Nitrous oxide and its current status

Anesthesia , inhalational agent , nitrous oxide

1. NITROUS OXIDE AND ITS CURRENT STATUS MODERATOR- Dr. NEELKAMAL PRESENTER- Dr. RICHA

2. NITROUS OXIDE

3. Prepared first by JOSEPH PRIESTLY in 1772

4. Anesthetic properties first demonstrated by HUMPHERY DAVY in 1800

5. Used for painless tooth extraction first by HORACE WELLS

6. PRODUCTION AND STORAGE Nitrous oxide is produced commercially by heating ammonium nitrate to 240C. Water vapour and impurities, including higher oxides of nitrogen, ammonia and nitric acid, are subsequently removed by passage through a series of washers and scrubbers . Nitrous oxide is stored in French-blue cylinders (pin-index 3, 5) pressurized to 4400kPa at room temperature. Nitrous oxide is usually stored below its critical temperature, and thus exists simultaneously in liquid and vapour phases .

7. PHYSICAL PROPERTIES Only Non Organic Gas In Use Regularly Today Non Irritating, Sweet Smelling And Colourless NON-inflammable/ NON-explosive but supports combustion of other agents as it dissociates to N2 and O2 above 450°C Gas at room temperature and ambient pressure Can be kept as a liquid under pressure as its critical temperature lies above room temperature

8. Molecular Weight - 44.01 Specific Gravity - 1.527 Boiling Point - - 89°C Blood/Gas Solubility Coefficient - 0.47 Vapour Pressure At 20°C - 800psi Maximum Safe Concentration - 80% MAC - 105

9. PHARMACOKINETICS Rapidly absorbed from the alveoli because nitrous oxide diffuses more rapidly across alveolar basement membranes than does nitrogen (s 30 times more water soluble) 100 ml of blood will carry 45 ml of nitrous oxide in its plasma E limination is as fast as the absorption because it does not combine with hemoglobin or undergo any chemical combination in the body POOR BLOOD SOLUBILITY  permits rapid achievement of an alveolar and brain partial pressure Analgesic effect is prominent but short lived inhibitory action at N-methyl-D-aspartate (NMDA ) glutamate receptors & stimulatory activity at dopaminergic, a1 and a2 adrenergic and opioid receptors.

10. The concentration effect: A high P I delivered from anesthetic machine is required during initial administration of the anesthetic. A high initial input offsets the impact of uptake  accelaration of induction of anaesthesia  reflected by rate of rise in P A & P BRAIN The impact of PI on rate of rise in PA of inhaled anesthetic is known as concentration effect. Thus it states that higher the PI more rapidly PA approaches PI by offsetting uptake

11. The concentrating effect results from: A) a concentrating effect B) augmentation of tracheal flow Concentrating effect reflects concentration of inhaled anesthetic in smaller lung volume due to uptake of all gases in lung At the same time , anesthetic input is increased to fill the void produced by uptake of gases in blood.

12. The second gas effect The second gas effect is a direct result of the concentration effect . It reflects ability of high volume of one gas to accelerate increase in PA of concurrently administered “second gas”

13.     65 35   (augmentation of tracheal inflow) Second gas effect Due to conc. Effect of N2O = 53.8%  

14. The reverse may occur at the end of anaesthesia, when the administration of nitrous oxide ceases. Nitrous oxide enters the alveoli far more rapidly than nitrogen leaves, causing dilution of the gaseous contents of the alveolus. This results in the dilution of oxygen within the alveoli of patients breathing air and may cause ‘ diffusion hypoxia ’. The dilution of the alveolar content may also dilute the concentration of volatile agents, enhancing their elimination, and speeding wakening.

15. PHARMACODYNAMICS Nitrous oxide has effects on many physiological systems RESPIRATORY SYSTEM : decrease in TV increase in RR (by CNS + and possibly activation of pulmonary stretch receptors ) MV is maintained. reduction in the ventilatory response to hypoxia and hypercapnia . Depresses tracheal mucociliary flow and neutrophil chemotaxis  increase incidence of post-operative respiratory complications. At low concentrations nitrous oxide has a negligible effect on HPV; however, at higher concentrations it may be impaired

16. CARDIOVASCULAR : direct myocardial depression , Increases central sympathetic outflow. In general :arterial pressure is little affected by nitrous oxide. Pulmonary vascular resistance is increased due to constriction of the pulmonary vascular smooth muscle  increase in RA pressure  best avoided in pulmonary HTN Other vascular beds are also altered  decrease in renal and hepatic blood flow due to an increase in vascular resistance of these beds

17. CENTRAL NERVOUS SYSTEM Increases CBF, cerebral metabolism & ICP increase in cerebral metabolism  increase in cerebral blood flow . These changes are particularly marked when there is disruption of normal cerebral autoregulation  may result in a significant (and potentially detrimental) decrease in cerebral perfusion. Important in patients undergoing neurosurgical procedures, but must also be considered in those with cerebral or cerebrovascular pathology (e.g. head injury or cerebrovascular disease) for extracranial surgery.

18. NEUROMUSCULAR Most volatile anaesthetic agents depress the neuromuscular junction and augment the effects of non-depolarizing neuromuscular blockers In contrast, nitrous oxide has the potential to increase skeletal muscle activity and has less depressant activity at the neuromuscular junction. It does not potentiate the action of non-depolarizing neuromuscular blocking agents .

19. ANALGESIC ACTIONS mediated by activation of opioid receptors in the periaqueductal grey of midbrain modulation of nociceptive pathways through the release of norepinephrine and activation of a2 adrenoceptors in the dorsal horn of the spinal cord. This may explain tolerance to nitrous oxide that may be seen as a consequence of depletion of central opioid peptides

20. CLINICAL APPLICATION 1.General anaesthesia Although nitrous oxide has anaesthetic properties, it is not suitable as a sole anaesthetic agent under standard atmospheric conditions . Its minimum alveolar concentration (MAC) is 105% at 1 atmosphere pressure. However , it is used extensively in combination with other volatile anaesthetic agents : This reduces the required dose of volatile agent reduces the cardiovascular depression that occurs with most volatile agents. Reduces cost

21. 2. Obstetrics Nitrous oxide was first used as an analgesic during labour in 1881 Although not a potent analgesic during labour , it appears safe for pregnant women, their babies and healthcare workers who are in attendance. For many women, it provides adequate labour analgesia but co-ordination of administration with contractions can be difficult. Maternal side effects include nausea, dizziness, paraesthesia and dry mouth.

22. 3. Pain management E xcellent analgesia for acutely painful procedures such as fracture reduction and changes of burns dressings . In the emergency department setting has a role in the management of the pain of ureteric colic and sickle cell crises and positioning for radiological procedures . Repeated or long-term use is discouraged because of its risks useful in the theatre for supplementation of regional techniques

23. ADVERSE EFFECTS OF NITROUS OXIDE POSTOPERATIVE NAUSEA AND VOMITING PONV is a major cause of anaesthetic morbidity and nitrous oxide has been implicated in its aetiology. The mechanism for the emetogenic potential of nitrous oxide is not fully understood but changes in middle ear pressure, bowel distension and activation of dopaminergic neurones may all be involved. Omission of nitrous oxide reduces PONV by nearly 30%, maximally seen in female patients. When considering the potential benefits of nitrous oxide omission, the incidence of adverse outcomes (such as awareness) must also be considered

24. AIR-FILLED SPACES The relative solubilities of nitrous oxide and nitrogen cause rapid expansion of nitrogen-containing spaces when nitrous oxide is commenced . Pressure or volume changes or both depending upon the nature of the space (e.g. pneumothorax, bowel, middle ear ). These changes can have deleterious consequences. There are several clinical situations where nitrous oxide should be avoided owing to the potentially dangerous effects of space expansion

25. Cuff pressures of endotracheal tubes and laryngeal masks can increase significantly during prolonged administration of nitrous oxide . This may lead to local ischaemia and mucosal damage. Regular checks of cuff pressure should be made using a pressure gauge during prolonged surgery.

26. POTENTIAL ADMINISTRATION OF A HYPOXIC MIXTURE It is possible to deliver a hypoxic mixture of gases to a patient from anaesthetic machines where no hypoxic guard is fitted. T o prevent this catastrophe the Medical Device Agency has stated that all anaesthetic machines in use must be fitted with either a hypoxic-guard or an oxygen analyser

27. EFFECTS OF CHRONIC EXPOSURE

28. HEMATOLOGICAL Prolonged administration of nitrous oxide causes inhibition of methionine synthetase  interference with DNA synthesis in both leukocytes and erythrocytes. Vitamin B12 is required as a coenzyme for methionine synthetase . However, vitamin B12 is oxidized by nitrous oxide and so is unable to interact with methionine synthetase . In addition, nitrous oxide reduces the motility and chemotactic response of leucocytes. Oxidation of the cobalt atom in B12 by nitrous oxide can precipitate megaloblastic changes in the bone marrow and a neuropathy in experimental animals.

29. INCREASED HOMOCYSTEINE Causes endothelial dysfunction Induce oxidative stress Destabilize coronary artery plaques Impair myocardial substrate utilization Enhances platelet aggregation

30. It is well recognized that long term increase of plasma concentration of homocysteine are an independent risk factor of Coronary artery disease and cerebrovascular disease Such changes may also be observed in humans and are of particular concern where there is clinical or subclinical B12 or folate deficiency Mild megaloblastic changes are seen in healthy people after 12 h of anaesthesia and these changes become marked after 24 h. The neurological alteration can range from transient mild paraesthesia through to a picture that resembles subacute combined degeneration of the cord.

31. Some studies support that Vitamin B12 and folate supplementation preoperatively can help to prevent these unwanted actions. On other hand some suggest treatment with vitamin B 12 did not alleviate the symptoms or enhance recovery; thus, it occurs in those who abuse N 2 O on a long-term basis.

32. OCCUPATIONAL EXPOSURE In the pre-scavenging era, there were concerns that nitrous oxide might contribute to the increased relative risk of miscarriage and reduced fertility seen in female theatre workers. Provided that anaesthetic gases are scavenged and the levels of ambient nitrous oxide are maintained below 100 p.p.m ., it appears that the safety of those who have long-term occupational exposure is not compromised.

33. TERATOGENICITY The mechanism of the teratogenicity is thought to be multifactorial and not simply a consequence of impaired DNA synthesis. Stimulation of a1 adrenergic neurones  leads to decreased ciliary activity  which may cause disordered organogenesis and explain why situs inversus has been observed .

34. Human studies have generally focused on the long-term behavioral effects of maternal obstetric medication . Claims have been made that the medication given at delivery to the mother produces depressed motor skills and impaired language ability in the infant and child for several years. Such claims, however, are controversial. Behavioral abnormalities in offspring whose mothers received inhaled anesthetics at any time during delivery have not been well studied Furthermore , studies have not been done to assess the neurobehavioral function of children of operating room personnel who have been exposed to waste anesthetic gases. Firm conclusions await further investigation as there is no evidence that the modern fluorinated inhaled anesthetics are mutagenic or carcinogenic.

35. ENVIRONMENTAL CONCERNS Nitrous oxide, like carbon dioxide, methane and perflurocarbons , is a greenhouse gas . Most environmental nitrous oxide is produced via the use of nitrogen-based fertilizers in agriculture, burning of fossil fuels and sewage management programmes. It is 200–300 times more effective at trapping heat than is carbon dioxide, and contributes to global warming . However , nitrous oxide only constitutes 5 % of greenhouse gases. Concerns about the environmental impact of anaesthetic use of nitrous oxide are probably unfounded ; anaesthesia accounts for < 1% of total nitrous oxide emissions. The contribution of anaesthetic gases may be even lower with the increasing use of low-flow systems.

36. ENIGMA - I TRIAL EVALUATION OF NITROUS OXIDE IN GAS MIXTURE FOR ANESTHESIA It was a randomized controlled trial-2007 Entitled “ AVOIDANCE OF NIROUS OXIDE FOR PATIENTS UNDERGOING MAJOR SURGERIES” Recruited 2050 patients randomly assigned to either nitrous oxide free group ( 80% oxygen 20% nitrogen) or nitrous oxide based group ( 70% nitrous oxide , 30% oxygen) All patients were scheduled to undergo major surgery of atleast 2 hours duration.

37. Primary endpoint (duration of hospital stay): no difference in two groups Secondary endpoints ( ICU stay, PONV, pneumonia, pneumothorax, pulmonary embolism, wound infection,MI , venous thromboembolism, stroke , awareness and death within 30 minutes) : showed lower rates in nitrous free group No significant difference in major adverse cardiac events or death was reported

38. CONCLUSION OF ENIGMA I TRIAL: Avoidance of nitrous oxide and concominant increase in inspired oxygen concentration decreases incidence of complications after major surgery, but does not significantly affect duration of hospital stay. Routine use of nitrous oxide in patients undergoing major surgery should be questioned. CRITICISM The difference results in two groups could be due to high oxygen concentration in nitrous free group The depth of anesthesia was not equivalent in two groups There may have been confounding factors like use of more propofol in nitrous oxide free group.. Therefore less PONV

39. ENIGMA II TRIAL NITROUS OXIDE AND SERIOUS LONG TERM MORBIDITY AND MORTALITy IN EVALUATION OF NITROUS OXIDE IN THE GAS MIXTURE FOR ANAESTHESIA PRIMARY OUTCOME: death and cardiovascular complications within 30 days of surgery CONCLUSION: Nitrous oxide should remain an option in contemporary anaesthesia . There are potential advantages in pain control and prevention , reduction in awareness with recall, as use in neurologically and cardiovascularly “at risk” patients .

40. CURRENT STATUS OF NITROUS OXIDE

41. (1) What is the place of N2O in today’s perioperative anaesthesia management? ( 2) What is the place of N2O in procedural analgesia and sedation? ( 3) Is administration of N2O associated with a health risk for patients and/or providers?

42. PLACE IN TODAY’S PRACTICE ? Provides faster and smoother induction with improved oxygenation During maintenance , allows the concentrations of the other drugs to be decreased which , in turn, may result in faster recovery at the end of the procedure I nduce anxiolysis  facilitating mask acceptance as well as peripheral venous line insertion especially in children BUT these goals can also be achieved with adequate child preparation, parental presence and/or pharmacological premedication

43. Though it may increase the incidence of PONV however this non-desirable side effect can easily be controlled with antiemetic prophylaxis. Moreover the incidence of PONV is insignificant when the duration of exposure is less than 1 hour

44. PLACE OF N2O IN PROCEDURAL ANALGESIA AND SEDATION ? N2O administered as the sole sedation/analgesic agent can safely be provided by even non-anaesthesiologists who are appropriately trained in the administration modalities of the drug & have thorough basic life support training . N2O can be used safely for procedural pain management (in the emergency room, in the normal ward or in a prehospital situation), for the management of labour pain, and for anxiolysis and sedation in dentistry N2O continues to be the mainstay for paediatric procedural sedation in a large variety of clinical setting

45. Is administration of N2O associated with a health risk for patients and/or for providers ? The contraindications to the use of N2O are few: the presence of closed gas containing cavities (e.g. pneumothorax) abnormalities of the metabolism of vitamin B12 (e.g . vegetarianism, some rare metabolic disorders ) The issue of repeated anaesthesia or sedation with N2O is poorly studied. Cases of chronic N2O abuse have shown that both polyneuropathy and megaloblastic anaemia can occur and some groups therefore recommend not to use N2O more than twice a week.

46. Properly operating scavenging systems reduce N2O concentrations by more than 70%, thereby efficiently keeping ambient N2O levels well below official limits an exposure limit to N2O of 25 parts per million (ppm) as a time-weighted average (TWA) during the period of anaesthetic administration is recommended

47. The potential teratogenic effect of N2O observed in experimental models cannot be extrapolated to Humans. There is a lack of evidence for an association between N2O and reproductive toxicity. The incidence of health hazards and abortion was not shown to be higher in women exposed to, or spouses of men exposed to N2O than those who were not so exposed. The incidence of congenital malformations was not higher among women who received N2O for anaesthesia during the first trimester of pregnancy nor during anaesthesia management for cervical cerclage , nor for surgery in the first two trimesters of pregnancy Though it is suggested to avoid N2O in first trimester of pregnancy

48. T here is currently no clinically relevant evidence for the withdrawal of N2O from the anaesthesia practice or procedural sedation . In procedural sedation, the use of N2O should be limited to procedures resulting in moderate pain intensity. Finally , there is no evidence indicating that the use of N2O in a modern clinically relevant setting increases health risk in patients or providers.