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High-pressure neurological syndrome (HPNS) is a condition that occurs during deep-sea dives exceeding 150 meters and is characterized by neurological, psychological, and electroencephalography (EEG) abnormalities. The severity of HPNS symptoms is influenced by both the rate of compression and the level of hydrostatic pressure reached. Rapid compression and increased pressure exacerbate symptoms, making HPNS a significant limiting factor in deep diving. Common clinical features of HPNS include tremors, myoclonic jerks, cognitive impairment, and mood disturbances. These symptoms are often accompanied by EEG abnormalities, complicating diagnosis and management. EEG changes, such as increased theta activity and decreased alpha waves, are common, along with alterations in sleep patterns. Early recognition and timely intervention are crucial to preventing long-term complications. This activity reviews the risk factors, pathophysiology, clinical presentation, diagnosis, and treatment strategies for HPNS. This activity also emphasizes the need for interprofessional collaboration among healthcare providers to ensure effective management and improved patient outcomes. Objectives: Identify the clinical manifestations of high-pressure nervous syndrome, including neurological, psychological, and electroencephalographic abnormalities. Assess the risk factors for developing high-pressure nervous syndrome, including individual susceptibility, compression speed, and breathing gas mixtures. Select the appropriate breathing gas mixtures and compression profiles to reduce the risk of high-pressure nervous syndrome. Collaborate with hyperbaric medicine specialists and neurologists to develop comprehensive management plans for divers exhibiting symptoms of high-pressure nervous syndrome. Access free multiple choice questions on this topic.

Human physiology is sensitive to elevated pressures, as this thermodynamic variable significantly affects the kinetics and steady-state equilibrium of biological processes.[1] High-pressure neurological syndrome (HPNS) is characterized by neurological, psychological, and electroencephalographic (EEG) abnormalities and typically occurs during dives deeper than 150 meters.[2] This feature requires the diver to use helium-oxygen gas mixtures. The pathophysiological signs and symptoms of HPNS depend on the compression speed and the level of hydrostatic pressure attained. The clinical presentation becomes more severe as the compression rate increases and the pressure rises. HPNS poses a significant limitation for deep diving.[3]

High-pressure neurological syndrome is believed to result from the increased atmospheric pressure on the central nervous system (CNS), leading to hyperexcitability of the CNS.[2] However, evidence suggests that this phenomenon is primarily caused by high-pressure helium rather than elevated pressure alone.[4] The CNS hyperexcitability associated with HPNS is largely mediated by NMDA receptors, presenting a potential avenue for future research.[5][6]

Several theories exist regarding the underlying mechanism of HPNS. Potential physiological vulnerabilities include changes in the fluidity of membrane phospholipids, alterations in ion channels, and disruptions in receptors, enzymes, and other protein functions under elevated pressures.[1] A prevailing assumption involves the compression effect of pressure on the lipid components of cell membranes of the CNS.[3] This compression effect may also influence molecular processes related to volume expansion, affecting transmembrane proteins, membrane receptors, and ion channels.[8][1] Likewise, anesthetic gases may alleviate the clinical manifestations of HPNS by restoring the original structure of CNS cell membranes through the pressure reversal effect of narcosis.[3][9] This phenomenon opens potential avenues for research on breathing mixture modifications, such as the use of trimix to manage HPNS.[9] The roles of various neurotransmitters in the pathogenesis of HPNS have been studied, including gamma-aminobutyric acid (GABA), dopamine, serotonin (5-hydroxytryptamine [5-HT]), acetylcholine, and N-methyl-d-aspartate (NMDA).[2] Sodium valproate, which increases GABA levels in the cortex, has been shown to reduce the severity of HPNS symptoms in baboons.[10] Serotonin may also induce hyperexcitability of the spinal cord in hyperbaric conditions. The behavior of rats in high-pressure environments resembles the clinical presentation of serotonin syndrome, which is characterized by altered mental status, restlessness, myoclonus, hyperreflexia, shivering, and tremors. This similarity suggests the activation of the 5-HT receptor subtype 1a (5-HT1a).[2] Likewise, studies have reported that increased striatal dopamine release and the development of enhanced locomotor and motor activity can be partially prevented by 5-HT1b receptor antagonists in rats exposed to high pressure.[11]

The roles of various neurotransmitters in the pathogenesis of HPNS have been studied, including gamma-aminobutyric acid (GABA), dopamine, serotonin (5-hydroxytryptamine [5-HT]), acetylcholine, and N-methyl-d-aspartate (NMDA).[2] Sodium valproate, which increases GABA levels in the cortex, has been shown to reduce the severity of HPNS symptoms in baboons.[10] Serotonin may also induce hyperexcitability of the spinal cord in hyperbaric conditions. The behavior of rats in high-pressure environments resembles the clinical presentation of serotonin syndrome, which is characterized by altered mental status, restlessness, myoclonus, hyperreflexia, shivering, and tremors. This similarity suggests the activation of the 5-HT receptor subtype 1a (5-HT1a).[2] Likewise, studies have reported that increased striatal dopamine release and the development of enhanced locomotor and motor activity can be partially prevented by 5-HT1b receptor antagonists in rats exposed to high pressure.[11] Hyperactivation of NMDA receptors has also been investigated as a potential mechanism for HPNS. Electrophysiological studies revealed a significant increase in synaptic NMDA receptor responses, followed by postsynaptic changes.[12] Research has demonstrated that the hyperexcitability observed in HPNS is primarily induced by NMDA receptors.[13][14][15][16][17][18] NMDA receptors belong to the inotropic glutamate receptor (iGluR) family, which also includes AMPA and kainate receptors. iGluRs convert transient glutamate release from presynaptic vesicles into postsynaptic neuronal excitation at synapses. The influx of calcium through activated NMDA receptors has a significant impact on cellular synaptic transmission.[19] Another study reported that pretreatment with NMDA antagonists in rats exposed to high pressure using helium and oxygen prevented convulsions.[20] Recently, findings suggest that HPNS and hyperbaric oxygen therapy–related oxygen toxicity may share a similar pathophysiological mechanism that activates NMDA receptors.[18]

Hyperactivation of NMDA receptors has also been investigated as a potential mechanism for HPNS. Electrophysiological studies revealed a significant increase in synaptic NMDA receptor responses, followed by postsynaptic changes.[12] Research has demonstrated that the hyperexcitability observed in HPNS is primarily induced by NMDA receptors.[13][14][15][16][17][18] NMDA receptors belong to the inotropic glutamate receptor (iGluR) family, which also includes AMPA and kainate receptors. iGluRs convert transient glutamate release from presynaptic vesicles into postsynaptic neuronal excitation at synapses. The influx of calcium through activated NMDA receptors has a significant impact on cellular synaptic transmission.[19] Another study reported that pretreatment with NMDA antagonists in rats exposed to high pressure using helium and oxygen prevented convulsions.[20] Recently, findings suggest that HPNS and hyperbaric oxygen therapy–related oxygen toxicity may share a similar pathophysiological mechanism that activates NMDA receptors.[18] Altered synaptic transmission is another potential explanation for HPNS.[1] Elevated pressure suppresses synaptic transmission through various mechanisms, including modulation of ionotropic receptor activity, decreased action potential amplitude, slowed kinetics, depression of neurotransmitter release, reduced vesicle fusion, and lowered Ca2+ currents.[21][22][23][24][25][26][27][28][29] Studies have also reported that high pressure mimics the effects of low Ca2+ levels.[28][30] In contrast, elevated Ca2+ levels can counteract the effects of high pressure.[23][31] Indirect and semi-direct evidence has demonstrated this high-pressure effect on voltage-dependent Ca2+ currents has been demonstrated.[30][23][32] Recently, Aviner et al suggested that high-pressure selective modulation of various presynaptic voltage-dependent calcium channels (VDCCs), along with somatic and dendritic channels, likely plays a significant role in altering synaptic transmission, which is strongly associated with HPNS.[1] Both intraspecies and interspecies variations of HPNS have been documented, with some individuals exhibiting greater susceptibility than others.[2][9] A genetic basis may be one of the mechanisms underlying adaptation to HPNS.[2][33]

HPNS is characterized by hyperexcitability of the central nervous system, leading to neurological and psychological abnormalities, which can be observed as changes in EEG recordings. Notably, it is essential to differentiate HPNS from nitrogen narcosis, decompression sickness, and oxygen toxicity.[2] Tremor is the most characteristic symptom of HPNS, occurring both at rest and during movement. Tremor typically begins in the distal extremities and may progress to involve the entire body. The frequency of these tremors ranges from 8 to 12 Hz.[8] The amplitude increases with faster compression speed and increasing hydrostatic pressure. In addition, spontaneous (constant) eye oscillations in random directions, known as opsoclonus, are among the earliest signs of HPNS.[2] Other possible symptoms of HPNS include headache, dizziness, fatigue, myoclonic jerking, muscular weakness, and euphoria.[3][8][9][34][35][36] While convulsions have been reported in animals, they have not been observed in humans.[2][37] Gastrointestinal symptoms such as nausea, vomiting, stomach cramps, diarrhea, and loss of appetite may also occur. Additionally, individuals may experience memory disturbances, cognitive deficits, impaired psychomotor performance, drowsiness, and sleep disturbances characterized by vivid dreams or nightmares.[8][9][34][38] The clinical presentation of HPNS may be influenced by factors such as the components of the breathing gas mixture, compression rates, and the attained hydrostatic pressure. For example, incorporating specific amounts of nitrogen or hydrogen into the helium-oxygen gas mixture can alleviate the signs and symptoms of HPNS.[2][3] Faster compression, on the other hand, increases the severity of clinical manifestations and can lead to earlier onset of symptoms.[2] Likewise, higher hydrostatic pressure correlates with more severe signs and symptoms.[3] In addition, individual variations in clinical presentation have been reported.[38]

Various monitoring tests have been conducted during compression to assess neuropsychological, neurophysiological, and performance responses in experimental dives. Vaernes et al used a static steadiness test to measure postural tremors in the hands, a finger oscillation test, a dynamometer to assess handgrip strength, and trials for evaluating visuomotor skills and coordination.[38] Additionally, a questionnaire was administered at different depths to gauge performance across motor, visuomotor, and cognitive tests. The assessments included tests for key insertion, visual reaction time, arithmetic, reasoning, long-term memory, and visual digit span.[38] EEG recordings have been analyzed in several studies, revealing distinct changes in divers with HPNS. Specifically, EEG records showed increased theta activity and decreased alpha waves.[9][34][35][38] Rostain et al reported a decline in alpha frequencies starting at 100 meters, accompanied by an increase in theta frequencies in the frontal area at around 200 meters during a dive to 450 meters of seawater using a helium-nitrogen-oxygen gas mixture.[39] Sleep EEG also exhibits notable alterations under high pressure, including an increase in stages I and II, a decrease in the duration of stages III and IV, and a reduction in REM periods.[39][40] Additionally, somatosensory evoked potentials may be influenced by pressure, with a shortened latency of peaks following the initial cortical P1 indicative of a state of hyperexcitability in the brain.[2]

HPNS poses a significant limitation for deep dives.[3] While HPNS cannot be entirely prevented, several existing approaches can delay its onset or modify its clinical presentation.[2][3] Reduction of Compression Speed Slowing the overall compression speed or incorporating stops during descent to facilitate acclimatization can improve or prevent HPNS symptoms.[2][3][9][38] However, achieving a sufficiently slow compression rate is essential for adaptation, particularly during staged descents for deeper dives, which poses a significant challenge for technical dives.[3] Nevertheless, as pressure increases, symptoms of HPNS become more pronounced and significantly impair the diver's performance. Even beyond 330 meters, divers may continue to experience HPNS symptoms, regardless of the compression speed.[3][9] Modification of the Breathing Gas Mixture Nitrogen has been used to counteract some HPNS symptoms due to its narcotic effect.[9] Adding about 5% to 10% nitrogen to a helium-oxygen mixture has been reported to alleviate certain signs and symptoms of HPNS.[2][41][42][43] Adding nitrogen to the helium-oxygen breathing gas mixture offers several advantages, including lower costs, improved thermal comfort, reduced speech distortion, and alleviation of HPNS symptoms.[44] However, divers should remain cautious of the potential risk of nitrogen narcosis.[9] Similarly, hydrogen has been used for the same purpose due to its advantageous properties for deep dives.[35] As hydrogen is less dense than helium, it offers improved respiratory mechanics.[3][43] A hydrogen-helium-oxygen mixture (with approximately 50% hydrogen) has enabled successful dives up to 500 meters without significant clinical manifestations of HPNS. Although EEG changes persisted, performance deterioration was minimal.[35][45] Similarly, a depth of 701 meters has been reached with reduced clinical symptoms of HPNS using a helium-hydrogen-oxygen breathing gas mixture. However, it is important to note that hydrogen becomes explosive when mixed with oxygen concentrations above 4%.[43] Pharmacological Treatment

Similarly, hydrogen has been used for the same purpose due to its advantageous properties for deep dives.[35] As hydrogen is less dense than helium, it offers improved respiratory mechanics.[3][43] A hydrogen-helium-oxygen mixture (with approximately 50% hydrogen) has enabled successful dives up to 500 meters without significant clinical manifestations of HPNS. Although EEG changes persisted, performance deterioration was minimal.[35][45] Similarly, a depth of 701 meters has been reached with reduced clinical symptoms of HPNS using a helium-hydrogen-oxygen breathing gas mixture. However, it is important to note that hydrogen becomes explosive when mixed with oxygen concentrations above 4%.[43] Pharmacological Treatment Currently, pharmacological treatment for HPNS does not exist; however, anesthetics, barbiturates, and anticonvulsants have been studied to prevent its clinical manifestations.[46] Ketamine has been shown to effectively control HPNS in rats.[47] Barbiturates have demonstrated anticonvulsant properties against HPNS.[2] Similarly, valproate demonstrated benefits in baboons exposed to pressures higher than 40 ATA.[10] Other anticonvulsants have shown insufficient effects on HPNS. Common anticonvulsants, such as phenytoin and carbamazepine, failed to inhibit tremors, myoclonus, and seizures in rats, although diazepam was effective.[48] This result suggests that HPNS-related seizures are an unusual type, making the usage of standard anticonvulsant treatments less effective in humans.[49] Furthermore, most of these pharmacological agents cannot be used to treat HPNS due to their adverse effects on diving performance. However, recent studies on 5-HT1a receptor antagonists have produced promising results.[2] Diver Selection Selecting divers who are less susceptible to HPNS may help mitigate its effects.[3][50] Several concerns have been raised regarding the control of HPNS. First, these methods may be effective only in alleviating certain symptoms, potentially resulting in a more severe presentation of initial HPNS signs. Secondly, delaying the onset of HPNS in baboons may lead to the emergence of new symptoms associated with brain damage. Additionally, there is a risk of developing pressure-related tissue injuries that remain symptom-free, potentially resulting in long-term complications.[51] Further studies are needed to draw reliable conclusions.

High pressure poses the greatest challenge to human physiology during deep diving. Factors such as the high concentration of gases, increased matter density, and alterations in the typical properties of heat and sound can also lead to neurological signs independent of HPNS.[8] Conditions associated with deep diving include oxygen toxicity, exposure to polluted breathing gases, nitrogen narcosis, HPNS, decompression illness, and carbon dioxide retention due to increased gas density.[3] Significant differentiating features include the symptoms experienced, the depths at which they arise and subside, the diving protocol (including the rates of ascent and descent and decompression stops), and the composition of the breathing gas mixture.

The clinical manifestations of HPNS persist but typically improve over time while maintaining constant pressure.[8][2][9] Rostain et al noted that changes in divers' sleep patterns began to show improvement after the first week under pressure. However, healthy sleep pattern values were recorded only during decompression at depths below 200 meters.[39] While symptoms generally ease after decompression, some, such as lethargy, may linger for a period. Divers who experience solely HPNS usually recover completely, and no permanent neurological sequelae or histopathological lesions in the brain associated with HPNS have been identified.[2]

Divers who only experience HPNS heal or recover eventually.[2] However, the symptoms can severely impair a diver's performance during a dive, leading to significant risks associated with poor decision-making or actions.[9]

Professional diver education encompasses diving-related diseases, preventive measures, and the properties of breathing gases. Divers should select the safest diving protocols, which involve a gradual compression rate and appropriate breathing gas mixtures. Adhering to safety guidelines serves as a crucial preventive strategy against diving-related illnesses. Additionally, medical professionals must assess psychological fitness during fitness-to-dive evaluations for professional divers. Safe diving necessitates well-informed divers who diligently follow established protocols.

HPNS poses a significant limitation for deep diving. Unfortunately, no drug has been successfully developed to prevent HPNS in humans. Generally, modifying breathing gas mixtures, adjusting compression profiles, and selecting divers who are less susceptible to HPNS may offer partial benefits in managing the condition. However, these approaches remain insufficient for extremely deep dives. Further research into the pathophysiology, prevention, and adaptation mechanisms of HPNS is essential to expand the boundaries of modern diving for humans.

HPNS is a significant consequence of modern deep diving, and several preventive approaches exist. Divers and diving supervisors should carefully consider these strategies. In this context, diving protocols may be developed in collaboration with diving experts. Diving supervisors should document any abnormal symptoms or signs that arise during deep dives and consult with a diving expert as needed. While symptoms typically ease after decompression, some, such as lethargy, may persist.[2] Divers experiencing these symptoms should undergo a thorough examination by a diving physician, with neurology consultations for further evaluation as necessary. An interprofessional healthcare team of specialists, including neurologists, undersea specialists, hyperbaric nurses, and occupational medicine physicians and nurses, are best equipped to manage and prevent HPNS. An initial evaluation by emergency department personnel is crucial. Intensive care and neuroscience nurses play a vital role in caring for patients, educating families about the condition, and providing updates to the rest of the medical team.