BJA Advance Access originally published online on September 8, 2006
British Journal of Anaesthesia 2006 97(5):647-653; doi:10.1093/bja/ael242
Inspired oxygen fraction of 0.8 compared with 0.4 does not further reduce postoperative nausea and vomiting in dolasetron-treated patients undergoing laparoscopic cholecystectomy
1 Department of Anaesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen D-67063 Ludwigshafen, Germany.
2 Department of Anaesthesia, Spital Menziken CH-5737 Menziken, Switzerland
3 Department of Anaesthesiology and Intensive Care Medicine, University of Würzburg D-97080 Würzburg, Germany
*Corresponding author: Department of Anaesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen, Bremserstrasse 79, D-67063 Ludwigshafen, Germany. E-mail: swen.n.piper{at}t-online.de
Accepted for publication July 26, 2006.
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Abstract |
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Background. Postoperative nausea and vomiting (PONV) is one of the most frequent complications after general anaesthesia. Single-dose antiemetic prophylaxis has limited efficacy in high-risk patients. Adding a simple potential antiemetic approach, such as increasing the inspired oxygen fraction, to the antiemetic portfolio would preserve pharmacological interventions for treatment of symptoms in the postoperative period. However, the antiemetic effect of a high inspired oxygen fraction is still discussed controversially. The aim of the study was to evaluate whether an inspired oxygen fraction of 0.8 decreases PONV in patients receiving the 5-HT3-antagonist dolasetron.
Methods. In a randomized, placebo-controlled, double-blinded trial we studied 377 patients (ASA I–III) undergoing elective laparoscopic cholecystectomy. Induction of anaesthesia was standardized, including thiopental fentanyl and cis-atracurium. For all patients the individual risk for PONV was calculated using the Koivuranta score and all patients received 12.5 mg dolasetron i.v. before surgery. Patients were allocated randomly to one of three groups: Group A (n=125) received 80% oxygen in air, Group B (n=125) 40% oxygen in air and Group C (n=127) 40% oxygen in nitrous oxide. Postoperative nausea, postoperative vomiting (PV), or nausea, vomiting, or both (PONV) was assessed in the early (0–4 h) and overall postoperative period (0–24 h) by an anaesthesiologist unaware of patient allocation.
Results. There was a significantly lower incidence of PONV and PV in Groups A (PONV: 11.2%; PV: 3.2%) and B (PONV: 10.4%; PV: 3.2%) compared with Group C (PONV: 26.7%; PV: 13.3%), but there were no significant differences between Groups A and B.
Conclusions. An inspired oxygen fraction of 0.8 does not further decrease PONV or vomiting in dolasetron-treated patients undergoing laparoscopic cholecystectomy. The lower incidence of PONV in Groups A and B compared with Group C is most likely caused by the omission of nitrous oxide.
Keywords: anaesthetics gases, nitrous oxide; cholecytectomy; dolasetron; oxygen; vomiting, nausea
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Introduction |
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Postoperative nausea and vomiting (PONV) is one of the leading side-effects after surgery performed under general anaesthesia.1 PONV is a major factor in causing discomfort and dissatisfaction.2 3 Marcario and colleagues showed that patients fear PONV more than pain.3 Apart from the discomfort, PONV may be associated with morbidity, for example an increased risk of pneumonia secondary to pulmonary aspiration, airway obstruction, oesophageal rupture and wound dehiscence.4 The incidence of PONV depends on numerous factors including female gender, non-smoking status, history of previous PONV or motion sickness, duration of anaesthesia and postoperative use of opioids.1 2 Although less important, the occurrence of PONV may be influenced by the type of surgery. Strabismus correction and laparoscopic surgery have been described as risk factors of PONV.5–7 Although various methods have been studied for preventing or treating this complication, the ideal drug has not yet been found and no gold-standard exists.8 9 Therefore, in patients with a high risk of PONV, for example non-smoking females of child-bearing age with a previous episode of PONV or kinetosis, combinations of antiemetic interventions have been recommended.1 10 Such multimodal solutions may be costly and have an additional risk of adverse drug reactions, including sedation, extrapyramidal symptoms and arrhythmogenic side-effects.9 11 12 Furthermore, the lower the baseline risk for PONV becomes by administering one effective antiemetic, the lower is the absolute efficacy of any additional prophylactic intervention.1 Therefore, it might be more cost-effective to preserve pharmacological interventions for treatment of symptoms in the postoperative period (rescue medication).
Recently, 5-HT3-antagonists have been recommended in a consensus guideline as first-line drugs for both prevention and treatment of PONV,13 albeit the preference over the equally effective droperidol was exclusively based on the FDA black box warning for droperidol, which has made its use in the United States difficult and which has led to the withdrawal from the German market. Some authors reported on an antiemetic effect by an increase in inspired oxygen fraction, for example 0.8.14 15 This study was designed to evaluate the hypothesis that the combination of dolasetron and an inspired oxygen fraction of 80% in air is more effective than dolasetron with 40% oxygen in air.
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Methods |
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After approval of the ethics committee and written informed consent 377 patients, classified as ASA physical status I, II or III undergoing elective laparoscopic cholecystectomy were studied. Patients with respiratory, cardiac, hepatic (aspartate aminotransferase >40 U litre–1, alanine aminotransferase >40 U litre–1) or renal insufficiency (creatinine >1.4 mg dl–1), predisposition for malignant hyperthermia, psychiatric disorders, febrile patients (>37.5°C), and patients taking chronic corticoids or drugs with known antiemetic activity within 24 h before surgery were excluded. Other exclusion criteria were severe obesity (>50% above ideal body weight), pregnancy, nausea and vomiting within 24 h before surgery, known allergy to any 5-HT3-receptor antagonist and known alcohol or drug abuse. All patients were fasting for at least 6 h, and received premedication with midazolam 7.5 mg orally 30–45 min before surgery. Induction of general anaesthesia was standardized including fentanyl (3 µg kg–1), thiopental (5 mg kg–1) and cis-atracurium (0.15 mg kg–1). A tracheal tube was inserted orally, a nasogastric tube was placed and suctioning applied to empty the stomach of air and secrets. Anaesthesia was maintained with 1.0–1.5 minimal alveolar concentration (MAC) desflurane. Additional fentanyl (1 µg kg–1) was given i.v. at the decision of the anaesthesiologist in charge of the patient. No other analgesics were allowed to be administered intraoperatively. Artificial ventilation (Julian®, Dräger, Lübeck, Germany) was performed in all patients with a positive end expiratory pressure (PEEP) of 5 mbar and tidal volume and ventilatory frequency were adjusted to maintain end expiratory CO2 between 4.3 and 4.8 kPa. Inspired oxygen fraction and the supplementation of air or nitrous oxide were chosen according to the randomization. The fresh gas flow was set at 2 litre min–1. At the end of surgery, the nasogastric tube was suctioned and removed, and the tracheal tube was removed when patients were fully awake. Crystalloids (Ringer's lactate or saline 0.9%) were administered at a rate of 3–4 ml kg–1 h–1 throughout anaesthesia.
Study protocol
Randomization was performed with closed envelopes containing the study assignment. These were opened immediately before induction of general anaesthesia (concealed allocation). Patients were thus allocated to one of three ventilation regimens: Group A received 80% oxygen plus desflurane in air, Group B received 40% oxygen plus desflurane in air and Group C received 40% oxygen plus desflurane in nitrous oxide. Regardless of group assignment, all patients received dolasetron 12.5 mg i.v. immediately after induction of general anaesthesia.
For all patients we calculated the individual expected incidence of PONV and vomiting using the individual and anaesthesia-related risk factors of the Koivuranta score2 to predict the occurrence of PONV and vomiting, respectively. This score includes the following risk factors: female gender, history of PONV secondary to general anaesthesia, non-smoking status, history of motion sickness and duration of general anaesthesia >60 min.2
Measurements
Recovery time (from end of application of desflurane until extubation) was noted. After surgery and extubation, patients were transferred to the postanaesthesia care unit (PACU). At discharge from PACU, 4 and 24 h after operation the patients were asked about occurrence of nausea and vomiting. Rescue medication—increments of droperidol 1.25 mg i.v.—was given for nausea lasting >5 min, for retching or vomiting, and if patients specifically asked for antiemetics. Postoperative pain was monitored using a visual analogue scale (VAS) of 0=‘no pain’ to 10=‘worst pain imaginable’. Pain was treated with i.v. doses of the opioid piritramide (increments of 3.75 mg) or diclofenac (100 mg) given rectally. The decision of whether to use piritramide, diclofenac, or both was at the discretion of the recovery room nurse, who was blinded to patients' grouping. Consumption of rescue antiemetic and postoperative pain medication was also documented. Furthermore postanaesthesia recovery was scored according to the Aldrete scoring system, which is based on the patient's activity, systolic and diastolic blood pressure, consciousness, and colour on arrival at the recovery room and at discharge.
As usual in our institution all patients received at least 2 litre min–1 oxygen via nasal prongs from arrival at PACU until a few minutes before discharge.
The postoperative inquiry of patients and the evaluation of patients' PONV score were carried out by an anaesthesiologist who was unaware of the patients' assignment (SNP or KDR). Several members of the department gave the anaesthetics, including JB, KLF, SWS and until the end of 2002 also WHM. PK was not involved in actual patient care.
Statistical analysis
Our primary defined outcome was the incidence of PONV over initial 24 h after operation. Based on the publication of Greif and colleagues,15 who showed a reduction of PONV from 30 to 17% as a result of an intraoperative inspired oxygen fraction of 0.8, we expected an incidence of PONV in Group B (40% oxygen in air) of at least 30% and a reduction of the incidence of PONV to approximately 15% with an effective antiemetic intervention (intraoperative ventilation with an inspired oxygen fraction of 0.8). Consequently, the present study was powered to detect such a reduction from 30 to 15% incidence with an 
-error of 0.05 (two-sided) and a ß-error was set of 0.2. Based on that assumption, a minimum of 121 patients needed to be included in each group. We decided to enrol at least 125 patients per group to take into account potential dropouts.
Demographic data, duration of surgery and anaesthesia, recovery time between the end of anaesthesia and extubation were analysed with the Student's t-test. The incidence of PONV and vomiting were analysed with the Fisher's exact test. The ranked sum test of Raatz16 was used to compare pain and Aldrete scores. The Raatz test is a modified rank order test to be used for values that fall into classes (e.g. school notes or scores). Postoperative consumption of piritramide, diclofenac and droperidol were analysed with ANOVA for repeated measurements. All values are expressed as mean (SD) or as median (range). The 95% CIs are given, for main outcomes. P-values <0.05 were considered significant.
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Results |
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The enrolment of the patients, randomization and drop-outs are given in Fig. 1, according to the recommendations of the CONSORT statement. The three groups were similar with regard to demographic, anaesthetic and surgical data (Table 1). No significant differences in recovery times between the end of anaesthesia and extubation were detected (Table 1). The risk scores for PONV and vomiting according to Koivuranta and colleagues2 showed no significant differences with respect to baseline risks for PONV or vomiting between the three groups (Table 1). At all evaluation times there were no significant differences in pain score and postoperative piritramide and diclofenac consumption to be noted (Table 2).
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The incidence of PONV is shown in Table 3. The analysis of these results revealed a significantly lower incidence (P<0.05) of PONV and vomiting in Group A and Group B compared with Group C throughout the study period of 24 h, whereas between Groups A and B no significant difference was observed. In the first 4 h we could also detect a benefit of the omission of nitrous oxide: patients receiving nitrous oxide suffered significantly more of PONV (21.3%) and vomiting (9.4%) compared with both nitrous oxide-free groups (Table 3), but we found no antiemetic effect of inspired oxygen fraction of 0.8 (PONV: 9.6%; vomiting: 0.8%) compared with an oxygen fraction of 0.4 (PONV: 8.0%; vomiting: 2.4%) (Table 3).
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The requirements for rescue medication (droperidol) were significantly lower (P<0.05) in the groups without nitrous oxide (Groups A and B) compared with the nitrous oxide group (Group C). There were no significant differences between Groups A and B (Table 3).
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Discussion |
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The main results of the present study were that an increased intraoperative inspired oxygen fraction of 0.8 did not reduce the incidence of PONV in dolasetron-treated patients undergoing laparoscopic cholecystectomy. In contrast to that, the addition of nitrous oxide was associated with a significantly higher incidence of emetic symptoms during the overall observation time.
Already 80 yr ago a German physician described an antiemetic effect of oxygen in patients suffering from seasickness.17 Nevertheless, this phenomenon was not further investigated in the following years. In 1996, John Hartung interpreted the results of a meta-analysis on emesis after nitrous oxide such that oxygen might be superior to air in this respect, triggering interest in this question.18
Since the publications of a single group of investigators some years ago,14 15 reporting on an antiemetic effect of supplemental oxygen, the use of oxygen as an antiemetic has been controversially discussed. These authors demonstrated a significant decrease of the incidence of PONV in patients undergoing colon resection and gynaecological laparoscopy, respectively.14 15 These studies raised hopes that oxygen might be a cheap, effective and safe antiemetic approach and may be used as a component of a multimode solution for high-risk patients. Apfel and colleagues1 could show in a multicentre trial that various antiemetic strategies are associated with a similar and constant relative reduction rate of about 25–30%. Interestingly, all antiemetics (ondansetron, dexamethasone, droperidol) used in this large study worked independently, so their combined benefit can be derived directly from the single effect. The potential advantages of a combination of an increased inspired oxygen fraction and an established antiemetic for prophylaxis include improved efficacy, extended duration of the antiemetic effect and the possibility of using smaller doses of individual drugs compared with monotherapies.19 Based on their findings Goll and Greif formulated the hypothesis that oxygen attenuates the release of emetogenic substances, for example 5-hydroxytryptamine, secondary to intraoperative intestinal hypoperfusion and ischaemia during colon surgery or pneumoperitoneum.14 15 It has been shown that pneumoperitoneum induces a release of vasoactive substances, especially 5-hydroxytryptamine reducing intestinal blood flow.20 21 However, there were no attempts in these studies to measure either 5-hydroxytryptamine concentrations in the plasma or 5-hydroxyindoleacetic acid concentrations in the urine, or tissue oxygenation.14 15 In a third study the same group found a 4-fold decrease of vomiting during ambulance transport in patients with minor trauma.22 The authors felt that this patient population was very unlikely to have an alteration of intestinal perfusion and proposed an alternative hypothesis that supplemental oxygen reduces the release of the emetogenic neurotransmitter dopamine from the carotid bodies.22
In our study, we found no decreased incidence of PONV because of an inspired oxygen fraction of 0.8. These results should prove quite robust because of the inclusion of a high number of patients undergoing laparoscopic cholecystectomy. A possible explanation for the difference observed between our results and those of Greif and Goll's results is that the 5-HT3-antagonist dolasetron used in our setting counteracted the increased release of emetogenic 5-hydroxytryptamine. Consequently, reducing the release of 5-hydroxytryptamine caused by intraoperative hyperoxygenation did not lead to an additional antiemetic effect. On the other hand, our results are in accordance with the findings of Purhonen and colleagues,8 who could not show any antiemetic effect of supplemental oxygen in patients undergoing gynaecological laparoscopy without pretreatment with 5-HT3-antagonists. Other authors have also failed to show a benefit of supplemental oxygen in diverse clinical settings: in a large study including 210 patients undergoing strabismus surgery Treschan and colleagues7 found no decrease of PONV secondary to increased inspired oxygen (80%) compared with 30% oxygen. Furthermore, no significant decrease of PONV secondary to increased inspired oxygen fraction was described in patients undergoing thyroidectomy, breast surgery and Caesarean birth, and in children undergoing dental work.21 23–25 Ziavra and colleagues26 demonstrated that breathing of supplemental oxygen had no advantage over breathing air in reducing motion sickness in healthy adults.
A limitation of our study is that the breathing gas mixture differed only during the anaesthetic, not in the PACU or on the ward. Consequently, one could argue that we did not apply increased oxygen during this period. However, all patients received supplemental oxygen in the PACU via nasal prongs. To give more oxygen requires complicated apparatus (non-rebreathing-mask) or postoperative tracheal ventilation. Neither seems adequate with simple laparoscopic cholecystectomies with prophylactic dolasetron.
In addition, we were able to show that the omission of nitrous oxide (N2O) significantly decreases the incidence of nausea and vomiting in this clinical setting. Our results are in accordance with the meta-analysis published by Divatia and colleagues,27 who demonstrated a reduction of relative risk of 28% of PONV when air was used instead of N2O. In contrast, Tramèr and colleagues28 could show in a meta-analysis including 24 studies that omitting N2O from general anaesthesia reduces vomiting significantly but does not affect nausea. However, in none of the 24 studies a 5-HT3-antagonist was given. In a large trial using a factorial design Apfel and colleagues1 found a reduction of postoperative nausea and vomiting by 12%, when N2O was omitted.
We found no influence of the study medication on the recovery time between the end of anaesthesia and extubation. These circumstances, in conjunction with the fact that there were also no significant differences in the pain and Aldrete scores or in postoperative piritramide or diclofenac consumption per patient, respectively, can be interpreted that there is little danger of confounding factors interfering with the findings of our study.
In summary, an inspired oxygen fraction of 0.8 does not further decrease PONV, nausea or vomiting compared with an inspired oxygen fraction of 0.4 in dolasetron-treated patients undergoing laparoscopic cholecystectomy. However, omitting nitrous oxide significantly reduced the incidence of PONV in this clinical setting.
Consequently, the use of nitrous oxide for laparoscopic cholecystectomies has been abandoned in our institution after the study.
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Acknowledgments |
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Financial support for this study was provided solely from departmental sources.
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Footnotes |
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Presented in part at the German Anaesthesia Congress (DAC 2004) Nuremberg, June 19–22, 2004. 
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