This is the first prospective, double-blinded, placebo-controlled randomized study to focus on the acute treatment of combat blast-related mTBI in a forward war zone. Supplementation of standard therapy with oral NAC had a significant impact on neuropsychological test results, number of mTBI symptoms, and complete symptom resolution by day seven of treatment when compared to placebo. Moreover, the pill form of NAC, the active ingredient in the FDA approved medication “Mucomyst”, produced no side effects in blast mTBI subjects. Although the study was powered only to examine the effects of NAC, there was a statistically significant secondary finding that standard treatment initiation within 24 hours had an independent benefit on neurological but not on neuropsychological outcome measures (TMT). A possible explanation for this difference is that the outcome measures assess the status of different neuronal circuitry components. The additive effects of NAC and early treatment produced 86% mTBI symptom resolution within seven days. Factors such as number of previous blast exposures, age and distance from the blast did not influence treatment outcomes significantly.
Headache and balance dysfunction are major clinical issues that arise acutely after blast exposure, impede return to duty, and can persist chronically 
. Because they seriously impair performance in a combat environment, the initiation of standard treatment with oral NAC within 24 hours of mTBI is likely to have a definitive impact on battlefield end-strength and the readiness of troops in theater.
Performance on TMT neuropsychological tests was impacted significantly by blast mTBI and ameliorated by NAC administration. The initial test times were prolonged significantly at enrollment. NAC administration within 72 hours of injury produced normal D7 TMT times, but performance remained abnormal for subject groups that received only standard therapy. Because all subjects were tested on the same schedule and the reliability of repeated TRAIL making tests 
is well documented, test-retest effects are not a confounding factor. Hence, TMTs are useful for documenting and monitoring cognitive status changes in acute blast mTBI.
The efficacy of NAC in early treatment of blast mTBI is consistent with its efficacy as a neuroprotective agent in ischemia-reperfusion cerebral stroke 
, closed head trauma 
, sensory nerve axotomy 
and in the prevention of mitochondrial damage and loss of dendritic spines in hippocampal neurons 
in animal models of closed head trauma and ischemia-reperfusion brain injury. A single, low level shock wave exposure to rodents can produce persistent biochemical changes in the hippocampus and cerebral cortex, accompanied by apoptotic cell death 
. Even relatively low exposures produce very small parenchymal and subarachoid hemorrhages in 30–40% of exposed animals 
. These findings suggest that vascular primary injury contributes to symptoms of mTBI, with slower development of neuronal damage 
. Post-treatment with NAC has afforded protection against neuronal death in animal models. These neuroprotective effects reflect known antioxidant and anti-inflammatory effects 
. The cellular bases for memory and regulation of motivation properties within the nucleus accumbens may be improved by NAC activating neuronal cysteine-glutamate exchange and indirect effects on mGluR2/3 and mGluR5 
transmission. Finally, enhanced local bioavailability of NAC may be a natural consequence of vascular disruption in mTBI. Because NAC has limited capability to cross the normal blood-brain barrier 
, increased local brain permeability during vascular remodeling 
may facilitate selective delivery to affected sites. A delayed opening of the blood-brain barrier from neuroinflammatory responses 
, could create longer-term therapeutic opportunities.
Early symptomatic treatment initiation produced improvement that was statistically independent of effects of NAC treatment. The early and late subjects came from the same set of combat units with a shared history of living environment, combat exposure and similar clinical presentations. Although we believe that the time of enrollment was determined only by distance from TQ and availability of transport, it is impossible to know if there were unknown confounders between the two groups. However, we believe that the improvement seen in early subjects can be attributed to the concurrent standard symptomatic medical treatment and balance rehabilitation exercises begun earlier in the early treatment group. Exercise, in particular, can have neuroprotective pharmacomimetic effects on structures such as the hippocampus, possibly mediated by trophic factors 
Clinical trials in an active combat theater are subject to outside factors for “early termination” that do not arise in standard clinical environments. For this study, the opportunity for subject enrollment ended when combat operations terminated in this part of Iraq, prior to reaching the pre-determined number of enrollees for the trial. Because the available data were powered sufficiently to test the effects of NAC, we proceeded with analysis after all patients completed the protocol. The enthusiasm about the large treatment effect must be tempered by a recent review of the Cochran database 
, showing that studies with relatively small patient numbers and large odds ratios often show smaller odds ratios when the study is repeated. In this regard, we do note that the lower bounds of the 95% confidence intervals for early NAC treatment are reasonably large. It also should be noted that although we were able to draw some statistical conclusions the study was not powered to look at early vs. late treatment which argues for caution in interpreting that data.
One must be cautious to assert the therapeutic implications of NAC treatment for TBI within the limited scope of this study. While the results are very promising, the study was limited to evaluating a relatively small but representative sample of combat troops with acute mild head trauma and other minor injuries over one week of treatment. Some additional caveats are also inherent in the far-front battlefield environment. For example, study participants came from the same set of combat units with similar environmental exposure histories, living conditions (including the same forward operating bases), training, missions, and combat environments; combat personnel are predominantly males in their twenties. Therefore, it is prudent to consider several caveats for our findings. The study results do not imply any benefit for moderate or severe head trauma with significant surgical injuries. Because only one female was enrolled, the study may not generalize to all females. Although the study endpoint was only D7 there is some evidence to suggest that these effects may be long lasting. Tweedie, et al 
have shown that mTBI triggers biochemical cascades within the first 24 hours which produce long term sequelae. Their work suggests that it is important to interrupt these cascades as early as possible. D7 resolution may indicate the lack of significant apoptotic and inflammatory changes in both grey and white matter. Nevertheless, the effects of treatment on longer term outcomes will need to be the subject of further study in a larger number of subjects.
The study can then, at least, be interpreted in a narrow fashion as showing a benefit of using NAC and early intervention for blast mTBI in an acute combat setting after mild blast exposure. The study brings up the intriguing possibility that NAC may be useful in other mTBI settings, but before this conclusion be reached much more study in the area and using this agent is required.
Summary and Conclusions
We report the first double blinded placebo- controlled randomized study of a pharmaceutical countermeasure for the symptoms of blast-induced mTBI. All 81 subjects were seen within 72 hours of blast exposure by the same clinician-investigator at a forward location in an active combat zone. All medications and treatments were witnessed by a nurse, corpsman, or medic. The outcomes demonstrate that supplementation with oral NAC had a significant impact on neuropsychological test results, number of mTBI symptoms, and complete symptom resolution by day seven of treatment when compared to placebo. A secondary finding was that standard treatment initiation within 24 hours had an independent benefit on the neurological but not on neuropsychological outcome measures. Early treatment with NAC and standard therapy administered by a provider with expertise in mTBI care resulted in a seven day symptom resolution rate of 86% as compared to 11% in those receiving the same standard care by the same provider but who received placebo and began therapy between 24–72 hours after blast exposure. Additionally it should be noted that during this trial the pill form of NAC, the active ingredient in the FDA approved medication Mucomyst, produced no side effects in blast mTBI subjects. Mucomyst has an excellent safety profile in over forty years of use in hospitals worldwide. As such use of this medicine appears to be the first described pharmaceutical countermeasure for mTBI. These results while promising are still preliminary. This outcome needs to be supported by other studies of NAC for this pathophysiology examining neurosensory symptoms over a variety of time points both acute and chronic. Additionally, these findings argue for investigations of this therapy for other causes of traumatic brain injury.