed initially in muscle cells, was also seen in erythrocytes.41 In discussing this article, Gann observed that there must be a circulating substance mediating this effect.41 The sodium pump, Na/K ATPase, is the principal factor maintaining cellular transmembrane potential. Na/K ATPase activity is inhibited in all forms of circulatory shock. Inhibition was thought to result from decreased delivery of oxygen. The previously mentioned finding was the final demonstration that failure of oxygen delivery could not be the sole factor in decreasing activity of Na/K ATPase, since the red blood cell does not consume oxygen. Evans et al.42 reported that a protein that depolarized diverse cells from several species, including human, appeared in rats within 20 minutes of large hemorrhage. This finding was confirmed by Boulanger et al.43 in dogs for large hemorrhage. Subsequently, Eastridge et al.44 found identical time courses of what seemed to be very similar material in rats with either large hemorrhage or intravenous injection of shock-producing Escherichia coli. Jones et al.45 found that this material decreased both contractility and heart rate of isolated, perfused rat hearts and suggested that the depolarizing protein might also be active in the evolution of cardiogenic shock. Thus, the hypothetical protein might be a unifying factor in the development of all three of the principal forms of circulatory shock. However, further attempts at isolation of the protein led repeatedly to the purification of the same protein with no depolarizing activity. Sequencing identified it as fetal rat albumin (Darlington and Gann, unpublished data). Further examination of the extract showed that it contained low (G1,000) molecular weight substances that affected activity of Na/K ATPase. Fractionation demonstrated four active components. The heaviest, at the front, was probably the protein-bound substance previously purified and analyzed. The other three were much lighter and included two inhibitory regions separated by a stimulatory region. The studies of Shires40 had led to the general acceptance of the ubiquitous phenomenon of cell depolarization of cells in shock, but most persons believed that depolarization was incidental in shock, not implicated in the development or lethality of the response. To test the hypothesis that cell depolarization might have important consequences, the group proceeded to isolate the stimulatory material, identified as adenosine.46 Adenosine was shown to increase activity of ATPase in vitro and to prolong survival of rats in hemorrhagic shock for several hours. All three of the purine nucleosides had identical effects on both enzyme 890
activity and survival.47 The beneficial effects of enzyme stimulation suggested that inhibition of Na/K ATPase is important in shock. Conversely, inhibition of the sodium pump by the putative inhibitor may be an important contributor to mortality in shock. Because of the finding by Eastridge et al.44 that sepsis elicited a similar response to hemorrhage, Darlington and Gann48 tested the effect of one purine nucleoside, inosine, on rats in shock produced by endotoxin. Infusion of the purine reversed shock and prevented mortality. The results again suggest a common element in different forms of circulatory shock. Darlington and Gann have identified the inhibitor as a bufadienolide, a class of inhibitors of Na/K ATPase, but have not excluded additional active components. The work to this time remains unpublished.
IRREVERSIBLE SHOCK The previously mentioned findings relate to an evolving consideration of irreversible shock. As sodium accumulates in the cells in response to inhibition of Na/K ATPase, the sodium/ calcium exchange reverses its normal direction, and calcium accumulates within cells. Trump49 found that at high levels, calcium activates proteolytic enzymes, leading to destruction of organelles and death. This phenomenon was observed by Holden et al.50 in the first electron microscopic study of shock and is clearly irreversible.
RESUSCITATIVE THERAPY Estimation of Shock Severity Recently, attention has focused on two aspects of severity of injury and/or shock. First, who is likely to die? Second, is massive transfusion needed? With regard to mortality, one group has examined the use of the shock index, first described by Allgower and Burris.51 Cannon et al.52 evaluated changes in index from the field to the emergency department. They found that an increase of the index of 0.3 or greater was highly predictive of mortality. They proposed that responses of the index to resuscitation might be useful in evaluating success. Interest has increased in predicting the need for massive transfusion (Q10 U of blood or red blood cells). Cancio et al.53 noted the combined needs for prediction of mortality and for logistical adjustment for massive transfusion in battlefield situations. Both the shock index and severity were included in two equations. The authors also validated the modifications of the Revised Trauma Score (RTS) by Champion et al.54 and a substitute proposed by Eastridge et al.55 to obviate the need for calculation under battle conditions. Both scores gave similar results, although the RTS was superior for precision. Vandromme et al.56 evaluated the utility of the shock index alone in a civilian population. They found that a shock index of greater than 0.9 (normal up to 0.7) predicted massive transfusion, rising to an incidence of 20% with an index of greater than 1.3. Magnotti et al.57 found that ionized calcium correlated with the need for massive transfusion and mortality. Yanagawa et al.58 measured the diameter of the inferior vena cava sonographically before and after initial fluid resuscitation. Failure of the vessel to expand with fluid infusion implied inadequate treatment. Ferrada et al.59 examined the * Lippincott Williams & Wilkins
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inferior vena cava during rapid echocardiography to estimate volume status in critically injured patients. They used the technique to guide pharmacologic intervention and fluid administration. Callcut et al.60 found that multiple variables suggested as criteria for massive transfusion had very different predictive values. The two elements most predictive of the need for massive transfusion are systolic blood pressure and international normalized ratio.
DELAYED FLUID RESUSCITATION; COAGULOPATHY Bickell et al.61 compared immediate and delayed fluid resuscitation in hypotensive patients with penetrating injuries. Delayed resuscitation improved survival. Survival difference was 62% versus 70%, and serious complication rate was 30% versus 23%. There seemed to be no disadvantage, which might have been expected, and time was saved. The principal motivation for the study was the irresolvable difference between those favoring a ‘‘scoop-and-run’’ approach in the management of acute injury and those content with primary stabilization. Now, there are a number of studies in animals showing that standard resuscitation is accompanied by decreased oxygen delivery, increased rate of hemorrhage, reperfusion injury, organ failure, and coagulopathy. Dutton et al.62 challenged the conclusions of Bickell et al. The authors chose an intermediate approach, fluid administration to a targeted systolic pressure of 70 mm Hg instead of the customary standard of 100 mm Hg. The findings of the new study showed no significant benefit in mortality. However, the actual achieved systolic pressure was 100 mm Hg in the group with 70 mm Hg and 114 mm Hg in the group with 100 mm Hg, both values in the range recommended by the advanced trauma life support course. The lack of a demonstrable effect of lowering pressure may have resulted solely from an inability to maintain lower pressure. A combination of limited volume and substitution of plasma for crystalloid was proposed by Holcomb63 as damagecontrol resuscitation (DCR), with limited support of systolic blood pressure and early use of plasma. Plasma helps prevent coagulopathy resulting from acidosis and hypothermia. Duchesne et al.64 have reported on DCR in civilian practice, comparing patients with DCR with those treated conventionally. DCR improved results. Expansion of blood volume should ameliorate both acidosis and hypothermia. Plasma contains coagulation factors, activated as temperature, and hydrogen ion concentration are normalized. The appropriate ratio of plasma to red blood cells was not clear. Borgman et al.65 stratified the response to massive transfusion into three groups of wounded patients with approximately equal severity of injury, according to the ratio of plasma to red blood cells. Mortality decreased from 64% to 19% as the ratio increased from 1:8 to 1:1.4. Kashuk et al.66 reported improvement in mortality with a 1:2 ratio and noted that international normalized ratio was elevated with resuscitation with lactated Ringer’s (LR) solution. Subsequently, a multicenter study by Wafaisade et al.67 reported that in civilians, 24-hour mortality was halved as the plasmaYtoYred blood cell ratio was increased to 1:1 or greater. Davenport et al.68 reported the first
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prospective study in human patients. The findings of these and other articles suggest that the optimal ratio may be less than 1:1 but greater than 1:2.
BLOOD Studies of blood have held center stage in resuscitative therapy through the life of the Journal. An assessment of blood and blood products was made by a panel chaired by Sheldon et al.69 They warned that blood is possibly the most dangerous ‘‘drug’’ we use. Crystalloid without colloid is probably the best overall substitute for blood; its use should be followed by typespecific blood according to the specific need of a patient. The use of fresh whole blood helped constrain continued bleeding after an exchange transfusion. A single-unit transfusion replaced the need for multiple-component therapy. In the state after injury, there is no advantage in raising the hematocrit to greater than 30% early in therapy.70 Review of whole blood and blood ‘‘expanders’’ used in Viet Nam led Sheldon et al.71 to recommend type-specific fresh whole blood as preferable. Although experts agree that blood usually is the best replacement fluid for blood loss, transfusions still possess sufficient shortcomings to warrant use of a ‘‘blood substitute’’ or blood component therapy or acellular oxygen carriers. Gervin and Fischer72 found type-specific nonYcross-matched blood to be safe as an alternative to cross-matched blood. Many problems with massive transfusion of banked blood related to defective coagulation factors and platelet function, supporting the recommendation of fresh whole blood for massive blood replacement by Lim et al.73 Gould et al.74 found both stroma-free hemoglobin and a fluorocarbon emulsion, Fluosol-DA, to be effective acellular oxygen carriers as hematocrit was reduced to 10%. Greenburg et al.75 found that the oxyhemoglobin dissociation curve of stroma-free hemoglobin shifted to the left and was responsive to pH changes.
CRYSTALLOID, COLLOID, AND TONICITY Monafo76 attempted to define the optimal solute composition and volume of asanguinous fluids used to replace blood. Debate raged between treatment with colloids versus crystalloids, between different types of colloids and between isotonic versus hypertonic fluid.77 Pruitt et al.78 found saline to be an adequate replacement fluid in man for moderate hemorrhage when administered in volume equivalent to loss of blood plus sequestered extravascular fluid. LR solution was deemed to be superior presumably because of decreased chloride load and absence of acetate or magnesium.79 The danger of producing hyperchloremic acidosis by normal saline as well as the indiscriminate use of crystalloid fluids have been reemphasized in more recent articles.80,81 Schumer82 found that dextran matched blood in rapidity and degree of improving hemodynamic activity despite diluting the hematocrit. Experience in combat83 demonstrated that protein-free fluid may be combined with blood in the resuscitation of severely wounded humans without producing a significant dilution of serum albumin and without producing edema. Trunkey et al.84 proposed infusion of calcium to counteract its presumed
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movement into cells during massive transfusions. However, because of the deleterious and even lethal effects of a rapid increase in intracellular calcium,49 extreme caution is advised if used in patients.
HYPERTONIC SALINE Velasco et al.85 have championed the use of hypertonic saline (HTS) in resuscitation of hemorrhagic shock. They conducted studies in both animals and patients in hemorrhagic and septic shock with HTS alone or with 6% dextran. Rotstein86 proposed that HTS can also attenuate immune-mediated cellular injury. Sheppard et al.87 found that a number of subcellular pathways are influenced by the administration of HTS. Vassar et al.88 reported on the effectiveness of this combination solution in injured patients in this country. The rationale for the combination was that HTS moved water from cells to the extracellular space and the dextran retains a greater part in the vascular bed. When tested, relative effectiveness of 7.5% NaCl with and without dextran showed no significant differences in survival but increased cost.89 Coimbra et al.90 examined the effectiveness of HTS versus LR solution on sepsis after hemorrhagic shock in mice with a second insult of cecal ligation and puncture. Mortality was reduced in the group treated with HTS. Cultured blood showed significantly more bacterial colonies and increased pulmonary inflammation in the LR group. Rhee et al.91 showed that in swine, neutrophil activation was twice as great with LR resuscitation as with HTS, was sustained with LR solution, but was normal with HTS. LR solution alone also caused activation. The mechanisms involved are not clear. In head injury combined with shock, Battistella and Wisner92 reported HTS reduced brain swelling while expanding blood volume. They found reductions in intracranial pressure and brain water in response to HTS in contrast to LR, despite similar change in hemodynamics. Schmoker et al.93 demonstrated in swine increased cerebral oxygen delivery with decreased intracerebral pressure with HTS relative to LR. Shackford et al.94 compared groups of patients with head injuries, resuscitated with either LR or HTS. Patients with HTS showed significant falls in intracranial pressure compared with no significant change in those given LR, but no differences were seen in survival or Glasgow Coma Scale (GCS) scores at discharge. Nonetheless, HTS seems to be a safe mode of therapy.
HYPOTHERMIA Several investigators have explored ancillary procedures. A survey of severely injured trauma patients demonstrated that 60% presented with a body temperature less than 36-C. This raised the question whether hypothermia was an independent risk factor predisposing patients to increased morbidity or a physiologic response to trauma. Jurkovich et al.95 suggested that hypothermia presenting in trauma patients is an ominous predictor of death. However, mild hypothermia (30Y34-C) protected the microvasculature, presumably by inhibiting expression of reactive oxidation species. There has been progress with hypothermia with circulatory arrest in severe hemorrhagic shock. Tisherman et al.96 found in dogs that deep hypothermia of 892
15-C led to survival of greater than 72 hours. Neurologic deficits were measured after various periods of hypothermia. There was no deficit at 60 minutes but mild deficit at 90 minutes. The authors suggested that such periods might permit repair of otherwise lethal injuries without significant brain damage. When more severe hypothermia (temperature of G10-C for the head and G15-C for the rest of the body), with immersion of the head in ice water for 120 minutes, deficit was not significantly different from controls.97 The authors concluded that cooling of the head with circulatory arrest could be used clinically, along with other brainprotective therapies. Kim et al.98 found in rats that hypothermia combined with infusion of LR to a mean arterial pressure of 40 mm Hg permitted survival without brain damage in 7 of 10 rats. Neither hypothermia alone or fluid infusion alone produced significant survival. The authors cautioned against the standard practice of attempting to maintain normal body temperature in treating shock.
ADULT RESPIRATORY DISTRESS SYNDROME Viet Nam casualties focused attention on the lung. Pulmonary failure in shock was attributed to a variety of changes.99 The primary change was increased pulmonary interstitial fluid, with resulting impaired oxygen diffusion. Demling et al.100 analyzed the Starling forces in sheep, showed the major force to be increased pulmonary microvascular pressure, and showed that sepsis produced different changes. The treatment of adult respiratory distress syndrome became increased positive endexpiratory pressure.101
BACTERIAL TRANSLOCATION AND MULTIPLE-ORGAN FAILURE In our search on shock, the most frequently cited article was one from Deitch’s laboratory on bacterial translocation.102 The concept of translocation of bacteria from the bowel following shock, mediated by mucosal injury from xanthine oxidase-generated oxidants, and the concept of a ‘‘two-hit’’ mechanism are believed to be responsible for organ failure after traumatic injury.103,104 Baker et al.105 found focal necrosis in guts of rats in hemorrhagic shock and were able to recover bacteria, primarily E. coli and Enterococcus, from several tissues. Subsequently, Moore et al.106 reported that translocation might produce a systemic inflammatory cascade characterized by release of proinflammatory cytokines and activation of the complement system from a combination of shock and hydroxyl radicals formed by reperfusion injury. In an additional study, Deitch et al.107 demonstrated that the intestinal barrier might be destroyed by injection of an inflammatory agent, zymosan, leading to gut origin sepsis, a term first used by Border et al.108 Rush’s group found positive blood cultures in 56% of patients with severe trauma within 3 hours of injury.109 However, Peitzman et al.110 found that positive cultures in mesenteric lymph nodes were relatively rare and were not correlated with subsequent infections, most of which were pulmonary. Braithwaite et al.111 confirmed that positive cultures of mesenteric lymph nodes were rare but discovered fragments of E. coli * Lippincott Williams & Wilkins
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in macrophages in all nodes by an immunocytochemical method. There was, however, no correlation with the presence of hemorrhagic shock. Thus, the question of the role of bacterial translocation in the development of clinical sepsis after hemorrhagic shock in humans remains unresolved. Moore et al.112 pursued the earlier finding of flowdependent increased oxygen consumption. They treated 39 patients with this condition with supplemental oxygen, with a goal of increasing oxygen delivery to attain increased VO2. This regimen was successful in 24 patients. However, the remaining 15 patients did not achieve the goal but instead had in addition elevation of plasma lactate. The failure of response correlated with the development of multiple-organ failure. The authors felt that the inability to increase oxygen consumption could result from inadequate blood flow, maldistribution of flow or defective oxygen consumption, alone or in combination. They felt that reperfusion injury could be a major contributor or simply from shock-induced changes in bioenergic cellular processes. Alternatively, Botha et al.113 suggested that early neutrophil sequestration after injury led to multiple-organ failure. Nast-Kolb et al.114 reported on a variety of plasma factors known to be elevated with inflammation after trauma in 66 severely injured patients (Injury Severity Score [ISS] 9 18). Of these, 11 died from multiple-organ failure, 38 survived despite single- or multiple-organ failure, and 17 recovered without organ failure. They used the latter group to attempt to discern a pattern of response that could be used to predict organ failure. As noted in discussion, no real prediction was possible since the measurements were observed during the evolution of the clinical response. However, all of the factors reported, including neutrophil elastase, antithrombin III, lactate, interleukin 6, and interleukin 8, were elevated early after injury in patients who developed organ failure compared with those who did not. Most returned toward levels seen in patients recovering without organ failure in 1 day or 2 days. Patients who then developed organ failure later had increases in lactate and the two interleukins at the same time.
CONCLUSION On reflection, we feel that our efforts, despite their inadequacies, have confirmed our initial judgment. In its early years, the Journal did not reflect the focus of research in trauma. Much of the research in the 1960s was directed toward the renal response to injury, but publications appeared in other journals. In contrast, under the leadership of the last several editors-in-chief, the Journal has actually dominated in reports of major new findings leading to better understanding of the pathophysiology associated with injury and rewarding advances in therapy. A sobering conclusion, however, is that advances in prevention have failed to displace accidental death and injury from its position of dominance for infants and young adults. The Journal of Trauma merits commendation as a preferred site for publication of thoughtful studies devoted to better understanding and management of injuries. We hope that the finding of effective preventive measures will be included. DISCLOSURE The authors declare no conflicts of interest.
REFERENCES 1. Celsus AC. (trans. W.G. Spencer). De Medicina, vol. 3, books 7Y8. London, UK: Loeb Classical Library; 1938. 2. LeDran HF. A treatise, or reflections, drawn from practice on gunshot wounds. London, UK: John Clarke; 1743. 3. Cannon WB. Traumatic Shock. New York, NY: D Appleton & Co.; 1923. 4. Dale HH. Conditions conducive to the production of shock by histamine. J Exper Pathol. 1920;1:103. 5. Blalock A. Principles of Surgical Care: Shock and Other Problems. St Louis, MO: C.V. Mosby; 1940. 6. Moon VH, Kennedy PJ. Pathology of shock. Arch Pathol. 1932;14: 360Y371. 7. Gurd FN. A symposium on shock: foreword. J Trauma. 1962;2:355Y357. 8. Artz CP, Fitts CT. Replacement therapy in shock. J Trauma. 1962;2: 358Y369. 9. Shires GT. Pathophysiology and fluid replacement in hypovolemic shock. Ann Clin Res. 1977;8:144Y150. 10. Kinney JM, Wells RE. Problems of ventilation after injury and shock. J Trauma. 1962;2:370Y385. 11. Lansing AM, Stevenson JAF, McLachlin AD. The use of vasopressor agents in the treatment of shock. J Trauma. 1962;2:386Y398. 12. Nickerson M, Gourzis JT. Blockade of sympathetic vasoconstriction in the treatment of shock. J Trauma. 1962;2:399Y411. 13. MacLean LD. Shock due to sepsisVa summary of current concepts of pathogenesis and treatment. J Trauma. 1962;2:412Y422. 14. Hobler K, Napodano R. Tolerance of swine to acute blood volume deficit. J Trauma. 1974;14:716Y718. 15. Wiggers CJ. Physiology of Shock. New York, NY: The Commonwealth Fund; 1950:1Y459. 16. Drucker WR, Davis HS, Burget D, Powers AL, Sieverding R. Effect of halothane and cyclopropane anesthesia on energy metabolism in hypovolemic animals. J Trauma. 1965;5:503Y514. 17. Bernard C. Lec¸ons sur le Diabe`te et la Glycoge`nese Animale. 1st ed. Paris, France: Baillie`re; 1877. 18. Cuthbertson DP. Observations on the disturbance of metabolism by injury to the limbs. Q J Med. 1932;1:233. 19. Stoner HB, Threlfall CJ. The Biochemical Response to Injury. Oxford, England: Blackwell; 1960. 20. Stoner HB. Energy metabolism after injury. J Clin Pathol. 1970;23(Suppl 4): 47Y55. 21. Engle F. The significance of metabolic changes during shock. Ann N Y Acad Sci. 1952;55:381Y393. 22. Drucker WR, DeKiewiet JC. Glucose uptake by diaphragms from rats subjected to hemorrhagic shock. Am J Physiol. 1964;206:317Y320. 23. Cowley RA, Attar S, LaBrosse E, McLaughlin J, Scanlan E, Wheeler S, Hanashiro P, Grumberg I, Vitek V, Mansberger A, Firminger H. Some significant biochemical parameters found in 300 shock patients. J Trauma. 1969;9:926Y938. 24. Vigas M, Hetenyi GJ, Haist RE. Glucose metabolism in posthemorrhagic shock in the dog. J Trauma. 1971;11:615Y618. 25. Pearce FJ, Drucker WR. Glucose infusion arrests the decompensatory phase of hemorrhagic shock. J Trauma. 1987;27:1213Y1220. 26. Gann DS, Foster AH. Endocrine and metabolic response to injury. In: Schwartz SI, ed. Principles of Surgery. New York, NY: McGraw-Hill; 1993:1Y59. 27. Dahn MS, Lange MP, Mitchell RA, Lobdell K, Wilson RF. Insulin production following injury and sepsis. J Trauma. 1987;27:1031Y1038. 28. Clemens MG, Chaudry IH, Daigneau N, Baue AE. Insulin resistance and depressed glyconeogenesis capability during early hyperglycemic sepsis. J Trauma. 1984;24:701Y708. 29. Baue AE, Tragus ET, Parkins WM. A comparison of isotonic and hypertonic solutions and blood on blood flow and oxygen consumption in the initial treatment of hemorrhagic shock. J Trauma. 1967;7: 743Y756. 30. Drucker WR, Holden WD, Kingsbury B, Hofmann N, Graham L. Metabolic aspects of hemorrhagic shock. II: metabolic studies on the need for erythrocytes in the treatment of hypovolemia due to hemorrhage. J Trauma. 1962;2:567Y584.
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56. Vandromme HJ, Griffin RL, Kerby JD. Identifying risk for massive transfusion in the relatively normotensive patient: utility of the prehospital shock index. J Trauma. 2011;70:384Y390. 57. Magnotti LJ, Bradburn EH, Webb DL. Admission ionized calcium levels predict the need for multiple transfusions: a prospective study of 591 critically ill trauma patients. J Trauma. 2011;70:391Y397. 58. Yanagawa Y, Sakamoto T, Okada Y. Hypovolemic shock evaluated by sonographic measurement of the inferior vena cava during resuscitation in trauma patients. J Trauma. 2007;63:1245Y1248. 59. Ferrada P, Murthi S, Anand RJ, Bochicchio GV, Scalea T. Transthoracic rapid echocardiographic examination real-time evaluation of fluid status in critically ill trauma patients. J Trauma. 2011;70:56Y64. 60. Callcut RA, Johannigman JA, Kadon KS, Hanseman DJ, Robinson BR. All massive transfusion criteria are not created equal: defining the predictive value of individual transfusion triggers to better determine who benefits from blood. J Trauma. 2011;70:794Y801. 61. Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994; 331:1105. 62. Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation during active hemorrhage: impact on in-hospital mortality. J Trauma. 2002;52: 1141Y1146. 63. Holcomb JB. Damage control resuscitation directly addressing the early coagulopathy of tissues. J Trauma. 2007;62:307Y310. 64. Duchesne JC, Kimonis K, Marr AB, Rennie KV, Wahl G, Wells JE, Islam TM, Meade P, Stuke L, Barbeau JM, Hunt JP, Baker CC, McSwain NE Jr. Damage control resuscitation in combination with damage control laparotomy: a survival advantage. J Trauma. 2010;69:46Y52. 65. Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007; 64(4):805Y815. 66. Kashuk JL, Moore EE, Johnson JL, Haenel J, Wilson M, Moore JB, Cothren CC, Biffl WL, Banerjee A, Sauaia A. Postinjury life threatening coagulopathy: is 1:1 fresh frozen plasma:packed red blood cells the answer? J Trauma. 2008;65:261Y270. 67. Wafaisade A, Maegele M, Lefering R, Braun M, Peiniger S, Neugebauer E, Bouillon B; Trauma Registry of DGU. High plasma to red blood cell ratios are associated with lower mortality rates in patients receiving multiple transfusion (4ered blood cell unitsG10 during acute trauma resuscitation. J Trauma. 2011;70:81Y89. 68. Davenport R, Curry N, Manson J, De’Ath H, Coates A, Rourke C, Pearse R, Stanworth S, Brohi K. Hemostatic effect of fresh frozen plasma may be maximal at red cell ratios of 1:2. J Trauma. 2011;70:90Y96. 69. Sheldon GF, Watkins GM, Glover JL, Greenburg AG, Friedman BA. Panel: ‘‘present use of blood and blood products’’. J Trauma. 1981;21: 1005Y1012. 70. Fortune JB, Feustel PJ, Saifi J, Stratton HH, Newell JC, Shah DM. Influence of hematocrit on cardiopulmonary function after acute hemorrhage. J Trauma. 1987;27:243Y249. 71. Sheldon GF, Lim RC, Blaisdell FW. The use of fresh blood in the treatment of critically injured patients. J Trauma. 1975 Aug;15: 670Y677. 72. Gervin AS, Fischer R. Resuscitation of trauma patients with typespecific uncrossmatched blood. J Trauma. 1984;24(4):327Y331. 73. Lim RC Jr, Olcott C 4th, Robinson AJ, Blaisdell FW. Platelet response and coagulation changes following massive blood replacement. J Trauma. 1973;13(7):577Y582. 74. Gould SA, Rosen AL, Sehgal LR, Sehgal HL, Rice CL, Moss GS. Red cell substitutes: hemoglobin solution or flurocarbon? J Trauma. 1982;22(9):736Y740. 75. Greenburg AG, Elia C, Levine B, Belsha J, Peskin GW. Hemoglobin solutions and the oxyhemoglobin dissociation curve. J Trauma. 1975; 15(11):943Y850.
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76. Monafo WW, Deitz F, Bradley RE, Ayvazian VH. Bioassay of murine hemorrhagic shock. II. The relationship of sodium, osmolal, anionic, and water loads to survival. J Trauma. 1971;11:940Y946. 77. Maier S, Holz-Holzl C, Pajik W. Microcirculatory parameters after isotonic and hypertonic colloidal fluid resuscitation in acute hemorrhagic shock. J Trauma. 2009;66(2):337Y345. 78. Pruitt BA, Moncrief JA, Mason AD. Efficacy of buffered saline as the sole replacement fluid following acute measured hemorrhage in man. J Trauma. 1967;7:767Y782. 79. Traverso LW, Lee WP, Langford MJ. Fluid resuscitation after an otherwise fatal hemorrhage: I. Crystalloid solutions. J Trauma. 1986;26: 168Y175. 80. Healey MA, Davis RE, Lui FC. Lactated Ringer’s is superior to normal saline in a model of massive hemorrhage and resuscitation. J Trauma. 1998;45:899. 81. Balogh Z, McKinley BA, Holcomb JB. Both primary and secondary abdominal compartment syndrome can be predicted early and are harbingers of multiple organ failure. J Trauma. 2003;54:848Y859. 82. Schumer W. Physiochemical and metabolic effects of low molecular weight dextran in oligemic shock. J Trauma. 1967;7:40Y47. 83. Cloutier CT, Lowery BD, Carey LC. The effect of hemodilutional resuscitation on serum protein levels in humans in hemorrhagic shock. J Trauma. 1961;9:517Y521. 84. Trunkey D, Holcroft J, Carpenter MA. Calcium flux during hemorrhagic shock in baboons. J Trauma. 1976;16:633Y638. 85. Velasco IT, Pontieri V, Rocha e´ Silva M , Jr, Lopes OU. Hyperosmotic NaCl and severe hemorrhagic shock. Am J Physiol. 1980;239: H664YH673. 86. Rotstein OD. Novel strategies for immunomodulation after trauma: revisiting hypertonic saline as a resuscitation strategy for hemorrhagic shock. J Trauma. 2000;49:580Y583. 87. Sheppard FR, Moore EE, McLaughlin N. Clinically relevant osmolar stress inhibits priming-induced PMN NADPH oxidase subunit translocation. J Trauma. 2005;58:752Y757. 88. Vassar MJ, Perry CA, Holcroft JW. Prehospital resuscitation of hypotensive trauma patients with 7.5% NaCl versus 7.5% NaCl with added dextran: a controlled trial. J Trauma. 1993;34(5):622Y632. 89. Freshman SP, Battistella FD, Matteucci M, Wisner DH. Hypertonic saline (7.5%) versus mannitol: a comparison for therapy of acute head injuries. J Trauma. 1993;35:344Y348. 90. Coimbra R, Porcides R, Loomis W, Melbostad H, Lall R, Deree J, Wolf P, Hoyt DB. HSPTX protects against hemorrhagic shock resuscitationYinduced tissue injury: an attractive alternative to Ringer’s lactate. J Trauma. 2006;60:41Y51. 91. Rhee P, Burris D, Kaufmann C. Lactated Ringer’s solution resuscitation causes neutrophil activation after hemorrhagic shock. J Trauma. 1998; 44:313Y319. 92. Battistella FD, Wisner PH. Combined hemorrhagic shock and head injury, effects of hypertonic saline (7.5%) resuscitation. J Trauma. 1991;31:182Y188. 93. Schmoker JD, Zhuang J, Shackford SR. Hypertonic fluid resuscitation improves cerebral oxygen delivery and reduces intracranial pressure after hemorrhagic shock. J Trauma. 1991;31:1607Y1613. 94. Shackford SR, Bourguignon PR, Wald SL, Rogers FB, Osler TM, Clark DE. Hypertonic saline resuscitation of patients with head injury: a prospective, randomized clinical trial. J Trauma. 1998;44:50Y58. 95. Jurkovich GJ, Greiser WB, Luterman A, Curreri PW. Hypothermia in trauma victims: an ominous predictor of survival. J Trauma. 1987; 27:1019.
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96. Tisherman SA, Safar P, Radovsky A, Peitzman A, Sterz F, Kuboyama K. Therapeutic deep hypothermic circulatory arrest in dogs; a resuscitation modality for hemorrhagic shock with ‘‘irreparable injury’’. J Trauma. 1990;30:836Y847. 97. Tisherman SA, Safar P, Radowsky A, Peitzman A, Marrone G, Kuboyama K, Weinrauch V. Profound hypothermia (10-C) compared with deep hypothermia (15-C)improves neurologic outcome in dogs after 2 hours circulatory arrest induced to enable resuscitative surgery. J Trauma. 1991;31:1051Y1061. 98. Kim SH, Stezoski SW, Safar P. Hypothermia and minimal fluid resuscitation increase survival after uncontrolled hemorrhagic shock in rats. J Trauma. 1997;42:213Y222. 99. Lewin I, Weil MH, Shubin H, Sherwin R. Pulmonary failure associated with clinical shock states. J Trauma. 1971;11(1):22Y35. 100. Demling RH, Manohar M, Proctor R. Comparison between lung fluid filtration rate and measured starling forces after hemorrhagic and endotoxic shock. J Trauma. 1980;2:856Y860. 101. Falke KJ. The introduction of positive endexpiratory pressure into mechanical ventilation: a retrospective. Intensive Care Med. 2003;29: 1233Y1241. 102. Deitch EA. Effect of oral antibiotics and bacterial overgrowth on the translocation of the GI tract microflora in burned rats. J Trauma. 1985; 25:385Y392. 103. Deitch EA. Bacterial translocation of the gut. J Trauma. 1990;30:S184YS189. 104. Moore EE, Moore FA, Franciose RJ, Kim FJ, Biffl WL, Banerjee A. The postischemic gut serves as a priming bed for circulating neutrophils that provoke multiple organ failure. J Trauma. 1994;37:881Y887. 105. Baker JW, Deitch EA, Li M, Berg RD, Specian RD. Hemorrhagic shock induces bacterial translocation from the gut. J Trauma. 1988 Jul;28(7): 896Y906. 106. Moore FA, Moore EE, Poggetti R, McAnena OJ, Peterson VM, Abernathy CM, Parsons PE. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma. 1991;31:629Y636; discussion 636Y8. 107. Deitch EA, Bridges W, Berg R, Specian RD, Granger DN. Hemorrhagic shock-induced bacterial translocation: the role of neutrophils and hydroxy radicals. J Trauma. 1990;30:942Y952. 108. Border JR, Hassett J, LaDuca J. The gut origin septic state in blunt multiple trauma (TSS-40) in the ICU. Ann Surg. 1987;296:427Y448. 109. Koziol JM, Rush BF Jr, Smith SM, Machiedo GW. Occurrence of bacteremia during and after hemorrhagic shock. J Trauma. 1988; 28:10Y16. 110. Peitzman AB, Udekwu AO, Ochoa J, Smith S. Bacterial translocation in trauma patients. J Trauma. 1991;31:1083Y1086. 111. Braithwaite CE, Ross SE, Nagele R. Bacterial translocation occurs in humans after traumatic injury: evidence using immunofluorescence. J Trauma. 1993;34:586Y590. 112. Moore FA, Haenel JB, Moore EE, Whitehill TA. Incommensurate oxygen consumption in response to maximal oxygen availability predicts postinjury multiple organ failure. J Trauma. 1992;33:58Y65; discussion 65Y67. 113. Botha AJ, Moore FA, Moore EE, Sauaia A, Banerjee A, Peterson VM. Early neutrophil sequestration after injury: a pathologic mechanism for multiple organ failure. J Trauma. 1995;39:411. 114. Nast-Kolb D, Waydhas C, Gippner-Steppert C, Schneider I, Trupka A, Ruchholtz S, Zettl R, Schweiberer L, Jochum M. Indicators of the posttraumatic inflammatory response correlate with organ failure in patients with multiple injuries. J Trauma. 1997;42:446Y455.
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Hemorrhagic shock Donald S. Gann, MD and William R. Drucker, MD
M
ore than 600 articles on shock have been published in the Journal of Trauma during its initial 50 years. This review has been guided by studies that advanced understanding of mechanisms, provided clarification of controversies, or introduced challenging concepts worthy of further study. Clearly some exceptional articles in the Journal of Trauma were overlooked, and for this, the authors apologize. Some citations from other journals have been included when their omission would have compromised the perspective of history and possibly confused the reader. We have come to appreciate the growth and development of the Journal and welcome the opportunity to share our findings. The word shock entered our lexicon almost by accident, following at least 18 centuries of descriptions of the body’s reaction to wounds with massive blood loss. Some historians claim that Celsus (AD 20)1 provided the first written description of a condition following a penetrating wound of the heart, ‘‘The pulse fades away, the color is extremely pallid, cold and malodorous sweats break out of the body as if the body has been wetted by dew, the extremities become cold and death quickly follows.’’ Other colorful descriptions appeared until the word shock was coined in a publication in 1743 by LeDran,2 a French military surgeon, in his Treatise or Reflections on Gunshot Wounds describing (in French) ‘‘The bullet-thrown from the gunpowder acquires such rapid force that the whole animal participates in the jarring (shock and agitation).’’ From that time, shock became a word to describe a large number of probably unrelated conditions ranging from massive hemorrhage to the modern posttraumatic shock disorder. These and many other intermediate conditions have found their way into the Journal of Trauma but do not allow any synoptic description. In this brief review, we limit ourselves to circulatory shock caused primarily by hemorrhage associated with trauma, with some references to septic, cardiogenic, or dehydration shock.
States and Sir Henry Dale in Great Britain.4 They thought that the toxin was the recently defined substance histamine. Numerous articles supported this hypothesis. This notion was discarded when it was determined that histamine produced local reactions that were not seen in shock and failed to mimic shock in other ways. As other vasoactive amines were identified, one after another became a candidate as the ‘‘shock toxin,’’ without success. In the late 1920s and 1930s, Blalock5 developed an alternative hypothesis that shock is the direct result of loss of fluid from the bloodstream, culminating in peripheral vascular failure, that is, persisting poor peripheral perfusion. He showed that the fluid accumulating in tissues after injury contained all the components of plasma and that a sudden injury, with fluid accumulation at the injured site, could produce shock rapidly and did not require postulating a toxin. Nonetheless, many workers continued the search, without success. In part, the reluctance to abandon the search for a toxin resulted from the work of Moon and Kennedy,6 who showed that whereas in small hemorrhage, there was consistent hemodilution, in shock (with large hemorrhage), there was no dilution and even hemoconcentration. The tide of opinion gradually flowed to favor Blalock’s hypothesis, and fluid therapy became the principal therapy for circulatory shock.
SHOCK TOXIN
1. Volume therapy. It is not widely appreciated that in their review, Artz and Fitts8 noted a frequent need to give additional salt water as well as blood in treating volume deficiency after hemorrhage. This concept was soon to be highlighted by the seminal work of Shires9 on supplemental saline therapy in the resuscitation of persisting hemorrhagic shock. 2. Ventilation. Kinney and Wells10 criticized the then current immediate therapeutic attention to the many problems associated with trauma without regard to the patient’s ventilation. Their writing established a new objective: therapy in all injured patients should look beyond blood pressure to assure provision and maintenance of effective tissue gas exchange. 3. ‘‘Irreversible shock.’’ Lansing et al.11 advocated the use of vasoactive drugs to increase perfusion pressure of vital
Serious scientific study of the pathogenesis of circulatory shock did not start until the beginning of the 20th century, facilitated by the emergence of biologic chemistry. Most of the physiologists of this period joined in the hypothesis that shock involves the appearance of a toxin released into the circulation in response to the initial injury. The search was led by two distinguished physiologists, Walter Cannon3 in the United Submitted: March 19, 2013, Revised: July 2, 2013, Accepted: July 8, 2013. From the Departments of Surgery and Physiology (D.S.G., W.R.D.), R Adams Cowley Shock Trauma Center, University of Maryland, Baltimore, Maryland; and Department of Surgery (D.S.G., W.R.D.), University of Vermont, Burlington, Vermont. Corresponding author: Donald S. Gann, MD, 1127 Greenspring Valley Rd, Lutherville, MD, 21093; email: [email protected]. DOI: 10.1097/TA.0b013e3182a686ed
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SYMPOSIUM ON SHOCK (1962) In 1962, during the second year of its publication, the Journal of Trauma held a symposium on shock chaired by Fraser Gurd.7 He selected four ‘‘areas of greatest difficulty for those charged with the intelligent care of severely injured patients.’’ The goal of the symposium was to stimulate thought about a subject and to ‘‘provide considered practical advice as to therapy.’’ This dual philosophical construct, academic and pragmatic, has endured 50 years of studies of shock presented in the Journal of Trauma. The areas were as follows:
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organs with due observance of the primary need for restoration of circulatory volume. Nickerson and Gourzis12 advanced an opposing pharmacologic view by their advocacy of blocking an ultimately disadvantageous vasoconstriction. 4. Sepsis. MacLean13 cited numerous studies that indicate bacteria assume an important detrimental role when hypovolemic shock is prolonged. His analysis anticipated recent work distinguishing sepsis from infection, identifying the cytokines, bacterial translocation, and multiple-organ failure.
STUDIES OF SHOCK PATHOPHYSIOLOGY Shock Model Advances in understanding the physiology of hemorrhagic shock led to interest in developing a shock model more analogous to human shock than the widely used Wiggers model.14,15 Dissatisfaction with the Wiggers’ model also led to the search for an anesthetic agent less likely to impose its own constraints on metabolism. Comparison by Drucker et al.16 of cyclopropane with halothane for the management of patients injured by trauma moved to favor halothane for studies of shock. Current experimental and clinical work leans toward induction and maintenance with isoflurane, a halothane derivative. The physiologic signs of anesthesia are dispelled within 5 minutes. Nevertheless, concern with results induced by the anesthetic agent remains challenging.
METABOLIC ALTERATIONS The metabolic alterations during hemorrhagic shock have been believed to serve a teleologic goal, that is, to maintain energy homeostasis. Claude Bernard17 discovered in 1877 that hemorrhage stimulates liver glycogen to provide glucose, the ubiquitous body fuel. The experiences of the World War II stimulated investigators to seek better understanding of shock pathophysiology. Cuthbertson18 characterized the metabolic changes produced by injury by dividing them into an early ‘‘ebb’’ phase with reduced consumption of oxygen and heat production, followed by a ‘‘flow’’ phase characterized by increased consumption of energy and oxygen and a rising body temperature. When the injury or blood loss was fatal, death was preceded by a period, termed by Stoner19,20 necrobiosis, characterized by continuing decrease in heat production and reduced consumption of oxygen. Most of the early in-depth studies of metabolic alterations during hypovolemic shock published in the Journal drew on studies by Engle.21 These studies demonstrated that the hypoxia of shock impaired the use of energy, while simultaneously, the neurohumoral defense of homeostasis created a hypermetabolic state that increased glucose uptake for consumption by muscles.22 Failure of exogenous glucose to suppress gluconeogenesis suggested a link among gluconeogenesis and the hypermetabolism, intolerance for glucose, and increased production of urea in hypovolemic patients.23 If shock persisted, the glycogen store became depleted, and glucose was maintained by hormonally driven gluconeogenesis.24 Ultimately, the process failed, and hypoglycemia replaced hyperglycemia. The finding by Pearce and Drucker25 that glucose infusion during persisting hemorrhagic shock prolonged survival suggested that it can serve as an energy substrate in defense of homeostasis. The finding that
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glucose is a major factor in moving fluid from cells to facilitate blood volume restitution and thus cardiovascular stabilization as well as the finding that glucose uptake into cells is inhibited by the hormonal response to injury led Gann and Foster26 to the alternative explanation that this nonmetabolic role of glucose is the critical factor.
VOLUME RESTORATION Rapid expansion of depleted circulatory volume is the primary means for overcoming the distortion of energy metabolism in hypovolemic shock. Dahn et al.27 found depressed insulin production in trauma and sepsis. Clemens et al.28 found insulin resistance instead. Baue et al.29 found that both erythrocyte-free and colloidal solutions improved the metabolic indices of oxidative metabolism, but their use produced an ‘‘obligatory’’ increase in cardiac output, cardiac work, and peripheral flow resulting from rapid dilution of the hematocrit. Drucker et al.30 found that circulatory volume has greater influence on protecting energy metabolism than on the mass of circulating erythrocytes. However, slow return of lost volume was not protective. Acute reduction of circulating volume less than 25% required urgent attention, whereas the hematocrit could be diluted more than 50% before a critical shortage of red blood cells became evident. For many years, the rapid refill of plasma volume following hemorrhage was ascribed to the osmotic action across the capillary by hyperglycemia produced by hypovolemic shock. There is no transcapillary osmotic gradient, so this must be incorrect. However, osmolality increases after hemorrhage, and this is a dominant factor (discussed later). Friedman et al.31 found that fed animals had better plasma refill and longer survival times. Chadwick et al.32 discovered that if the starved rats were well hydrated, they could achieve 80% of the plasma refill found in well-fed animals. Survival times were similar in the two groups. Expansion of extracellular volume by hydration can substitute for osmotically driven movement of water into that space. Haller et al.33 found that cardiac output was a reliable method to study the influence of controlled reduction of blood flow on oxidative metabolism and catecholamines response. Halmagyi et al.34 found no correlation between the levels of glucagon or epinephrine and the development of hyperglycemia during shock. Consistent with Blalock’s observation that blood pressure is an inadequate guide to the state of the circulation in incipient shock, Halmagyi et al. also found no relation between the concentration of blood glucose during hypovolemia and either the hemodynamic alterations or the plasma level of insulin. Gann’s laboratory focused attention on the mechanisms restoring blood volume after hemorrhage. There are two phases. The first, initiated by a fall in capillary hydrostatic pressure, stops when the sum of capillary hydrostatic and oncotic pressures equals the sum of interstitial hydrostatic and oncotic pressures. The second phase is mediated by movement of albumin, with interstitial fluid, into capillaries in response to a rise in interstitial pressure. This rise is driven by an increase in extracellular glucose that generates an osmotic gradient across cell membranes. Glucose is derived from hepatic glycogen by action of the counterregulatory hormones,26 including increased cortisol,
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glucagon, catecholamines, vasopressin, and angiotensin II, and inhibited insulin release. Blockade of any of these hormones prevents complete restitution of blood volume. The most important factor is the increased cortisol, without which restitution of blood volume fails completely.35 If hepatic glycogen is inadequate, other molecules will be substituted, primarily glycolytic products such as lactate and pyruvate.36 Complete restitution of blood volume is required for complete restoration of cardiovascular variables such as cardiac output.37,38 For hemorrhages up to 25% of initial blood volume, restoration is complete within 48 hours. If the hemorrhage exceeds 26%, restitution of blood volume fails.39 This is the same level at which Shires40 found the threshold for decreased transmembrane potential. Subsequently, Shires’ laboratory reported that this phenomenon, observed initially in muscle cells, was also seen in erythrocytes.41 In discussing this article, Gann observed that there must be a circulating substance mediating this effect.41 The sodium pump, Na/K ATPase, is the principal factor maintaining cellular transmembrane potential. Na/K ATPase activity is inhibited in all forms of circulatory shock. Inhibition was thought to result from decreased delivery of oxygen. The previously mentioned finding was the final demonstration that failure of oxygen delivery could not be the sole factor in decreasing activity of Na/K ATPase, since the red blood cell does not consume oxygen. Evans et al.42 reported that a protein that depolarized diverse cells from several species, including human, appeared in rats within 20 minutes of large hemorrhage. This finding was confirmed by Boulanger et al.43 in dogs for large hemorrhage. Subsequently, Eastridge et al.44 found identical time courses of what seemed to be very similar material in rats with either large hemorrhage or intravenous injection of shock-producing Escherichia coli. Jones et al.45 found that this material decreased both contractility and heart rate of isolated, perfused rat hearts and suggested that the depolarizing protein might also be active in the evolution of cardiogenic shock. Thus, the hypothetical protein might be a unifying factor in the development of all three of the principal forms of circulatory shock. However, further attempts at isolation of the protein led repeatedly to the purification of the same protein with no depolarizing activity. Sequencing identified it as fetal rat albumin (Darlington and Gann, unpublished data). Further examination of the extract showed that it contained low (G1,000) molecular weight substances that affected activity of Na/K ATPase. Fractionation demonstrated four active components. The heaviest, at the front, was probably the protein-bound substance previously purified and analyzed. The other three were much lighter and included two inhibitory regions separated by a stimulatory region. The studies of Shires40 had led to the general acceptance of the ubiquitous phenomenon of cell depolarization of cells in shock, but most persons believed that depolarization was incidental in shock, not implicated in the development or lethality of the response. To test the hypothesis that cell depolarization might have important consequences, the group proceeded to isolate the stimulatory material, identified as adenosine.46 Adenosine was shown to increase activity of ATPase in vitro and to prolong survival of rats in hemorrhagic shock for several hours. All three of the purine nucleosides had identical effects on both enzyme 890
activity and survival.47 The beneficial effects of enzyme stimulation suggested that inhibition of Na/K ATPase is important in shock. Conversely, inhibition of the sodium pump by the putative inhibitor may be an important contributor to mortality in shock. Because of the finding by Eastridge et al.44 that sepsis elicited a similar response to hemorrhage, Darlington and Gann48 tested the effect of one purine nucleoside, inosine, on rats in shock produced by endotoxin. Infusion of the purine reversed shock and prevented mortality. The results again suggest a common element in different forms of circulatory shock. Darlington and Gann have identified the inhibitor as a bufadienolide, a class of inhibitors of Na/K ATPase, but have not excluded additional active components. The work to this time remains unpublished.
IRREVERSIBLE SHOCK The previously mentioned findings relate to an evolving consideration of irreversible shock. As sodium accumulates in the cells in response to inhibition of Na/K ATPase, the sodium/ calcium exchange reverses its normal direction, and calcium accumulates within cells. Trump49 found that at high levels, calcium activates proteolytic enzymes, leading to destruction of organelles and death. This phenomenon was observed by Holden et al.50 in the first electron microscopic study of shock and is clearly irreversible.
RESUSCITATIVE THERAPY Estimation of Shock Severity Recently, attention has focused on two aspects of severity of injury and/or shock. First, who is likely to die? Second, is massive transfusion needed? With regard to mortality, one group has examined the use of the shock index, first described by Allgower and Burris.51 Cannon et al.52 evaluated changes in index from the field to the emergency department. They found that an increase of the index of 0.3 or greater was highly predictive of mortality. They proposed that responses of the index to resuscitation might be useful in evaluating success. Interest has increased in predicting the need for massive transfusion (Q10 U of blood or red blood cells). Cancio et al.53 noted the combined needs for prediction of mortality and for logistical adjustment for massive transfusion in battlefield situations. Both the shock index and severity were included in two equations. The authors also validated the modifications of the Revised Trauma Score (RTS) by Champion et al.54 and a substitute proposed by Eastridge et al.55 to obviate the need for calculation under battle conditions. Both scores gave similar results, although the RTS was superior for precision. Vandromme et al.56 evaluated the utility of the shock index alone in a civilian population. They found that a shock index of greater than 0.9 (normal up to 0.7) predicted massive transfusion, rising to an incidence of 20% with an index of greater than 1.3. Magnotti et al.57 found that ionized calcium correlated with the need for massive transfusion and mortality. Yanagawa et al.58 measured the diameter of the inferior vena cava sonographically before and after initial fluid resuscitation. Failure of the vessel to expand with fluid infusion implied inadequate treatment. Ferrada et al.59 examined the * Lippincott Williams & Wilkins
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inferior vena cava during rapid echocardiography to estimate volume status in critically injured patients. They used the technique to guide pharmacologic intervention and fluid administration. Callcut et al.60 found that multiple variables suggested as criteria for massive transfusion had very different predictive values. The two elements most predictive of the need for massive transfusion are systolic blood pressure and international normalized ratio.
DELAYED FLUID RESUSCITATION; COAGULOPATHY Bickell et al.61 compared immediate and delayed fluid resuscitation in hypotensive patients with penetrating injuries. Delayed resuscitation improved survival. Survival difference was 62% versus 70%, and serious complication rate was 30% versus 23%. There seemed to be no disadvantage, which might have been expected, and time was saved. The principal motivation for the study was the irresolvable difference between those favoring a ‘‘scoop-and-run’’ approach in the management of acute injury and those content with primary stabilization. Now, there are a number of studies in animals showing that standard resuscitation is accompanied by decreased oxygen delivery, increased rate of hemorrhage, reperfusion injury, organ failure, and coagulopathy. Dutton et al.62 challenged the conclusions of Bickell et al. The authors chose an intermediate approach, fluid administration to a targeted systolic pressure of 70 mm Hg instead of the customary standard of 100 mm Hg. The findings of the new study showed no significant benefit in mortality. However, the actual achieved systolic pressure was 100 mm Hg in the group with 70 mm Hg and 114 mm Hg in the group with 100 mm Hg, both values in the range recommended by the advanced trauma life support course. The lack of a demonstrable effect of lowering pressure may have resulted solely from an inability to maintain lower pressure. A combination of limited volume and substitution of plasma for crystalloid was proposed by Holcomb63 as damagecontrol resuscitation (DCR), with limited support of systolic blood pressure and early use of plasma. Plasma helps prevent coagulopathy resulting from acidosis and hypothermia. Duchesne et al.64 have reported on DCR in civilian practice, comparing patients with DCR with those treated conventionally. DCR improved results. Expansion of blood volume should ameliorate both acidosis and hypothermia. Plasma contains coagulation factors, activated as temperature, and hydrogen ion concentration are normalized. The appropriate ratio of plasma to red blood cells was not clear. Borgman et al.65 stratified the response to massive transfusion into three groups of wounded patients with approximately equal severity of injury, according to the ratio of plasma to red blood cells. Mortality decreased from 64% to 19% as the ratio increased from 1:8 to 1:1.4. Kashuk et al.66 reported improvement in mortality with a 1:2 ratio and noted that international normalized ratio was elevated with resuscitation with lactated Ringer’s (LR) solution. Subsequently, a multicenter study by Wafaisade et al.67 reported that in civilians, 24-hour mortality was halved as the plasmaYtoYred blood cell ratio was increased to 1:1 or greater. Davenport et al.68 reported the first
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prospective study in human patients. The findings of these and other articles suggest that the optimal ratio may be less than 1:1 but greater than 1:2.
BLOOD Studies of blood have held center stage in resuscitative therapy through the life of the Journal. An assessment of blood and blood products was made by a panel chaired by Sheldon et al.69 They warned that blood is possibly the most dangerous ‘‘drug’’ we use. Crystalloid without colloid is probably the best overall substitute for blood; its use should be followed by typespecific blood according to the specific need of a patient. The use of fresh whole blood helped constrain continued bleeding after an exchange transfusion. A single-unit transfusion replaced the need for multiple-component therapy. In the state after injury, there is no advantage in raising the hematocrit to greater than 30% early in therapy.70 Review of whole blood and blood ‘‘expanders’’ used in Viet Nam led Sheldon et al.71 to recommend type-specific fresh whole blood as preferable. Although experts agree that blood usually is the best replacement fluid for blood loss, transfusions still possess sufficient shortcomings to warrant use of a ‘‘blood substitute’’ or blood component therapy or acellular oxygen carriers. Gervin and Fischer72 found type-specific nonYcross-matched blood to be safe as an alternative to cross-matched blood. Many problems with massive transfusion of banked blood related to defective coagulation factors and platelet function, supporting the recommendation of fresh whole blood for massive blood replacement by Lim et al.73 Gould et al.74 found both stroma-free hemoglobin and a fluorocarbon emulsion, Fluosol-DA, to be effective acellular oxygen carriers as hematocrit was reduced to 10%. Greenburg et al.75 found that the oxyhemoglobin dissociation curve of stroma-free hemoglobin shifted to the left and was responsive to pH changes.
CRYSTALLOID, COLLOID, AND TONICITY Monafo76 attempted to define the optimal solute composition and volume of asanguinous fluids used to replace blood. Debate raged between treatment with colloids versus crystalloids, between different types of colloids and between isotonic versus hypertonic fluid.77 Pruitt et al.78 found saline to be an adequate replacement fluid in man for moderate hemorrhage when administered in volume equivalent to loss of blood plus sequestered extravascular fluid. LR solution was deemed to be superior presumably because of decreased chloride load and absence of acetate or magnesium.79 The danger of producing hyperchloremic acidosis by normal saline as well as the indiscriminate use of crystalloid fluids have been reemphasized in more recent articles.80,81 Schumer82 found that dextran matched blood in rapidity and degree of improving hemodynamic activity despite diluting the hematocrit. Experience in combat83 demonstrated that protein-free fluid may be combined with blood in the resuscitation of severely wounded humans without producing a significant dilution of serum albumin and without producing edema. Trunkey et al.84 proposed infusion of calcium to counteract its presumed
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movement into cells during massive transfusions. However, because of the deleterious and even lethal effects of a rapid increase in intracellular calcium,49 extreme caution is advised if used in patients.
HYPERTONIC SALINE Velasco et al.85 have championed the use of hypertonic saline (HTS) in resuscitation of hemorrhagic shock. They conducted studies in both animals and patients in hemorrhagic and septic shock with HTS alone or with 6% dextran. Rotstein86 proposed that HTS can also attenuate immune-mediated cellular injury. Sheppard et al.87 found that a number of subcellular pathways are influenced by the administration of HTS. Vassar et al.88 reported on the effectiveness of this combination solution in injured patients in this country. The rationale for the combination was that HTS moved water from cells to the extracellular space and the dextran retains a greater part in the vascular bed. When tested, relative effectiveness of 7.5% NaCl with and without dextran showed no significant differences in survival but increased cost.89 Coimbra et al.90 examined the effectiveness of HTS versus LR solution on sepsis after hemorrhagic shock in mice with a second insult of cecal ligation and puncture. Mortality was reduced in the group treated with HTS. Cultured blood showed significantly more bacterial colonies and increased pulmonary inflammation in the LR group. Rhee et al.91 showed that in swine, neutrophil activation was twice as great with LR resuscitation as with HTS, was sustained with LR solution, but was normal with HTS. LR solution alone also caused activation. The mechanisms involved are not clear. In head injury combined with shock, Battistella and Wisner92 reported HTS reduced brain swelling while expanding blood volume. They found reductions in intracranial pressure and brain water in response to HTS in contrast to LR, despite similar change in hemodynamics. Schmoker et al.93 demonstrated in swine increased cerebral oxygen delivery with decreased intracerebral pressure with HTS relative to LR. Shackford et al.94 compared groups of patients with head injuries, resuscitated with either LR or HTS. Patients with HTS showed significant falls in intracranial pressure compared with no significant change in those given LR, but no differences were seen in survival or Glasgow Coma Scale (GCS) scores at discharge. Nonetheless, HTS seems to be a safe mode of therapy.
HYPOTHERMIA Several investigators have explored ancillary procedures. A survey of severely injured trauma patients demonstrated that 60% presented with a body temperature less than 36-C. This raised the question whether hypothermia was an independent risk factor predisposing patients to increased morbidity or a physiologic response to trauma. Jurkovich et al.95 suggested that hypothermia presenting in trauma patients is an ominous predictor of death. However, mild hypothermia (30Y34-C) protected the microvasculature, presumably by inhibiting expression of reactive oxidation species. There has been progress with hypothermia with circulatory arrest in severe hemorrhagic shock. Tisherman et al.96 found in dogs that deep hypothermia of 892
15-C led to survival of greater than 72 hours. Neurologic deficits were measured after various periods of hypothermia. There was no deficit at 60 minutes but mild deficit at 90 minutes. The authors suggested that such periods might permit repair of otherwise lethal injuries without significant brain damage. When more severe hypothermia (temperature of G10-C for the head and G15-C for the rest of the body), with immersion of the head in ice water for 120 minutes, deficit was not significantly different from controls.97 The authors concluded that cooling of the head with circulatory arrest could be used clinically, along with other brainprotective therapies. Kim et al.98 found in rats that hypothermia combined with infusion of LR to a mean arterial pressure of 40 mm Hg permitted survival without brain damage in 7 of 10 rats. Neither hypothermia alone or fluid infusion alone produced significant survival. The authors cautioned against the standard practice of attempting to maintain normal body temperature in treating shock.
ADULT RESPIRATORY DISTRESS SYNDROME Viet Nam casualties focused attention on the lung. Pulmonary failure in shock was attributed to a variety of changes.99 The primary change was increased pulmonary interstitial fluid, with resulting impaired oxygen diffusion. Demling et al.100 analyzed the Starling forces in sheep, showed the major force to be increased pulmonary microvascular pressure, and showed that sepsis produced different changes. The treatment of adult respiratory distress syndrome became increased positive endexpiratory pressure.101
BACTERIAL TRANSLOCATION AND MULTIPLE-ORGAN FAILURE In our search on shock, the most frequently cited article was one from Deitch’s laboratory on bacterial translocation.102 The concept of translocation of bacteria from the bowel following shock, mediated by mucosal injury from xanthine oxidase-generated oxidants, and the concept of a ‘‘two-hit’’ mechanism are believed to be responsible for organ failure after traumatic injury.103,104 Baker et al.105 found focal necrosis in guts of rats in hemorrhagic shock and were able to recover bacteria, primarily E. coli and Enterococcus, from several tissues. Subsequently, Moore et al.106 reported that translocation might produce a systemic inflammatory cascade characterized by release of proinflammatory cytokines and activation of the complement system from a combination of shock and hydroxyl radicals formed by reperfusion injury. In an additional study, Deitch et al.107 demonstrated that the intestinal barrier might be destroyed by injection of an inflammatory agent, zymosan, leading to gut origin sepsis, a term first used by Border et al.108 Rush’s group found positive blood cultures in 56% of patients with severe trauma within 3 hours of injury.109 However, Peitzman et al.110 found that positive cultures in mesenteric lymph nodes were relatively rare and were not correlated with subsequent infections, most of which were pulmonary. Braithwaite et al.111 confirmed that positive cultures of mesenteric lymph nodes were rare but discovered fragments of E. coli * Lippincott Williams & Wilkins
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in macrophages in all nodes by an immunocytochemical method. There was, however, no correlation with the presence of hemorrhagic shock. Thus, the question of the role of bacterial translocation in the development of clinical sepsis after hemorrhagic shock in humans remains unresolved. Moore et al.112 pursued the earlier finding of flowdependent increased oxygen consumption. They treated 39 patients with this condition with supplemental oxygen, with a goal of increasing oxygen delivery to attain increased VO2. This regimen was successful in 24 patients. However, the remaining 15 patients did not achieve the goal but instead had in addition elevation of plasma lactate. The failure of response correlated with the development of multiple-organ failure. The authors felt that the inability to increase oxygen consumption could result from inadequate blood flow, maldistribution of flow or defective oxygen consumption, alone or in combination. They felt that reperfusion injury could be a major contributor or simply from shock-induced changes in bioenergic cellular processes. Alternatively, Botha et al.113 suggested that early neutrophil sequestration after injury led to multiple-organ failure. Nast-Kolb et al.114 reported on a variety of plasma factors known to be elevated with inflammation after trauma in 66 severely injured patients (Injury Severity Score [ISS] 9 18). Of these, 11 died from multiple-organ failure, 38 survived despite single- or multiple-organ failure, and 17 recovered without organ failure. They used the latter group to attempt to discern a pattern of response that could be used to predict organ failure. As noted in discussion, no real prediction was possible since the measurements were observed during the evolution of the clinical response. However, all of the factors reported, including neutrophil elastase, antithrombin III, lactate, interleukin 6, and interleukin 8, were elevated early after injury in patients who developed organ failure compared with those who did not. Most returned toward levels seen in patients recovering without organ failure in 1 day or 2 days. Patients who then developed organ failure later had increases in lactate and the two interleukins at the same time.
CONCLUSION On reflection, we feel that our efforts, despite their inadequacies, have confirmed our initial judgment. In its early years, the Journal did not reflect the focus of research in trauma. Much of the research in the 1960s was directed toward the renal response to injury, but publications appeared in other journals. In contrast, under the leadership of the last several editors-in-chief, the Journal has actually dominated in reports of major new findings leading to better understanding of the pathophysiology associated with injury and rewarding advances in therapy. A sobering conclusion, however, is that advances in prevention have failed to displace accidental death and injury from its position of dominance for infants and young adults. The Journal of Trauma merits commendation as a preferred site for publication of thoughtful studies devoted to better understanding and management of injuries. We hope that the finding of effective preventive measures will be included. DISCLOSURE The authors declare no conflicts of interest.
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