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