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Table of Contents    
Year : 2011  |  Volume : 59  |  Issue : 1  |  Page : 1-3

Neurosurgery and nitrous oxide: Not time yet for the last laugh?

National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

Date of Submission11-Oct-2010
Date of Decision11-Oct-2010
Date of Acceptance11-Oct-2010
Date of Web Publication18-Feb-2011

Correspondence Address:
G S Umamaheswara Rao
National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.76847

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How to cite this article:
Umamaheswara Rao G S. Neurosurgery and nitrous oxide: Not time yet for the last laugh?. Neurol India 2011;59:1-3

How to cite this URL:
Umamaheswara Rao G S. Neurosurgery and nitrous oxide: Not time yet for the last laugh?. Neurol India [serial online] 2011 [cited 2023 Dec 11];59:1-3. Available from:

Traditionally, nitrous oxide (N 2 O) has been an integral component of general anesthesia. However, in recent years, evidence on complications associated with N 2 O has raised arguments against the use of N 2 O in anesthesia, particularly for patients with cerebral pathology. In this issue of Neurology India, Singh et al. [1] challenge the need to withhold N 2 O from anesthesia for brain tumour surgery by demonstrating that N 2 O did not significantly influence the duration of intensive care stay or mortality. The study raises a debate on the propriety of using N 2 O during neurosurgery.

By contributing to the depth of anesthesia, [2] N 2 O decreases the need for the primary anesthetic agent, and thus helps in rapid awakening of the patient, which facilitates immediate post-operative neurological examination. Arguments for avoiding N 2 O in anesthesia, in general, are based on its adverse effects: (1) Potential to interfere with vitamin B 12 and folate metabolism, leading to megaloblastic anemia; [3] (2) expansion of the volume of gas-filled cavities (eg, pneumothorax, distended bowel); [4] and (3) post-operative nausea and vomiting (PONV). [5] The ENIGMA trial, [6] comprising 2,050 patients, showed that avoidance of N 2 O during anesthesia decreased the incidence of major post-operative complications such as severe PONV, wound infection, pneumonia, and atelectasis. The hospital stay was not significantly affected by N 2 O; however, among the patients admitted to the intensive care unit (ICU), the probability of discharge from ICU, on any given day, was higher in the N 2 O-free group.

There are additional concerns also for using N 2 O in neurosurgery. Studies have documented increase in cerebral blood flow (CBF), [7] cerebral blood volume (CBV), and cerebral metabolism. [8] Background anesthetic and the degree of ventilation seem to influence the magnitude of these changes. Intravenous anesthetic agents like propofol [9] and hyperventilation [10] limit the increase in CBF and CBV. N 2 O-induced PONV may confound post-operative vomiting caused by raised intracranial pressure (ICP) due to acute intracranial complications (eg, post-operative hematoma). Venous air embolism during neurosurgery, with the patient in a sitting position and post-operative tension pneumocephalus due to subdural air collection during craniotomy may be accentuated by N 2 O. [11] N 2 O can decrease the amplitude of cerebral electrophysiological signals, [12],[13] dissuading its use when crucial electrophysiological monitoring is required. It has been implicated in the reversal of neuronal protection offered by thiopentone in experimental cerebral injury. [14] N 2 O interferes with homocysteine metabolism by oxidising the cobalt atom in vitamin B 12 , which, in turn, leads to defects of neuronal myelination. [15],[16] Neurological manifestations such as numbness, decreased deep tendon reflexes, cognitive dysfunction with histological evidence of neuronal mitochondrial swelling, vacuolation, and apoptosis have been reported. [17] N 2 O has also been implicated as a cause of post-operative dementia and cognitive deficits. [18],[19] By increasing serum homocysteine concentration, N 2 O may increase platelet aggregation, cause vasoconstriction, and impair endothelial function. [20]

Do all the aforementioned effects of N 2 O influence the outcome of neurosurgery? Two recent publications address this issue, both of which are posthoc analyses of the Intra-operative Hypothermia for Aneurysm Surgery trial (IHAST) data. [21] The first study [22] analysed the effect of N 2 O on neurologic and neuropsychological function after intracranial aneurysm surgery. Of the 1,000 patients studied, 373 received N 2 O. N 2 O did not influence the development of delayed ischaemic neurological deficit (DIND). Outcomes at three months, as assessed by Glasgow Outcome Scale (GOS), National Institutes of Health (NIH) stroke scale, Rankin Disability Score, Barthel Index and neuropsychological testing, were similar between the groups. The authors speculate on the cause for the lack of difference between the groups: First, the study is posthoc in nature. Second, many of the patients may not have suffered ischemia that could have been influenced by N 2 O. In a subsequent study, [23] where only patients subjected to temporary vascular occlusion intraoperatively were included, N 2 O increased the risk of DIND [odds ratio (OR) = 1.78; 95% confidence interval (CI) = 1.08-2.95, P = 0.025). However, at three months, there was no difference in the neurological outcome scores. The data suggest that N 2 O may influence the short-term, if not the long-term neurological morbidity.

Although Singh et al [1] . showed that there was no effect of N 2 O on post-operative ICU stay or mortality, the data obtained are not reassuring with regard to the use of N 2 O during craniotomy. The major limitation is the grossly inadequate sample size. The study data do not have any measure of raised ICP or cerebral ischemia in the study population. The subjects of the study being elective brain tumour patients, who would have been substantially optimised with pre-operative ICP control measures, the possibility of finding adverse influence of any therapeutic intervention is low. An adequately powered outcome trial, where raised ICP or cerebral ischemia is objectively quantified, is required to address the issue. The issue of using ICU stay and survival rates as the primary outcome measures of clinical interventions of low, but not negligible, risk also needs to be further debated.

 » References Top

1.Singh GP, Prabhakar H, Bithal PK, Dash HH. A comparative evaluation of nitrous oxide-isoflurane vs isoflurane anesthesia in patients undergoing craniotomy for supratentorial tumors: A preliminary study. Neurol India 2011;59:18-24.   Back to cited text no. 1
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2.Ramesh VJ, Umamaheswara Rao GS. Does nitrous oxide affect Bispectral index in patients under Isoflurane anaesthesia? J Neurosurg Anesthesiol 2006;18:267-8.  Back to cited text no. 2
3.Erbe RW, Salis RJ. Severe methylene tetrahydrofolate reductase deficiency, methionine synthase, and nitrous oxide: A cautionary tale. N Engl J Med 2003;349:5-6.  Back to cited text no. 3
4.Pasternak JJ, Lanier WL. Is nitrous oxide use appropriate in neurosurgical and neurologically at-risk patients? Curr Opin Anaesthesiol 2010;23:544-50.  Back to cited text no. 4
5.Tramer M, Moore A, McQuay H. Omitting nitrous oxide in general anaesthesia: Meta-analysis of intraoperative awareness and postoperative emesis in randomized controlled trials. Br J Anaesth 1996;76:186-93.  Back to cited text no. 5
6.Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, et al. Avoidance of nitrous oxide for patients undergoing major surgery: A randomized controlled trial. Anesthesiology 2007;107:221-31.  Back to cited text no. 6
7.Umamaheswara Rao GS, Girish V. The effects of nitrous oxide on cerebral blood flow velocities in the absence of extraneous modifiers in healthy volunteers. Indian J Anaesth 2001;45:104-7.  Back to cited text no. 7
8.Kolbitsch C, Lorenz IH, Hörmann C, Kremser C, Schocke M, Felber S, et al. Sevoflurane and nitrous oxide increase regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) in a drug-specific manner in human volunteers. Magn Reson Imaging 2001;19:1253-60.  Back to cited text no. 8
9.Fox J, Gelb AW, Enns J, Murkin JM, Farrar JK, Manninen PH. The responsiveness of cerebral blood flow to changes in arterial carbon dioxide is maintained during propofol-nitrous oxide anesthesia in humans. Anesthesiology 1992;77:453-6   Back to cited text no. 9
10.Reinstrup P, Ryding E, Ohlsson T, Dahm PL, Uski T. Cerebral blood volume (CBV) in humans during normo- and hypocapnia: Influence of nitrous oxide (N2O). Anesthesiology 2001;95:1079-82.  Back to cited text no. 10
11.Biyani N, Silbiger A, Ben-Ari J, Constantini S. Postoperative brain stem tension pneumocephalus causing transient locked-in syndrome. Pediatr Neurosurg 2007;43:414-7.  Back to cited text no. 11
12.da Costa VV, Saraiva RA, de Almeida AC, Rodrigues MR, Nunes LG, Ferreira JC. The effect of nitrous oxide on the inhibition of somatosensory evoked potentials by sevoflurane in children. Anaesthesia 2001;56:202-7.   Back to cited text no. 12
13.Kunisawa T, Nagata O, Nomura M, Iwasaki H, Ozaki M. A comparison of the absolute amplitude of motor evoked potentials among groups of patients with various concentrations of nitrous oxide. J Anesth 2004;18:181-4.  Back to cited text no. 13
14.Hartung J, Cottrell JE. Nitrous oxide reduces thiopental-induced prolongation of survival in hypoxic and anoxic mice. Anesth Analg 1987;66:47-52.  Back to cited text no. 14
15.Badner NH, Drader K, Freeman D, Spence JD. The use of intraoperative nitrous oxide leads to postoperative increases in plasma homocysteine. Anesth Analg 1998;87:711-3.  Back to cited text no. 15
16.Felmet K, Robins B, Tilford D, Hayflicks SJ. Acute neurologic decompensation in an infant with cobalamin deficiency exposed to nitrous oxide. J Pediatr 2000;137:427-8.  Back to cited text no. 16
17.Zhen Y, Dong Y, Wu X, Xu Z, Lu Y, Zhang Y, et al. Nitrous oxide plus isoflurane induces apoptosis and increases beta-amyloid protein levels. Anesthesiology 2009;111:741-52.  Back to cited text no. 17
18.Culley DJ, Raghavan SV, Waly M, Baxter MG, Yukhananov R, Deth RC, et al. Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg 2007;105:83-8.  Back to cited text no. 18
19.El Otmani H, El Moutawakil B, Moutaouakil F, Gam I, Rafai MA, Slassi I. Postoperative dementia: Toxicity of nitrous oxide. Encephale 2007;33:95-7.  Back to cited text no. 19
20.Myles PS, Chan MT, Kaye DM, McIlroy DR, Lau CW, Symons JA, et al. Effect of nitrous oxide anesthesia on plasma homocysteine and endothelial function. Anesthesiology 2008;109:657-63.  Back to cited text no. 20
21.Todd MM, Hindman BJ, Clarke WR, Torner JC; Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005;352:135-45.  Back to cited text no. 21
22.McGregor DG, Lanier WL, Pasternak JJ, Rusy DA, Hogan K, Samra S, et al. Effect of nitrous oxide on neurologic and neuropsychological function after intracranial aneurysm surgery. Anesthesiology 2008;108:568-79.  Back to cited text no. 22
23.Pasternak JJ, McGregor DG, Lanier WL, Schroeder DR, Rusy DA, Hindman B, et al. Effect of nitrous oxide use on long-term neurologic and neuropsychological outcome in patients who received temporary proximal artery occlusion during cerebral aneurysm clipping surgery. Anesthesiology 2009;110:563-73.  Back to cited text no. 23


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