Central necrosis of the spinal cord induced by hyperbaric oxygen exposure

Central necrosis of the induced by hyperbaric

spinal cord oxygen exposure

J. DOUGLAS BALENTINE, M.D.

Department of Pathology ( Neuropathology), Medical University of South Carolina, Charleston, South Carolina

Seventy-six adult rats were exposed to 60 psig of oxygen on consecutive days until death. At autopsy, 17 of the animals revealed segmental foci of central necrosis of the spinal cord gray matter, often associated with small ball- and flame-shaped hemorrhages in either the cervical and/or lumbosacral enlargements. Paraplegia or quadriplegia were clinically observed prior to death. The oxygen-induced spinal cord lesions are similar though not identical to those observed in experimental and human spinal cord trauma. These observations indicate that the therapeutic use of hyperbaric oxygen in patients with spinal cord injury has a potential danger of causing central spinal cord necrosis.

K E v W o a o s �9 hyperbar i c o x y g e n �9 sp ina l cord �9 necros i s �9 sp ina l cord t r a u m a �9 o x y g e n t o x i c i t y

C URRENTLY there is much interest in basic research on various ways of treating traumatic injuries of the

human spinal cord. Experimental spinal cord trauma has been followed by decreased blood flow and oxygen tensions in the injured area of the cord? 4,~ Since regional hypoxia may contribute to the pathological and clinical consequences of spinal cord trauma, hyperbaric oxygenation appears to be a logical therapeutic approach in the patient with traumatic spinal cord disease. Kelly, et al., 22 have had favorable results using hyperbaric oxygen in experimentally-induced traumatic paraplegia in dogs.

Oxygen toxicity is a well known hazard of oxygen therapy in man. 3,9,11,1a,17'2z,25,28'29-31 Central nervous system (CNS) oxygen toxicity in man primarily causes grand mal seizures, but may include focal seizures, con-

striction of visual fields, deafness, hyperac- tivity, and hallucinations? 1'~3 A single 30- minute exposure to 5 atm oxygen may cause selective degeneration of dendrites and axons in rats with no clinical symptoms.' An ac- cumulative delayed type of CNS oxygen poisoning causing permanent limb paralysis in laboratory animals was noted 30 years ago by Bean and Siegfried. ~~ Balentine and Gutsche e demonstrated random necrosis of anterior horn cells with sparing of supporting structures in the spinal cord of rats paralyzed by exposure for 1 hour/day on consecutive days to 5 atm oxygen.

In the present study of the pathological effects of fatal exposures to hyperbaric oxygen, the predominance of a different pattern of spinal cord necrosis was observed. This study emphasizes the similarity of the oxygen-induced spinal cord necrosis to

150 J. Neurosurg. / Volume 43 / August, 1975

Cord necrosis from hyperbaric oxygen exposure

traumatic cord necrosis, and stresses the potential paradoxical hazard of hyperbaric oxygen in the therapy of traumatic injuries of the spinal cord.

Material and Methods

Seventy-six 3- to 4-month-old adult Charles River (CDF) inbred rats were exposed to 60 psig of oxygen for 1 hour a day on consecutive days until death. The group in- cluded 39 males and 37 females. A Bethlehem No. 1836H small animal hyperbaric chamber* was used for all exposures. The chamber was flushed for 10 minutes prior to compres- sion and oxygen tensions were measured directly from an outflow valve with a Ser- vomex oxygen meterf to insure that 99% to 100% oxygen was present prior to compres- sion. The latter was staged over a 3- to 4- minute period and the chamber was con- tinuously ventilated at greater than 15 1/min during exposure. Carbon dioxide tensions were measured directly from an outflow valve periodically during exposure with a Harvard Apparatus Electronic CO2 Analyzer.~ Usu- ally at the end of each exposure time prior to decompression carbon dioxide was undetec- table and was no greater than .05%. Decom- pression was staged over 8 minutes with periodic 1- to 2-minute stops. No more than 10 animals were exposed at one time. All of the animals were autopsied within a few hours after death. The spinal columns, including the entire spinal cords, were removed, fixed in 10% neutral buffered formaldehyde for a minimum of 7 days, decalcified overnight, and cut into 2 to 3 mm serial blocks. The blocks were embedded in paraffin. Routine 6- to 10-u sections were cut from each block and stained with hematoxylin and eosin. Selected blocks from 10 animals with spinal cord necrosis were serially sectioned 25 to 50 times. Special stains for axons (Bodian),

*Bethlehem No. 1836H small animal hyperbaric chamber manufactured by Bethlehem Corpora- tion, 225 West Second Street, Bethlehem, Penn- sylvania.

fServomex oxygen meter manufactured by Ser- vomex Controls Limited, Crowborough, Sussex, England.

:[:Harvard Apparatus Electronic COs Analyzer manufactured by Harvard Apparatus, Inc., Millis, Massachusetts.

myelin (luxol fast blue), and blood vessels (Verhoeff Van Gieson, Masson's trichrome, and PAS) were used on selected blocks.

Twenty 3- to 4-month-old clinically normal Charles River adult (10 male, 10 female) CDF rats were killed with pentobarbital and autopsied in the same manner as the rats exposed to oxygen. The sections of spinal cord from these control animals were processed similarly to those from the experimental rats.

Results

All of the experimental rats developed grand mal seizures and/or dyspnea prior to death. A few animals developed these signs and symptoms during the end of only one exposure while the majority developed them during subsequent exposures. Sixteen of the adult rats became paralyzed before they died. One animal was severely quadriplegic and the others exhibited principally paraplegia. The deaths occurred during the last half of, or within 10 minutes following, a given exposure in all but four rats. The latter died within 2 hours of their last exposure. The mean time of death was during or following 4.1 exposures, with a standard deviation of 2.3.

A comprehensive autopsy was done on each animal, but only spinal cord lesions are reported in this communication. Permanent pathological changes were observed in the spinal cords of approximately one third (27 out of 76) of the experimental animals. In the other oxygen-exposed rats the spinal cords were interpreted as normal. Seventeen of the experimental animals revealed segmental loci of central necrosis of the spinal cord (Figs. 1 and 2), frequently associated with ball- and flame-shaped hemorrhages. The lesions were characteristically found in the cervical and lumbosacral enlargement and only occasionally involved both; other areas of the cord were spared. Selective neuronal necrosis with preservation of supporting structures was found at all cord levels in some of the animals with central cord necrosis and in 10 rats without these lesions. The necrosis characteristically involved neurons within anteromedial and pericentral gray matter. The 10 animals exhibiting only selective necrosis of neurons died sooner (mean time of death during or after 4.1 exposures) than those with necrosis of the entire gray matter (mean time of death during or after 6.5 exposures); this suggests that selective neuronal

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Fic. 1. Coronal section of previously fixed spinal column and cord shows central necrosis of cervical spinal cord. The rat was exposed to 60 psig oxygen for 1 hour/day until death after the fourth exposure. • 8.

necrosis preceded central gray matter necrosis. The former lesion occurred in some animals dying after only two exposures while the latter was not observed in animals dying after less than four exposures. The progres- sion from selective neuronal to complete gray matter necrosis could not be elucidated since this study was designed to investigate the pathology when exposure had resulted in death.

Central cord necrosis involved part or nearly all of the gray matter, especially the pericentral region. The necrosis involved neurons, glia, neuropile, and vessels. Phagocytosis of necrotic tissue by macro- phages was commonly observed. Only rarely was the white matter involved and in such in- stances only a few degenerating axons could be seen immediately adjacent to the gray matter. The hemorrhages also involved primarily gray matter, but occasionally ex- tended out to involve significant areas of white matter. They did not have any consis- tent relationship to arteries, veins, or capillaries. No thrombosis of blood vessels was found in any of the animals. No vascular necrosis was found except in the regions of central necrosis, and the hemorrhages were probably the result of blood vessel involve- ment in the central necrosis.

In a few of the animals, necrosis was associated with cysts within the cord (Fig. 3), which had no lining other than the adjacent cord parenchyma but which appeared at

Fro. 2. Central necrosis of cervical cord gray matter, with the white matter spared. The rat died after four 1-hour exposures to 60 psig oxygen. Cracks between necrotic gray matter and sur- rounding viable cord and the radial cracks in the white matter are interpreted as artifact. H & E, X 14.

times to communicate with the central canal and to contain proteinaceous fluid.

No histological abnormalities appeared in control animals.

Discussion

This study reveals that central necrosis of spinal cord gray matter may be a significant pathological sequence of repeated exposure to hyperbaric oxygen. The central necrosis observed in this study is similar, although not entirely identical to, the necrotic patterns of injury observed in human and experimental spinal cord trauma. 8,28 The necrosis of trauma characteristically involves white matter more extensively than did the hyperbaric oxygen- induced cord lesions.

The pathogenesis of central spinal cord necrosis induced by hyperbaric oxygen exposure is probably related to excessive tissue oxygenation. This interpretation is supported by the fact that ischemia protects the CNS against the necrotic lesions of hyperbaric oxygen exposure, 2 and by the more direct obser- vation that oxygen tensions are markedly elevated and sustained in spinal cord gray matter during a l-hour exposure to 5 atm oxygen. ~7 These data are inconsistent with the alternative possibility of an ischemic mechanism due to oxygen-induced vasospasm, which should result in a progressive decline of oxygen tension during exposure.

In view of the elevated spinal cord oxygen tensions during hyperbaric oxygen exposure 27



FI~. 3. Gray matter necrosis and hemorrhage associated with a central cyst containing proteinaceous fluid. The rat died after seven 1-hour exposures to 60 psig oxygen. H & E, X 14.

Ft~. 4. Central necrosis of sacral spinal cord. The rat was anesthetized with pentobarbital and exposed in the anesthetized state for 1 hour/day to 57 psig until paralysis occurred after two exposures; it was killed3 days later (from Balentine and GutscheT). H & E, • 15.

and the known adverse biochemical effects of excessive oxygen on numerous en- zymes, t2,16,~9,32 it would be reasonable to suggest that the necrotic cord lesions are the direct result of oxygen toxicity on cellular metabolism. However, other factors have to be considered. The occurrence of cysts within the necrotic cord regions brings up the question of oxygen bubbling in the pathogenesis of central cord necrosis. However, gaseous bubbling did not appear to be significant in this study for the following reasons. The observed relative sparing of white matter con- trasts with known susceptibility of spinal cord white matter to gaseous embolization. 2~ Also, relatively rapid decompression from pure high oxygen tensions has not been associated with clinical abnormal i t ies in man or laboratory animals; ~ this has been confirmed by observations in the author's laboratory, where rats have been decompressed in less than 10 seconds after a single l-hour exposure to 60 psig of pure oxygen without ill effects. 5 More important ly , the decompression schedules used in this laboratory for oxygen exposures have not been associated with clinical or pathological abnormalities in animals that have been similarly decompressed from 60 psig on compressed air. 4 Other tenable hypotheses for the occurrence of cavities in the cord include cavitation secondary to necrosis and postmortem artifact. The necrosis hypothesis is supported by previous findings of similar cysts in ex-

perimentally induced traumatic spinal cord necrosis in rats. s

Another important consideration in the development of spinal cord necrosis following hyperbaric oxygen exposure is that of t rauma itself related to oxygen-induced seizure activity. This possibility, however, was not supported by the postmortem findings. No soft tissue contusions or spinal column fractures were found. More importantly, central spinal cord gray matter necrosis has been observed in animals exposed to hyperbaric oxygenation during pentobarbi ta l anesthesia in the absence of seizure activity 7 (Fig. 4).

The precise pathobiological mechanism for the occurrence of central cord necrosis following hyperbaric oxygen exposure is un- known. Based on the data cited above, it is highly probable that excessive tissue oxygenation has fundamenta l significance. This potential adverse effect of high oxygen tensions creates a paradoxical hazard for the use of hyperbaric oxygen in the therapy of traumatic spinal cord injuries. Although in this investigation the necrotic spinal cord lesions of hyperoxia occurred under pressures of oxygen higher than those used therapeutically in man, similar central cord necrosis has been observed in rats subjected to a single exposure of 30 psig (3 atm) of oxygen for 5 continuous hours. 1 The occurrence of these necrotic lesions at lower pressures, within the upper limits employed therapeutically, emphasizes the principle that oxygen

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J. D. Balentine

toxicity is a function of exposure duration as well as pressure and that there is probably no absolute threshold of oxygen pressure for the development of C N S oxygen toxicity.

Whether oxygen toxicity might enhance or reduce the chances of developing cord necrosis following t r aum a is a question of ut- most concern, and is presently under investigation. Both oxygen toxicity and t rauma may have some similar effects on the spinal cord, since each has been associated with alterations of C N S neurotransmitters. 15,1~'18' 21,~4,28 There is much controversy as to which substances are elevated or depressed in both t r auma and hyperbaric oxygen exposure; however , it is genera l ly agreed that norepinephrine is reduced in the CNS by hyperbaric oxygen) 5,1e:s H~iggendal TM has reported a decrease in norepinephrine and an increase in serotonin in the spinal cord of rats following exposure to 5 or 7 a tm oxygen. A detailed comparat ive study of neurotransmitters in the spinal cord during hyperbaric oxygenation and t r auma would help to eluci- date the pathogenesis of the necrotic lesions associated with each condition and to deter- mine if similar mechanisms of injury are involved.

References

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This work was supported by Grant NS09837 from the National Institute of Neurological Diseases and Stroke, United States Public Health Service.

Portions of this work were presented at the 49th Annual Meeting of the American Association of Neuropathologists and the Fifth International Hyperbaric Medicine Conference.

Address reprint requests to: J. Douglas Balen- tine, M.D., Department of Pathology (Neuro- pathology), Medical University of South Carolina, Charleston, South Carolina 29401.

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Central necrosis of the spinal cord induced by hyperbaric oxygen exposure