Evidence For Use Of Hyperbaric Oxygen Therapy For Acute Traumatic Brain Injury- Continued
HBOT also has beneficial effects on cellular reperfusion injury. Both Zamboni and Thom have reported inhibition of white blood cell mediated reperfusion injury at 2.0 and from 2.0 to 2.8 ATA, respectively, when HBOT is initiated within approximately one hour after brain insult. This is consistent with the data above on high pressure HBOT in cerebral edema immediately after brain injury. Unfortunately, this may not be applicable to human TBI and its associated reperfusion injury since time to initiation of HBOT is often many hours after injury.
The non-controlled human data is equally positive and consistent with the animal data. Mogami, in 66 acute coma cases, 50 of which were severe TBI, reported neurological improvement in 50% and EEG improvement in 33% of cases with a decrease in CSF pressure, occurring mostly at depth, that regressed or rebounded post treatment. The patients also exhibited a slight improvement in cerebral aerobic metabolism with a slight decrease in the lactate/pyruvate ratio. The best responses were in the least injured patients. Treatment pressures were 2 ATA/60 minutes, once or twice/day with an average of two treatments. The preponderance of benefit at depth with regression/rebound post treatment suggests an excessive pressure of oxygen as reviewed above in the cerebral edema animal studies. Hayakawa achieved similar results in 9 acute TBI and 4 post-op brain tumor patients at 2ATA/60 minutes, measuring CSFP. He found three patterns of response, the most common of which was a reduction of CSFP at the beginning and a rise at the end of HBOT. He proposed the edema reducing effect of HBOT on injured brain and edema producing effect on normal brain mentioned above. Both of these studies are reinforced by the two companion studies of Holbach on EEG and rCBF above in 14 acute severe TBI patients exposed to different pressure profiles.. This data is strongly supported by Holbach’s additional report in 1977 on metabolic data in the same or a similar group of severe acute TBI (n=23) and CVA (n=7) patients, also noted above. This metabolic data is further supported by Holbach’s 1974 report on crude outcomes of 102 patients, 43 with “life-threatening” acute TBI, who were treated with an average 2.6 HBOT’s within a few days of injury: 52 at 2-3 ATA and 50 at 1.5 ATA. The TBI subset treated at 1.5 ATA demonstrated a 33% increase in the number of markedly improved patients. Additionally, Lareng published two cases of deepening coma secondary to TBI who were treated 4 and 10 days post TBI at 2.0 ATA/45 bid for 42 treatments. One patient was completely well with a normal EEG and the other had complete neurological recovery. Belokurov treated 23 acute pediatric coma cases, 13 of which were traumatic, at 1.7-2.0 ATA/60, once/day for four days. He found: a 50% reduction in time of coma if HBOT was initiated within the first 24 hours after injury (indicating HBOT responsive pathology in this period of time), a statistically significant improvement in coma score after the first HBOT, especially in the TBI patients, and further improvement in eight of ten patients who were retreated with HBOT after relapse into vegetative coma. In contrast, Artru measured CBF and metabolism in 6 severe acute TBI patients 5-47 days post injury with 2.2 or 2.5 ATA/90 minute HBOT exposures and found variable responses due to differential effects of HBOT on injured and normal brain. Curiously, systemic arterial PO2 declined in 8 of 9 measurement trials, indicating a pulmonary or severe brainstem toxicity/complication with this profile.
All of the above human studies were performed on severe acute TBI patients a few days post injury. The data is remarkably consistently positive, but the exact dose of oxygen is less clear. In general, the data suggests that approximately 48 hours or more after injury pressures from 1.5 to 2.0 ATA and treatment times less than or equal to one hour have reproducible beneficial effects and that pressures above 2.0 ATA have negative effects on CBF, EEG, CSFP, and aerobic metabolism. Specifically, higher pressures seem to reverse the brain’s protective vasoconstrictive capacity leading to a marked increase in CBF/CSFP and simultaneous deterioration in EEG/aerobic metabolism. Moreover, there may be competing effects in injured and normal brain that determine whether the final result is positive or negative based on the relative proportions and possibly locations of the two types of tissue. Unfortunately, due to small numbers of patients and inadequate data this complex relationship cannot be adequately defined for all of the different levels of injury at different times of intervention.
The more rigorously controlled human clinical studies recapitulate all of the above data/conclusions and lead to more powerful conclusions. Holbach followed his 1971 study with a randomized prospective controlled study of HBOT vs. standard intensive care in 99 acute TBI coma (mid-brain syndrome) patients, 2-10 days post injury. The HBOT patients received 1-7 treatments at 1.5 ATA/45 minutes. The HBOT group achieved a 21% decrease in mortality and the apallic state (vegetative coma) and a 450% increase in complete recovery. Artru published a similar RPCT on 60 acute coma TBI patients 4.5 days post injury. HBOT patients were delivered 2.5 ATA/90 minute treatments once/day on a 10 day schedule with a four day break and then repeat of the cycle until consciousness or death. Despite multiple breaks in protocol, delays to treatment, and use of the a high pressure, one of 9 subgroups, the brainstem contusion group, experienced a significantly higher rate of recovery of consciousness at one month. Lastly, and most importantly, Rockswold in 1992 reported the most exhaustive, rigorous, and important study to date in acute TBI in an attempt to refute or affirm all of the above animal and human data. Conducted from 1983 to 1989 the study enrolled 168 patients with GCS of 9 or less in a RPCT design and stratified the patients by age and GCS. Patients were treated at 1.5 ATA/60 every 8 hours for a maximum of two weeks immediately post TBI or until awake or deceased during these two weeks. The average patient entered treatment 26 hours post TBI and received 21 treatments. Overall mortality was significantly reduced 50% in the HBOT group and as high as 56% and 60% in the elevated ICP and GCS 4-6 subgroups, respectively, however there was no difference in the good outcome categories between the groups at 12 months.
A summarization of the above data demonstrates an undeniable beneficial effect of HBOT on mortality and recovery of consciousness and a suggestion of improved neurological outcome. The best results were achieved at pressures less than 2.0 ATA, specifically 1.5 ATA. Unfortunately, there is not a large amount of data generated from finely adjusted dose escalations of HBOT, but rather a preponderance of studies performed at 1.5 ATA based on early dose escalation studies, with some comparison data at 2.0 ATA and higher. These conclusions are derived from a number of RPCT’s that en block constitutes one of the most powerful and consistent bodies of scientific evidence for any accepted indication for HBOT. The TBI controlled trials alone already exceed the data for at least six of the thirteen indications, including the last addition, cerebral abscess. While internally consistent and stand alone sufficient this body of data was recently strengthened by the addition of the followup article of the Rockswold group in March, 2001.
On a group of severe TBI patients similar to those in the 1992 study the authors methodically and meticulously studied brain metabolism at 1.5 ATA, once/day for 5-7 days post injury. They found that HBOT improved the cerebral metabolic rate for oxygen and decreased CSF lactate , especially in those with reduced CBF or with ischemia, normalized the coupling of CBF and cerebral metabolism, exerted a persistent effect on CBF and metabolism, and reduced elevated levels of ICP and CBF. Notably, HBOT’s recoupling of flow and metabolism is the only demonstration of such in the history of science. They recommended that shorter (30 minutes) more frequent (every 8 hours—identical to their first study) treatments would optimize treatment.
This final study reaffirms the multiple studies above at both lower and higher pressures that show reversal or deterioration of a beneficial HBOT effect after 30+ minutes in the chamber. The data and scientific argument is strong and supports/demands low pressure HBOT in acute severe traumatic brain injury. Some of the studies suggest that even a few treatments can have a profound effect. The protocol is uncertain beyond the first two weeks, but should probably be delivered according to the principle employed in medicine for any therapeutic modality: treat until clinical plateau. While the data is not so consistent on long-term neurological outcome, this goal should be left to further research and multi-modality therapy. After all, the first priority in life-threatening illness is to save the patient.
As a matter of perspective, the American Heart Association has spent hundreds of millions if not billions of dollars on CPR education, training, and research, yet has still have made very little progress in successful resuscitation of cardiac arrest. Very few survive and almost all who survive are severely neurologically impaired. Despite these dismal results the research largesse continues in an effort to find even the smallest improvement in mortality. At our fingertips is possibly the therapeutic modality with the greatest and most dramatic effect on reduction of acute TBI mortality in the history of medicine. The neurosurgeon authors of the Rockswold study conclude that “HBOT should be initiated as soon as possible after acute severe traumatic brain injury.” I believe the UHMS and medical profession should follow their lead and the UHMS list acute TBI as an accepted indication for HBOT. I am ready, willing, and eager to defend this position. Thank you for the opportunity.
Sincerely,
Paul G. Harch, M.D.
Clinical Assistant Professor
Department of Medicine
LSU School of Medicine
New Orleans, Louisiana
