N-acetylcysteine protects striated muscle in a model of compartment syndrome

Abstract

Background: To avoid ischemic necrosis, compartment syndrome is a surgical emergency treated with decompression once identified. A potentially lethal, oxidant-driven reperfusion injury occurs after decompression. N-acetylcysteine is an antioxidant with the potential to attenuate the reperfusion injury.

Questions/purposes: We asked whether N-acetylcysteine could preserve striated muscle contractility and modify neutrophil infiltration and activation after simulated compartment syndrome release.

Materials and methods: Fifty-seven rats were randomized to control, simulated compartment syndrome, and simulated compartment syndrome plus N-acetylcysteine groups. We isolated the rodent cremaster muscle on its neurovascular pedicle and placed it in a pressure chamber. Chamber pressure was elevated above critical closing pressure for 3 hours to simulate compartment syndrome. Experiments were concluded at three times: 1 hour, 24 hours, and 7 days after decompression of compartment syndrome. We assessed twitch and tetanic contractile function and tissue myeloperoxidase activity. Ten additional rats were randomized to control and N-acetylcysteine administration after which neutrophil respiratory burst activity was assessed.

Results: The simulated compartment syndrome decreased muscle contractility and increased muscle tissue myeloperoxidase activity compared with controls. Treatment with N-acetylcysteine preserved twitch and tetanic contractility. N-acetylcysteine did not alter neutrophil infiltration (myeloperoxidase activity) acutely but did reduce infiltration at 24 hours, even when given after decompression. N-acetylcysteine reduced neutrophil respiratory burst activity.

Conclusion: N-acetylcysteine administration before or after simulated compartment syndrome preserved striated muscle contractility, apparently by attenuating neutrophil activation and the resultant oxidant injury.

Clinical relevance: Our data suggest a potential role for N-acetylcysteine in the attenuation of muscle injury after release of compartment syndrome and possibly in the prophylaxis of compartment syndrome.

Fig. 1

A line drawing illustrates the compartment syndrome simulation chamber. The cremaster muscle pedicle is shown passing into the chamber through Portal A. Warmed saline was introduced through Portal B. Temperature and pressure were monitored at Portal C.

Fig. 2

A flowchart shows the study protocol.

Fig. 3A–B

(A) A photograph and (B) schematic diagram illustrate the apparatus for assessing muscle contractile force after twitch and tetanic stimulation. The muscle sample was mounted as shown and lowered into the tissue chamber. Optimal fiber length of the specimen was determined using a micropositioner to identify the length producing maximal contractile force. Measurements were taken using an isometric force transducer.

Fig. 4

NAC attenuated the detrimental effects of CS on skeletal muscle twitch contraction at 1 hour and 7 days after release of CS and prevented the effects of CS at 24 hours. NAC prevented CS-induced loss of contractile force at 24 hours even when given after the release of CS. Bar = mean; error bar = SD; control = control group; CS = compartment syndrome group; NAC = group given N-acetylcysteine before CS; NACd = group given N-acetylcysteine at CS decompression.

Fig. 5

Administration of NAC before onset of CS attenuated the CS-induced reduction in tetanic contraction at all times. This effect was reproduced even when NAC was given after the release of CS. Bar = mean; error bar = SD; control = control group; CS = compartment syndrome group; NAC = group given N-acetylcysteine before CS; NACd = group given N-acetylcysteine at CS decompression.

Fig. 6

CS increased MPO activity at 1 hour. NAC did not reduce MPO activity compared with CS initially. NAC reduced MPO activity at 24 hours compared with CS alone, whether given before onset of CS or after CS release. Bar = mean; error bar = SD; control = control group; CS = compartment syndrome group; NAC = group given N-acetylcysteine prior to CS; NACd = group given N-acetylcysteine at CS decompression.

Fig. 7

NAC inhibited respiratory burst activity as measured by mean channel fluorescence (mcf) in unstimulated and rat opsonized E coli stimulated neutrophil populations. Bar = mean; error bar = SD; control = control group; NAC = group given N-acetylcysteine.