Nitrogen narcosis

Inert gas narcosis is a neurological syndrome inducing several psychomotor disorders. Nitrogen narcosis represents the major cause of performances decrease concerning divers, in the depth range of 30 to 90 meters (0.3 to 0.9 MegaPascal).

It is a reversible alteration in consciousness that occurs while diving at high pressures. The apparatus that consents breathing in the water consists in a cylinder with compressed gas, that can be delivered during the inspiration. Amongst the gases contained in the cylinder there’s the nitrogen and high partial pressure of this gas can affect directly the central nervous system , causing euphoria, loss of memory, motor disco-ordination and irrational behaviour.

The most dangerous aspects of narcosis are the impairment of judgement, multi-tasking and coordination, and the loss of decision-making ability and focus. Other effects include vertigo and visual or auditory disturbances. The syndrome‘s symptoms can be variable, depending on the individual diver and the diver's medical or personal history. When more serious, the diver may feel overconfident, disregarding normal safe diving practices.

Neurochemical studies of narcosis
Nitrogen narcosis

Causes of narcosis

The cause of narcosis is related to the increased solubility of gases in body tissues, as a result of the elevated pressures at depth (Henry's law). The Henry's law says that at constant temperature, the solubility of a gas is directly proportional to the pressure that the gas exerts on the solution. Reached equilibrium, the liquid is defined saturated with that gas at that pressure. This equilibrium state persists until the external pressure of the gas will remain unchanged, otherwise, if it increases, more gas will enter into solution. A mathematical expression of the Henry's law may be as follows:

where P is the gas pressure on the solution, C is the concentration of the gas in the solution and k is a constant typical of each gas that correlates the gas pressure on the solution and its concentration.

Henry’s law

Increasing the external pressure at depth the partial pressure of dissolved nitrogen in the blood increases, enhancing the possibility of binding oxygen, forming nitrous oxide. The latter is also known as laughing gas and is used in medicine as an analgesic and anesthetic. In anesthesiology nitrous oxide is used to obtain different levels of sedation.

Nitrogen
Nitrogen narcosis

Modern theories have suggested that inert gases dissolving in the lipid bilayer of cell membranes causes narcosis. More recently, researchers have been looking at neurotransmitter receptor protein mechanisms as a possible cause of narcosis. The breathing gas mix entering the diver's lungs will have the same pressure as the surrounding water, known as the ambient pressure. After any change of depth, the pressure of gases in the blood passing through the brain catches up with ambient pressure within a minute or two, which results in a delayed narcotic effect after descending to a new depth. Rapid compression potentiates narcosis owing to carbon dioxide retention. Returning at less high pressure the gas it’s not yet soluble and it turns in the volatile form, remaining in the brain.
As narcosis affects motor functions, it was chosen to study the nigro-striatal dopaminergic pathway owing to its involvement in psychomotor disorders. Previous microdialysis studies performed in rats have revealed a decrease of striatal dopamine and glutamate induced by nitrogen narcosis. Studies sought to establish the hypothetical role of the glutamatergic corticostriatal pathway because of the glutamate deficiency which occurs in the basal ganglia in this hyperbaric syndrome. So Nicolas Vallee, Jean-Claude Rostain, and Jean-Jacques Risso in 2009 try to explain how can an inert gas counterbalance a NMDA-induced glutamate release. They sought to establish the hypothetical role of glutamate and its main receptor, the N-methyl-D-aspartate (NMDA) receptor, in this syndrome. They aimed to counteract the nitrogen narcosis-induced glutamate and dopamine decreases by stimulating the NMDA receptor in the striatum. They used bilateral retrodialysis on awake rats, submitted to nitrogen under pressure (3 MPa). Continuous infusion of 2 mM of NMDA under normobaric conditions (0.01 MPa) significantly increased extracellular average levels of glutamate, aspartate, glutamine, and asparagine . The same infusion conducted under nitrogen at 3 MPa revealed significant lower levels of these aminoacids. So the results highlight that the NMDA receptor is not directly affected by nitrogen under pressure as indicated by the elevation in NMDA-induced dopamine release under hyperbaric nitrogen. On the other hand, the NMDA-evoked glutamate increase is counteracted by nitrogen narcosis . No improvement in motor and locomotor disturbances was observed with high striatal concentration in dopamine. Further experiments have to be done to specify why the striatal glutamate pathways, in association with the inhibition of its metabolism, only are affected by nitrogen narcosis in this study. Under nitrogen narcosis, extracellular glutamate, glutamine and asparagine levels in the striatum were recorded, and no change in aspartate development was observed. This present results complete those of previous studies and confirm the action of NMDA on its glutamatergic receptor. Under atmospheric conditions, NMDA-Receptor stimulation by NMDA retrodialysis in the striatum induces increases in dopamine and glutamate in this structure. This is a good evidence for interactions between these transmitters. NMDA retrodialysis also involves an increase in glutamine, aspartate and asparagine levels. The interactions between glutamate and dopamine disappear under nitrogen narcosis. Indeed nitrogen at 3 MPa did not change the increase of dopamine induce by striatal NMDA infusion but suppressed the increase of glutamate, glutamine, aspartate, and asparagine . First these results indicate that NMDA receptors remain functional under nitrogen narcosis, as NMDA infusion significantly potentiates dopamine increase. Second, they show that there is no more NMDA-induced interaction between glutamate and dopamine under nitrogen pressure. The activation of the NMDA receptor in the striatum is not sufficient to increase extracellular concentration of glutamate under nitrogen exposure. Dopamine cells follow the same developments after NMDA stimulation, whether under nitrogen exposure or not. Dopamine cells seem to be resistant to nitrogen narcosis, whereas glutamatergic cells are affected directly or indirectly. Dopamine axon terminals in the striatum are relatively insensitive to a variety of glutamate agonists. The striatal action of NMDA on nigrostriatal dopaminergic neurons is not more clearly established . Under atmospheric conditions it was suggested that NMDA-induced dopamine increase appears to be a result of the activation of the striatonigral pathway. Indeed, in this study, this means that GABAergic cells of the striatonigral pathway are thus not directly inhibited by nitrogen under pressure. Glutamate level, which is decreased under nitrogen narcosis, cannot be restored by the activation of striatal NMDA receptor .

How can an inert gas counterbalance a NMDA-induced glutamate release?

Then Nicolas Vallée, Jean-Jacques Rissoe and Jean-Eric Blatteau in 2011 made a research about the effect of an hyperbaric nitrogen narcotic ambience on arginine and citrulline levels, the precursor and co-product of nitric oxide, in rat striatum. Once it was established that the glutamatergic pathways were mainly affected in this hyperbaric syndrome they had to understand the reason why. Hence they sought to establish what happens in the vicinity of the plasma membrane, downstream the NMDA-Receptor, and they used the hypothesis that there could be neuronal nitric oxide synthase ( nNOS ) disturbances .

A microdialysis study was performed in rat striatum in order to analyse levels of citrulline, the NO co-product, and arginine, the NO precursor. Exposure to pressurized nitrogen induced a reduction in citrulline and arginine levels. Under the control normobaric conditions, the striatal NMDA infusion enhanced the citrulline level, whereas under 3 MPa of nitrogen, the same NMDA infusion did not change the citrulline level which remains equivalent to that of the baseline. The level of arginine increased under normobaric conditions but a decrease occurred in pressurized nitrogen . The synthesis of citrulline/NO is reduced in nitrogen narcosis while it seems possible to activate it artificially by infusion. We have suggested that the low glutamate levels recorded in nitrogen narcosis induced these dopamine and NO reductions in the striatum . Actually, the retrograde action of endogenous NO is known to regulate the synaptic level of various neurotransmitters by modulating endocytosis, vescicle maturation and the opening frequency of the NMDA-receptor . For instance, a molecular analysis had revealed a direct action site for NO on the NMDA-receptor . Besides, the neuronal NO Synthase (nNOS) produces NO almost exclusively after activation of the NMDA receptor. The gaseous neuronal messenger in turn modulates glutamate transmission, but this is not all. NO diffusion is also known to modulate DA release in the striatum. NO is synthesized from a unique precursor, arginine , by NO synthase (NOS) , that produces as much NO from arginine as it does the by-product, citrulline. The entire citrulline- NO cycle, which consists of an enzymatic recycle of arginine from citrulline, is present in the striatum. The aim of this study was to check whether neuronally derived NO levels were changed under nitrogen narcosis, and what was the influence of this change on extracellular striatal glutamate and dopamine concentration. Arginine and citrulline concentrations were measured by microdialysis, and compared with glutamate and dopamine developments whether the striatum was stimulated or not. The hypothesis was that a reduction in striatal glutamate and dopamine levels recorded under the effect of nitrogen narcosis could be coupled with a decrease in arginine and citrulline levels, the precursor and the co-product of NO. Exposure to pressurized nitrogen at 3 MPa induced a reduction in extracellular citrulline levels, compared with the baseline. In atmospheric conditions (0.01 MPa), and compared with the baseline, NMDA infusion increased extracellular citrulline levels from the start to the end of the experiment. When both conditions were combined, NMDA retrodialysis and high nitrogen pressure, extracellular citrulline levels remained unchanged from the compression stage to the end of the 3MPa period In atmospheric conditions (0.01 MPa), and compared with the baseline, with striatum’s stimulation it was increased extracellular citrulline level from the start to the end of the stimulation. Exposure to pressurized nitrogen at 3 MPa induced a reduction in extracellular arginine levels, compared with the baseline In atmospheric conditions (0.01 MPa), and compared with the baseline, NMDA infusion increased extracellular arginine levels compared with the baseline. When both conditions were combined, NMDA retrodialysis and high nitrogen pressure, a significant decrease was revealed in extracellular arginine. Arginine levels were significantly lower when values recorded during NMDA infusion in the atmospheric pressure group were compared with those recorded during nitrogen exposure with NMDA. In atmospheric conditions (0.01 MPa), as in nitrogen at 3MPa, and compared with the baseline, with striatum’s stimulation it was decreased extracellular arginine level. So the scientist have highlighted for the first time that extracellular citrulline and arginine levels were also reduced by nitrogen at 3MPa. Helium control was used to dissociate the effect of pressure from that of narcosis. Compared with nitrogen at 3MPa, helium at 3MPa does not induce narcosis, as it has very low narcotic potency.
In nitrogen narcosis, it was firstly remarked that there is less glutamate for the potent induction of NO and citrulline production from arginine. NO was not synthesized despite the NMDA-Receptor stimulation. Although it was not significant, there was an increase in arginine and citrulline levels at the beginning of the NMDA stimulation that was counteracted when nitrogen raised 3MPa and its strongest narcotic effect. So the nitrogen effect acts at a level affecting NO synthesis. In conventional conditions but not in nitrogen narcosis, the strong NMDA-R stimulation promotes dopamine, glutamate and citrulline/NO increases, due to the fact that NO synthesis is under glutamate control and dopamine regulation. As a result of these reduced levels, NO cannot enhance neurotransmitter exocytosis, and more particularly glutamate exocytosis at the presynaptic level. This could lead to a weak activity of thalamostriate and corticostriate pathways involving those nitrogen narcosis symptoms. If I evoked the NMDA pathway I can increase a little bit glutamate and dopamine levels. Arginine availability, which is dependent on the activation of ionotropic non-NMDA receptors, controls the NMDA-induced nitric oxide synthesis. In narcosis, glutamate is not available for stimulating non-NMDA-Receptors and this lack could limit the arginine shuttle.

Effect of an hyperbaric nitrogen narcotic ambience on arginine and citrulline levels, the precursor and co-product of nitric oxide, in rat striatum

Predisposing factors

1. Physical causes:
   1. Fatigue and lack of sleep predispose to an increased sensitivity to the nitrogen narcosis. A diver untrained or tired tend not to control his breathing and his body gets tired first. This requires a greater intake of ventilation volume, which, if not controlled, can lead to narcosis.
   2. Alcohol has a depressant effect on the nerve centers, effects which are added to the narcotic effect of nitrogen at high pressures, causing more suffering to the scuba.
   3. Some drugs have effects that may predispose to narcosis, such as drugs against seasickness and others that act on the brain as hypnotics, sedatives, etc. .. The drugs must be carefully monitored by doctors before diving.
2. Psycological causes:
   1. Anxiety due to an unfavorable psychological state, to a state of pre-existing nervousness, fear, coercion, to an unexpectedly during the dive, and so on. This type of mental state can cause an abnormal situation of the individual psychic balance, urging our nervous system negatively.
   2. Stress , which can be both physically and mentally. Stress is the result of a reaction to the inability of our body, conscious or unconscious, to satisfy the physical and psycological needs of the moment. Greater the difficulty in dealing with a given situation, greater the physical and mental load. This condition can lead the subject to not control his own emotions and to not think with the more normal coldness.
3. Environmental and operational causes:
   1. Rate of descent . It's 'an important factor. The fall should slow down quickly if we have symptoms of narcotic fast rise. If we don't do this, the narcosis could turn into violent crisis, due to the sudden increase in pressure. The moment of greatest sensitivity to narcosis is once you have reached the depth established. At that moment, it is appropriate to take a short break before proceeding to exploration, which allow you to adjust to the pressure.
   2. Poor visibility . If constant it's predisposing, if sudden it's triggering . The same applies to the lack of reference points.
   3. Work or effort . Anything that leads to fatigue, bad breath, kicking or rapid tiring, wrong attitude, work or effort, etc.., Create a basis for susceptibility to narcosis.
   4. The cold is also a predisposing factor, triggering if becoming rapid and intense.

Nitrogen narcosis’ causes

Prevention

The most straightforward way to avoid nitrogen narcosis is for a diver to limit the depth of dives. Since narcosis becomes more severe as depth increases, a diver keeping to shallower depths can avoid serious narcosis. Most recreational dive schools will only certify basic divers to depths of 18 m (60 ft), and at these depths narcosis does not present a significant risk. Further training is normally required for certification up to 30 m (100 ft) on air, and this training should include a discussion of narcosis, its effects, and cure. Some diver training agencies offer specialized training to prepare recreational divers to go to depths of 40 m (130 ft), often consisting of further theory and some practice in deep dives under close supervision. Scuba organizations that train for diving beyond recreational depths, may forbid diving with gases that cause too much narcosis at depth in the average diver, and strongly encourage the use of other breathing gas mixes containing helium in place of some or all of the nitrogen in air because helium has no narcotic potential. The use of these gases forms part of technical diving and requires further training and certification.

Narcosis while deep diving is prevented by filling dive cylinders with a gas mixture containing helium. Helium is stored in brown cylinders

While the individual diver cannot predict exactly at what depth the onset of narcosis will occur on a given day, the first symptoms of narcosis for any given diver are often more predictable and personal. For example, one diver may have trouble with eye focus (close accommodation for middle-aged divers), another may experience feelings of euphoria, and another feelings of claustrophobia. Some divers report that they have hearing changes, and that the sound their exhaled bubbles make becomes different. Specialist training may help divers to identify these personal onset signs, which may then be used as a signal to ascend to avoid the narcosis, although severe narcosis may interfere with the judgement necessary to take preventive action. Deep dives should be made only after a gradual training to test the individual diver's sensitivity to increasing depths, with careful supervision and logging of reactions. Diving organizations such as Global Underwater Explorers (GUE) emphasize that such sessions are for the purpose of gaining experience in recognizing the onset symptoms of narcosis for an individual, which are somewhat more repeatable than for the average group of divers. Scientific evidence does not show that a diver can train to overcome any measure of narcosis at a given depth or become tolerant of it. The National Oceanic and Atmospheric Administration (NOAA) Diving Manual now states that oxygen and nitrogen should be considered equally narcotic. Standard tables, based on relative lipid solubilities, list conversion factors for narcotic effect of other gases. For example, hydrogen at a given pressure has a narcotic effect equivalent to nitrogen at 0.55 times that pressure, so in principle it should be usable at more than twice the depth. Argon, however, has 2.33 times the narcotic effect of nitrogen, and is a poor choice as a breathing gas for diving (it is used as a drysuit inflation gas, owing to its low thermal conductivity). Some gases have other dangerous effects when breathed at pressure; for example, high-pressure oxygen can lead to oxygen toxicity. Although helium is the least intoxicating of the breathing gases, at greater depths it can cause high pressure nervous syndrome, a still mysterious but apparently unrelated phenomenon. Inert gas narcosis is only one factor influencing the choice of gas mixture; the risks of decompression sickness and oxygen toxicity, cost, and other factors are also important.

Nitrogen narcosis