Reperfusion after prolonged ischemia results in a metabolic insult to the affected tissue greater than the ischemic injury alone [21, 58]. IRI also results in a systemic inflammatory response with the potential to affect tissues distant from the reperfused area. Acute respiratory distress syndrome, multiorgan failure, and death have been described as consequences of IRI [7, 15]. Neutrophil activation and infiltration have been identified as primary protagonists in the pathophysiology of IRI [10, 21, 22]. CS results in a much greater level of metabolic strain and cellular deterioration than IRI alone, and its treatment is urgent surgical decompression by fasciotomy once identified [18, 19, 37, 40, 49]. Despite the major morbidity associated with CS, there is no widely accepted clinical treatment to attenuate the reperfusion injury that follows fasciotomy. NAC is a potent free-radical scavenger that has intrinsic antioxidant properties and replenishes depleted glutathione stores . It has a well-described, acceptable toxicity profile, proven in a critical-care setting . We hypothesized NAC in a simulated CS injury in a rodent model would preserve striated muscle contractility, decrease neutrophil sequestration, and reduce neutrophil respiratory burst activity.
We recognize certain limitations of our study. First, this is an animal model of simulated compartment syndrome using cremaster muscle, which therefore may not necessarily reflect the human physiologic responses to CS of an extremity and the model does not address neural injury in the involved compartment. The study was designed to determine the potential of NAC to attenuate the reperfusion injury to striated muscle after CS. Although our data suggest improved muscle function in terms of contractility in this model at as much as 7 days recovery, the data do not address nerve injury or long-term recovery of muscle function, therefore functional clinical outcomes cannot be directly inferred. Second, we assessed one dose of NAC (0.5 mg/kg) delivered parenterally but did not investigate the dose-response relationship; additional studies will be required to determine the optimum dose. Despite these limitations, we believe the data provide a valid argument for additional investigation of NAC's ability to reduce reperfusion injury following CS. Even if clinical muscle function is not maintained owing to nerve impairment, the improved muscle tissue viability as shown by improved contractility, and the reduced oxidant injury as evidenced by reduced myeloperoxidase and respiratory burst activity may correlate to a decrease in the inflammatory activity of the reperfusate and therefore, the systemic consequences of reperfusion.
We found muscle contractility was preserved using NAC given before or after decompression of CS. Liu et al. noted a similar protective effect after IRI as measured by improved arteriolar dilatation and tetanic contraction . NAC also decreases muscle cell death attributable to IRI in mice as measured by malonyldialdehyde levels . Thus, the apparent benefits of NAC seen in IRI models apparently apply in our CS model.
The increased neutrophil infiltration after CS release was not attenuated by NAC at 1 hour, suggesting NAC pretreatment did not alter neutrophil transmigration acutely. At 24 hours, however, there was a definite reduction in MPO activity in the NAC groups, whether given before or after CS. This indicates reduced neutrophil sequestration, implying a delayed protective effect of NAC. Two other studies have shown NAC decreases vascular permeability in rats after free-radical-induced injury [46, 53]. The ability of NAC to maintain endothelial integrity and decrease vascular permeability may explain the reduced neutrophil infiltration.
Activated neutrophils produce superoxide anions, ROS, and proteolytic enzymes, which mediate their injurious effects in reperfusion injury. Neutrophil respiratory burst activity correlates to the level of neutrophil activation and ROS production [38, 58]. The decrease in respiratory burst activity when animals were pretreated with NAC suggests it modulates its effects directly on the neutrophils, reducing their propensity to produce free radicals, possibly by its combined antioxidant and glutathione-replenishing activities.
Making the diagnosis of a CS is a critical clinical episode, particularly in the unconscious patient [34, 35]. Delay to diagnosis and treatment is the most important prognostic factor in CS [40, 48]. Fasciotomy may be associated with substantial surgical morbidity, but even after decompression, focal areas of muscle ischemia and hypoxia may persist [23, 24, 43, 47]. Preadministration with NAC to high-risk patients (such as patients with high-energy tibial fractures) may help reduce muscle injury and edema induced by CS. The efficacy of this agent, even when administered after decompression, has potential clinical applications in the trauma setting and warrants additional assessment.
Our data suggest antioxidant administration may represent a potential therapeutic strategy for management of striated muscle CS. In our experiments, NAC administration appeared to protect striated muscle against CS-induced injury by attenuating neutrophil activation. This effect was reproduced with NAC administration after the injury, suggesting a potential role for NAC in the attenuation of muscle injury even after release of CS. We suggest NAC may be an appropriate agent for a clinical trial in such a setting.
1. Anner, H., Kaufman, RP., Kobzik, L., Valeri, CR., Shepro, D. and Hechtman, HB. Pulmonary hypertension and leukosequestration after lower torso ischemia. Ann Surg.
1987; 206: 642-648. 10.1097/00000658-198711000-00015
2. Anner, H., Kaufman, RP., Kobzik, L., Valeri, CR., Shepro, D. and Hechtman, HB. Pulmonary leukosequestration induced by hind limb ischemia. Ann Surg.
1987; 206: 162-167. 10.1097/00000658-198708000-00008
3. Anner, H., Kaufman, RP., Valeri, CR., Shepro, D. and Hechtman, HB. Reperfusion of ischemic lower limbs increases pulmonary microvascular permeability. J Trauma.
1988; 28: 607-610. 10.1097/00005373-198805000-00007
4. Barry, MC., Kelly, CJ., Abdih, H., Watson, RW., Stapleton, P., Sheehan, SJ., Redmond, HP. and Hayes, DB. Differential effects of lower limb revascularisation on organ injury and the role of the amino acid taurine. Eur J Vasc Endovasc Surg.
1997; 13: 193-201. 10.1016/S1078-5884(97)80018-4
5. Barry, MC., Wang, JH., Kelly, CJ., Sheehan, SJ., Redmond, HP. and Bouchier-Hayes, DJ. Plasma factors augment neutrophil and endothelial cell activation during aortic surgery. Eur J Vasc Endovasc Surg.
1997; 13: 381-387. 10.1016/S1078-5884(97)80080-9
6. Bernard, GR. N-acetylcysteine in experimental and clinical acute lung injury. Am J Med.
1991; 91: 54S-59S. 10.1016/0002-9343(91)90284-5
7. Blaisdell, FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg.
2002; 10: 620-630. 10.1016/S0967-2109(02)00070-4
8. Bolcal, C., Yildirim, V., Doganci, S., Sargin, M., Aydin, A., Eken, A., Ozal, E., Kuralay, E., Demirkilic, U. and Tatar, H. Protective effects of antioxidant medications on limb ischemia reperfusion injury. J Surg Res.
2007; 139: 274-279. 10.1016/j.jss.2006.10.043
9. Burton, AC. On the physical equilibrium of small blood vessels. Am J Physiol.
1951; 164: 319-329.
10. Cavanagh, SP., Gough, MJ. and Homer-Vanniasinkam, S. The role of the neutrophil in ischaemia-reperfusion injury: potential therapeutic interventions. Cardiovasc Surg.
1998; 6: 112-118. 10.1016/S0967-2109(97)00133-6
11. Clayton, JM., Hayes, AC. and Barnes, RW. Tissue pressure and perfusion in the compartment syndrome. J Surg Res.
1977; 22: 333-339. 10.1016/0022-4804(77)90152-4
12. Crinnion, JN., Homer-Vanniasinkam, S., Parkin, SM. and Gough, MJ. Role of neutrophil-endothelial adhesion in skeletal muscle reperfusion injury. Br J Surg.
1996; 83: 251-254. 10.1002/bjs.1800830234
13. Davreux, CJ., Soric, I., Nathens, AB., Watson, RW., McGilvray, ID., Suntres, ZE., Shek, PN. and Rotstein, OD. N-acetyl cysteine attenuates acute lung injury in the rat. Shock.
1997; 8: 432-438. 10.1097/00024382-199712000-00007
14. Flanagan, RJ. and Meredith, TJ. Use of N-acetylcysteine in clinical toxicology. Am J Med.
1991; 91: 131S-139S. 10.1016/0002-9343(91)90296-A
15. Haimovici, H. Muscular, renal, and metabolic complications of acute arterial occlusions: myonephropathic-metabolic syndrome. Surgery.
1979; 85: 461-468.
16. Hartsock, LA., O'Farrell, D., Seaber, AV. and Urbaniak, JR. Effect of increased compartment pressure on the microcirculation of skeletal muscle. Microsurgery.
1998; 18: 67-71. 10.1002/(SICI)1098-2752(1998)18:2<67::AID-MICR1>3.0.CO;2-R
17. Heller, AR., Groth, G., Heller, SC., Breitkreutz, R., Nebe, T., Quintel, M. and Koch, T. N-acetylcysteine reduces respiratory burst but augments neutrophil phagocytosis in intensive care unit patients. Crit Care Med.
2001; 29: 272-276. 10.1097/00003246-200102000-00009
18. Heppenstall, RB., Sapega, AA., Izant, T., Fallon, R., Shenton, D., Park, YS. and Chance, B. Compartment syndrome: a quantitative study of high-energy phosphorus compounds using 31P-magnetic resonance spectroscopy. J Trauma.
1989; 29: 1113-1119. 10.1097/00005373-198908000-00008
19. Heppenstall, RB., Sapega, AA., Scott, R., Shenton, D., Park, YS., Maris, J. and Chance, B. The compartment syndrome: an experimental and clinical study of muscular energy metabolism using phosphorus nuclear magnetic resonance spectroscopy. Clin Orthop Relat Res.
1988; 226: 138-155.
20. Heppenstall, RB., Scott, R., Sapega, A., Park, YS. and Chance, B. A comparative study of the tolerance of skeletal muscle to ischemia: tourniquet application compared with acute compartment syndrome. J Bone Joint Surg Am.
1986; 68: 820-828.
21. Huda, R., Solanki, DR. and Mathru, M. Inflammatory and redox responses to ischaemia/reperfusion in human skeletal muscle. Clin Sci.
2004; 107: 497-503. 10.1042/CS20040179
22. Iwahori, Y., Ishiguro, N., Shimizu, T., Kondo, S., Yabe, Y., Oshima, T., Iwata, H. and Sendo, F. Selective neutrophil depletion with monoclonal antibodies attenuates ischemia/reperfusion injury in skeletal muscle. J Reconstr Microsurg.
1998; 14: 109-116. 10.1055/s-2007-1000152
23. Jerome, SN., Akimitsu, T. and Korthuis, RJ. Leukocyte adhesion, edema, and development of postischemic capillary no-reflow. Am J Physiol.
1994; 267: H1329-1336.
24. Jerome, SN., Kong, L. and Korthuis, RJ. Microvascular dysfunction in postischemic skeletal muscle. J Invest Surg.
1994; 7: 3-16. 10.3109/08941939409018278
25. Kearns, SR., Daly, AF., Sheehan, K., Murray, P., Kelly, C. and Bouchier-Hayes, D. Oral vitamin C reduces the injury to skeletal muscle caused by compartment syndrome. J Bone Joint Surg Br.
2004; 86: 906-911. 10.1302/0301-620X.86B6.14177
26. Kearns, SR., Kelly, CJ., Barry, M., Abdih, H., Condron, C., Leahy, A. and Bouchier-Hayes, D. Vitamin C reduces ischaemia-reperfusion-induced acute lung injury. Eur J Vasc Endovasc Surg.
1999; 17: 533-536. 10.1053/ejvs.1999.0833
27. Kearns, SR., Moneley, D., Murray, P., Kelly, C. and Daly, AF. Oral vitamin C attenuates acute ischaemia-reperfusion injury in skeletal muscle. J Bone Joint Surg Br.
2001; 83: 1202-1206. 10.1302/0301-620X.83B8.11754
28. Koksal, C. Attenuation of ischemia/reperfusion injury by N-acetylcysteine in a rat hind limb model. J Surg Res.
2003; 111: 236-239. 10.1016/S0022-4804(03)00094-5
29. Laight, DW., Lad, N., Woodward, B. and Waterfall, JF. Assessment of myeloperoxidase activity in renal tissue after ischemia/reperfusion. Eur J Pharmacol.
1994; 292: 81-88.
30. Liu, K., Chen, LE., Seaber, AV. and Urbaniak, JR. S-nitroso-N-acetylcysteine protects skeletal muscle against reperfusion injury. Microsurgery.
1998; 18: 299-305. 10.1002/(SICI)1098-2752(1998)18:5<299::AID-MICR1>3.0.CO;2-J
31. Matsen, FA., Winquist, RA. and Krugmire, RB. Diagnosis and management of compartmental syndromes. J Bone Joint Surg Am.
1980; 62: 286-291.
32. McKenna, MJ., Medved, I., Goodman, CA., Brown, MJ., Bjorksten, AR., Murphy, KT., Petersen, AC., Sostaric, S. and Gong, X. N-acetylcysteine attenuates the decline in muscle Na+, K+-pump activity and delays fatigue during prolonged exercise in humans. J Physiol.
2006; 576: 279-288. 10.1113/jphysiol.2006.115352
33. McLaughlin, R., Bowler, D., Kelly, CJ., Kay, E. and Bouchier-Hayes, D. Taurine protects against early and late skeletal muscle dysfunction secondary to ischaemia reperfusion injury. Eur J Surg.
2000; 166: 375-379. 10.1080/110241500750008916
34. McQueen, MM. and Court-Brown, CM. Compartment monitoring in tibial fractures: the pressure threshold for decompression. J Bone Joint Surg Br.
1996; 78: 99-104.
35. McQueen, MM., Gaston, P. and Court-Brown, CM. Acute compartment syndrome: who is at risk? J Bone Joint Surg Br.
2000; 82: 200-203. 10.1302/0301-620X.82B2.9799
36. Ortolani, O., Conti, A., Gaudio, AR., Moraldi, E., Cantini, Q. and Novelli, G. The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock. Am J Respir Crit Care Med.
2000; 161: 1907-1911.
37. Perler, BA., Tohmeh, AG. and Bulkley, GB. Inhibition of the compartment syndrome by the ablation of free radical-mediated reperfusion injury. Surgery.
1990; 108: 40-47.
38. Robinson, JM. Phagocytic leukocytes and reactive oxygen species. Histochem Cell Biol.
2009; 131: 465-469. 10.1007/s00418-009-0565-5
39. Rocksén, D., Lilliehöök, B., Larsson, R., Johansson, T. and Bucht, A. Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation. Clin Exp Immunol.
2000; 122: 249-256. 10.1046/j.1365-2249.2000.01373.x
40. Rorabeck, CH. The treatment of compartment syndromes of the leg. J Bone Joint Surg Br.
1984; 66: 93-97.
41. Rothe, G., Emmendörffer, A., Oser, A., Roesler, J. and Valet, G. Flow cytometric measurement of the respiratory burst activity of phagocytes using dihydrorhodamine 123. J Immunol Methods.
1991; 138: 133-135. 10.1016/0022-1759(91)90074-P
42. Rumack, BH. Acetaminophen overdose. Am J Med.
1983; 75: 104-112. 10.1016/0002-9343(83)90240-1
43. Sadasivan, KK., Carden, DL., Moore, MB. and Korthuis, RJ. Neutrophil mediated microvascular injury in acute, experimental compartment syndrome. Clin Orthop Relat Res.
1997; 339: 206-215. 10.1097/00003086-199706000-00029
44. Saricaoglu, F., Dal, D., Salman, AE., Atay, OA., Doral, MN., Salman, MA., Kilinç, K. and Aypar, U. Effect of low-dose N-acetyl-cysteine infusion on tourniquet-induced ischaemia-reperfusion injury in arthroscopic knee surgery. Acta Anaesthesiol Scand.
2005; 49: 847-851. 10.1111/j.1399-6576.2005.00722.x
45. Schmidt, H., Schmidt, W., Müller, T., Böhrer, H., Gebhard, MM. and Martin, E. N-acetylcysteine attenuates endotoxin-induced leukocyte-endothelial cell adhesion and macromolecular leakage in vivo. Crit Care Med.
1997; 25: 858-863. 10.1097/00003246-199705000-00023
46. Schmidt, W., Walther, A., Gebhard, MM., Martin, E. and Schmidt, H. Influence of N-acetylcysteine treatment on endotoxin-induced microcirculatory disturbances. Intensive Care Med.
1998; 24: 967-972. 10.1007/s001340050697
47. Shaw, CJ. and Spencer, JD. Late management of compartment syndromes. Injury.
1995; 26: 633-635. 10.1016/0020-1383(95)00112-M
48. Sheridan, GW. and Matsen, FA. Fasciotomy in the treatment of the acute compartment syndrome. J Bone Joint Surg Am.
1976; 58: 112-115.
49. Sirsjö, A., Gidlöf, A., Nilsson, G. and Povlsen, B. Skeletal muscle blood flow after prolonged tourniquet ischaemia and reperfusion with and without intervening reoxygenation: an experimental study in rats using laser Doppler perfusion imaging. Scand J Plast Reconstr Surg Hand Surg.
1999; 33: 281-285. 10.1080/02844319950159244
50. Sjödin, K., Nilsson, E., Hallberg, A. and Tunek, A. Metabolism of N-acetyl-L-cysteine: some structural requirements for the deacetylation and consequences for the oral bioavailability. Biochem Pharmacol.
1989; 38: 3981-3985. 10.1016/0006-2952(89)90677-1
51. Spies, CD., Reinhart, K., Witt, I., Meier-Hellmann, A., Hannemann, L., Bredle, DL. and Schaffartzik, W. Influence of N-acetylcysteine on indirect indicators of tissue oxygenation in septic shock patients: results from a prospective, randomized, double-blind study. Crit Care Med.
1994; 22: 1738-1746.
52. Tepel, M., Giet, M., Schwarzfeld, C., Laufer, U., Liermann, D. and Zidek, W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med.
2000; 343: 180-184. 10.1056/NEJM200007203430304
53. Laan, L., Oyen, WJ., Verhofstad, AA., Tan, EC., ter Laak, HJ., Gabreels-Festen, A., Hendriks, T. and Goris, RJ. Soft tissue repair capacity after oxygen-derived free radical-induced damage in one hindlimb of the rat. J Surg Res.
1997; 72: 60-69. 10.1006/jsre.1997.5167
54. Wagner, PD., Mathieu-Costello, O., Bebout, DE., Gray, AT., Natterson, PD. and Glennow, C. Protection against pulmonary O2 toxicity by N-acetylcysteine. Eur Respir J.
1989; 2: 116-126.
55. Walker, PM., Lindsay, TF., Labbe, R., Mickle, DA. and Romaschin, AD. Salvage of skeletal muscle with free radical scavengers. J Vasc Surg.
1987; 5: 68-75. 10.1067/mva.1987.avs0050068
56. Wang, JX., Li, Y., Zhang, LK., Zhao, J., Pang, YZ., Tang, CS. and Zhang, J. Taurine inhibits ischemia/reperfusion-induced compartment syndrome in rabbits. Acta Pharmacol Sin.
2005; 26: 821-827. 10.1111/j.1745-7254.2005.00128.x
57. Weiss, SJ. Tissue destruction by neutrophils. N Engl J Med.
1989; 320: 365-376. 10.1056/NEJM198902093200606
58. Welbourn, CR., Goldman, G., Paterson, IS., Valeri, CR., Shepro, D. and Hechtman, HB. Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br J Surg.
1991; 78: 651-655. 10.1002/bjs.1800780607
59. Xiao, F., Eppihimer, MJ., Young, JA., Nguyen, K. and Carden, DL. Lung neutrophil retention and injury after intestinal ischemia/reperfusion. Microcirculation.
1997; 4: 359-367. 10.3109/10739689709146800