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Muscle Microdialysis to Confirm Sublethal Ischemia in the Induction of Remote Ischemic Preconditioning

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Abstract

Exposure of one tissue to ischemia–reperfusion confers a systemic protective effect, referred to as remote ischemic preconditioning (RIPC). Confirmation that the desired effect of ischemia is occurring in tissues used to induce RIPC requires an objective demonstration before this technique can be used consistently in the clinical practice. Enrolled patients underwent three to four RIPC sessions on non-consecutive days. Sessions consisted of 4 cycles of 5 min of leg cuff inflation to 30 mmHg above the systolic blood pressure followed by reperfusion. Absence of leg pulse was confirmed by Doppler evaluation. To evaluate limb transient ischemia, patients were monitored with muscle microdialysis. Glucose, lactate, lactate/pyruvate ratio, and glycerol levels were measured. Fourteen microdialysis sessions were performed in seven patients undergoing RIPC (42.8 % male; mean age, 51.8; Fisher grade 4 in all seven patients, Hunt and Hess grade 5 in five patients, four in one patient and one in one patient). An average follow-up of 29 days demonstrated no complications associated with the procedure. Muscle microdialysis during RIPC sessions showed a significant increase in lactate/pyruvate ratio (21.2 to 26.8, p = 0.001) and lactate (3.0 to 3.9 mmol/L, p = 0.002), indicating muscle ischemia. There was no significant variation in glycerol (234 to 204 μg/L, p = 0.43), indicating no permanent cell damage. The RIPC protocol used in this study is safe, well tolerated, and induces transient metabolic changes consistent with sublethal ischemia. Muscle microdialysis can be used safely as a confirmatory tool in the induction of RIPC.

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References

  1. Chen YS, Chien CT, Ma MC, Tseng YZ, Lin FY, Wang SS, et al. Protection "outside the box" (skeletal remote preconditioning) in rat model is triggered by free radical pathway. J Surg Res. 2005;126(1):92–101.

    Article  PubMed  CAS  Google Scholar 

  2. Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26(5):248–54.

    Article  PubMed  CAS  Google Scholar 

  3. Hausenloy DJ, Yellon DM. The evolving story of "conditioning" to protect against acute myocardial ischaemia–reperfusion injury. Heart. 2007;93(6):649–51.

    Article  PubMed  Google Scholar 

  4. Muramatsu H, Kariko K, Welsh FA. Induction of tolerance to focal ischemia in rat brain: dissociation between cortical lesioning and spreading depression. J Cereb Blood Flow Metab. 2004;24(10):1167–71.

    Article  PubMed  CAS  Google Scholar 

  5. Ren C, Yan Z, Wei D, Gao X, Chen X, Zhao H. Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res. 2009;1288:88–94.

    Article  PubMed  CAS  Google Scholar 

  6. Kanoria S, Jalan R, Seifalian AM, Williams R, Davidson BR. Protocols and mechanisms for remote ischemic preconditioning: a novel method for reducing ischemia reperfusion injury. Transplantation. 2007;84(4):445–58.

    Article  PubMed  Google Scholar 

  7. Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106(23):2881–3.

    Article  PubMed  CAS  Google Scholar 

  8. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87(3):893–9.

    PubMed  CAS  Google Scholar 

  9. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J Surg Res. 2008;150(2):304–30.

    Article  PubMed  Google Scholar 

  10. Takagi H, Manabe H, Kawai N, Goto SN, Umemoto T. Review and meta-analysis of randomized controlled clinical trials of remote ischemic preconditioning in cardiovascular surgery. Am J Cardiol. 2008;102(11):1487–8.

    Article  PubMed  Google Scholar 

  11. Kloner RA. Clinical application of remote ischemic preconditioning. Circulation. 2009;119(6):776–8.

    Article  PubMed  Google Scholar 

  12. Chan MT, Boet R, Ng SC, Poon WS, Gin T. Effect of ischemic preconditioning on brain tissue gases and pH during temporary cerebral artery occlusion. Acta Neurochir Suppl. 2005;95:93–6.

    Article  PubMed  CAS  Google Scholar 

  13. Koch S, Katsnelson M, Dong C, Perez-Pinzon M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke. 2011;42(5):1387–91. doi:10.1161/STROKEAHA.110.605840.

    Article  PubMed  Google Scholar 

  14. Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics. 2004;19(1):143–50.

    Article  PubMed  CAS  Google Scholar 

  15. Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, et al. The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg. 2005;130(5):1326–32.

    Article  PubMed  CAS  Google Scholar 

  16. Dahl NA, Balfour WM. Prolonged anoxic survival due to anoxia pre-exposure: brain ATP, lactate, and pyruvate. A J Physiol. 1964;207(2):452.

    CAS  Google Scholar 

  17. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.

    Article  PubMed  CAS  Google Scholar 

  18. Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, et al. Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke. 1998;29(9):1937–50.

    Google Scholar 

  19. Das M, Das DK. Molecular mechanism of preconditioning. IUBMB Life. 2008;60(4):199–203.

    Article  PubMed  CAS  Google Scholar 

  20. Janier MF, Vanoverschelde J, Bergmann SR. Ischemic preconditioning stimulates anaerobic glycolysis in the isolated rabbit heart. Am J Physiol Heart Circ Physiol. 1994;267(4):H1353.

    CAS  Google Scholar 

  21. Bolte CS, Liao S, Gross GJ, Schultz Jel J. Remote preconditioning-endocrine factors in organ protection against ischemic injury. Endocr Metab Immune Disord Drug Targets. 2007;7(3):167–75.

    Article  PubMed  CAS  Google Scholar 

  22. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res. 2008;79(3):377–86.

    Article  PubMed  CAS  Google Scholar 

  23. Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009;374(9700):1557–65.

    Article  PubMed  Google Scholar 

  24. Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol Heart Circ Physiol. 1997;273(4):H1707.

    CAS  Google Scholar 

  25. Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation. 1997;96(5):1641–6.

    PubMed  CAS  Google Scholar 

  26. Sun XC, Li WB, Li QJ, Zhang M, Xian XH, Qi J, et al. Limb ischemic preconditioning induces brain ischemic tolerance via p38 MAPK. Brain Res. 2006;1084(1):165–74.

    Article  PubMed  CAS  Google Scholar 

  27. Ren C, Gao X, Steinberg GK, Zhao H. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience. 2008;151(4):1099–103.

    Article  PubMed  CAS  Google Scholar 

  28. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia–reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol. 2005;46(3):450–6.

    Article  PubMed  CAS  Google Scholar 

  29. Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol. 2006;47(11):2277–82.

    Article  PubMed  Google Scholar 

  30. Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 2007;370(9587):575–9.

    Article  PubMed  Google Scholar 

  31. Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation. 2007;116(11 Suppl):I98–105.

    PubMed  Google Scholar 

  32. Hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, et al. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial. Circulation. 2009;119(6):820–7.

    Article  PubMed  Google Scholar 

  33. Venugopal V, Hausenloy DJ, Ludman A, Di Salvo C, Kolvekar S, Yap J, et al. Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart. 2009;95(19):1567–71.

    Article  PubMed  CAS  Google Scholar 

  34. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375(9716):727–34.

    Article  PubMed  Google Scholar 

  35. Muller M, Schmid R, Nieszpaur-Los M, Fassolt A, Lonnroth P, Fasching P, et al. Key metabolite kinetics in human skeletal muscle during ischaemia and reperfusion: measurement by microdialysis. Eur J Clin Investig. 1995;25(8):601–7.

    Article  CAS  Google Scholar 

  36. Korth U, Merkel G, Fernandez FF, Jandewerth O, Dogan G, Koch T, et al. Tourniquet-induced changes of energy metabolism in human skeletal muscle monitored by microdialysis. Anesthesiology. 2000;93(6):1407.

    Article  PubMed  CAS  Google Scholar 

  37. Ostman B, Michaelsson K, Rahme H, Hillered L. Tourniquet-induced ischemia and reperfusion in human skeletal muscle. Clin Orthop Relat Res. 2004;418:260.

    Article  PubMed  Google Scholar 

  38. Desvigne N, Barthelemy JC, Bertholon F, Gay-Montchamp JP, Freyssenet D, Costes F. Validation of a new calibration method for human muscle icrodialysis at rest and during exercise. Eur J Appl Physiol. 2004;92:312–20.

    Article  PubMed  CAS  Google Scholar 

  39. Hansen DK, Davies MI, Lunte SM, Lunte CE. Pharmacokinetic and metabolism studies using microdialysis sampling. J Pharm Sci. 1999;88(1):14–27.

    Article  PubMed  CAS  Google Scholar 

  40. Davies MI, Cooper JD, Desmond SS, Lunte CE, Lunte SM. Analytical considerations for microdialysis sampling. Adv Drug Deliv Rev. 2000;45(2–3):169–88.

    Article  PubMed  CAS  Google Scholar 

  41. Rosdahl H, Ungerstedt U, Jorfeldt L, Henriksson J. Interstitial glucose and lactate balance in human skeletal muscle and adipose tissue studied by microdialysis. J Physiol. 1993;471(1):637.

    PubMed  CAS  Google Scholar 

  42. Rosdahl H, Hamrin K, Ungerstedt U, Henriksson J. Metabolite levels in human skeletal muscle and adipose tissue studied with microdialysis at low perfusion flow. Am J Physiol Endocrinol Metab. 1998;274(5):E936–E45.

    CAS  Google Scholar 

  43. Ren G, Eiskjaer S, Kaspersen J, Christensen FB, Rasmussen S. Microdialysis of paraspinal muscle in healthy volunteers and patients underwent posterior lumbar fusion surgery. Eur Spine J. 2009;18(11):1604–9.

    Article  PubMed  Google Scholar 

  44. Ungerstedt U. Microdialysis—principles and applications for studies in animals and man. J Intern Med. 1991;230(4):365–73.

    Article  PubMed  CAS  Google Scholar 

  45. Birke-Sorensen H, Toft G, Bengaard J. Pure muscle transfers can be monitored by use of microdialysis. J Reconstr Microsurg. 2010;26(9):623–9.

    Article  PubMed  Google Scholar 

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The authors declare that they have no conflict of interest.

Support Acknowledgments

NRG research supported by the Ruth and Raymond Stotter Chair Endowment in Neurosurgery.

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Correspondence to Nestor R. Gonzalez.

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Bilgin-Freiert, A., Dusick, J.R., Stein, N.R. et al. Muscle Microdialysis to Confirm Sublethal Ischemia in the Induction of Remote Ischemic Preconditioning. Transl. Stroke Res. 3, 266–272 (2012). https://doi.org/10.1007/s12975-012-0153-1

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  • DOI: https://doi.org/10.1007/s12975-012-0153-1

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