Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 59, Num. 1, 2011, pp. 18-24

Neurology India, Vol. 59, No. 1, January-February, 2011, pp. 18-24

Original Article

A comparative evaluation of nitrous oxide-isoflurane vs isoflurane anesthesia in patients undergoing craniotomy for supratentorial tumors: A preliminary study

Gyaninder P Singh, Hemanshu Prabhakar, Parmod K Bithal, Hari H Dash

Department of Neuroanaesthesiology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address: Hemanshu Prabhakar, Department of Neuroanesthesiology, Neurosciences Center, 7th Floor, All India Institute of Medical Sciences, New Delhi - 110 029 , India, prabhakarhemanshu@rediffmail.com

Date of Submission: 22-Jul-2010
Date of Decision: 16-Aug-2010
Date of Acceptance: 29-Sep-2010

Code Number: ni11005

PMID: 21339653
DOI: 10.4103/0028-3886.76851

Abstract

Keywords: Complications, controversy, neuroanesthesia, nitrous oxide

Introduction

Nitrous oxide is the only anesthetic agent that has been used continuously and safely for over 162 years. Neuroanesthesiologists are a highly biased group; so far the use of nitrous oxide in their patient population is concerned. Nitrous oxide increases cerebral metabolic rate, cerebral blood flow, and intracranial pressure, and in animals, exacerbates ischemic neurologic injury, all theoretically undesirable effects in the setting of intracranial neurosurgery. ^[1] Several well-controlled studies involving patients undergoing ambulatory/short stay surgical procedures have not found any clinically significant differences between patients receiving or not receiving nitrous oxide during surgery. ^[2],[3] Recent publications have questioned the routine use of nitrous oxide in neuroanesthesia practice. ^[4],[5] However, the study by McGregor et al. ^[5] involved patients with only subarachnoid hemorrhage and had intracranial surgery for aneurysm clipping; in the larger trial by Myles et al., ^[4] neurosurgical patients formed only a small subgroup. We hypothesized that any adverse consequence with use of nitrous oxide should affect the patient so as to prolong his/her stay in the hospital. This assumption was made on the basis of various adverse events associated with the use of nitrous oxide: increased incidence of nausea and vomiting, ^[6],[7] myocardial ischemia and infarction due to rise in plasma homocysteine levels, ^[8],[9],[10] increase in size of air-containing cavities, e.g., venous air embolism, pneumothorax, pneumoperitoneum, or pneumocephalus in neurosurgical patients undergoing craniotomy, and benefits of using higher concentrations of O ₂ when N ₂ O is avoided during anesthesia like less of diffusion hypoxia and decreased wound infection. ^[11],[12] Also, there is evidence that longer the duration of N ₂ O use, more are the chances of complications, ^{[8],[13],[14],[15]} which is again the concern in neurosurgical patients where the duration of surgery and anesthesia is usually long. All these complications may in some way prolong either the intensive care unit (ICU) or hospital stay of these patients. To date, no study has evaluated the avoidance of nitrous oxide in neurosurgical patients undergoing surgery for supratentorial tumors. The primary aim of this preliminary trial was to evaluate if avoidance of nitrous oxide could decrease the duration of ICU stay and hospital stay after elective surgery for supratentorial tumors. The secondary aim was to compare the rate of various perioperative complications and intraoperative requirement of analgesic and muscle relaxant.

Patients and Methods

After obtaining approval from the institutional ethical committee for this prospective, double blinded and randomized study, 116 consecutive patients posted for elective craniotomy for various supratentorial tumors were enrolled between April 2008 and November 2009. Patients were randomly divided into two groups by a computer-generated randomization chart: Group I: patients received 60% nitrous oxide (end-tidal concentration 0.6%) and 40% oxygen as carrier gases (nitrous oxide-based group) and Group II: patients received 60% medical air and 40% oxygen as carrier gases (nitrous oxide-free group).

Attending anesthesiologist was aware of the group identity (for safe administration of anesthesia), but it was concealed from the surgeons (using drapes to cover the anesthesia machine). Staff conducting the postoperative follow-ups (i.e., those responsible for postoperative data collection and outcome assessment) was blinded to the group identity. Our inclusion criteria were patients between 18 and 60 years of age, either gender, American Society of Anesthesiologists (ASA) physical status grade I and II, scheduled for elective supratentorial tumor surgery, with anticipated duration of anesthesia more than 4 hours. We excluded patients with history of smoking, patients with history of megaloblastic anemia, those requiring postoperative mechanical ventilation, patients receiving vitamin B ₁₂ /folic acid supplementation, history of exposure to general anesthesia in the last one month, history of motion sickness/postoperative emesis, evidence of pneumothorax/pneumocephalus, and bleeding disorders.

A standard fasting protocol was followed for all the patients. Glycopyrrolate 0.2 mg intramuscularly was given one hour before the scheduled surgery. Regular medications for any comorbid illness (like hypertension, diabetes mellitus, asthma, etc) if any, were continued till the day of surgery. In the operating room, intravenous access was secured and the baseline recordings of heart rate (HR), mean blood pressure, electrocardiogram (ECG), and oxygen saturation (SpO ₂ ) were noted before induction of anesthesia.

Anesthesia

Patients were preoxygenated with 100% oxygen for 3 minutes. General anesthesia was induced with fentanyl 2 mcg/kg and thiopentone 4 to 6 mg/kg and tracheal intubation facilitated with rocuronium 1 mg/kg. Additional dose of thiopentone 1 to 2 mg/kg was given before laryngoscopy and intubation to prevent the pressor response. Anesthesia was maintained using isoflurane (end-tidal concentration: 0.7% [Group I] and 1.2% [Group II]). The flow rate of inhaled gas mixture was kept at 2 l/min in both the groups. In Group I, flow rate of nitrous oxide and oxygen were 1.2 and 0.8 l/min, respectively, and in Group II flow rates of medical air and oxygen were 1.5 and 0.5 l/min, respectively (Datex Ohmeda S/5 Avance Datex Ohmeda Division, Instrumentarium Corp. Helsinki, Finland). Intermittent doses of fentanyl (1 mcg/kg) and vecuronium (0.01 mg/kg) were repeated as and when required. Use of other drugs and intravenous fluids was at the discretion of the attending anesthesiologist. Blood transfusion was considered when the blood loss exceeded 20% of the estimated blood volume. Intraoperative monitoring included HR, NIBP, SpO ₂ , ECG, temperature, end-tidal carbon dioxide (EtCO ₂ ), minimum alveolar concentration (MAC), peak airway pressure, and invasive blood pressure. Central venous pressure monitoring was done if deemed necessary. The values were recorded every 15 minutes, and the mean values of these readings were charted at the end of each hour. Dorsalis pedis artery was cannulated for continuous blood pressure monitoring and obtaining samples for arterial blood gas analysis. Mannitol (1 gm/kg) was given to all patients over a period of 20 to 30 min, starting at the time of skin incision. Assessment of the brain condition (i.e., degree of brain bulge if present) was done by the operating surgeon (who was unaware of the group allocation) immediately after opening the cranial cavity. ^[16] Anesthetic depth was adjusted according to clinical judgment. Core body temperature was maintained between 35.6 and 37 ^o C in all patients. EtCO ₂ was kept within the range of 32 to 34 mm Hg.

At the end of the surgery, anesthetic agent (isoflurane) was discontinued at the beginning of skin closure and the nitrous oxide or medical air switched off at the time of dressing of the surgical site. Residual neuromuscular block was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg, and trachea extubated after neurologic assessment. We also noted the time to follow commands and time to tracheal extubation after reversal of neuromuscular block. Patients requiring postoperative ventilation were excluded from final analysis of the study. All patients were shifted to Neuro-ICU for observation and supportive care. The patients were evaluated in the ICU at regular intervals for their readiness to discharge using Aldrete score. When patients were having Aldrete score of 9 and above and did not complaint of pain/vomiting/discomfort, they were considered fit to be discharged from ICU. Postoperative recollection of intraoperative events were identified using a structured questionnaire ^[17] at 24 hours after surgery. Patients were assessed for any postoperative complications till the discharge from hospital. Staff responsible for postoperative follow-up of patients was unaware of the group allocation. The various intraoperative events and postoperative complications recorded are mentioned in Appendix 1[SUPPORTING:1].

Statistical analyses were done using software STATA 9.1 (College Station, TX, US). Data are presented as mean (standard deviation), median (range), and number (percentage). Demographic characteristics and intraoperative data between the groups were compared using the two-sample t-test with equal variance. Mann-Whitney test was applied to compare the primary outcomes (ICU and hospital stay) between the two groups. Postoperative complications were compared using Fisher's exact test. The value of P less than 0.05 was considered significant.

Results

A total of 116 patients were enrolled for the study [Figure - 1]. Of these, 56 patients received nitrous oxide-based anesthesia (Group I) and 60 patients received nitrous oxide-free anesthesia (Group II). Of the 116 patients, 29 patients could not be tracheally extubated at the end of surgery (15 patients in group I and 14 in group II), and so the data of these patients were excluded from final analysis. Demographic data of patients in group I (n = 41) and group II (n = 46) is tabulated [Table - 1]. Tumor characteristics were similar between the two groups [Table - 2]. The trend of hemodynamic parameters, that is, HR and MAP were comparable in both the groups during intraoperative periods. [Table - 3] presents the intraoperative data of both the groups. Episodes of intraoperative hypertension and tachycardia occurred in more number of patients in group II compared with group I (P<0.01). The total fentanyl requirement was more in group II (323 mcg vs 211 mcg; P<0.001). Similarly, patients in group II had higher requirement of muscle relaxant (13.3 mg vs 8.7 mg; P<0.001) [Table - 3]. It was also observed that patients in group II took longer time to follow commands and get tracheally extubated as compared with the nitrous group (P<0.001) [Table - 3]. The postoperative complications observed in the two groups are summarized in [Table - 4] and were comparable. The duration of ICU and hospital stay was 1 (1 - 11) days and 4 (2 - 16) days in the nitrous group and 1 (1 - 3) days and 3 (2 - 9) days in the nitrous-free group, respectively, which was comparable [Table - 5]. No patient in either group reported awareness of intraoperative events.

Discussion

There is controversy regarding the use of nitrous oxide during neurosurgical procedures, especially if the patient is at the risk of cerebral ischemia. There are studies to support ^[18],[19] and refute ^[20],[21] this controversy. Lam and Matta ^[22] examined the effect of nitrous oxide on cerebral blood flow velocity of middle cerebral artery (Vmca) during propofol-induced electrical silence of the electroencephalogram (EEG) in 10 patients undergoing anesthesia for non-neurosurgical procedures. Nitrous oxide increased Vmca, and occasional bursts of EEG activity were observed in eight patients studied during the N ₂ O stage. They concluded that in patients with propofol-induced isoelectric EEG, the increase seen in Vmca with the introduction of N ₂ O was mainly due to cerebral stimulation and increase in cerebral metabolic rate.

The finding of this preliminary study suggests that omission of nitrous oxide from anesthetic regime in patients undergoing supratentorial craniotomies does not reduce the duration of ICU and hospital stay. However, the secondary aim of our study revealed an increased consumption of opioids and muscle relaxants in the nitrous-free group. This could probably be the reason of delayed emergence of patients after surgery in this group, as assessed by time to follow commands and time to tracheal extubation.

Myles et al. ^[4] questioned the routine use of nitrous oxide in patients undergoing major surgeries. However, this study received a lot of criticism, mainly because of improper study design, nonstandardized anesthesia technique, and failure to achieve its primary end point that was duration of hospital stay. Of the 2050 patients that were recruited, only 295 underwent neurosurgical procedures. The details of these patients have not been provided by the authors. In our study, we followed standardized anesthetic regime and a proper randomization which eliminated selection bias and group allocation in our patient population. Our study is in accordance with Myles et al. ^[4] in that the presence of nitrous oxide did not influence the length of ICU and hospital stay. Arellano et al. ^[2] also concluded that omission of nitrous oxide from a propofol-based anesthetic for ambulatory gynecologic surgery does not affect time to home readiness or the incidence of postoperative adverse events up to 24 hours after discharge from the hospital.

In this study the analgesic requirement was significantly less in the nitrous oxide group. This emphasizes again on the analgesic potency of nitrous oxide. Recently, this property was again demonstrated in an animal study by Richebe et al. ^[23] The authors demonstrated that nitrous oxide prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl, and opposed acute morphine tolerance. Their results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.

Recently McGregor et al. ^[5] examined the relation between the nitrous oxide use and outcome using data from the Intraoperative hypothermia for Aneurysm Surgery Trial. ^[24] The authors concluded that in a population of patients at risk for ischemic brain injury, nitrous oxide use had no overall beneficial or detrimental effect on neurologic or neuropsychological outcomes. A number of potential effects of nitrous oxide have been reported in the literature, although their clinical relevance is unclear. ^[25] However, nitrous oxide has been implicated in the causation of postoperative nausea and vomiting and wound infection by several authors. ^{[4],[26],[27]} According to Hopf, ^[28] there are two main reasons for avoiding nitrous oxide; first, it produces postoperative nausea and vomiting and second, it prevents using higher concentration of oxygen, which also reduces nausea and vomiting and more importantly might reduce surgical site infection. In contrast, Fleischmann et al. ^[29] found no difference in surgical site infection rate when comparing 70% nitrogen - 30% oxygen vs 70% nitrous oxide - 30% oxygen as the intraoperative gas mixture. In our study, the complications noted were comparable in both the groups.

In our clinical experience with the use of nitrous oxide, the intraoperative course remains smooth and stable. Patients not receiving nitrous oxide showed wide fluctuations in HR and blood pressure intermittently. With the use of nitrous oxide, we experienced a smoother recovery and early tracheal extubation. Large requirements of opioids as analgesics along with frequent administration of muscle relaxant might be responsible for delayed arousal and longer duration for tracheal extubation. To maintain the desired MAC, volatile anesthetics are required in higher inspired concentrations in nitrous-free group. This may have its own consequences and deleterious effects. The authors feel that higher requirements of analgesics, muscle relaxants, and volatile anesthetics should raise concerns regarding cost factors. However, cost analysis was not the aim of our study. On the basis of a meta-analysis of intraoperative awareness, Tramer et al. ^[26] suggested a clinically important risk of intraoperative awareness with a nitrous oxide-free anesthesia. However, in a recent review of the reported cases in the literature, Ghoneim et al. ^[30] concluded that avoidance of nitrous oxide use does not seem to increase awareness during anesthesia.

The present study is not without limitations, one of the major limitations being its small sample size. When we carried out the power analysis of this preliminary study, the sample size of n = 740 in each group were required to provide statistical power of more than 90%. For practical reasons, carrying out this study in such a large population within the stipulated time span was difficult. Anesthesiologist managing the case was aware of the group identity and thus the bias on the part of anesthesiologist cannot be ruled out as a possible cause of increased opioid and muscle relaxant consumption in the nitrous free group. However, blinding the attending anesthesiologists was not possible due to safety concerns of the patients. Again, more than five surgeons with varying years of experience (range: 8 - 25 years) operated on these patients. The experience of the surgeons could have influenced the outcome in some way or the other. There was an unequal distribution of males and females in both the groups as the randomization was not gender-based. However, this could have affected our results. Another limitation of our study was that we selected patients of good ASA physical status. On the basis of our observations, we cannot comment how patients with poor ASA grades might behave with the use of nitrous oxide, if at all there is any undesirable effect of nitrous oxide. At the same time, we excluded patients requiring postoperative mechanical ventilation. It is difficult to blame nitrous oxide for this condition in the present study, as an equal number of patients were excluded from both the groups for a similar reason. Logistics did not allow long-term follow-up of our patients and thus, the long-term outcome could not be assessed.

Some of the recent surveys on the use of nitrous oxide in anesthesia practice have shown a declining interest for this 'laughing gas' among anesthesiologists. ^[31],[32] Some authors believe that although there may be specific situations where nitrous oxide be avoided, not only its routine use be questioned but also its routine avoidance. ^[33] Further studies are needed to address this issue before discarding the only anesthetic drug that has withstood the test of time.

References

1.	Culley DJ, Crosby G. Nitrous oxide in neuroanesthesia - tried and true or toxin? Anesthesiology 2008;108:553-4.  Back to cited text no. 1
2.	Arellano RJ, Pole ML, Rafuse SE, Fletcher M, Saad YG, Friedlander M, et al. Omission of nitrous oxide from a propofol based anesthetic does not affect the recovery of women undergoing outpatient gynaecologic surgery. Anesthesiology 2000;93:332-9.  Back to cited text no. 2
3.	Tang J, Chen L, White PF, Wender RH, Naruse R, Kariger R, et al. Use of propofol for office - based; effect of nitrous oxide on recovery profile. J Clin Anesth 1999;11:226-30.  Back to cited text no. 3
4.	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. 4
5.	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. 5
6.	Tramer M, Moore A, McQuay H. Meta-analytic comparison of prophalytic antiemetic efficancy for postoperative nausea and vomiting: Propofol anaesthesia versus omitting nitrous oxide versus total i.v. anaesthesia with propofol. Br J Anaesth 1997;78:256-9.  Back to cited text no. 6
7.	Apfel CC, Korttila K, Abdalla M, Kreger H, Turan A, Vedder I, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2441-51.   Back to cited text no. 7
8.	Ermens AA, Refsum H, Rupreht J, Spijkers LJ, Guttormsen AB, Lindemans J, et al. Monitoring cobalamin inactivation during nitrous oxide anesthesia by determination of homocysteine and folate in plasma and urine. Clin Pharmacol Ther 1991;49:385-93.  Back to cited text no. 8
9.	Badner NH, Drader K, Freeman D, Spence JD. The use of intraoperative nitrous oxide leads to the postoperative elevation in plasma homocysteine. Anesth Analg 1998;87:711-3.  Back to cited text no. 9
10.	Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: A risk factor for vascular disease. N Eng J Med 1991;324:1149-55.  Back to cited text no. 10
11.	Grief R, Laciny S, Rapf B, Hickle RS, Sessler DI. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999;91:1246-52.  Back to cited text no. 11
12.	Belda FJ, Augilera L, Garcia de la Asuncion J, Vicente R, Ferrandiz L, Rodriguez R, et al. Supplemental perioperative oxygen and the risk of surgical wound infection. JAMA 2005;294:2035-42.  Back to cited text no. 12
13.	Nunn JF. Clinical aspects of the interaction between nitrous oxide and vitamin B12. Br J Anaesth 1987;59:3-13.  Back to cited text no. 13
14.	Maze F, Fuginaga M. Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia 2000;55:311-4.  Back to cited text no. 14
15.	Amos RJ, Amess JA, Hinds CJ, Mollin DL. Incidence and pathogenesis of acute megaloblastic bone marrow changes in patients receiving intensive care. Lancet 1982;2:835-8.  Back to cited text no. 15
16.	Gelb AW, Craen RA, Rao GS, Reddy KR, Megyesi J, Mohanty B, et al. Does hyperventilation improve operative condition during supratentorial craniotomy? A multicentre randomised cross trial. Anesth Analg 2008;106:585-94.  Back to cited text no. 16
17.	Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during anesthesia. Br J Anaesth 1970;42:535-42.  Back to cited text no. 17
18.	Baughman VL, Hoffman WE, Thomas C, Albrecht RF, Miletich DJ. The interaction of nitrous oxide and isoflurane with incomplete cerebral ischemia in the rat. Anesthesiology 1989;70:767-74.  Back to cited text no. 18
19.	Hartung J, Cottrel 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. 19
20.	Yokoo N, Sheng H, Mixco J, Homi HM, Pearlstein RD, Warner DS. Intraischemic nitrous oxide alters neither neurologic nor histologic outcome: A comparision with dizocilpine. Anesth Analg 2004;99:896-903.  Back to cited text no. 20
21.	David HN, Leveille F, Chazalviel L, MacKenzie ET, Buisson A, Lemaire M, et al. Reduction of ischemic brain damage by nitrous oxide and Xenon. J Cereb Blood Flow Metab 2003;23:1168-73.  Back to cited text no. 21
22.	Matta BF, Lam AM. Nitrous oxide increases cerebral blood flow velocity during pharmacologically induced EEG silence in humans. J Neurosurg Anesthesiol 1995;7:89-93.  Back to cited text no. 22
23.	Richebé P, Rivat C, Creton C, Laulin JP, Maurette P, Lemaire M, et al. Nitrous oxide revisited: Evidence for potent antihyperalgesic properties. Anesthesiology 2005;103:845-54.   Back to cited text no. 23
24.	Todd MM, Hindman BJ, Clarke WR, Torner JC. Introperative 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. 24
25.	Myles PS, Leslie K, Silbert B, Paech MJ, Peyton P. A review of the risks and benefits of nitrous oxide in current anesthesia practice. Anaesth Intensive Care 2004;32:165-72.  Back to cited text no. 25
26.	Tramer M, Moore A, McQuay H. Omitting nitrous oxide in general anesthesia; Metaanalysis of intraoperative awareness and post operative emesis in randomized controlled trials. Br J Anaesth 1996;76:186-93.  Back to cited text no. 26
27.	Leslie K, Myles PS, Chan MT, Paech MJ, Peyton P, Forbes A, et al. Risk factors for severe postoperative nausea and vomiting in a randomized trial of nitrous oxide-based vs nitrous oxide-free anesthesia. Br J Anaesth 2008;101:498-505.  Back to cited text no. 27
28.	Hopf HW. Is it time to retire high-concentration nitrous oxide? Anesthesiology 2007;107:200-1.  Back to cited text no. 28
29.	Fleischmann E, Lenhardt R, Kurz A, Herbst F, Fülesdi B, Greif R, et al. Nitrous oxide and risk of surgical wound infection: A randomised trial. Lancet 2005;366:1101-7.  Back to cited text no. 29
30.	Ghoneim NM, Block RI, Haffarnan M, Mathews MJ. Awareness during anesthesia: Risk factors, causes and sequelae: A review of reported cases in the literature. Anesth Analg 2009;108:527-35.  Back to cited text no. 30
31.	Mitra JK, Jain V, Sharma D, Prabhakar H, Dash HH. A survey on use of nitrous oxide in current anesthesia practice in India. Indian J Anaesth 2007;51:405-8.  Back to cited text no. 31
32.	Henderson KA, Raj N, Hall JE. The use of nitrous oxide in anesthesia practice: A questionnaire survey. Anesthesia 2002;57:1155-8.  Back to cited text no. 32
33.	Sharma D, Dash HH. Nitrous oxide: Time to laugh it off? Not quite. Anesthesiology 2008;108:541.  Back to cited text no. 33

Copyright 2011 - Neurology India

The following images related to this document are available:

Photo images