Fluid Resuscitation State of the Science for Treating Combat Casualties and Civilian Injuries (1999) / Chapter Skim
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2 Pathophysiology of Acute Hemorrhagic Shock
2 Pathophysiology of Acute Hemorrhagic Shock
Pages 19-46
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From page 19... ...
They may cascade in a variety of ways such as decreased cardiac output, which leads to a decreased blood pressure, which in turn leads to decreased tissue per 19
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From page 20... ...
Decreased tissue perfusion at the cellular level leads to m~croc~rculatory damage, cellular aggregation, and m~croc~rculatory obs~uction, followed by cell hypoxia, transfer of salts and fluid into the cells, and decreased venous return. These events lead to metabolic acidosis, which, if it becomes deep, can result in decreased myocardial contraction.
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From page 21... ...
Septic shock is manifested by high-output cardiac failure in which there is increased cardiac output but decreased systemic vascular resistance and decreased myocardial contractility. Low-output cardiac failure can also develop in sepsis and reflects a loss of response to catecholamines.
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From page 22... ...
By contrast, in septic shock the cellular injury is the initiated event and hemodynarnic changes occur as a consequence of the cellular insult. The gastrointestinal consequences of shock include increased acid production and increased permeability of the gastric mucosa.
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From page 23... ...
A further reduction in circulating blood volume results in decreased arterial pressure and diminished stimulation of aortic arch and carotid sinus baroreceptors and further decreased stimulation of intracardiac receptors. These alterations cause reduced vagal tone to the heart and increased sympathetic nervous system activity to the heart, arterial vessels, and venous capacitance vessels.
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From page 24... ...
Shock Decompensation Loss of the ability of the compensatory mechanisms described above to maintain arterial blood pressure and cardiac output in the presence of prolonged hemorrhage is usually the result of decreased cardiac function and failure to maintain sympathetically induced arterial and venous vasoconstriction. The decline in cardiac function and vasoconstriction may be the result of toxic peptides (Lefer, 1978, 1985)
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From page 25... ...
the secretion of and cellular responsiveness to growth factors. , lipid metabolism, and Although during the last 30 years there has been considerable controversy regarding the ionic content and concentration of intravenous fluids used for resuscitation of patients in hemorrhagic shock, this controversy has not led to further consistent reductions in mortality.
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From page 26... ...
Mitochondria utilize the energy derived from the reduction of O2 to drive the pumping of protons out of the inner mitochondrial volume into the space between the inner and outer mitochondrial membranes. The phosphorylation of adenosine diphosphate (ADP)
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From page 27... ...
In the situation of high cytosolic Ca2+ concentrations, mitochondria utilize the proton gradient across the inner mitochondrial membrane to drive the influx of Ca2+ rather than to drive the production of ATP (Carafoli and Crompton, 1978~. Free fatty acids, and in particular arachidonate, are released from membrane lipids during brain ischemia as a consequence of the activity of both phospholipase C (Abe et al., 1987)
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From page 28... ...
, which is essential for inducible TNF-a transcription (Im et al., 1997~. Hemorrhagic shock induces increased levels of macrophage mRNA for TNF-a and IL6 and increased levels of mesenteric TNF-a and IL-6, and these effects are exacerbated by fluid resuscitation (Tamion et al., 1997~.
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From page 29... ...
Fundamental Alterations in Transcription and Translation: Apoptosis During the public presentations made to the committee as background for the preparation of this report, apoptosis was repeatedly implicated in the progression of tissue injury associated with hemorrhagic shock and volume resuscitation. Apoptosis is a complex mechanism of cell suicide and is triggered by intracellular molecular signals that may originate from a variety of subcellular organelles including the plasmalemma, mitochondria, endoplasmic reticulum, and nucleus (Bredesen, 1996; Hale et al., 1995~.
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From page 30... ...
, and it is clear that apoptosis is involved in ~e postischemic death of cardiac myocytes (Bromine and Holtz, 1996~. The situation with regard to plasmalemma receptor-induced apoptosis during brain reperfusion is different.
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From page 31... ...
Reduction of Nedd2 synthesis by antisense mRNA rescues both sympathetic neurons and PC12 cells from apoptosis caused by growth factor withdrawal (Troy et al., 1997~. However, in these same cells apoptosis induced by superoxide dismutase rl .
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These observations suggest that the ratio of Bc1-2 to Bax is important in the regulation of apoptosis. It is becoming clear that major changes in the translation initiation system for protein synthesis are crucial in apoptosis.
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From page 33... ...
and activation of CPP32 (Kaufman et al., 1998~. The proteolytic degradation of eIF4G and phosphorylation of eIF2a not only will result in general depression of overall protein synthesis, but will also exert a major effect on message selection for residual translation.
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From page 34... ...
However, ER Ca2+ depletion, eIF2a phosphorylation, and suppression of protein synthesis are induced by free arachidonate concentrations above 10 micromolar (pM) in cell culture models (Fleming and Mellow, 1995; Rotman et al., 1992~.
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From page 35... ...
These observations indicate that both apoptosis and viral resistance to apoptotic mechanisms emerged after the development of multicelled eukaryotes and suggest that execution mechanisms of inhibition of protein synthesis, proteolytic degradation of a DNA recombination mechanism (PARP) , and degradation of polynucleotides are all primarily antiviral strategies.
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From page 36... ...
This can lead to PKR activation, the consequent inhibition of protein synthesis, and the stimulus of transcription for FAS, which invites activation of the caspase system followed by degradation of PARP and induction of DNase activity. Similarly, primary DNA damage would induce PARP activity followed by pS3 activation, Bax expression, ER Ca2+ depletion, formation of pathologic mitochondrial pores, and so on.
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From page 37... ...
Both pancreatic insulin secretion and the kinase activity of the insulin receptor are markedly downregulated by adrenergic signaling mediated through cyclic adenosine monophosphate and protein kinase A (PKA) , and hypovolemia is clinically well known to be associated with insulin resistance.
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From page 38... ...
The above adrenergic and TNF-a signaling mechanisms that down-regulate insulin secretion, the tyrosine kinase activity of the insulin receptor, and the major intracellular substrates of the insulin receptor are in play in shock and are likely involved in the associated insulin resistance and hyperglycemia. HEMATOLOGIC ABNORMALITIES ASSOCIATED WITH SHOCK AND RESUSCITATION The administration of blood products and the management of bleeding disorders are important therapeutic modalities used by surgeons caring for patients with a wide variety of acute and chronic problems.
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From page 39... ...
Because fluid resuscitation became more prevalent during the Korean and Vietnam conflicts, the incidence of acute tubular necrosis dramatically decreased. Although acute tubular necrosis after hypovolemic shock became less of a problem with better fluid resuscitation, the shock lung syndrome (i.e., adult respiratory distress syndrome)
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From page 40... ...
Normal saline solution is an acceptable alternative to lactated Ringer's solution, but large volumes can produce a hyperchlo remic metabolic acidosis, which may complicate the care of the patient in shock. Massive Transfusion Massive transfusion has been defined as replacement of the patient's blood volume with stored red blood cells in 24 hours or as transfusion of more than 10 units of blood over a few hours.
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From page 41... ...
A transfusion of incompatible red blood cells is potentially fatal, but other significant concerns exist when a patient receives blood products, including the transfusion of infectious pathogens and immunologic effects. Because a transfusion exposes the recipient to a complex mixture of donor cells and proteins, it is in many ways a transplant.
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From page 42... ...
At present they have no clinical application as red blood cell substitutes. Early attempts to prepare hemoglobin solutions consisted of pooling outdated blood, breaking the red blood cells open, and extracting the hemoglobin molecules.
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From page 43... ...
CONCLUSIONS AND RECOMMENDATIONS Traditionally, clinicians have evaluated patients for the presence and progression of cellular injury or death by assay of cellular proteins in serum that are not specific to injury processes. The new understanding of lethal cellular processes suggests that serum should be examined for the products of these processes.
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From page 44... ...
Therefore, Me committee recommends Me following: Recommendation 2.1 Develop and validate diagnostic assays for substances in serum that indicate the specific mechanisms involved in the molecular processes of cellular injury and cell death induced by shock and resuscitation. Recommendation' 2.2 Expand the use of transgenic experimental animals to further evaluate the role of specific proteins and enzymes in cellular injury and death induced by shock and resuscitation.
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