Narcosis

[raxafarian]

This article was written by de_spook:



The depths always lure divers. What is down there? How deep can I go? As divers go deeper their mental capacity to remember what they saw decreases, as does their ability to function at a high mental level – they become subject to a condition called narcosis. High mental capacity is a requirement when subjected to harsh environments such as being deep under the water. What is causing the reduction in comprehension and mental activity? Is it the effect of pressure? Or the effect of the gases breathed by the divers? There are possibly many mechanisms at work in the overall effect of narcosis, and as such there are several possible factors that will affect the rate and degree of narcosis in divers. Some divers even claim that they can “adapt” to the narcosis, and reduce its affects after several dives. If the specific mechanisms of narcosis are known it may then be possible to reduce the effects and allow divers greater concentration during a dive. It may even be possible for divers to then find well-proven methods of adapting to even deeper dives.


Diving Environmental Conditions

Divers are exposed to an increase in pressure that is relative to the depth of the water they reach. At sea level, atmospheric pressure is 0.1 MPa (1 atm or 1 bar) and pressure increases by 0.1 MPa every 10 meters of seawater (msw). Thus, at 10 msw the absolute pressure is 0.2 Mpa, the sum of both 0.1MPa of atmospheric pressure and 0.1MPa of hydrostatic pressure and at a depth of 40 msw, the absolute pressure is 0.5 MPa.

Dalton’s Law states: “The total pressure exerted by a mixture of gases is equal to the sum of the pressures of each of the different gases making up the mixture – each gas acting as if it alone were present and occupied the total volume.”(Richardson et al, 2001) At the surface the percentage of oxygen and nitrogen in the air is ~21 % and ~79% respectively, resulting in a partial pressure (pp) of 0.21bar and 0.79bar respectively. Gases can dissolve in a liquid and will approach equilibrium or saturation between the liquid and the surrounding gas conditions: “The amount of gas that will dissolve into a liquid at a given temperature is directly proportional to the partial pressure of that gas”(Richardson et al 2001) – Henry’s Law. Therefore at the surface the ppO2 and ppN2 dissolved in the body, which is mostly liquid, are 0.21bar and 0.79bar respectively.

For a diver’s lungs to be able to counter the increased external pressure at depth underwater, the inspired air is delivered at a pressure slightly greater than the ambient pressure, resulting in partial pressures of the gases in the breathing mixture being greater than that of sea level. Due to the pp of the inspired gases in the lungs being greater than the pp of the gases in the body, larger amounts of theses gases are absorbed during the dive in order to approach equilibrium or saturation in the body. As the different gases increase in pp, they affect the normal functioning of the body. One of these alterations in function is called narcosis or “Rapture of the Deep”(Cousteau, 1953). The symptoms are commonly likened to being under the influence of alcohol, hence its other name, “the Martini-effect”(Chowdhury, 2001).

Signs And Symptoms

Among the first authors to report in detail the signs and symptoms of narcosis was Behnke et al. (1935). They described that breathing air at depths deeper than 20 msw induces a narcosis characterized by behavioural changes. Deeper, at a depth of 30 msw, these authors further described a feeling of “stimulation, excitement, and euphoria”. They also reported a “slowing of mental activity as evidenced by delayed responses to visual, auditory, olfactory, and tactile stimuli”. “Impairments of memory, and errors in recording data and arithmetic calculations” were also noted as the depths increased. Although fine movements were more difficult, they noted that intellectual functions were generally affected more severely than manual dexterity. At 91 msw, they further reported that the signs and symptoms of narcosis amounted to stupefaction, with greatly impaired muscular activity. The difference between control over intellectual functions and manual dexterity has given rise to some of the theories surrounding narcosis. Intellectual functions appear to decrease as a result of narcosis, the effect of narcotic gases, whereas manual dexterity is affected by a different mechanism: high-pressure neurological syndrome (HPNS), the affect of the hydrostatic pressure (Abraini, 1997). As diving is related to pressure, most of the experiments in this area have been performed in dry hyperbaric chambers.


Difference in symptoms as a result of pressure and partial pressure of inspired gases

When divers or experimental mammals are exposed to increased pressure, both the absolute pressure and the partial pressure of each gas in the breathing mixture affect the subject. Breathing air at pressures beyond 4 atm absolute (ATA) induces the first definitely discernible signs of narcosis (Bennett and Elliott, 1993). The narcosis is shown to reduce when the breathing mixture is diluted with helium (Dean et al, 2003). However, at pressures higher than 15 ATA breathing mixtures containing helium and oxygen (heliox) the set of symptoms referred to as HPNS become factorial in a diver’s ability to function. The symptoms of hydrostatic pressure (HPNS) include muscular tremors, EEG changes, loss of coordination and seizures (though only in animal subjects, perhaps because humans have not yet reached depths that would result in seizures) (Bennett 1997 and Halsey 1982).

Recent studies have shown that mild to severe inert gas narcosis in humans shows the same remarkable positive relationship with the lipid solubility of the gases as has been shown previously in animal models involving deep levels of anaesthesia. The first lipid solubility theory, referred to as the Meyer-Overton model, states that “narcosis commences when any gaseous or volatile substance reaches a specific molar concentration in the cell lipids of the central nervous system, regardless of the type of narcotic” (Overton 1901). Further studies by Lever (1971), Halsey and Wardley-Smith(1975), and Miller and Wilson (1978) have shown that pressure reverses the narcosis and anaesthesia, and this appears to be common to all classes of narcotic agents. The reverse of this phenomenon has also been shown to hold true, that small amounts of N2 added into a narcotic free breathing gas would increase the depth and pressure a diver can reach before onset of symptoms of HPNS. (Bennett, 1997 and Brauer and Way, 1970) These results lead to the formulation of the hydrophobic site expansion model. The expansion model claims that a hydrophobic (lipid soluble) molecule is dissolving in the membrane expanding its volume. The pressure is simply compressing the membrane, which will then reverse the effect of the dissolved molecules (Lever, 1971).



High Pressure Neurological Syndrome

In a hyperbaric (increased pressure) environment the soft tissues in the body act as a fluid and rapidly transmit any pressure exerted on the externals of the body to the adjacent fluid compartments. This results in hydrostatic compression of the cerebral spinal fluid and the extracellular and intra cellular fluid compartments of the CNS (Halsey, 1982). Examples of the effects of pressure on animal models have been performed in invertebrates and rat dorsal root ganglions (McCarter et al, 1999). Early studies were completed at extremely high pressures (100 – 800 ATA), though the practical applications of these studies are questionable, as humans will doubtfully ever go that deep. Mulkey et al (2003) therefore began to apply the study of pressure on neurons to a more practical scenario and performed studies at three and four ATA. These studies focused on the excitability and membrane potential of neurons under pressure, and under the effects of chemical antagonists. The chemical antagonists were used to confirm that it was the mechanical effects of pressure that were the cause. Typically the membrane potential was depolarised <= 3mV at pressures of 3 ATA (Mulkey et al, 2003). This indicates that 3 ATA pressure caused an increase in membrane conductance or decrease in membrane resistance. The study by Mulkey et al (2003) also showed that there is an increased firing rate response of the post synaptic cell, which is retained during chemical antagonists to synaptic transmission. This indicates that the increased pressure is causing an alteration to both the “synaptic and intrinsic membrane properties”, though not via chemical actions.

The specific mechanisms of pressure on neurons are not completely known. Mulkey et al (2003) concluded “that moderate pressure stimulates certain solitary complex neurons by a mechanism that possibly involves an increased cation conductance, but that does not involve free radicals” (Mulkey et al, 2003) Other studies have also found that the pressure caused the Na2+ current to increase linearly in other types of neurons with compression up to 101 ATA (Shushakov and Demchenko, 1996). From these studies it is possible to deduce that hydrostatic pressure is acting in some mechanical fashion to alter the flow of ions, most likely cations, across the cell membrane. This movement of ions causes a change in the resting membrane potential that results in a lower resistance and greater excitability. The results from studies on HPNS and from further studies of human and animal subjects on narcosis have demonstrated that such a simplistic view of the process is not justifiable (Abraini, 1995).

The previously noted studies on HPNS and its oppositional effects to narcosis were originally based on the critical volume hypothesis, that pressure reduced the volume of the membrane and narcotics increased the volume. Studies on HPNS have shown that this is not directly the case – though pressure is causing an increase in excitability of the membrane These studies, however, did not discount the possibilities that narcotics, including inert gases, could be dissolving in the membrane and thus causing the opposing effects to pressure.


Effects and similarities of inert gases and anaesthetics

The inert gases constitute a subgroup of the gaseous and volatile anaesthetics. They are defined as “producing their effects with no change in their own chemical structure or the primary chemical structure of biological tissue” (Bennett, 1993). The inert gases, mostly the noble gases xenon, krypton, argon, nitrogen, hydrogen, neon, and helium, produce narcosis through actions very similar to the affects of anaesthetics. Other gases, including SF6, N2O and other inhalants result in some form of anaesthesia and narcosis and as such have been used within studies to emphasise the inert gas theory.

The first lipid solubility theory, referred to as the Meyer-Overton model states “narcosis (or anaesthesia) commences when any gaseous or volatile substance reaches a specific molar concentration in the cell lipids of the central nervous system, regardless of the type of narcotic” (Overton, 1901 and Abraini, 1997). It is, therefore, assumed that narcosis resulting from the inert gases is fundamentally similar to the effects produced by general anaesthetics (Bennett et al, 1975). The actions of the inert gases, which cause the anaesthesia, are under contention. The two that are most feasible following recent studies are firstly that the inert gas perturbs the lipid bi-layer of the membrane – either expanding the volume and/or indirectly affecting the receptor proteins – and secondly that the inert gas binds to receptor proteins directly affecting their actions.

The inert gas theory is based on the solubility of the gases in the lipid bi-layer of cells. Concerning the noble gases, there is an excellent correlation between lipid solubility and narcotic potency (Table 1). Xenon and krypton are narcotic, to a greater or lesser extent, at atmospheric pressure. Breathing argon, nitrogen, or hydrogen induces narcosis only at progressively higher pressures. Owing to their very low narcotic potency, neon and helium are generally considered as non-narcotic gases. The potential danger of breathing air at depths beyond 30-40 msw (100-133 ft) has led the diving community to investigate inert gas mechanisms (Bennett, 1993).

Gas		Solubility In Lipid	Relative Narcotic Potency
Helium	           0.015	            4.26 (least narcotic)
Neon	           0.019	            3.58
Hydrogen	   0.036	            1.83
Nitrogen	   0.067	            1
Argon	           0.140	            0.43
Krypton	           0.430	            0.14
Xenon	           1.700	            0.039 (most narcotic)

Table 1. The narcotic potency of some inert gases and their lipid solubility (Bennett, 1993)


Osterlund et al (1994) set out to confirm the Meyer-Overton model and observed the different levels of narcosis under the influence of sulphur hexaflouride SF6, nitrogen N2 and nitrous oxide N2O (Osterlund et al, 1994). Tests relating to psychomotor, perceptual, and cognitive ability were used at different pp of the gases to test narcosis. The battery included three tests of different complexity. The three tests were 1) serial response time, a reaction time test; 2) perceptual speed; and 3) acquisition-retention, a test of learning/short-term memory using a display position of l-unit digits as the stimulus. The results for an effective 20 per cent decrease in performance for each gas was recorded and compared to the pressure of the narcotic gas. This resulted in the relative narcotic potencies of the three gases being 1.0:8.5:39, in the order of N2, SF6 and N2O. The solubility of N2, SF6 and N2O in lipids follows the same order. Hence this study came to the conclusion that mild to moderate inert gas narcosis in humans shows the same positive relationship to lipid solubility that was shown in previous animal studies that utilized much deeper levels of anesthesia (Eger et al, 1969).

Once the inert gases dissolve in the lipid bi-layer of the cells they were thought to then expand the membrane, disrupting some of its dynamic properties – including excitability (Seeman, 1972). This theory has also been supported through studies of the reduction in the effects of HPNS through the addition of lipid soluble gases into the breathing mixture (Bennett, 1997). This is otherwise known as the critical volume hypothesis. The dynamic property that is altered the most is the speed of signaling, more specifically the synaptic communications. The increase in membrane volume resulting from the dissolved gases will increase the distance that the receptor proteins in the postsynaptic membrane are from each other, i.e. reducing the concentration of receptors in the membrane. This then causes the postsynaptic cell to become less excitable (Miller, 1977).

This theory holds for the fact that pressure and narcotics (anaesthetics) oppose each other with regard to membrane excitability (Miller, 1978). Early possibilities for divers that stemmed from this theory were that mammals could tolerate greater pressures via the introduction of narcotics into the breathing gas. Vaernes et al (1983) attempted to prove this by adding 10% N2 to a narcotic free gas for divers at 500msw. This had little to no effect on the symptoms of HPNS (Vaernes, 1983). As mentioned earlier the biological mechanisms of HPNS are not simply the direct effects of pressure. The combinations of results from these studies led to further investigation into what the specific mechanisms of narcotics and anaesthetics are which causes the decrease in excitability of the membrane. Once the specific mechanics of anaesthetics and narcosis are known possible methods of either adaptation or reduction of the effects for divers can be implemented.

Recent studies addressed the effects of different anaesthetics on the membrane at atmospheric pressure. The lipid theories have then been refined and subsequently it has been postulated that the boundary lipids surrounding membrane proteins (annular lipids) are preferentially affected, resulting in the membrane proteins becoming less excitable (Halsey, 1992). As it appeared that anaesthetics were affecting the protein receptors in the membrane, confirmed by Halsey, Franks et al (1991) demonstrated that the anaesthetic isoflurane (1-chloro-2, 2,2-trifluoroethyldifluoromethyl ether) affects neuronal ion channels, but not pure lipid bi-layers, has been interpreted as evidence for an anaesthetic-protein interaction as opposed to a direct action in the lipid membrane causing an indirect effect on the receptors. More specifically, general anesthetics, including inhalational agents, have been shown to enhance -amino butyric acid A (GABAA) receptor activity (Macdonald, 1994). This effect occurs by a direct activation of the GABAA receptor as well as the potentiation of the response of the receptor to the inhibitory neurotransmitter GABAA. This is thought to be the consequence of an allosteric modulation caused by the binding of the anesthetic to one of several sites on the receptor (Abraini et al, 1998).

GABBAA receptors are g-coupled receptors that react to the inhibitory neurotransmitter GABBAA. Inhibitory neurotransmitters reduce the potential for the postsynaptic cell to fire when an action potential comes from the presynaptic cell. In other words when there is an increase in GABBAA neurotransmitter the likelihood that an action potential in the postsynaptic cell will fire is lower. (For further discussion of the effects of transmitters and receptors see Kandel and Schwartz (1985) p152) Anaesthetics are therefore acting either as inhibitory neurotransmitters or are increasing the actions of existing inhibitory neurotransmitters. This results in a slowing of neural connections and a decrease in mental capacity. Pressure per se increases the possibility that an action potential from the presynaptic cell will fire an action potential in the postsynaptic cell via altering the cation flow thereby altering the resting membrane potential. This supports the original findings that pressure and anaesthetics are oppositional factors. However, are narcotic agents that only affect divers at depth, including nitrogen and argon, following the same mechanism?


Anaesthetics and narcotic gases under pressure

A further study into the effects of anaesthetics and GABAA receptors addressed the specifics of narcotic gases under pressure i.e. more specific to diving. This study by Abraini et al (2003) looked at the effects of GABAA and GABBAB receptor antagonists to the narcotic effects of nitrogen and argon at depth. Pre-treatment with the GABAA receptor antagonist gabazine, but not the GABAB receptor antagonist 2-hydroxysaclofen, led to a significant increase of the nitrogen and argon threshold pressure for the onset of narcosis, but neither change the threshold pressure of nitrous oxide (Abraini, et al 2003). This confirmed the theory that the nitrogen is acting similarly to an anaesthetic and that the actions affect the receptor proteins on the postsynaptic membrane. More specifically the nitrogen is acting as if it were an inhibitory neurotransmitter and assisting in increasing the effect of the inhibitory neurotransmitters released by the presynaptic cell.

There are many factors that potentiate nitrogen narcosis, such as decent rate, CO2 build up, anxiety, O2 levels and perhaps even intelligence levels (Bennett, 1993 and Fowler et al, 1985). Thus, there is interest, from a practical point of view, in determining the effects of nitrogen narcosis in combination with factors that could be present during diving. Carbon dioxide was once thought to be the prime cause, though it has become apparent that CO2 retention simply facilitates the feelings of narcosis (Bean, 1950 and Seussing and Drube, 1960). Anxiety studies have been generally performed during open-water diving experiments with relatively inexperienced subjects who were likely to develop anxiety in these environmental conditions. To a lesser extent, these studies have been also used as a means to better understand the causal mechanisms of nitrogen narcosis. Many of these factors are difficult to manipulate and hence difficult to test. Perhaps a more practical and useful study would be whether or not it is possible to adapt to narcosis as opposed to the factors that potentiate it. Can trained divers, with low levels of anxiety and proper decent techniques, “learn” to cope with nitrogen narcosis?

Further study
There have been few studies that have confirmed that nitrogen narcosis is a result of the action of nitrogen on the receptors, either via direct or allosteric action, but it appears that the original theories of lipid solubility have been, to some extent, disproved. It is important for further research this area as the exact mechanism of action will assist in possible future benefits for divers. Based on the current research it is possible to suggest some future possible ventures with regards to divers. The ability to learn and form memories is modulated by the ability to alter the strength of synaptic communication. The effects of nitrogen narcosis are such that the level of inhibitory input to the synapses is increased. With repeated dives over a short time frame the brain may be able to adjust the complementary amount of excitatory transmissions to in some way “adapt” to the narcosis. The research done previously does not support this theory but brain slices and studies on specific synapses in rats may help in deciphering adaptability. Also from the study by Abraini et al (2003) he found that treatment with a GABBAA antagonist increased the narcosis threshold pressure. Perhaps with further study drugs could be synthesised which would reduce narcosis in humans. But for now, much of this is simply conjecture, and the diving community will still be divided as to whether a diver can or cannot adapt to nitrogen narcosis.





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