Prevention and Control of High-Pressure Neurological Syndrome

It is unlikely that HPNS will be able to be entirely prevented. Nevertheless, several approaches are possible either to delay onset or to modify its clinical effects.

Reduction in the rate of compression reduces the incidence and severity of HPNS. This can be achieved by a slower overall rate or by inserting stops to allow for acclimatization as greater depths are reached. Very slow rates of compression do improve or even prevent symptoms of HPNS in some subjects. Indeed, nausea can be virtually eliminated. Nevertheless, at depths exceeding 300 metres, even with 6 days of compression, some signs of HPNS are still present. With increasing depth, symptoms become more serious and severely limit the ability to perform useful work13. Performance decrements induced by compression improve during a stop at constant pressure, but total recovery has not been recorded at pressures greater than 300 msw14. Very slow compression rates are economically disadvantageous in occupational (saturation diving) settings, and they simply cannot be considered in technical ‘bounce’ diving applications. Thus, at a practical level, slowing compression rates is frequently not particularly useful.

Modification of the breathing gas mixture has been used to delay or modify HPNS. Interestingly, the narcotic effect of nitrogen has been used to counter some of the symptoms. Small amounts of nitrogen (5 to 10 per cent) introduced into the helium-oxygen mixture have been shown to markedly reduce tremor but not EEG abnormalities.

Hydrogen has also been studied in breathing gas mixtures14,15. Hydrogen is less dense than helium and thus would be even better for respiratory mechanics. Being more lipid soluble than helium, hydrogen has a greater narcotic potency, and this can be used to reduce some of the symptoms of HPNS. It appears that the narcotic potency of hydrogen is too great for it to be used alone with oxygen in very deep applications, but hydrogen-helium-oxygen mixtures with about 50 per cent hydrogen have allowed working dives to 500 metres to be achieved without significant symptoms of HPNS and with minimal performance decrement15. Electrophysiological changes and sleep disruptions were still present.

The advantages of added nitrogen include decreased cost, increased thermal comfort, a reduced distortion of speech and a reduction in the HPNS. In adding nitrogen to a deep diving mixture to reduce HPNS, the user must be careful not to increase the narcotic potency of the gas to a higher level than desired at the intended depth of use (see Chapter 62). The advantages of helium and hydrogen include a reduction in the narcotic effect and a reduction in the work of breathing.

Drugs such as alcohol, anaesthetics and anticonvulsants have been suggested to control HPNS. Ketamine is effective in preventing HPNS in rats. Barbiturates have an anticonvulsive effect over a wide range of pressures. Valproate is effective in baboon experiments in reducing HPNS at pressures greater than 40 ATA16. Other anticonvulsants have only a limited effect. Common anticonvulsant drugs such as phenytoin and carbamazepine had no effect on prevention of tremor, myoclonus and seizures in rats. This finding suggests that HPNS-induced seizures are of an unusual type, and that conventional anticonvulsant treatment would be of limited value for HPNS in humans17. Currently, the use of drugs to modify HPNS has no place in human exposure.

Brauer raised two possible problems in trying to control HPNS. First, the efforts to ameliorate HPNS may be effective only on the early manifestations. In so doing, a situation may be created where the first sign may be more serious HPNS, which, in animals, has been fatal. The second problem is that, in baboons, delaying the development of HPNS can induce a new set of symptoms that may involve brain damage5. This is all speculative, and it is clear that more work is required in this area.

HPNS is a major limiting factor in deep diving14. The extremely long duration of deep dives that involve very slow rates of compression to mitigate HPNS followed by slow decompression to avoid decompression sickness have curbed commercial interest in such diving. Thus, research into HPNS has progressed little since the 1990s. Extrapolation from lower primates to humans suggests that human divers are approaching depths at which seizures may be anticipated.

Clinical Manifestations of High-Pressure Neurological Syndrome

The components of the breathing gas mixture, the rate of compression and the time for adaptation influence the presentation. Breathing helium-oxygen, mild effects are seen at pressures of 100 metres, and these effects progress to become debilitating at depths greater than 300 metres. Adding 5 to 10 per cent nitrogen (or hydrogen) to the helium-oxygen respiratory gas mixture reduces symptoms and may permit useful work to be performed after more rapid compression and/or deeper exposure (see later). There is a marked individual variation in susceptibility.


Many different symptoms have been reported from various studies, but most symptoms seem to involve a disturbance of central nervous system function. Effects reported include tremor of the hands and arms that may extend to the whole body, occasional muscle jerks, light-headedness or dizziness, headache, euphoria, drowsiness and loss of consciousness. There is a tendency to fall asleep if not stimulated. Dysphoria and even paranoia are possible. Gastro-intestinal symptoms such as nausea sometimes progressing to vomiting, epigastric sensations, diarrhoea, loss of appetite and aversion to food (leading to weight loss in prolonged exposures) and abdominal cramps may result from a disturbance of the vestibulo-ocular reflex.

Dyspnoea at depths in excess of 300 metres may be a manifestation of HPNS, but this can be difficult to separate from the effects of dense gas and increases in the work of breathing. It can develop or intensify suddenly and may be precipitated by exercise. The distress is greater during inspiration, but surprisingly it is ameliorated by using nitrogen in the breathing mixture, which paradoxically increases gas density and thus the work of breathing.


Tremor may appear in depths as shallow as 150 metres (16 ATA), and it progressively intensifies with increasing depth and pressure. This sign is increasingly reported on deep technical dives where the compressions are extremely fast. The tremor is seen both at rest and on movement. The tremor frequency is 8 to 12 Hz, which differs from that caused by Parkinson’s disease and cerebellar disease, which have a frequency of 3 to 8 Hz. It may be thought of as an extension or exaggeration of the normal physiological resting tremor. The amplitude but not the frequency of the tremor increases with faster rates of compression or increasing absolute pressure. There is a gradual return toward normal following cessation of compression, but it may not be complete until the diver is decompressed. Divers learn to adapt to the tremor, thus leading to an apparent improvement after a day or two.

Opsoclonus is an involuntary, constant, random jittering of the eyes. It is said to be one of the earliest signs of HPNS, and it develops at a depth of 160 metres (17 ATA).

Disturbances of long-term memory and decreases in psychomotor performance have been reported following exposures that produced HPNS. The performance impairment abates somewhat during a stay at constant pressure, but at depths greater than 300 metres, full recovery has not been recorded. Other neuropsychological changes have been reported in some divers. The question remains as to what degree of cognitive performance decrement is acceptable from an occupational and safety standpoint.

Psychomotor tests involving manual dexterity reveal a considerable performance decrement, correlated with the tremor, and averaging 1 per cent, for each 20 metres of depth. Manual dexterity gradually starts returning toward normal levels after 1½ hours at a constant pressure.

Electrophysiological changes

The EEG records during exposure of divers reveal an increase in theta activity and a decrease in alpha waves. Increased theta activity may be seen from depths of 60 metres while breathing air or from 150 metres while breathing helium-oxygen mixtures.

Sleep disruptions such as an increase of awake periods and a decrease in sleep stages 3 and 4 and rapid eye movement sleep has been reported at depths of 450 metres.

Somatosensory evoked potentials increase in amplitude, but they are accompanied by an increase in threshold for sensory stimulation. Shortened latency of peaks following the initial cortical P1 is consistent with a state of hyperexcitability in the brain.

The evoked cortical responses may also be altered during deep dives. A progressive decline in the auditory evoked response, by as much as 50 per cent at 457 metres, has been observed. This may be the result of increased sound conduction in high-density gas. Visual evoked responses have not shown any consistent changes.

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.

The History of High-Pressure Neurological Syndrome

Alternative respiratory gases to compressed air have been sought because of the restriction to effective diving at depths greater than 40 to 60 metres of sea water (msw) as a result of nitrogen narcosis and the high density of air (see Chapter 15). Projection of knowledge concerning inert gas narcosis, especially lipid solubilities, suggested that substituting helium for nitrogen would prevent severe narcosis until pressures were greater than 40 ATA. However, in the 1960s, difficulties were encountered beyond a depth of 200 metres (pressure of 20 ATA) when using a helium-oxygen breathing mixture. This syndrome, which is also characterized by a disturbance of the nervous system, is quite different from the effects of nitrogen (i.e. inert gas narcosis). Because the most prominent feature noted was tremors, the condition was initially referred to as helium tremors1, although it is now realized that the use of helium is merely an association and that helium itself is not the cause.

In retrospect, a series of experiments in the 1880s recorded abnormal excitement, disturbed locomotion and paralysis in marine animals exposed to a high-pressure environment. During the 1920s, a series of publications dealt with the effects of high hydrostatic pressures. Halsey3 cited a paper published in 1936 in which manifestations that may have been the high-pressure neurological syndrome (HPNS) were reported in vertebrate animals.

In the 1960s, British, US, Russian, and French investigators noted tremors and performance impairment in divers compressed to depths of 200 to 400 msw (20 to 40 ATA)4. Coarse tremors were often associated with other symptoms such as nausea, vomiting, dizziness and vertigo. Decreased ability to carry out fine movements was observed. In animals, similar changes were noted that, under further pressure, progressed to generalized convulsions.

This complex of features has become known as the ‘high-pressure neurological syndrome’ or the ‘high-pressure nervous syndrome’, abbreviated HPNS in either case. HPNS should not be confused with inert gas narcosis (see Chapter 15), neurological decompression sickness (see Chapter 11), central nervous system oxygen toxicity (see Chapter 17) or other gas toxicities.