Is there a role for the autochthonous bubble in the pathogenesis of spinal cord decompression sickness?

Histological examination by light and electron microscopy of the spinal cords of four dogs rapidly perfusion-fixed after the onset of decompression sickness revealed the presence of numerous non-staining, space-occupying lesions that were absent in similarly prepared sections of control or ischemic spinal cords. We propose the hypothesis that these lesions are caused by the liberation of a gas phase. The possible significance of these lesions in the evolution of spinal cord dysfunction is discussed with reference to the principal theories of the pathogenesis of spinal cord decompression sickness.

Background review and current concepts of reperfusion injury.

We define the concept of reperfusion injury, and we present a background chronology of experimental work supporting and questioning this concept. We identify several new influences, such as current clinical interest in thrombolytic therapy for acute ischemia of heart and brain and the growing recognition of endothelium as a regulator of homeostasis. We propose that these influences will encourage a reexamination of reperfusion injury as a factor in the ultimate outcome of tissue exposed to reversible ischemia. We briefly discuss the major mechanisms presently implicated in reperfusion injury--loss of calcium homeostasis, free radical generation, leukocyte-mediated injury, and acute hypercholesterolemia.

Cerebral air embolism treated by pressure and hyperbaric oxygen.

We used pressure and hyperbaric oxygen to treat 2 patients with cerebral air embolism, occurring as the result of invasive medical procedures, and neither suffered any permanent damage detectable by clinical examination and MRI. This outcome contrasts with reports of infarct and disability among untreated victims of air embolism.

Bubble-induced dysfunction in acute spinal cord decompression sickness.

Five anesthetized dogs undertook a chamber dive, on air, to 300 feet of seawater for 15 min. After the dive, spinal cord decompression sickness was detected by recording a reduced amplitude of the somatosensory evoked potential compared with predive base-line values. After the diagnosis of decompression sickness and rapid perfusion fixation of the animal, the spinal cord was removed and examined histologically. Numerous space-occupying lesions (SOL) that disrupted the tissue architecture were found in each cord, mainly in the white matter. The size and distribution of the SOL were determined using computerized morphometry. Although SOL occupied less than 0.5% of the white matter volume, we tested a number of algorithms to assess whether the SOL may have been directly involved in the loss of spinal cord function that followed the dive. We determined that the loss of somatosensory evoked potential amplitude may be attributed to the SOL if 30-100% of the spinal cord fibers that they displaced were rendered nonconducting. A number of possible mechanisms by which SOL may interfere with spinal nerve conduction are discussed.

Lipopolysaccharide-induced production of tumor necrosis factor activity in rats with and without risk factors for stroke.

Rats produced more TNF activity in cerebrospinal fluid (CSF) than in blood after intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS). After intravenous (i.v.) LPS, blood TNF levels exceeded CSF levels. Thus, brain cells appear to produce TNF in response to LPS. Rats with the stroke-risk factors hypertension or combined hypertension and genetic stroke-proneness produce more TNF in response to a provocative dose of LPS i.v. than control animals free of these risk factors. The possible relevance to stroke vulnerability is discussed.

Platelet activating factor receptor blockade enhances recovery after multifocal brain ischemia.

We treated four anesthetized dogs (Canis familiaris) with the platelet activating factor (PAF) receptor antagonist kadsurenone prior to 60 min of multifocal ischemia induced by air embolism, and measured neuronal recovery, blood flow and autologous 111In-labeled platelet accumulation for 4 h after ischemia. Four anesthetized animals with identical ischemia served as controls. Kadsurenone (3 mg/kg) administered 5 min prior to ischemia and continuously (1 mg/kg/hr) throughout ischemia and recovery significantly enhanced recovery of cortical somatosensory evoked response (CSER) amplitude (% of baseline) when compared to controls (27-36% vs 9-14%, p less than 0.05). We estimated platelet accumulation as 111In activity (cmp/g tissue) in the injured hemisphere minus that in the non-injured hemisphere. Kadsurenone treated animals did not exhibit significantly altered 111In-labeled platelet accumulation when compared to controls (6158 +/- 2386 vs 9979 +/- 3852, mean +/- SEM). Beneficial effects of PAF receptor blockade other than those on platelet accumulation may be involved.

Pharmacologic therapy for ischemic cerebrovascular disease.

This article considers pharmacologic therapy for the prevention and treatment of ischemic cerebrovascular disease. The emphasis is on prevention of stroke, since current pharmacologic treatments do not reliably reduce morbidity or mortality once a stroke has occurred. Antihypertensive treatment, anticoagulants, and antiplatelet agents are discussed along with general guidelines for poststroke therapy.

Failure to prevent decompression illness in rats by pretreatment with a soluble complement receptor.

Controversy exists over the role of complement activation in the natural history of decompression illness (DCI), and whether an individual's predisposition to DCI might be influenced by susceptibility to activation of complement by intravascular gas bubbles. Treatment with a soluble complement receptor (sCR-1), which neutralizes activated complement components, is known to be beneficial in other complement-dependent disease processes. This study investigated the effect of treating rats with sCR-1 or saline before decompression from a dive profile known to produce a high incidence of DCI. No statistical difference in the incidence of DCI was observed between the 27 rats treated with sCR-1 and 26 control rats treated with saline. The study was unable to confirm the previously reported observation in rats of a positive correlation between DCI incidence and increasing weight.

Exercise conditioning reduces the risk of neurologic decompression illness in swine.

During development of a pig model of neurologic decompression illness (DCI) we noted that treadmill-trained pigs seemed less likely to develop DCI than sedentary pigs. The phenomenon was formally investigated. Twenty-four immature, male, castrated, pure-bred Yorkshire swine were conditioned by treadmill running, while 34 control pigs remained sedentary. All pigs (weight 18.75-21.90 kg) were dived on air to 200 feet of seawater (fsw) in a dry chamber. Bottom time was 24 min. Decompression rate was 60 fsw/min. Pigs that developed neurologic DCI were treated by recompression. Pigs without neurologic signs were considered neurologically normal if they ran on the treadmill without gait disturbance at 1 and 24 h postdive. Of the 24 exercise-conditioned pigs, only 10 (41.7%) developed neurologic DCI, compared to 25 of 34 (73.5%) sedentary pigs (X2 = 5.97; P = < 0.015). Neither mean carcass density (adiposity) nor mean age were significantly different between groups. No patent foramen ovale was detected at necropsy. An additional control group of 24 pigs was dived to clarify the influence of weight. The results suggest that the risk of neurologic DCI is reduced by physical conditioning, and the effect is independent of differences in age, adiposity, and weight.

Complement activation during saturation diving.

In this study, the levels of activated complement fragments C3a and C5a were measured on 11 U.S. Navy divers as they performed a 28-day saturation dive to a pressure equivalent of 1,000 feet of seawater (fsw, 31.3 atm abs). Two subjects developed symptoms consistent with the high pressure nervous syndrome (HPNS) and three were treated for type I DCS (joint pain only). These events allowed us to test two hypotheses: a) alterations in C3a or C5a levels during compression are related to the occurrence of HPNS and b) increases in complement fragments are an indicator of decompression stress associated with type I DCS. There was no correlation between changes in C3a and C5a levels during compression and the diagnosis of HPNS. Our results suggest that an increase in C3a and C5a levels during saturation diving correlates with decompression stress and the clinical diagnosis of type I DCS.

A review of the pathophysiology and potential application of experimental therapies for cerebral ischemia to the treatment of cerebral arterial gas embolism.

This review considers the pathophysiology of air embolism that occurs as a result of diving and iatrogenic accidents. Various experimental therapies are classified according to their potential mechanism of action. The effectiveness and prospects for application to the clinical situation are assessed for each therapy. Hyperbaric oxygen remains the most effective therapy, and it is one that is simple to apply. The physiologic changes that occur after gas embolism are complex, however, and future improvements in therapy will demand close clinical supervision and multiple individually tailored therapeutic decisions rather than a simple protocol.

Methyl prednisolone in the treatment of acute spinal cord decompression sickness.

Sixteen anesthetized dogs undertook a chamber dive that was designed to induce decompression sickness. Somatosensory evoked potentials (SEP) were used to diagnose and quantify the outcome of spinal cord involvement in the disease. Following diagnosis, 8 animals were treated with methyl prednisolone (MP), 20 mg.kg-1 ("megadose"), as an adjuvant to recompression on an abbreviated U.S. Navy Treatment Table 6. Eight control animals were recompressed in a similar manner, but received the MP diluent only as an adjuvant. Analysis of the SEP at the conclusion of treatment showed that there was no significant difference in outcome for the 2 groups of animals. However, if all the SEP recorded during the treatment period are compared, the MP-treated animals experienced a significantly worse outcome than the diluent-treated controls. The risks and benefit of using corticosteroids in the treatment of human spinal cord DCS are discussed.

Hyperbaric oxygen after global cerebral ischemia in rabbits reduces brain vascular permeability and blood flow.

BACKGROUND AND PURPOSE: Hyperbaric oxygen (HBO) has been advocated as a therapy to improve neurological recovery after ischemia, since HBO may improve tissue oxygen delivery. We examined the effect of HBO treatment after global cerebral ischemia on early brain injury. METHODS: Rabbits were subjected to 10 minutes of global cerebral ischemia by cerebrospinal fluid compression. After 30 minutes of reperfusion, rabbits either were subjected to HBO for 125 minutes and then breathed 100% O2 at ambient pressure for 90 minutes or breathed 100% O2 for 215 minutes. At the end of reperfusion and 90 minutes after exposure, brain vascular permeability and cerebral blood flow were measured. Somatosensory evoked potentials were monitored throughout the experiment. RESULTS: HBO treatment reduced (P < .05) brain vascular permeability by 16% in gray matter and by 20% in white matter. Cerebral blood flow was lower (P < .05) in the HBO group (40.9 +/- 1.9 mL/min per 100 g, mean +/- SEM) compared with controls (50.8 +/- 2.0 mL/min per 100 g). Somatosensory evoked potential recovery was similar in the two groups (P > .05). CONCLUSIONS: HBO administered after global cerebral ischemia promoted blood-brain barrier integrity. HBO treatment also reduced cerebral blood flow; this effect was not associated with a reduction in evoked potential recovery. Since neurological outcome after global cerebral ischemia is generally poor and treatment options are limited, HBO should be further investigated as a potential therapy.

Hyperbaric oxygen after global cerebral ischemia in rabbits does not promote brain lipid peroxidation.

OBJECTIVE: To determine whether hyperbaric oxygen administered immediately after global cerebral ischemia increases free radical generation and lipid peroxidation in the brain or alters neurophysiologic recovery. DESIGN: Prospective, randomized, controlled trial. SETTING: Animal research laboratory. SUBJECTS: Adult male New Zealand white rabbits. INTERVENTIONS: Anesthetized rabbits were subjected to 10 mins of global cerebral ischemia by infusing a mock cerebrospinal fluid into the subarachnoid space and increasing intracranial pressure equal to mean arterial pressure. Immediately upon reperfusion, one group of rabbits (n = 9) was treated with hyperbaric oxygen at 2.8 atmospheres absolute for 75 mins while the control group (n = 9) breathed room air for an equivalent period of time. At the end of the reperfusion period, oxyradical brain damage was determined by measuring brain levels of oxidized and total glutathione and free malondialdehyde. Neurophysiologic brain injury was assessed with cortical somatosensory evoked potentials. MEASUREMENTS AND MAIN RESULTS: Both oxidized glutathione and the ratio of oxidized glutathione to reduced glutathione (total minus oxidized) were higher (p < .05) in the hyperbaric oxygen group, indicating that hyperbaric oxygen increased free radical generation. Nonetheless, brain malondialdehyde content, an index of lipid peroxidation, was similar (p > .05) in the two groups. Cortical somatosensory evoked potential recovery at the end of reperfusion was 50% higher (p < .05) in the hyperbaric oxygen-treated animals compared with controls. CONCLUSIONS: Treatment with hyperbaric oxygen after ischemia increased the amount of oxygen free radicals in the brain. However, this increase in free radical generation was not associated with an increase in lipid peroxidation or a reduction in neurophysiologic recovery when measured after 75 mins of recirculation. These results suggest that hyperbaric oxygen administered immediately after global ischemia does not promote early brain injury.

Allopurinol pretreatment improves evoked response recovery following global cerebral ischemia in dogs.

The reperfusion of previously ischemic tissue may lead to the formation of highly reactive free radicals that promote tissue injury. Xanthine oxidase has been implicated as one source of these free radicals. We examined the role of xanthine oxidase in brain injury using a cerebrospinal fluid compression model of global cerebral ischemia with 15 minutes of ischemia and 4 hours of reperfusion. Seven dogs were pretreated with the xanthine oxidase inhibitor allopurinol (50 mg/kg for 5 days). Neurophysiological recovery was monitored with cortical somatosensory evoked potentials. As an attempt to correlate brain recovery with the mechanism of protection, free brain malondialdehyde was measured at the end of reperfusion by high-performance liquid chromatography. Brain water content was measured by wet-dry weights. Compared with seven untreated control dogs, allopurinol pretreatment significantly improved recovery of somatosensory evoked potentials after 4 hours of reperfusion. However, the amount of free malondialdehyde in the allopurinol-treated dogs was 32% greater than that in the controls. Brain water content was similar in the two groups. These results suggest that xanthine oxidase contributes to brain injury after ischemia and reperfusion. However, tissue damage caused by xanthine oxidase may be mediated through mechanisms other than free radical production.

Release of dopamine from striatal synaptosomes: high pressure effects.

Adverse neurological manifestations of exposure to high hydrostatic pressure include tremor and convulsions, suggesting an alteration in synaptic transmission, particularly with inhibitory pathways. Because striatal transmission has been implicated in the high pressure neurologic syndrome (HPNS), we investigated the effect of pressure exposure on the release of a major inhibitory neurotransmitter in this region. Synaptosomes isolated from the guinea pig striatum were used to study the effect of compression to 67.7 ATA on [3H]dopamine release. Pressure was found to have a suppressive effect on the initial release of [3H]dopamine by synaptosomes isolated from the striatum of guinea pigs. This finding suggests that decreased inhibitory regulation at the level of the striatum contributes to the hyperexcitability associated with compression to high pressure.

Pressure suppresses serotonin release by guinea pig striatal synaptosomes.

Exposure to high pressure produces neurologic changes in humans which manifest as tremor, EEG changes, and convulsions. Since previous studies have implicated the involvement of the serotoninergic system in these symptoms, it was of interest to study serotonin release at high pressure. Synaptosomes isolated from guinea pig striatum were used to follow serotonin efflux at 68 ATA. The major observation was a decrease in [3H]serotonin release from depolarized striatal synaptosomes at 68 ATA. In view of the role of serotonin as an inhibitory neurotransmitter in this area, the observed decrease in synaptic release leads us to conclude that decreased serotoninergic activity in striatal neurons probably is contributing to the hyperexcitability associated with HPNS.

Experimental determination of latency, severity, and outcome in CNS decompression sickness.

Twenty-eight dogs underwent a 300 fsw chamber dive designed to generate spinal cord decompression sickness (DCS), which was detected by observing a reduction in the amplitude of the spinal somatosensory evoked potential (SEP). After an interval of 15 min on the surface following diagnosis, the animals received a therapeutic recompression. The latency was defined as the time between surfacing from the dive and the diagnosis of DCS, the severity as the minimum SEP amplitude, and the outcome as the amplitude of the SEP after 2 h of treatment. Significant correlations between latency and severity (P less than 0.05), latency and outcome (P less than 0.01), and severity and outcome (P less than 0.05) were found. Canine spinal cord latency is shown to be very similar to that found in man up to a surface interval of 30 min. The association between latency, severity, and outcome of spinal cord DCS is discussed with reference to the possible mechanisms involved in this disease.

Effect of pressure on the release of radioactive glycine and gamma-aminobutyric acid from spinal cord synaptosomes.

Exposure to high hydrostatic pressure produces neurological changes referred to as the high-pressure nervous syndrome (HPNS). Manifestations of HPNS include tremor, EEG changes, and convulsions. These symptoms suggest an alteration in synaptic transmission, particularly with inhibitory neural pathways. Because spinal cord transmission has been implicated in HPNS, this study investigated inhibitory neurotransmitter function in the cord at high pressure. Guinea pig spinal cord synaptosome preparations were used to study the effect of compression to 67.7 atmospheres absolute on [3H]glycine and [3H]gamma-aminobutyric acid ([3H]GABA) release. Pressure was found to exert a significant suppressive effect on the depolarization-induced calcium-dependent release of glycine and GABA by these spinal cord presynaptic nerve terminals. This study suggests that decreased tonic inhibitory regulation at the level of the spinal cord contributes to the hyperexcitability observed in animals with compression to high pressure.