The Etiology of High-Pressure Neurological Syndrome

HPNS has been observed in all animals studied that have a central nervous system at least as complex as that of a flatworm5. Studies in non–air-breathing aquatic animals demonstrate that the effect is not dependent on elevated gas pressure and is at least partly the result of increased hydrostatic pressure3. In air-breathing animals, including humans, HPNS develops while breathing helium and oxygen under high ambient pressure. The inspired gases may modify the manifestations of HPNS6 (see later), thus complicating comparative studies, but breathing gases under pressure per se is not the primary cause.

Animals breathing a helium-oxygen mixture under increasing pressure develop fine and then coarse tremors. These tremors proceed to localized myoclonic episodes and then to generalized clonic seizures. If compression is stopped, the animal will continue to show this seizure activity for as long as 12 hours. Reduction in pressure relieves the symptoms. If compression is continued, tonic-clonic seizures may continue and lead to death. HPNS is reversible up to a certain stage. Using a slower rate of compression can increase the depths at which convulsions occur.

The addition of nitrogen, hydrogen or nitrous oxide to oxygen-helium mixtures significantly delays the onset of both convulsions and tremor. The anti-tremor effect is only about one half that of the anticonvulsant effect. The potency of these gases in alleviating some features of HPNS is proportional to their narcotic potency.

Increased hydrostatic pressure appears to increase excitability of the central nervous system7, and this may be counteracted to some degree by the use of narcotic drugs8. These agents appear to act at different locations, and therefore a different clinical pattern develops if HPNS is modified by nitrogen, barbiturates or ketamine. Barbiturates and anticonvulsants significantly elevate the tremor and convulsion threshold pressures, and they may be synergistic with narcotic and anaesthetic gases. Studies in rats indicate that some of the adverse symptoms of HPNS can be reduced by intravenous alcohol; however, at higher doses, a characteristic pattern of unsteady locomotion was observed.

The exact mechanism of production of HPNS is not understood. Some aetiological factors that have been proposed in the past include a temperature effect, gas-induced osmosis, a modified form of inert gas narcosis and hypoxia or hypercapnia caused by the respiratory limitations imposed by increased gas density. Halsey presented evidence that tends to discount these theories.

At a simplistic level, one explanation may be a subtle pressure effect on the architecture of excitable membranes in the nervous system. Thus, if an excitable membrane is ‘crushed’ even subtly, in a way that alters geometry and function of transmembrane proteins, membrane surface receptors and ion channels, then derangement of normal function could result. Such a mechanism offers a convenient segue into explaining the ameliorating effect of narcotic gases whose ‘space-occupying dissolution’ into the membrane may restore the membrane’s original architecture, virtually the reciprocal explanation for pressure reversal of general anaesthesia by anaesthetic vapours.

In reality (and as is the case for explaining the mechanism of anaesthesia by anaesthetic vapours), the explanation is not likely to be as simple as that. There is considerable evidence for the role of neurotransmitters in pathogenesis. These include gamma-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and N-methyl-d-aspartate (NMDA). The monoamine-depleting drug reserpine lowers the pressure required to produce convulsions. Drugs such as sodium valproate, which enhance the activity of GABA, prevent or reduce some of the changes associated with the syndrome.

Focal injection of NMDA antagonists in rats has been shown to be protective against convulsions. At 81 ATA, primates pre-treated with an NMDA receptor antagonist showed a delayed onset of face tremor and myoclonus with abolished severe whole body tremor and seizure activity. The electroencephalographic (EEG) increase in alpha activity was also abolished, thereby indicating that NMDA transmission plays a significant part in the manifestations of HPNS.

The serotonin syndrome has features similar to those of HPNS. At least in rats, a modified form of the syndrome appears at increased pressure – consistent with the hypothesis that elevation of 5-hydroxytryptamine (5-HT) or activation of receptors has occurred. Elevation of striatal dopamine in rats exposed to pressure can be blocked by 5-HT receptor antagonists and, concurrently, observable motor features of HPNS can be reduced.

Changes in neuronal calcium ions induced by high-pressure helium have been postulated as a mechanism for the excitatory phenomena of HPNS.