0
Review Article |

Organ Preconditioning FREE

Christopher D. Raeburn, MD; Joseph C. Cleveland Jr, MD; Michael A. Zimmerman, MD; Alden H. Harken, MD
[+] Author Affiliations

From the Department of Surgery and the Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center, Denver.


Arch Surg. 2001;136(11):1263-1266. doi:10.1001/archsurg.136.11.1263.
Text Size: A A A
Published online

The initial discovery of cardiac preconditioning has evolved into an exciting series of practical surgical applications. An enormous amount of evidence demonstrating both the safety and efficacy of ischemic preconditioning is available from animal studies. The challenging premise of intentionally subjecting patients and their organs to transient ischemia has acted as a formidable psychological and ethical impediment to the widespread clinical application of organ preconditioning. A more palatable alternative to ischemic preconditioning now involves approved medications designed to manipulate the cellular machinery mediating ischemic preconditioning. Pharmacologically induced preconditioning seems to confer equal organ protection. The relatively brief (but surgically relevant) window of protection provided by strategies such as ischemic preconditioning or adenosine agonists and potassium–adenosine triphosphate channel openers may, in the future, be extended. We have developed and reported the feasibility of liposomal delivery of heat shock protein to cardiac myocytes with subsequent protection against sepsis-induced dysfunction. Targeted strategies will ultimately broaden the therapeutic potential of organ preconditioning.

Figures in this Article

Organ preconditioning is a process whereby a brief antecedent event, be it transient ischemia, oxidative stress, temperature change, or drug administration, bestows on an organ a temporary tolerance to further insults by the same or similar stressors. Regardless of your surgical discipline, organ preconditioning is on the horizon and promises to reduce morbidity during coronary revascularization, to provide improved graft and patient survival after transplantation, to protect kidneys and intestines during vascular surgery, to improve skin and muscle flap survival, and perhaps even to protect the editors of this journal from the cerebrovascular ischemic ravages of old age. The purposes of this review are as follows: (1) to describe the evolution and mechanisms of organ preconditioning, (2) to examine the evidence that organ preconditioning is accessible and relevant to surgery, and (3) to discuss future implications for organ preconditioning.

Murry et al1 first recognized organ preconditioning. Paradoxically, while trying to create a larger myocardial infarction in a dog, they subjected animals to several brief episodes of myocardial ischemia and reperfusion prior to a protracted ischemic injury. To their surprise, the area of infarction in these stressed animals was reduced by up to 75% compared with animals not subjected to antecedent brief ischemia.1 In addition to limiting infarct size, ischemic preconditioning reduces myocardial functional "stunning,"2,3 post-ischemic arrhythmias,4,5 and accelerates the recovery of muscle function after ischemia.6 These counterintuitive findings have been challenged, but confirmed in multiple organs across many species.

Though the mechanisms of preconditioning have been best studied in the heart, these cellular protective strategies have been identified in other organs.79 Ischemic preconditioning is psychologically repugnant to the active surgeon; we are reluctant to clamp a carotid artery even transiently prior to performing a carotid endarterectomy. Fortunately, ischemic preconditioning can be replicated by pharmacologic agonists to adenosine, α-adrenergic, opioid and/or bradykinin receptors, suggesting that tissues have evolved multiple parallel endogenous means of self-protection.6,1012 Intracellular signaling is a lot like the analog processing in a lap-top computer. In a computer, a fork in the network is transduced either yes/positive or no/negative. In a cell, kinases transmit the "yes" signal by phosphorylation, while phosphatases say "no" by cleaving a phosphate. A common theme among preconditioning receptors is that they are linked to protein kinase C,13 which is the first step in a complex cascade of phosphorylating (yes signal) kinases that activate the potassium–adenosine triphosphate (K-ATP) channel in the mitochondrial membrane (Figure 1). This K-ATP channel is the final common energy-producing pathway to organ preconditioning. We have reported that inhibition of this K-ATP channel completely abolishes the effects of ischemic preconditioning in the heart.14 Commonly prescribed drugs, such as oral hypoglycemic agents (inhibitors of the K-ATP channel) and L-type calcium channel blockers (inhibitors of the calcium "trigger"), compromise protective cardiac preconditioning and increase cardiac morbidity and mortality after an ischemic event.15,16 Conversely, the inhibition of bradykinin degradation in patients taking angiotensin-converting enzyme inhibitors may account for the reduced morbidity and mortality observed after a myocardial infarction.17

Place holder to copy figure label and caption

Cardiomyocyte preconditioning may occur via transient ischemia, oxidants, heat shock, osmolar stress, or by ligation of adenosine, α-adrenergic, bradykinin, or opioid receptors. All of these signal through protein kinase C (PKC), which initiates a complex kinase cascade that ultimately opens mitochondrial potassium–adenosine triphosphatase channels (K-ATP), protecting the cell from subsequent injury. Gp indicates G-protein; PLC, phospholipase C; and Ca++, calcium.

Graphic Jump Location

After the description by Murry et al1 of myocardial ischemic preconditioning, a myriad of publications corroborated this initial discovery. Although many laboratory studies have confirmed the existence of ischemic preconditioning in animals, care must be taken in extrapolating these findings to humans.18 In vitro studies using human atrial muscle strips exhibit preconditioning but an in vivo clinical strategy to investigate ischemic preconditioning is both logistically and ethically challenging.

Two important observational studies have provided strong evidence for the existence of ischemic preconditioning in human myocardium, and have thus paved the way for further clinical investigation of preconditioning as a therapeutic strategy. Patients undergoing coronary angioplasty experienced less pain and exhibited only mild S-T segment depression during sequential balloon inflation after an initial 90-second coronary artery occlusion.19 Similarly, patients experiencing preinfarction angina during the 24 hours preceding a myocardial infarction suffered smaller infarcts and enjoyed improved survival.20 Subsequent investigations revealed that adenosine antagonists and K-ATPase inhibition prevent protective preconditioning during angioplasty, confirming that the mechanisms of myocardial preconditioning are similar in animals and humans.21,22

Jenkins et al23 provided the first clinical evidence that ischemic preconditioning resulted in myocardial protection. During routine coronary artery bypass grafting (CABG), they applied two 3-minute periods of ischemia (aortic cross-clamping) followed by 3 minutes of reperfusion before the more extensive ischemia (10-15 minutes) obligatory for a coronary vascular anastomosis. Preconditioned patients released lower levels of serum troponin T at 72 hours postbypass.23

Despite these promising findings, the unnerving thought of intentionally inducing myocardial ischemia in patients is too difficult for many clinicians to bear, thus hindering the widespread clinical application of ischemic preconditioning. Fortunately, pharmacologic strategies have evolved that seem to mimic the mechanisms of ischemia while reaping the benefits of preconditioning without the actual ischemia (Figure 1). We and others have reported that adenosine administered prior to routine CABG decreases postoperative atrial arrhythmias,5 and a multi-institutional trial confirmed that adenosine administered immediately prior to cross-clamping the aorta improves ventricular function following CABG.24,25

Transplant surgery offers the perfect opportunity for preconditioning as it requires a scheduled, transient ischemic period during organ procurement and storage. Strong support for the application of organ preconditioning has been established in animals. In the rat, 2 short periods of ischemia and reperfusion, or administration of diazoxide (a K-ATP channel opener) prior to explantation and cold storage, improved postreperfusion left ventricular compliance and reduced creatine kinase leak.26

Yin et al27 have reported that rat livers subjected to ischemic preconditioning or adenosine administration prior to harvest prompted improved survival and reduced aspartate transaminase (AST) release after 16 hours of cold storage and transplantation. A clinical correlate to this study, again counterintuitively, reported that livers procured from donors suffering a brief cardiopulmonary arrest prior to procurement enjoyed similar graft function and host survival but lower posttransplant AST levels compared with the nonarrest group.28 Any rational surgeon would logically predict impaired posttransplantation hepatic function in the cardiopulmonary arrest donor group. Liver preconditioning, therefore, is the only plausible mode of protection.

Lung transplantation is associated with a 20% incidence of severe graft dysfunction in the early postoperative period.29 In animals, ischemic preconditioning of lungs prior to prolonged hypothermic storage is protective of both compliance30 and gas exchange.31

Elective vascular surgery also offers a unique opportunity for organ preconditioning, as it too involves an obligate period of transient ischemia. Preconditioning may improve functional recovery of skeletal muscle during peripheral vascular procedures8 and may also protect renal function during complex pararenal aortic aneurysm repair. Animal evidence has been overwhelming in showing that antecedent transient ischemia will protect the brain during carotid endarterectomy; however, the psychological hurdles for the surgeon who must intentionally clamp the carotid (of a university dean or even a trial lawyer) remain daunting.

Lee and Emala7 have reported that ischemic preconditioning prior to a 45-minute ischemic event resulted in improved renal function and morphological structure in rats. Moreover, these investigators found that A-1 adenosine agonists and A-3 adenosine antagonists reproduced the benefits of ischemic preconditioning.7 This study delineates and confirms the role of the various adenosine receptors in organ preconditioning.

Analogous to the study by Ottani et al20 correlating preinfarction angina with reduced morbidity after a myocardial infarction, several groups have reported that patients suffering transient ischemic attacks (TIA) experience a more favorable outcome after a subsequent ischemic stroke.32,33 Animal investigations have confirmed similar benefits with protective ischemic preconditioning in reducing neuronal damage after subsequent prolonged ischemia.34

Despite a better understanding of vascular anatomy and improved flap design, the devastating complication of partial or complete myocutaneous flap necrosis following reconstructive surgery still occurs.35 Zahir et al36 have reported that ischemic preconditioning reduces the incidence of skin and free-muscle flap necrosis in rats.36 Preliminary clinical trials using ischemic preconditioning have shown improved survival rates of both transverse rectus abdominis flaps and groin flaps.37,38

Despite the enormous amount of evidence demonstrating the safety and efficacy of ischemic preconditioning in animal studies, the challenge of intentionally subjecting patients to transient ischemia has acted as a formidable impediment to its widespread clinical application. The development of approved medications designed to replicate the cellular machinery involved in preconditioning offers a more palatable alternative to ischemic preconditioning. Moreover, the relatively brief window of protection provided by strategies such as ischemic preconditioning, adenosine agonists, and K-ATP channel openers may, in the future, be extended. For instance, we have developed and reported the feasibility of liposomal delivery of heat shock protein to cardiac myocytes, with subsequent protection against sepsis-induced cardiac dysfunction.39 Strategies such as this may ultimately broaden the therapeutic potential of organ preconditioning even further.

Corresponding author: Christopher D. Raeburn, MD, Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Campus Box C-320, Denver, CO 80262 (e-mail: christopher.raeburn@uchsc.edu).

Murry  CEJennings  RBReimer  KA Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;741124- 1136
Cleveland  JC  JrWollmering  MMMeldrum  DR  et al.  Ischemic preconditioning in human and rat ventricle. Am J Physiol. 1996;271H1786- H1794
Sun  JZTang  XLKnowlton  AAPark  SWQiu  YBolli  R Late preconditioning against myocardial stunning: an endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs. J Clin Invest. 1995;95388- 403
Shiki  KHearse  DJ Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias. Am J Physiol. 1987;253H1470- H1476
Pomerantz  BJJoo  KShames  BDCleveland  JC  JrBanerjee  AHarken  AH Adenosine preconditioning reduces both pre and postischemic arrhythmias in human myocardium. J Surg Res. 2000;90191- 196
Banerjee  ALocke-Winter  CRogers  KB  et al.  Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res. 1993;73656- 670
Lee  HTEmala  CW Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A(1) and A(3) receptors. Am J Physiol Renal Physiol. 2000;278F380- F387
Hopper  RAForrest  CRXu  H  et al.  Role and mechanism of PKC in ischemic preconditioning of pig skeletal muscle against infarction. Am J Physiol Regul Integr Comp Physiol. 2000;279R666- R676
Reshef  ASperling  OZoref-Shani  E Opening of K(ATP) channels is mandatory for acquisition of ischemic tolerance by adenosine. Neuroreport. 2000;11463- 465
Liu  GSThornton  JVan Winkle  DMStanley  AWOlsson  RADowney  JM Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation. 1991;84350- 356
Schultz  JEHsu  AKGross  GJ Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res. 1996;781100- 1104
Brew  ECMitchell  MBRehring  TF  et al.  Role of bradykinin in cardiac functional protection after global ischemia-reperfusion in rat heart. Am J Physiol. 1995;269 (pt2) H1370- H1378
Mitchell  MBMeng  XAo  LBrown  JMHarken  AHBanerjee  A Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res. 1995;7673- 81
Cleveland  JC  JrMeldrum  DRRowland  RTBanerjee  AHarken  AH Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive K+ channel. J Mol Cell Cardiol. 1997;29175- 182
Cleveland  JC  JrMeldrum  DRCain  BSBanerjee  AHarken  AH Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium: two paradoxes revisited [comments]. Circulation. 1997;9629- 32
Cain  BSMeldrum  DRCleveland  JC  JrMeng  XBanerjee  AHarken  AH Clinical L-type Ca(2+) channel blockade prevents ischemic preconditioning of human myocardium [comments]. J Mol Cell Cardiol. 1999;312191- 2197
Morris  SDYellon  DM Angiotensin-converting enzyme inhibitors potentiate preconditioning through bradykinin B2 receptor activation in human heart. J Am Coll Cardiol. 1997;291599- 1606
Tomai  FCrea  FChiariello  LGioffre  PA Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation. 1999;100559- 563
Deutsch  EBerger  MKussmaul  WGHirshfeld  JW  JrHerrmann  HCLaskey  WK Adaptation to ischemia during percutaneous transluminal coronary angioplasty: clinical, hemodynamic, and metabolic features. Circulation. 1990;822044- 2051
Ottani  FGalvani  MFerrini  D  et al.  Prodromal angina limits infarct size: a role for ischemic preconditioning [comments]. Circulation. 1995;91291- 297
Tomai  FCrea  FGaspardone  A  et al.  Effects of A1 adenosine receptor blockade by bamiphylline on ischaemic preconditioning during coronary angioplasty [comments]. Eur Heart J. 1996;17846- 853
Tomai  FCrea  FGaspardone  A  et al.  Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation. 1994;90700- 705
Jenkins  DPPugsley  WBAlkhulaifi  AMKemp  MHooper  JYellon  DM Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart. 1997;77314- 318
Mentzer  RM  JrBirjiniuk  VKhuri  S  et al.  Adenosine myocardial protection: preliminary results of a phase II clinical trial [discussion]. Ann Surg. 1999;229643- 649
Lee  HTLaFaro  RJReed  GE Pretreatment of human myocardium with adenosine during open heart surgery. J Card Surg. 1995;10665- 676
Kevelaitis  EOubenaissa  APeynet  JMouas  CMenasche  P Preconditioning by mitochondrial ATP-sensitive potassium channel openers: an effective approach for improving the preservation of heart transplants. Circulation. 1999;100II345- II350
Yin  DPSankary  HNChong  AS  et al.  Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats. Transplantation. 1998;66152- 157
Totsuka  EFung  JJUrakami  A  et al.  Influence of donor cardiopulmonary arrest in human liver transplantation: possible role of ischemic preconditioning. Hepatology. 2000;31577- 580
Novick  RJGehman  KEAli  ISLee  J Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg. 1996;62302- 314
Featherstone  RLChambers  DJKelly  FJ Ischemic preconditioning enhances recovery of isolated rat lungs after hypothermic preservation. Ann Thorac Surg. 2000;69237- 242
Du  ZYHicks  MWinlaw  DSpratt  PMacdonald  P Ischemic preconditioning enhances donor lung preservation in the rat. J Heart Lung Transplant. 1996;151258- 1267
Moncayo  Jde Freitas  GRBogousslavsky  JAltieri  Mvan Melle  G Do transient ischemic attacks have a neuroprotective effect? Neurology. 2000;542089- 2094
Weih  MKallenberg  KBergk  A  et al.  Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke. 1999;301851- 1854
Liu  YKato  HNakata  NKogure  K Protection of rat hippocampus against ischemic neuronal damage by pretreatment with sublethal ischemia. Brain Res. 1992;586121- 124
Banic  ABoeckx  WGreulich  M  et al.  Late results of breast reconstruction with free TRAM flaps: a prospective multicentric study [discussion]. Plast Reconstr Surg. 1995;951195- 1204
Zahir  KSSyed  SAZink  JRRestifo  RJThomson  JG Ischemic preconditioning improves the survival of skin and myocutaneous flaps in a rat model [discussion]. Plast Reconstr Surg. 1998;102140- 150
Restifo  RJThomson  JG The preconditioned TRAM flap: preliminary clinical experience. Ann Plast Surg. 1998;41343- 347
Cheng  MHChen  HCWei  FCSu  SWLian  SHBrey  E Devices for ischemic preconditioning of the pedicled groin flap. J Trauma. 2000;48552- 557
Meldrum  DRMeng  XShames  BD  et al.  Liposomal delivery of heat-shock protein 72 into the heart prevents endotoxin-induced myocardial contractile dysfunction. Surgery. 1999;126135- 141

Figures

Place holder to copy figure label and caption

Cardiomyocyte preconditioning may occur via transient ischemia, oxidants, heat shock, osmolar stress, or by ligation of adenosine, α-adrenergic, bradykinin, or opioid receptors. All of these signal through protein kinase C (PKC), which initiates a complex kinase cascade that ultimately opens mitochondrial potassium–adenosine triphosphatase channels (K-ATP), protecting the cell from subsequent injury. Gp indicates G-protein; PLC, phospholipase C; and Ca++, calcium.

Graphic Jump Location

Tables

References

Murry  CEJennings  RBReimer  KA Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;741124- 1136
Cleveland  JC  JrWollmering  MMMeldrum  DR  et al.  Ischemic preconditioning in human and rat ventricle. Am J Physiol. 1996;271H1786- H1794
Sun  JZTang  XLKnowlton  AAPark  SWQiu  YBolli  R Late preconditioning against myocardial stunning: an endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs. J Clin Invest. 1995;95388- 403
Shiki  KHearse  DJ Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias. Am J Physiol. 1987;253H1470- H1476
Pomerantz  BJJoo  KShames  BDCleveland  JC  JrBanerjee  AHarken  AH Adenosine preconditioning reduces both pre and postischemic arrhythmias in human myocardium. J Surg Res. 2000;90191- 196
Banerjee  ALocke-Winter  CRogers  KB  et al.  Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res. 1993;73656- 670
Lee  HTEmala  CW Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A(1) and A(3) receptors. Am J Physiol Renal Physiol. 2000;278F380- F387
Hopper  RAForrest  CRXu  H  et al.  Role and mechanism of PKC in ischemic preconditioning of pig skeletal muscle against infarction. Am J Physiol Regul Integr Comp Physiol. 2000;279R666- R676
Reshef  ASperling  OZoref-Shani  E Opening of K(ATP) channels is mandatory for acquisition of ischemic tolerance by adenosine. Neuroreport. 2000;11463- 465
Liu  GSThornton  JVan Winkle  DMStanley  AWOlsson  RADowney  JM Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation. 1991;84350- 356
Schultz  JEHsu  AKGross  GJ Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res. 1996;781100- 1104
Brew  ECMitchell  MBRehring  TF  et al.  Role of bradykinin in cardiac functional protection after global ischemia-reperfusion in rat heart. Am J Physiol. 1995;269 (pt2) H1370- H1378
Mitchell  MBMeng  XAo  LBrown  JMHarken  AHBanerjee  A Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res. 1995;7673- 81
Cleveland  JC  JrMeldrum  DRRowland  RTBanerjee  AHarken  AH Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive K+ channel. J Mol Cell Cardiol. 1997;29175- 182
Cleveland  JC  JrMeldrum  DRCain  BSBanerjee  AHarken  AH Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium: two paradoxes revisited [comments]. Circulation. 1997;9629- 32
Cain  BSMeldrum  DRCleveland  JC  JrMeng  XBanerjee  AHarken  AH Clinical L-type Ca(2+) channel blockade prevents ischemic preconditioning of human myocardium [comments]. J Mol Cell Cardiol. 1999;312191- 2197
Morris  SDYellon  DM Angiotensin-converting enzyme inhibitors potentiate preconditioning through bradykinin B2 receptor activation in human heart. J Am Coll Cardiol. 1997;291599- 1606
Tomai  FCrea  FChiariello  LGioffre  PA Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation. 1999;100559- 563
Deutsch  EBerger  MKussmaul  WGHirshfeld  JW  JrHerrmann  HCLaskey  WK Adaptation to ischemia during percutaneous transluminal coronary angioplasty: clinical, hemodynamic, and metabolic features. Circulation. 1990;822044- 2051
Ottani  FGalvani  MFerrini  D  et al.  Prodromal angina limits infarct size: a role for ischemic preconditioning [comments]. Circulation. 1995;91291- 297
Tomai  FCrea  FGaspardone  A  et al.  Effects of A1 adenosine receptor blockade by bamiphylline on ischaemic preconditioning during coronary angioplasty [comments]. Eur Heart J. 1996;17846- 853
Tomai  FCrea  FGaspardone  A  et al.  Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation. 1994;90700- 705
Jenkins  DPPugsley  WBAlkhulaifi  AMKemp  MHooper  JYellon  DM Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart. 1997;77314- 318
Mentzer  RM  JrBirjiniuk  VKhuri  S  et al.  Adenosine myocardial protection: preliminary results of a phase II clinical trial [discussion]. Ann Surg. 1999;229643- 649
Lee  HTLaFaro  RJReed  GE Pretreatment of human myocardium with adenosine during open heart surgery. J Card Surg. 1995;10665- 676
Kevelaitis  EOubenaissa  APeynet  JMouas  CMenasche  P Preconditioning by mitochondrial ATP-sensitive potassium channel openers: an effective approach for improving the preservation of heart transplants. Circulation. 1999;100II345- II350
Yin  DPSankary  HNChong  AS  et al.  Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats. Transplantation. 1998;66152- 157
Totsuka  EFung  JJUrakami  A  et al.  Influence of donor cardiopulmonary arrest in human liver transplantation: possible role of ischemic preconditioning. Hepatology. 2000;31577- 580
Novick  RJGehman  KEAli  ISLee  J Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg. 1996;62302- 314
Featherstone  RLChambers  DJKelly  FJ Ischemic preconditioning enhances recovery of isolated rat lungs after hypothermic preservation. Ann Thorac Surg. 2000;69237- 242
Du  ZYHicks  MWinlaw  DSpratt  PMacdonald  P Ischemic preconditioning enhances donor lung preservation in the rat. J Heart Lung Transplant. 1996;151258- 1267
Moncayo  Jde Freitas  GRBogousslavsky  JAltieri  Mvan Melle  G Do transient ischemic attacks have a neuroprotective effect? Neurology. 2000;542089- 2094
Weih  MKallenberg  KBergk  A  et al.  Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke. 1999;301851- 1854
Liu  YKato  HNakata  NKogure  K Protection of rat hippocampus against ischemic neuronal damage by pretreatment with sublethal ischemia. Brain Res. 1992;586121- 124
Banic  ABoeckx  WGreulich  M  et al.  Late results of breast reconstruction with free TRAM flaps: a prospective multicentric study [discussion]. Plast Reconstr Surg. 1995;951195- 1204
Zahir  KSSyed  SAZink  JRRestifo  RJThomson  JG Ischemic preconditioning improves the survival of skin and myocutaneous flaps in a rat model [discussion]. Plast Reconstr Surg. 1998;102140- 150
Restifo  RJThomson  JG The preconditioned TRAM flap: preliminary clinical experience. Ann Plast Surg. 1998;41343- 347
Cheng  MHChen  HCWei  FCSu  SWLian  SHBrey  E Devices for ischemic preconditioning of the pedicled groin flap. J Trauma. 2000;48552- 557
Meldrum  DRMeng  XShames  BD  et al.  Liposomal delivery of heat-shock protein 72 into the heart prevents endotoxin-induced myocardial contractile dysfunction. Surgery. 1999;126135- 141

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