Recent press reports have claimed that hyperbaric oxygenation (HBO) therapy may be beneficial for acute and even chronic spinal cord injury. HBO therapy involves placing a person inside a chamber that has been pressurized with an enriched oxygen atmosphere. What does HBO do? What are the benefits and drawbacks of HBO? Should people with spinal cord injury be trying HBO? In this article, I will attempt to answer these frequently asked questions.
HBO and Decompression Sickness
HBO has long been used to treat a condition called “decompression” sickness which occurs when a deep water or SCUBA diver comes from the depths too rapidly [1-3] or aviators move from high to low pressures [4, 5]. The sudden decrease in pressure results in the formation of nitrogen bubbles in the bloodstream. The bubbles occlude small blood vessels, blocking blood flow to many tissues including the brain and the spinal cord [6], producing multifocal lesions [7].
Decompression sickness used to be called “Caisson’s disease”. Engineers used caissons or inverted bells placed on the bottom of rivers, pumped the water out, and sent workers through elevators down into the caissons to dig on river floors. When the Brooklyn Bridge was built in the late 1800’s, the caissons were more than 400 feet under water. Many caisson workers, as well as the bridge designer John A. Roebling, succumbed to the disease. People thought that it was due to bad gases emanating from the riverbed and changed workers every few hours, aggravating the problem.
Placing a person who is suffering decompression sickness into a pressurized chamber effectively allow the bubbles to be reabsorbed. Normal air has about 16% oxygen. HBO uses air with a greater than normal percentage of oxygenation, sometimes as high as 100% oxygen. Thus, HBO increases oxygenation of tissue and directly addresses the two problems associated with the bends [2, 8-12] and Caisson’s disease [13]: bubbles and oxygenation.
Once symptoms of decompression sickness are present, HBO must be initiated rapidly [3]. Several studies indicated that HBO was most effective when started within minutes [14, 15] after onset of symptoms. In dogs that have been subjected to rapid decompression showed the most recovery when exposed to two bars of oxygen but higher pressures and 100% atmospheres were less effective [16-18]. Some benefit may accrue with HBO treatment days after onset of decompression sickness [8, 19]. Recompression after severe decompression sickness resulted in full recovery in only 16.4% in pigs [7].
HBO Treatment of Ischemia
Animal studies show that HBO can rapidly boost oxygen levels in ischemic spinal cords and improve the survival of neurons [31]. HBO has been reported to reduce myocardial damage in ischemic heart lesions in rats [21]. HBO can reduce tissue damage in animal models of spinal cord ischemia [32]. Likewise, HBO appears to be a significant predictor of a favorable response to surgical treatment of myelopathy in humans. Teng, et al. [33] reported reductions in prostaglandin levels in reperfusion injuries of rabbit brain. Several animal studies showed no significant beneficial effects of HBO on animal stroke models [34, 35]. However, many recent studies indicate that HBO can remarkably reduce infarct sizes in experimental models of cerebral ischemia [36-42], including global ischemia [43-45]. The difference between earlier and the current may be due to the addition of carbon dioxide and other HBO parameters.
HBO therefore appears to be most useful for clinical conditions where blood flow and oxygenation have been compromised [20]. In humans, HBO is used to treat carbon monoxide [22-24] and hydrogen sulfide [25, 26] poisoning. HBO has also used to treat ischemic stroke of the brain, post-hypoxic encephalopathy [27], as well as complications of angiographic procedures that cause ischemia to the brain or spinal cord [28]. It has been applied to human cases of spinal cord ischemia resulting from aortic aneurisms [29]. HBO may has some beneficial effects for compression injuries of Peripheral nerve [30].
Few randomized clinical trials have been done to evaluate HBO treatment of stroke. Nighoghossian, et al. [46] reviewed over 400 cases of human ischemic stroke treated with HBO. Beneficial effects were claimed in over half of the cases, on the basis of clinical or electrophysiological grounds. One Russian study [47] reported that HBO treatment of 124 patients during the acute phase of severe strokes reduced brain Edema. Kohshi, et al. [48] reported that HBO initially lowered intracranial pressure but gradually increased pressure with HBO in patients with stroke. Another study claimed some beneficial effects of HBO on 120 patients after thrombotic stroke [49]. None of these studies were randomized or controlled studies.
Nighoghossian, et al. [50] did a pilot study of 34 patients with middle cerebral artery occlusion randomized to hyperbaric air or hyperbaric oxygen (100%) treatments. They found no significant difference between the two groups although there was a trend for better recovery in the HBO treated group. The lack of a significant effect may have been partly due to the small number of patients and delays in initiating HBO therapy because treatments were often not initiated immediately after the stroke. Note that stroke may have depleted antioxidants and therefore increased the risk of oxygen-induced damage to the brain [51, 52]. Furthermore, HBO may lead to general vasoconstriction and reduction of cardiac function [53] and therefore must be carefully monitored.
HBO, however, appears to be beneficial for preventing impending stroke. For example, Kohshi, et al. [54] found that HBO significantly reduced the incidence of infarcts in patients who developed symptomatic vasospasm after acute aneurysm surgery. Similar results have been reported from Russia [55, 56]. Some patients with generalized small vessel disease may also benefit from HBO [57]. In short, the evidence for beneficial effects of HBO are most convincing when it is used to prevent stroke.
HBO Treatment of Other Conditions
HBO is used to treat many conditions besides decompression sickness. For example, HBO may increase healing of decubiti [97] and other types of ulcers [98], as well as burns [99]. It is used to resolve persistent inflammatory conditions, such as septic tuberculotic abscesses of the hip [100], spinal epidural abscesses [101], osteomyelitis [95, 102-104], gangrene [105-109], purulent peritonitis [110], experimental mandibular osteomyelitis [111], periwound edema [112]. HBO has been used to treat these conditions in adults and children [113].
HBO has also been used to accelerate wound healing in normal [114-118] and diabetic conditions [119, 120], as well in smokers [121]. It accelerates the healing of tissues damaged by the chemotoxin adriamycin [122], burns [123, 124], problem wounds in reconstructive plastic surgery [125, 126], microanastomotic procedures [127], tendon repairs [128], radical vulvectomy [129], bone [130-134] and other tissue grafts [135], and healing of irradiated bone [136, 137].
Boykin, et al. [138] suggests that HBO treatment of wounds not only enhances patient outcomes but reduces costs by as much as 30%. On the other hand, Ciaravino, et al. [139] evaluated 54 patients treated with HBO between 1989-1994 at the Orlando Regional Medical Center. The patients had a variety of lower extremity healing problems including diabetic, amputation, and operative wounds. They found that none of the patients experienced complete healing and only 11% showed improvement due to HBO. They concluded that the average cost of $14,000 patients was not justified given such dismal results. Wattel, et al. [140] suggests that monitoring of tissue oxygen levels predicts the effectiveness of HBO [140]. Also, animal studies suggest that too often treatment, i.e. twice a day, may be less effective than once a day [141].
HBO may improve wound-healing in several ways. First, it rapidly increases tissue oxygen in wounds, as well as vascular endothelial growth factor (VEGF) which [142] which may explain increased vascularization of wounds [143]. HBO alone enhanced wound-healing and these beneficial effects of HBO were not boosted by the addition of growth factor TGF-beta [144]. Finally, HBO stimulates fibroblast proliferation [145], possibly increasing the rate of scar formation.
HBO can prevent neurological symptoms in radiation myelitis where the radiation may have damaged blood vessels in the spinal cord [146-151]. However, HBO therapy does not necessarily reverse radiation myelopathy [152] and it may be most effective when used as a preventative measure during or shortly after radiation therapy [153]. This is true of radiation induced damage in other tissues [154-156], including the brain [157]. Several recent studies suggest that HBO therapy may enhance tumor-killing by radiation [158] and chemotherapy [159].
HBO Treatment of Acute Brain Injury
Given the importance of secondary ischemia in brain injury, HBO has been used extensively treating traumatic brain injury. HBO not only may improve the oxygenation of brain tissues but may protect against small vessel damage [58]. Animal studies, however, have provided mixed results. For example, in a rat brain contusion model, HBO therapy reduced the Lesion size but did not improve behavioral performance or hippocampal neuronal loss [59]. Several groups have reported that HBO reduces edema in brain compression models. Isakov, et al. [60, 61] found that HBO reduces edema in a rabbit closed head injury model [60, 61]. Contreras, et al. [62] found that HBO reduces edema in brain surrounding a freeze lesion. Livshits, et al. [63] found evidence of reduced edema in a rabbit brain compression model. HBO did not reduce edema in brains subjected to cortical contusions but did reduce after fluid Percussion injuries [64].
Clinical trials of HBO in traumatic brain injury likewise have yielded mixed results. Rockswold, et al. [65] treated 37 brain-injured patients for 60 minutes every 24 hours for 7 days. They found consistently reduced levels of cerebrospinal lactate levels, suggesting improved metabolic status. They concluded that HBO improves aerobic metabolism in patients with traumatic brain injury. Intracranial pressure decreased significantly at 1-6 hours after the treatment but rose again before the next session. Brown, et al. [66] likewise found that HBO only decreases intracranial pressure initially. Livshits, et al. [67] likewise reported modest declines in intracranial pressure in patients.
Several anecdotal cases of modest neurological improvements after head injury have been reported [68-70]. Usenko, et al. [71] reported that HBO and combination of HBO and barbiturate coma [72] improved biogenic amine metabolism. Isakov, et al. [73, 74] suggest that HBO may reduce the incidence of trauma-associated psychoses in patients after craniocerebral injuries. They suggest that the response of injured brain vasculature to HBO may differ from those of normal brain [75] and the importance of systemic autoregulatory mechanisms [76].
HBO Treatment of Acute Spinal Cord Injury
Many people have speculated that HBO would be useful for traumatic spinal cord injury [77-82]. Yeo, et al. [83] reported that treating sheep with HBO within 2 hours of spinal cord contusion reduced spinal cord damage [84, 85]. Gelderd, et al. [86, 87] reported the combination of HBO and the antioxidant solvent DMSO (dimethylsulfoxide) improved recovery of rats with transected spinal cords. Higgins, et al. [88] found possible slight improvements in somatosensory evoked potentials after moderate spinal cord contusions in cats but no beneficial effects after severe spinal cord injury or when the treatment was started more than 2 hours after injury. Narayana, et al. [15] reported that HBO reduced the lesion size on MRI images after compression injury of the spinal cord
Early studies suggested that HBO may be helpful in acute spinal cord injury in humans [89]. Yeo, et al. [90] applied HBO to 10 patients shortly after spinal cord injury and found no deterioration of Motor power or sensation during or after the treatments. Yeo [91] subsequently reported that 15 of 27 patients had recovery. Gamache, et al. [92] treated 50 patients with 7.5 hours of HBO after acute traumatic spinal cord injury and found no apparent difference in the extent of neurological recovery although some patients may have had accelerated recovery. Elinskii, et al. [93] suggested that patients treated to HBO had better neurological recovery. Recently, Asamato, et al. [20] randomized 34 patients with hyperextension injuries of the spinal cord and found results suggesting that HBO improved neurological recovery.
Some investigators have claimed potentially beneficial effects of HBO for chronic spinal cord injury [94]. Likewise, Lee, et al. [95] reported improvements in chronic spinal cord injury. However, little reliable controlled animal or clinical data support such claims. Ishihara, et al. [96] reported that HBO is a good predictor of response to decompressive surgery for Cervical myelopathy. However, since the myelopathy may be resulting from ischemia, this is consistent with HBO being useful for ischemia resulting from compression but not necessarily for spinal cord injuries without compression. Furthermore, since the treatment does not permanently alleviate the ischemia from the compression, it is useful as a diagnostic treatment indicating the need for surgical decompression.
Complications of HBO
HBO therapy is not innocuous. Since oxygen produces free radicals, prolonged exposure to high oxygen levels causes cell damage. In 1977, Balentine, et al. [160] reported that rats exposed to HBO showed evidence of axonal degeneration in the spinal cord. Prolonged exposure in fact can cause frank necrosis of the spinal cord [161]. HBO can cause DNA damage of cells and increased mutations [162, 163] and produce changes in cellular antioxidants [164, 165] and ion transport [166]. Prolonged exposure to HBO can cause neuronal damage [167], due to calcium overload [168]. While HBO can improve the contractile properties of regenerating muscles, it also may be damaging to muscles at pressures higher than 3.0 atmospheres [169]. Prolonged exposure to HBO (>3.5 hours) increased inflammatory infiltrates in the lungs of mice [177, 178]. Interestingly, starvation and dehydration reduced such toxicity [179].
Certain conditions may aggravate HBO toxicity. For example, monoamine depletion aggravates the neurotoxic effects of HBO in mice [170]. HBO causes seizures in mice [171] and repeated exposures increases susceptibility to seizures [172], as well as renal changes in the rats undergoing seizures [173]. In the presence of myocardial ischemia, HBO can increase post-ischemic myocardial damage [174, 175] and decreased myocardial function [176]. Finally, HBO increases doxyrubicin toxicity, a commonly used anti-cancer drug [180].
HBO treatment can induce DNA damage in lymphocytes and reduce synthesis of heat shock protein HSP70 in lymphocytes [187]. Rothfuss, et al. [188], however, also found that a single HBO treatment can produce long-lasting protective effects of lymphocytes against further oxidative damage in repeated HBO sessions, perhaps due to downregulation of nitric oxide synthetase [189]. The effects of HBO on lymphocytes may cause immunosuppression but one study [190] examined lymphocyte populations in burn patients treated with HBO and did not find any change in lymphocyte function.
In clinical practice, HBO therapy has several potential drawbacks. First, placement of a patient into a hyperbaric chamber during the early phases of spinal cord injury may delay surgery and other treatments. Second oxygen toxicity to the lungs [181, 182] may occur in some patients [95]. Third, repeated exposures to HBO therapy may increase susceptibility to seizures [183]. Pre-treatment EEG does not always predict susceptibility [184]. Fourth, HBO causes intrathecal pumps to backfill and leak [185]. Fifth, HBO is associated with a high incidence of middle ear discomfort due to pressure. In 782 patients treated for various indications, Plafki, et al. [186] report that over 17% of the patients experienced ear discomfort resulting from difficulties in equalizing middle ear pressure.
Several modifications of HBO therapy may ameliorate some of the toxic effects. For example, Torbati, et al. [191] and others [192] found that increasing carbon dioxide in the atmosphere may reduce HBO toxicity by causing vasodilation. This may be because HBO tends to cause vasoconstriction in adults whereas it does not in young animals, perhaps explaining the resistance of newborns to the toxic effects of HBO [193]. Likewise, several drugs may be neuroprotective during HBO [194-200] but standard anti-seizure medication may not be effective in preventing HBO-induced seizures [201]. However, pretreatment of rats with antioxidants and vitamins did not seem to reduce the incidence of HBO-induced seizures [202]. It is unclear whether susceptibility to HBO can be predicted beforehand [203].
In summary, HBO must be carefully administered by experienced groups. When applied in high doses, HBO can damage the lung and brain, cause seizures, and damage neurons. These effects can be minimized by careful observation of established guidelines. HBO causes DNA damage although the consequences of these effects are not clear and a single treatment seems to induce long-lasting protection against further oxidative damage. Finally, it is associated with middle ear discomfort in as many as 17% of patients.
Use in HBO in Chronic Brain and Spinal Cord Injury
There is little evidence to suggest that HBO will increase neural Regeneration in chronic Central Nervous System injury. In fact, HBO may inhibit neuronal growth and survival in culture [204]. HBO does not seem to enhance axonal growth in rats. For example, a recent study [205] examined the effects of HBO on nerve regeneration in acellular nerve and muscle grafts in rats. The study showed that rats treated with HBO (100% oxygen for 90 minutes at 2.5 atmospheres twice a day for 7 days) showed superior axonal outgrowth and Schwann cell migration in nerve grafts compared to muscle grafts but not between HBO- and non-HBO treated rats.
The beneficial effects of HBO on peripheral nerve injuries depend on specific treatment parameters and the nature of the lesions. One study reported that short (45 minutes) and early (every 8 hours for 24 hours starting immediately after injury) HBO treatments significantly increases sciatic nerve regeneration in rats [206] but more prolonged (4-day) treatments was not better than a 24-hour period. Santos, et al. [207] found that twice daily HBO for a week and then daily HBO treatments for a week did not improve Functional recovery after peroneal nerve crush in rats. On the other hand, Zamboni, et al. [208] reported that HBO treatment twice daily for a week improved functional recovery after sciatic nerve devascularization.
There is increasing interest in the use of HBO to chronic neurological conditions. However, little or no evidence is available to support beneficial effects of HBO on chronic neurological disorders that do not involve ischemia. Harpur, et al. [209] did a double-blind randomized study of HBO in 82 patients with chronic stable multiple scleroris (MS). Monks, et al. [210] did not find significant effects of HBO on subjective measures of function in patients with MS. Nyland, et al. [211] treated 10 MS patients (20 exposures of 90 minutes daily) and found a significant increase in total and helper T-lymphocyte counts, as well as activation of the cells. Ansari, et al. [212] reported a large increase in superoxide dysmutase and catalase activity in blood cells of MS patients treated with HBO. However, none of these studies report significant neurological improvements associated with HBO therapy of MS. Neretin, et al. [213] likewise report that HBO has little or only short-term HBO effects on amyotrophic lateral sclerosis (ALS). HBO also apparently has little beneficial effects on Parkinson’s disease [214] or Alzheimer’s disease [215, 216] although one Russian study [217] claimed beneficial effects on schizophrenia.
HBO treatment may be associated with higher incidence of complications in some neurological disorders. For example, two children with cerebral palsy had unusual complications from HBO therapy [218]. Likewise, Lambrou, et al. [219] reported a case of central scotamata developing in a woman with MS treated with HBO.
Given the possibility of increased risks of HBO therapies in such populations, rigorous randomized trials are necessary to establish a rationale for the use of HBO in chronic neurological conditions.
The Bottom Line
HBO therapy clearly has many applications and beneficial effects for a number of medical conditions. It is particularly effective when there is low blood flow and oxygenation. HBO seems to accelerate wound healing, resolution of chronic inflammatory conditions, radiation-induced tissue damage, and grafts, possibly because it enhances neo-vascularization of the tissues. HBO may also have beneficial effects in acute brain and spinal cord injury although the effects are mixed and dependent on both injury and treatment parameters.
HBO therapy is not innocuous. Prolonged and high pressure HBO can cause brain and spinal cord damage. It reduces myocardial and pulmonary function. HBO enhances the effects of chemotherapy and radiation therapy. In clinical practice, a small percentage of patients develop oxygen toxicity of the lung and seizures. The pressure may cause problems for patients who have baclofen pumps and a substantial number of patients have middle ear discomfort during treatments. HBO damages DNA but the consequences of such damage are not clear. Some of these side-effects can be reduced by increasing carbon dioxide and combining the therapy with antioxidants.
The evidence for beneficial effect of HBO on chronic brain and spinal cord injury is currently very limited. There is little or no credible data that HBO improves neurological function in chronic neurological conditions such as MS, ALS, AD, peripheral nerve injury, and stroke. Likewise, although many patients with chronic brain and spinal cord injury have been treated with HBO in the past four decades, there have been relatively few credible reports of improved neurological function in these conditions. Given the possible side-effects of HBO, there should be stronger justification for beneficial effects of HBO before it is applied routinely to people with chronic brain and spinal cord injury.
Certain situations may justify HBO therapy. For example, if there is reason to believe that blood flow or oxygenation of the brain is compromised, HBO can be tried. In fact, HBO may be useful as a diagnostic tool. For example, there is controversy over the significance of mild compression and tethering of the spinal cord and whether surgery should be carried out to decompress and untether the cord. If HBO restores neurological function in such situations, this would provide a stronger rationale for decompressive and untethering surgery. Finally, HBO may increase the rate of wound healing, as well as help resolve decubiti and chronic inflammatory conditions.
In conclusion, HBO may have beneficial effects on many conditions where there is ischemia and oxygenation problems. It has a strong track record of beneficial effects for conditions such as decubiti and infections. It also appears to be relatively safe when applied by experienced groups. It may even be useful for preventing stroke and for chronically injured spinal cord that are compressed. However, there is no convincing evidence that it is beneficial for chronic injured brain and spinal cord where ischemia is not a problem.
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, New Jersey 08854
