Surgeons performing emergency surgical procedures often treat patients with hemorrhagic shock or septic shock. While it is now possible initially to optimize organ hemodynamics with balanced salt solution resuscitation and mechanical and pharmacologic support, it is not uncommon for patients to succumb as a result of multiple system organ failure involving the liver, kidney and lung. Because damage is not isolated to a single organ system, it appears that current resuscitation regimens do not prevent some form of universal damage even when blood flow appears to return to preshock levels. This damage could be secondary to some intrinsic cell abnormality caused by ischemia that is uncorrectable, to change in intracellular calcium (Ca2+) ion concentration, to reperfusion damage to cell or mitochondrial membranes caused by oxygen (O2) free radicals or to reduced nutrient blood (in spite of normal total organ blood flow) caused by microthrombi produced at a capillary level during the low shock state. The research goal is to evaluate the relative contribution of these mechanisms using clinically applicable animal models for both hemorrhagic and septic shock in which the cellular metabolic and nutrient blood flow features outlined will be evaluated. Mitochondrial metabolism will be examined in intact cells removed from the liver and kidney of rabbits at 30 and 55 minutes after the initiation of hemorrhagic shock (25 ml/kg) and 30 minutes after crystalloid resuscitation. The same tissues will be examined from rabbits subjected to septic shock by cecal ligation at time periods 4 and 16 hours from ligation and 4 hours after cecal excision and crystalloid resuscitation. Respiratory control indexes and the redox state of cytochrome C will be measured and compared to control group values in all experiments. The possible role of intracellular Ca2+ in mitochondrial dysfunction will be determined by measuring cytosolic free Ca2+ levels using quinn 2, a new fluorescent indicator for Ca2+. The relationship between blood flow and organ dysfunction will be examined and compared to the in vitro data by measuring liver and kidney high energy phosphate utilization and blood flow during similar shock conditions using in vivo 31P NMR imaging and radioisotope labeled microspheres. As a result of these experiments it is envisaged that a series of metabolic and blood flow parameters will be identified as characteristic of the shock state. Attention will then be directed toward biochemical manipulation of these parameters using O2 free radical scavengers, calcium channel blockers, and plasminogen activator.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL001502-01
Application #
3081865
Study Section
Research Manpower Review Committee (MR)
Project Start
1985-04-01
Project End
1990-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Martin, L F; Tan, T L; Holmes, P A et al. (1995) Can morbidly obese patients safely lose weight preoperatively? Am J Surg 169:245-53
Martin, L F; Atnip, R G; Holmes, P A et al. (1994) Prediction of postoperative complications after elective aortic surgery using stepwise logistic regression analysis. Am Surg 60:163-8
Martin, L F (1994) Stress ulcers are common after aortic surgery. Endoscopic evaluation of prophylactic therapy. Am Surg 60:169-74
Martin, L F; Peter, A O; Fehr, D M et al. (1992) 31P-NMR evaluation of postischemia renal ATP and pH levels after ATP-MgCl2 treatment in rabbits. Am J Surg 164:132-9
Martin, L F; Tan, T L; Holmes, P A et al. (1991) Preoperative insurance status influences postoperative complication rates for gastric bypass. Am J Surg 161:625-34
Scaduto Jr, R C; Gattone 2nd, V H; Martin, L F et al. (1991) Elevation of renal glutathione enhances ischemic injury. Ren Physiol Biochem 14:259-70
Peter, A O; Spangler, S; Martin, L F (1991) Evaluation of three techniques for documenting Staphylococcus epidermidis vascular prosthetic graft infections. Am Surg 57:80-5
Martin, L F; Vary, T C; Davis, P K et al. (1991) Intravascular plastic catheters. How they potentiate tumor necrosis factor release and exacerbate complications associated with sepsis. Arch Surg 126:1087-93
Martin, L F; Klim, C M; Vannucci, S J et al. (1990) Alterations in adipocyte adenylate cyclase activity in morbidly obese and formerly morbidly obese humans. Surgery 108:228-34;discussion 234-5
Pawlush, D G; Musch, T I; Bannar, S M et al. (1990) Cardiac dysfunction in a rat model of chronic bacteremia. Circ Shock 31:269-79

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