Fluid Resuscitation State of the Science for Treating Combat Casualties and Civilian Injuries (1999) / Chapter Skim
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6 Future Directions
6 Future Directions
Pages 109-124
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From page 109... ...
For example, greater blood loss has been exhibited in studies of isobaric models of hemorrhagic shock in species with a large splenic red blood cell reserve, such as the dog. This variable can also affect the severity of the shock when the blood loss is based on percent body weight in fixed-volume models of hemorrhagic shock.
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From page 110... ...
Models of hemorrhagic shock are of two basic types: controlled and uncontrolled with respect to the manner in which ongoing blood loss is allowed to proceed. Controlled models are either of the fixed-volume or constant-pressure varieties and are generally more reproducible than uncontrolled bleeding models, which usually involve laceration, puncture, or transection.
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From page 111... ...
The advantage of mouse models in studying both the pathologic changes that occur during shock and the physiologic responses to acute hemorrhage is that inbred strains of mice have greater uniformity at the species level. Also, transgenic or gene-knockout strains provide animal models that are deficient in various mediators and that therefore add important information that often is not available by traditional pharmacologic approaches.
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From page 112... ...
The simian models exhibit a more robust response, and the animals usually sustain a more prolonged survival and better outcome with exposure to the same level of hemorrhagic stress to which humans are exposed. Technical Models Two principal models of hemorrhagic shock exist: the controlled hemorrhage model and the uncontrolled hemorrhage model.
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From page 113... ...
It has been stated that the model that most closely approximates battlefield casualty conditions is one that uses the uncontrolled hemorrhage in the absence of anesthesia in subjects who were previously dehydrated and exposed to various stresses. Although this might be a closer approximation to battlefield conditions, the ability to measure responses and outcomes would appear to be better with controlled hemorrhage models, simply because additional experimental variability is introduced by uncontrolled hemorrhage.
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From page 114... ...
Greater controversy exists with regard to ketamine, which may produce transient stimulating effects on the heart and peripheral circulation, but these effects are eliminated in animal models when the sympathetic nervous system is blocked or inhibited (Pager et al., 1992~. The minimal depressant effects of newer narcotics such as fentanyl and its derivatives have been confirmed by studies with animals and humans, but such efforts are found only at higher narcotic levels if ventilation is maintained since respiratory depression is a common finding at higher doses (Merin, 1996~.
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From page 115... ...
Experimental designs should look realistically at establishing a repeatable 50 percent lethal dose for the control group. If animal models are chosen to develop a consensus for application of novel treatment regimens and agents to potential human trials, then these interventions should be applied in an identical animal model with identical experimental protocols with defined endpoints or outcomes.
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From page 116... ...
Clinical trials often provide the most definitive proof of the safety and efficacy of diagnostic and therapeutic interventions in humans. Although studies with animals and uncontrolled clinical observations contribute to the understanding of a clinical entity, such studies usually cannot definitively demonstrate whether a new treatment has made a difference in clinical outcome.
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From page 117... ...
, a speaker from FDA stated that mortality will be the endpoint of choice for clinical trials on hemorrhagic shock or exsanguinating hemorrhage. If a resuscitation solution studied in a clinical trial on trauma is not anticipated to improve the rate of mortality associated with trauma, then the ability of such a product to improve a major cause of morbidity can be used to demonstrate the efficacy of the product, whereas a solution that does not worsen the mortality rate but that results in major irreversible morbidity in the survivors would not be judged to be effective.
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From page 118... ...
The applicability of these scores as surrogate endpoints has been the subject of considerable debate. Evaluation of Resuscitation Protocols The existing trauma indexing systems have contributed a great deal to the triage of trauma patients and to the development of systems for assessment of quality of care (Champion et al., 1996, 1990, 1989, 1983, 198 1; Copes et al., 1990, 1988; Gennarelli et al., 1994, 1989; Sacco et al., 1988, 1984~; however, the current trauma indexing systems are inadequate for use in the evaluation of future research (Brenneman et al., 1998; Demetriades et al., 1998; Hoyt, 1998; Roorda et al., 1996; Rutledge and Osler, 1998; Rutledge et al., 1998~.
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From page 119... ...
Although the Glasgow Coma Score affects RTS and the score has a significant influence on the probability of survival, it may still not be sufficient to control for this confounding. In addition, the American College of Surgeons Penetrating Injury database comprises data for civilian penetrating trauma victims who have mainly sustained knife or gunshot wounds.
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From page 120... ...
Unique Problems of Clinical Trials of Trauma Heterogeneity of Subject Population The heterogeneity of the subject population has been alluded to before in this report, but it is a central issue and warrants attention. The patients who would be studied in a clinical trial designed to test an intervention for hemorrhagic shock might have suffered blunt or penetrating trauma or a combination of these; they may have a discrete injury to a single organ or multiorgan lesions; the trauma might be a small lesion in a major vessel or a large lesion affecting a diffuse vascular bed.
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From page 121... ...
In this regard, it is noteworthy that civilian trauma facilities are now used for the training of military medical personnel. Clinical Research and Clinical Trials in Trauma Centers The United States has regional trauma centers that are mostly selfdesignated and has accredited and verified trauma centers that are very organized.
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From page 122... ...
for career officers. The comittee found that much of the earlier work in the field of traumatic shock has been tainted by the failure to recognize the differences between pure hemorrhagic shock and traumatic shock associated with tissue injury, the failure to standardize animal models with regard to anesthesia, and the failure to observe subjects for longer-term survival.
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From page 123... ...
Recommendation 6.1 Laboratory research should be reproducible and relevant to the clinical scenario. For fluid resuscitation research, the experimental design of animal research should be guided by the following principles: · when feasible, the experimental model should include softtissue injury in addition to hemorrhage; · controlled hemorrhage protocols are preferred to uncontrolled hemorrhage models; · when feasible, protocols that do not require anesthesia are preferred.
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From page 124... ...
124 FLUID RESUSCITA TION Federal agencies, including the U.S. Department of Defense, the U.S.
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