Gas toxicities
Capita Selecta AMC Non DCI related disorders
18-3-2017
Mattijn Buwalda Anaesthesiologist-intensivist & DMP
www.mattijnb.nl Runtime: 50 min
Slides: 43
• some pathophysiological aspects of: • oxygen toxicity
• nitrogen narcosis
• hypercapnia
Content
What is a radical?
atom or molecule with one or more
unpaired electrons in its outer shell
Oxidative damage
•neurological oxygen toxicity – Paul Bert effect
– > 1.7 bar, on/off, unpredictable
•pulmonary oxygen toxicity – Lorraine Smith effect
– > 0.5 bar, cumulatieve
•ocular toxicity – cumulatieve
also relevant for:
• astronauts
• hyperbaric oxygen treatment (HBO)
• neonates
• ventilated ICU patients
• post CPR
• during ACS
Oxygen toxicity in diving
A convulsion during diving is almost always fatal!
Neurological oxygen toxicity
•1942-43 (Donald 1947)
•single diver 20 x
•in 3 months
•100% O2 @ 3.7 bar
•time to convulsion
Donald, Kenneth W. (1947). "Oxygen Poisoning in Man: Part I". British Medical Journal 1 (4506): 667–672.
Huge variation!
Day to day variation
• inter & intra- individual variation in susceptibility
• screening on susceptibility not useful
• warning signs are unreliable or not perceived
• many risk factors
• lethal
The problem.....
• 4 hours 100% O2 at 7 meter = PO2 1.7 = safe
• limit depends on situation/ training:
– 1.4 rec scuba diving
– 1.6 Tec, deco stops
– 2.0 short periods under operational circumstances (military)
Butler FK, Thalman ED. Central nervous system oxygen toxicity in closed circuit scuba divers II. Undersea Biomed Res 1986;13:193-223
MOD = (14 : fiO2) – 10
Oxygen limits in diving
• 36 incidents leading to symptoms of O2 toxicity and/or LOC (and survival)
• recalled or observed symptoms preceding LOC or termination of dive
O2 CCR diving < 7 msw
ARIELI R, ARIELI Y, DASKALOVIC Y, EYNAN M, ABRAMOVICH A. CNS oxygen toxicity in closed circuit diving: signs and symptoms before loss of consciousness. Aviat Space Environ Med
2006; 77:1153–7.
15
• CCR set was tested in 17 cases
• 11 sets delivered a high insp CO2 (2.5-8%) = A
O2 CCR diving < 7 msw
Exact mechanism of NOTOX is not well understood but...
• free radical theory of O2 poisoning:
– directly by affecting cell membrane (especially PUFA’s), ion channels, membrane transporters and receptors
– affecting both inhibitory and excitatory neurotransmitters
• cerebral vasoconstriction breakthrough
– hyperoxia causes general vasoconstriction
– cerebral vasoconstriction protects the brain against free radicals and excitatory neurotransmitters
– breakthrough explains sudden onset of convulsions
D’agostino DP, Colomb DG, Dean JB. Effects of hyperbaric gases on membrane nanostructure and function in neurons. JAP 2009;106:996-1003
Neurophysiology
Free radicals & the brain
• rise in free radical levels in the blood during hyperoxia.
• free radical generation in the brain precedes hyperoxia induced convulsion
• ROS damage lipid bilayer, receptors, channels
Torbati D, et al. Free radical generation in th brain precedes hyperbaric oxygen induced convulsions. Free Rad Biol Med 1992;13:101-106
Narkowicz CK. Hyperbaric oxygen therapy increases free radical levels in the blood of human. Free Radic res Commun 1993;19:71-80
Neurotransmitters
• increased spontaneous neurotransmitter release • misbalance between inhibitory and excitatory neurotransmitters
• affects: – GABA – acetylcholine – glutamate – dopamine – ammonia – norepinephrine – aspartate
Bitterman N. CNS oxygen toxicity UHM 2004;31:63-72
Hyperoxia induced vasoconstriction
• protection!
• almost all vascular beds:
– brain, heart, skeletal muscle, retina, skin, kidney
– linear effect
• two exceptions:
– hypoxic pulmonary vasoconstriction
– maternal – placental circulation
Rousseau A, et al. Acute hyperoxaemia-induced effects on regional blood flow, oxygen consumption and central circulation in man. Acta Physiol Scand 2005; 183: 231–40.
Floyd T.F. Et al. Independent cerebral vasoconstrictive effects of hyperoxia and accompanying arterial hypocapnia at 1 ATA. J. Appl. Physiol. 2003;95:2453–2461.
Omae T et al. Effects of high atmospheric pressure and oxygen on middle cerebral blood flow velocity in humans measured by transcranial Doppler. Stroke.1998;29:94–97.
Cerebral vasoconstriction
Watson NA et al. The effect of hyperoxia on cerebral blood flow: a study in healthy volunteers using magnetic resonance phase-contrast angiography. Eur J Anaesthesiol 2000; 17: 152–9.
Radicals and NO
Mak S, Vitamin C prevents hyperoxia-mediated vasoconstriction and impairment of endothelium-dependent vasodilation. Am J Physiol Heart Circ Physiol 2002; 282: H2414–21.
Demchenko IT, Oury TD, Crapo JD, Piantadosi CA. Regulation of the brain’s vascular responses to oxygen. Circ Res 2002; 91: 1031–7.
Superoxide anion
scavenges NO
Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol Heart Circ Physiol 250: H822–H827, 1986.
CBF biphasic response
•initial vasoconstriction due to decreased NO levels –NO scavenging
•secondary increase (hyperemic phase) –upregulation of cNOS & eNOS
Demchenko IT, Boso AE, O’Neill TJ, Bennett PB, Piantadosi CA. Nitric oxide and cerebral blood flow responses to hyperbaric oxygen. J Appl Physiol 88: 1381–1389, 2000.
The big picture
ROS
brain
radicals
NO
damage:
• lipid bilayer
• receptors
• channels
disbalance
inhibitory/
excitatory
neurotransmitters
cerebral
vasoconstriction
blood
radicals
excitation
VENTID
convulsion
protective
-
hypercapnia
exercise -
provocative
-
eNOS & cNOS
upregulation
• slowing of mentation
• loss of memory
• overconfidence
• excitement
• euphoria
• hallucinations
• stupefaction
• coma
N2 narcosis - symptoms
•Noticeable from 30 msw (average)
•10–20 msw: impairment of unrehearsed mental and physical tasks, such as sorting cards
•30-50 msw: central processing affected > amnesia
•decreased pain perception!
•decreased manual dexterity, reaction times
•linear to depth
•automated motor skills are relatively preserved
Poulton EC, Catton MJ, Carpenter A. Efficiency at sorting cards in compressed air. Br J Ind Med. 1964;21:242–5.
Kneller W, Hobbs M. Inert gas narcosis and the encoding and retrieval of long-term memory. Aviat Space Environ Med. 2013;84:1235–9.
Kowalski JT, Seidack S, Klein F, Varn A, Rottger S, Kahler W, et al. Does inert gas narcosis have an influence on perception of pain? Undersea Hyperb Med. 2012;39:569–76.
Neuro cognitive effects
Neuro cognitive effects
• cold
• hypercapnia
• exertion
• anxiety
• reduced sensory input
• alcohol
Predisposing/ risk factors
Adolfson J, Muren A. Air breathing at 13 atmospheres. Psychological and physiological observations. Forsvarsmedicin. 1965;1:31–7.
Fothergill DM, Hedges D, Morrison JB. Effects of CO2 and N2 partial pressures on cognitive and psychomotor performance. Undersea Biomed Res. 1991;18:1–19.
Bennett PB, Rostain JC. Inert gas narcosis. In: Braubakk AO, Neuman TS, editors. Bennett and Elliott’s physiology and medicine of diving. 5th ed. Toronto: Saunders; 2003. p. 300–22.
• Australian database:
–N2 narcosis contributed to 9% of diving deaths
• DAN data base 2010 annual report:
–3.6% of diving fatalities caused by N2 narcosis
• Depths > 30 msw associated with a 3.5- fold increase in N2 narcosis related incidents
Vann R, Lang M. Recreational diving fatalities. Undersea Hyperb Med. 2011;38:257–60.
Statistics
•Early report by Colladon 1826: “a state of exicitement as if I had drunk some alcoholic liquor”
•Green 1861: sleepiness, hallucinations •Damant 1930: loss of memory •Hill 1933: semi loss of consciousness attributed to:
–impure air from faulty compressors –carbon dioxide
•Behnke 1935 recognized N2 as the culprit
N2 narcosis - history
• traditional view: – expansion of the phospholipid bilayer by uptake of inert gas
– fluidization of the gel like bilayer
– pressure reversal of anaesthetic effect
• modern view: – interaction with membrane proteins
– ligand-gated ion channels
Inert gas narcosis
Molecular and basic mechanisms of anaesthesia (postgraduate issue). Br J Anaesth 2002; 89: 1–183.
• N2 has 0.03 – 0.05 x narcotic potency of N2O
• also analgesic effect: 50 msw on air.
27
Inert gas narcosis
Kowalski JT, et al. Does inert gas narcosis have an influence on perception of pain? UHM 2012;39:569-576
• regulation of motor, locomotor and cognitive functions
• dopamine level in striatum (rats)
• 3 bar N2: – decrease glutamate
– increase serotonin
– decreased striatal dopamine level
Nigrostriatal pathway (rats)
Glutamate:
excitation
Serotonin &
GABA:
inhibition
J.C. Rostain, C. Lavoute, J.J. Risso, N. Vallée, M. Weiss. A review of recent neurochemical data on inert gas narcosis. UHM 2011;38:49-59
Nigrostriatal pathway (rats)
J.C. Rostain, C. Lavoute, J.J. Risso, N. Vallée, M. Weiss. A review of recent neurochemical data on inert gas narcosis. UHM 2011;38:49-59
Entonox vs nitrogen narcosis
n=1 research
Grotto del cane
cave is 10 m long
volcanic release of CO2 1 meter high CO2 layer (near ground)
https://en.wikipedia.org/wiki/Cave_of_Dogs
Refresher CO2
• normal PaCO2 = 40 mmHG, mixed venous PCO2 = 46 mmHg
• solubility CO2 20 x compared to O2 •100 ml arterial blood:
– 3 ml dissolved
– 3 ml as carbamino compound
– 44 ml as HCO3
•CO2 production:
– at rest 200 ml/min
– apnea > + 3-6 mmHg/min
dry air @ 1 bar:
0.04 % CO2 PCO2 = 0.3 mmHg
Hypercapnia
The problem.....
vasoconstriction breakthrough >
neurological oxygen toxicity
seizure!
sedative effect!
clinical medicine: LOC due to
hypercapnic respiratory failure:
PaCO2 > 100 mmHg (12 kPa)
Loss of consciousness
• hypercapnia is often not recognized by diver • abrupt progression to confusion and LOC
•n=2, simulated wet dives to 6.8 atm, with added breathing resistance
• PaCO2 10.7 kPa (80 mmHg)/ 9.3 kPa (70 mmHg) were not recognized!
Warkander DE, et al. CO2 retention with minimal symptoms but severe dysfunction during wet simulated dives to 6.8 atm abs. UHM 1990;17:515-523
Increased gas density
↑ gas density > ↑ breathing resistance
– turbulent flow
– dynamic airway compression
density of air
@ 1 bar = 1.3 kg/m3
@ 4 bar = 5.7 kg/m3
@10 bar = 13 kg/m3
Hydrostatic pressure
• pulmonary vascular engorgement
– thoracic blood shift 700 ml
– V/Q mismatch (↑dead space)
– ↓lung compliance
• static lung load
Moon RE, Cherry AD, Stolp BW, Camporesi EM. Pulmonary gas exchange in diving. J Appl Physiol. 2009;106:668–677
Hypercapnia during diving
increased breathing
effort relative to
ventilation
reset ventilatory
drive
breathing resistance:
increased gas density at depth
mouthpiece/ regulator
rebreather loop
elastic lung load:
hydrostatic lung loading
central blood shift
tight wetsuit/ BCD
increased Pinsp CO2
at depth CCR fault
OC contaminated
gas
HYPERCAPNIA
Long term
adaptation
skip
breathing
elevated dead space
Ventilatory response to CO2
• experienced divers have a blunted response to hypercapnia!
• CO2 rebreathing in 11 divers and 11 matched controls (surface)
• divers: 15 yrs of diving/ 1045 dives/ max depth 52 msw
Kerem, D., Y. Melamed, and A. Moran. Alveolar PCO2 during rest and exercise in divers and non-divers breathing O2 at 1 ATA. Undersea Biomed. Res. 7: 17-26, 1980. Earing CM, et al. Divers revisited: The ventilatory response to carbon dioxide in experienced scuba divers. Resp med 2014;108:758-765
mean
ventilatory
response:
- 40%
rest moderate
exercise
• the blunted response to hypercapnia does not occur after 1 yr shallow (< 5 msw) oxygen diving
• increased gas density at depth is probably the main mechanism
Eynan M, Arieli R, Adir Y. Response to CO2 in novice closedcircuit apparatus divers and after 1 year of active oxygen diving at shallow depths. J Appl Physiol 2005;98:1653e9. http://www.gue.com/carbon-dioxide-narcosis-and-diving
• scrubber failure
• O-ring or spacer....
• mushroom valves
Hypercapnia & rebreathers
• 5 min prebreathing test is not reliable!
• 25% does not recognize hypercapnia
Deng C, et al. The five minute prebreath in evaluating carbon dioxide absorption in closed-circuit rebreather: a randomized single blind study. DHM 2015;45:16-24
TTH
N2 narcosis
hypercapnia
LOC
neurological
O2 tox
Gelfand R, Lambertsen CJ, Peterson RE. Human respiratory control at high ambient pressures and inspired gas densities. Journal of Applied Physiology . 1980 ;48 :528-539
father son team
open water course
dive nr 3!
Cairns GBR
slides available @
www.mattijnb.nl