Resuscitation of the trauma victim: Early intervention impacts on patient outcome
By: Ori Rotstein, M.D.
Civilian trauma represents a significant health care problem. It ranks first among diseases in terms of years of life lost and fourth in overall mortality 1. Virtually any physician, when asked about the initial management of the trauma victim, will rhyme off the mnemonic- the ABCs- Airway, Breathing, Circulation. All represent critical components of the early interventions aimed at sustaining life until necessary definitive treatment of the injury occurs. The restoration of circulating blood volume in patients who have had significant blood loss related to the trauma is primarily intended to ensure that oxygen delivery to vital organs in the body is sustained. With timely and appropriate interventions, including transport to designated trauma centres, morbidity and mortality in the trauma victims can be minimized but not totally prevented.
While most early deaths are due to uncontrolled blood loss and brain injury, delayed mortality often occurs related to progressive deterioration of vital organs, so called “Multiple Organ Dysfunction Syndrome (MODS)”. The precise reason why organs throughout the body fail following trauma, even though they have not actually been injured during the initial traumatic event, has been the subject of intensive investigation over the past few decades. One prevailing concept is that major trauma induces a “systemic” inflammatory response and this overwhelming and sustained inflammation in the various organs leads to injury and deterioration of function. Any organ can be involved in this inflammatory response, but the lung, kidney and liver seem to be particularly common targets. In particular, lung dysfunction occurs frequently in trauma victims. In its fullest manifestation, lungs exhibit profound infiltration with inflammatory cells, particularly neutrophils, which injure the lung tissue causing leakiness of the vasculature and flooding of the lungs with fluid. This clinical scenario, called the Acute Respiratory Distress Syndrome (ARDS) has been shown to be an important contributor to late morbidity and mortality 2. Our research group has a longstanding interest in understanding how hemorrhagic shock followed by resuscitation is able to render patients more susceptible to the development of MODS and in particular, lung injury. We have focused our work on understanding the mechanism of these events with a view to developing and testing new therapeutic approaches first in animal models and then in humans.
Several models have been proposed to explain the clinical course of patients sustaining major trauma and developing organ dysfunction later on during their hospitalization. Among these, the “two-hit” model has evolved as a paradigm of human disease explaining the development of late organ injury following survival of an initial sublethal trauma insult 3. In the context of hemorrhagic shock, the “two-hit” model suggests that shock/resuscitation primes the immune system for increased responsiveness to a second delayed inflammatory stimulus, and the resulting excessive tissue inflammation leads to organ injury. This hypothesis was supported by early studies from the scientists at the University of Colorado 4. These investigators took blood from both normal individuals and from trauma patients and studied the responsiveness of circulating neutrophils to stimulation. They showed that trauma neutrophils were profoundly more responsive to stimulation than those from normal controls. This observation firmly established in man the concept that shock/resuscitation might serve to predispose trauma victims to subsequent organ injury by making their immune response more exuberant. Based on these clinical observations, several groups including our own, established in vitro and in vivo model systems to study the “two-hit” hypothesis as it relates to lung injury following shock resuscitation 5,6. Using these models we have studied both mechanisms of injury and potential treatment strategies.
Our early work focused on model development. We reported that resuscitated hemorrhagic shock in rodents serves as the initial or priming event for the development of endotoxin-induced lung injury. Interestingly, while neither shock nor low dose endotoxin alone caused injury, the sequential insults of shock/resuscitation (S/R) followed by intratracheal endotoxin lead to marked lung neutrophil accumulation and profound lung injury. This phenomenon is measured by lung leakiness and histopathological changes. In these studies, we further demonstrated that macrophages in the lung following S/R elaborated far more proinflammatory molecules in response to endotoxin than naïve animals. Among these, the chemokine cytokine-induced neutrophil chemoattractant (CINC), the rat homologue of Interleukin 8, was shown to be responsible for the excessive lung neutrophilia and the resulting injury. S/R was shown to cause earlier and heightened nuclear translocation of the transcription factor NF-kB in lung alveolar macrophages, leading to increased transcription of the a number of proinflammatory genes including CINC and tumour necrosis factor. Several studies have shown that the generation of oxidative stress is central to this priming event. Ischemia/reperfusion of the GI tract with the generation of the circulating xanthine oxidase has traditionally been implicated as the source of oxidative stress. However, recent studies by investigators at the University of Pittsburgh have suggested that neutrophil (PMN) derived reactive oxygen species generated through activation of the PMN NADPH oxidase system may also be important 6. Furthermore, we observed that, not only was the heightened response due to increased proinflammatory molecules, but the failure of the lungs to generate an anti-inflammatory response also appeared to be contributory. Interleukin 10, normally upregulated by endotoxin, failed to increase in response to endotoxin in cells recovered from animals following S/R, and in addition, exogenous IL-10 administration proved protective in this model. Together, these finding suggested the possibility that intervention during shock/resuscitation might prove beneficial in preventing macrophage activation. We therefore investigated a number of interventions that were initiated during the resuscitation phase, with a view to preventing lung injury. Among these, the use of a hyperosmolar resuscitation strategy proved most interesting.
In a series of animal studies, we investigated the ability of 7.5% hypertonic saline (HTS) used as a resuscitation fluid to alter lung injury in our two-hit model. In these studies, hypertonic saline resuscitation prevented lung injury by impairing lung neutrophil accumulation 7. This beneficial effect appeared to be due to a number of mechanisms. Relevant to those discussed above, we showed that HTS resuscitation prevented elaboration of oxidants from the gastrointestinal tract during S/R and by doing so, prevented priming of lung macrophages for increased responsiveness to endotoxin 8. We also found that HTS had a profound direct effect on neutrophils. HTS-treated neutrophils were incapable of expressing their surface adhesion molecules and were therefore unable to bind and transmigrate into the lung tissue, thereby further mitigating pulmonary injury. This worked spawned a number of studies by our group and others to investigate whether HTS could prevent ischemia/reperfusion injury of other organs including the heart, the liver, the gastrointestinal tract and the brain. In each of the organs, HTS was shown to lessen neutrophil sequestration and minimize injury.
These studies in the animal setting really begged the question as to whether resuscitation with HTS in trauma patients with hemorrhagic shock might minimize organ injury and improve outcome. With Dr. Sandro Rizoli’s research group at Sunnybrook Health Sciences Centre, we performed a pilot study investigating the ability of HTS resuscitation in trauma victims to alter the immune system, in an anti-inflammatory manner as we had shown in rodents. Using a randomized, controlled and double-blinded protocol, the studies demonstrated that HTS exhibited profound anti-inflammatory effects in man, including reducing both neutrophil and macrophage activation following shock/resuscitation 9. Obviously, the small number of patients studied in this pilot investigation was insufficient to judge mortality endpoints. However, these studies set the stage for a multicenter North American collaborative study aimed at looking at the ability of HTS resuscitation to improve outcome in trauma victims. The results of these clinical studies have recently been published. While HTS has clear immunomodulatory effects in man, the studies clearly demonstrated that HTS administrated as a resuscitation fluid in trauma patients did not significantly improve mortality or lessen traumatic brain injury 10. The precise reason for this outcome is not clear, but it likely speaks to the complexity of the trauma patient and the fact that a short-lived transient intervention may be insufficient to exert clear benefit in this patient population. Moving forward, the potential anti-inflammatory effect of HTS may have benefits in other ischemia/reperfusion settings, a question that bears investigation in man.
While HTS did not prove to be effective in the trials, the progression of studies from fundamental through to clinical trials is an excellent example of translational research. During these investigations, we learned a great deal about the mechanisms underlying development of lung injury in patients sustaining hemorrhagic shock. These may suggests alternate approaches in the future to lessen organ injury in this patient population. It is also important to observe that this basic and applied research was predominantly the work of Surgeon-Scientist trainees working in the laboratory. These individuals are ideally suited to discover new solutions to clinical problems by applying their knowledge of disease to the generation of hypotheses aimed at understanding pathological processes and defining new treatments. This is an important mandate of the Institute of Medical Science, one that is key to medical discovery and improved patient care.
1. Rose ME, Huerbin MB, Melick J, Marion DW, Palmer AM, Schiding JK, et al. Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury. Brain Res. 2002;935(1-2):40-6.
Ori D. Rotstein, M.D.
Professor and Associate Chair of Surgery, University of Toronto
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