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The Impact of Anesthesia on Glycine Absorption in Operative Hysteroscopy: A Randomized Controlled Trial

Bergeron, Marie-Eve MD*; Ouellet, Pascale MD; Bujold, Emmanuel MD, MSc*; Cote, Maxime MD; Rhéaume, Caroline MD*; Lapointe, Daniel MD; Beaudet, Christine MD*; Lemyre, Madeleine MD*; Laberge, Philippe MD*

doi: 10.1213/ANE.0b013e31822649d4
Ambulatory Anesthesiology: Research Reports
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BACKGROUND: Operative hysteroscopy requires the use of a distension medium and its absorption can lead to serious consequences from intravascular volume overload and water intoxication. We compared the impact of 2 types of anesthesia (general anesthesia and local anesthesia with sedation) on the absorption of glycine solution in operative hysteroscopy.

METHODS: A randomized controlled trial was conducted over a 17-month period. Eligible patients undergoing operative hysteroscopy for abnormal uterine bleeding were randomized in 2 groups: a general anesthesia group and a local anesthesia with sedation group. The primary outcome was the median absorption of the glycine solution (10th–90th percentile) measured with an automated tandem canister system. Secondary outcomes included incidence of absorption >1000 mL, discontinued surgery because of excessive absorption, median change in serum sodium, postoperative hyponatremia, and patients' postoperative quality of life at 24 hours (8-item Short Form Health Survey questionnaire). Nonparametric analyses (Mann-Whitney U test, χ2 test, and Fisher exact test) were used.

RESULTS: Of 142 eligible patients, 95 agreed to participate and were randomized. Women who underwent general anesthesia had a higher median absorption of the glycine solution (10th–90th percentile) compared with women who underwent local anesthesia with sedation (480 mL [76–1300 mL] vs 253 mL [70–728 mL]; P = 0.005). General anesthesia was also associated with a higher rate of glycine solution absorption (>1000 mL [20% vs 4%; P = 0.009]) and a more rapid rate of decrease in serum sodium (≥10 mEq/L [8% vs 0%; P = 0.005]) than local anesthesia with sedation. Postoperative quality of life measures as rated by the patients were comparable between the 2 groups.

CONCLUSION: Compared with general anesthesia, local anesthesia with sedation is associated with less glycine absorption and should be considered the preferred method of anesthesia for operative hysteroscopy.

Published ahead of print July 25, 2011 Supplemental Digital Content is available in the text.

From the Departments of *Obstetrics and Gynecology and Anesthesiology, Centre Hospitalier Universitaire de Québec, Faculty of Medicine, Universite Laval, Québec, Québec, Canada.

Supported by the President's Grant for Resident Research of The Association of Professors of Obstetrics & Gynaecology of Canada (APOG).

Conflict of Interest: See Disclosures at the end of the article.

This report was previously presented, in part, at the Association Anesthesiologistes du Québec, Canadian Anesthesiologists' Society, Societe des Obstericiens et Gynecologues du Canada, and Association des Obstetriciens Gynecologues du Québec.

Reprints will not be available from the authors.

Address correspondence to Pascale Ouellet, MD, Department of Anesthesiology, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2145 Blvd. Laurier, Québec, QC, Canada, G1V 4G2. Address e-mail to pascale.ouellet.1@ulaval.ca.

Accepted May 12, 2011

Published ahead of print July 25, 2011

It is estimated that up to 30% of women will experience abnormal uterine bleeding during their reproductive life.1 As a minimally invasive procedure, operative hysteroscopy has gained popularity in the past 2 decades and has become a standard and safe surgical treatment for abnormal uterine bleeding unresponsive to medical management.24 Despite the increasing use of operative hysteroscopy, little information is available regarding the systemic absorption of the fluid distension medium, the principal source of complications of operative hysteroscopy that may lead to life-threatening conditions.5,6 Intraoperative absorption of the glycine solution (referred to as glycine in the remainder of the text), an electrolyte-free solution widely used as a distension medium because of its good optical and conductive properties, can cause intravascular volume overload and water intoxication that can lead to hyponatremia, hypoosmolality, cerebral or pulmonary edema, visual disturbances, and death in the most severe cases.24,7,8 Symptomatic excessive glycine absorption has been reported as the most common complication of operative hysteroscopy affecting up to 6% of those procedures.7,9,10

The incidence of this excessive glycine absorption can be limited by close monitoring of fluid deficit, control of irrigation pressure, and preoperative thinning of the endometrium.2,1012 However, 2 studies suggested that the type of anesthesia could have a significant impact on glycine absorption in operative hysteroscopy.13,14 The first study, a randomized control trial by Goldenberg et al.,13 showed a larger glycine absorption with epidural anesthesia compared with general anesthesia. The second study, a retrospective cohort study published by our team, showed that general anesthesia could be associated with greater glycine absorption than local anesthesia with sedation or than regional anesthesia.14 Therefore, we aimed to confirm this last finding in a prospective trial with the specific objective of comparing the absorption of glycine during operative hysteroscopy between women under general anesthesia and women under local anesthesia with IV sedation.

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METHODS

This randomized controlled trial was conducted in 2 centers, namely, a tertiary care center (Centre Hospitalier Universitaire de Québec, Québec, QC, Canada) and a community hospital (Centre Hospitalier Affilié, Pavillon Paul-Gilbert, Charny, QC, Canada) from August 2008 to December 2009. Local ethics board approval was received from both institutions (Centre Hospitalier Universitaire de Québec: #118.05.07, and Centre Hospitalier Affilié: #CER-019-001). During this period, all women between 18 and 70 years old, ASA physical status I or II, undergoing an operative hysteroscopy for abnormal uterine bleeding were eligible. Exclusion criteria included any contraindication to hysteroscopy (suspicion of pelvic or vaginal and cervical infections, severe hemorrhage, pregnancy, suspicion of neoplasia, and previous uterine perforation), patients presenting an ASA physical status ≥III, women who had undergone a previous endometrial resection, diabetic patients, and women requiring a predetermined type of anesthesia because of a specific medical condition. Eligible women were offered the opportunity to participate in the study at least 48 hours before their surgery. Documentation explaining the study was made available at the preoperative consultation. After explaining the procedure and the possible side effects of both general anesthesia and local anesthesia with sedation, written informed consent was obtained from all patients on the day of surgery. Women were then randomly assigned to either group using prenumbered opaque and sealed envelopes that had been prepared by an administrative assistant not involved in the study. Randomization was stratified according to patients' menopausal status and preoperative use of gonadotropin-releasing hormone analogs for endometrial thinning. Randomization numbers and sequence were computer-generated (www.randomizer.org) by groups of 10 in both stratification groups.

Preoperative determination of hemoglobin and serum sodium was performed upon arrival in the operating room. All patients were monitored with electrocardiography, pulse oximetry, arterial blood pressure, and capnography for end-tidal carbon dioxide. A thermometer and a gas analyzer were added for patients undergoing general anesthesia. In both groups, a saline solution (only 0.9% NaCl allowed) was used for IV hydration, starting with a bolus of 5 to 7 mL/kg and then adjusted for fluid maintenance requirements. Anesthetic protocols were built and approved by all anesthesiologists of both departments. For women in the general anesthesia group, general anesthesia was induced using 1 to 3 mg midazolam, 0.15 to 0.25 μg/kg sufentanil, and 1 to 3 mg/kg propofol. Rocuronium (0.6 mg/kg) was allowed. Anesthesia was maintained with sevoflurane titrated to maintain arterial blood pressure within 20% of preoperative normal and, if needed, ephedrine was allowed for the latter purpose. Patients' lungs were mechanically ventilated within a normocapnic range using positive pressure ventilation and a positive end-expiratory pressure of 3 to 5 mm Hg. Patients presenting risk factors for postoperative nausea and vomiting received dexamethasone and ondansetron prophylaxis.15 For women in the local anesthesia group, a paracervical block was performed by the gynecologist using a total of 20 mL of 1% lidocaine intracervically at 2-, 4-, 7-, and 10-o'clock positions and in the area of uterosacral ligaments.16,17 Once the block was completed, the surgeon waited at least 5 minutes before performing cervical dilation to allow for sufficient analgesia. IV sedation consisted of midazolam, sufentanil, and propofol administered by the anesthesiologist in sufficient doses to maintain a spontaneous ventilation with a Ramsay score ≤4.18 Ramsay scores were noted every 5 minutes and 2 consecutive scores ≥5 were considered as a conversion to general anesthesia.

Operative hysteroscopies were performed by 3 gynecologists with a standard 27F continuous-flow resectoscope fitted with a cutting loop and a coagulating roller ball. The surgery included endometrial resection with or without polypectomy or myomectomy. A 1.5% glycine solution was used for irrigation at a flow rate of 300 mL/min under a continuous pressure of 100 mm Hg. The pressure outflow was electronically controlled by an automatic surgical irrigator (Hamou canister; Karl Storz Endoscopy, Tuttlingen, Germany). The amount of fluid absorbed by the patient equals the volume of fluid infused into the uterine cavity minus the volume that passes out through the cervix into the collection system and onto drapes and floor. This is defined as the glycine absorption in the current study. Fluid absorption was measured using an automated tandem canister system (Equimat/ Endomat; Karl Storz Endoscopy) as recommended by the American College of Obstetricians and Gynecologists and the American Association of Gynecologic Laparoscopists.10,19 Fluid loss on the floor was recuperated with a vacuum and included in the count. A strict balance record was kept and the standard protocol for hysteroscopic procedure to stop the surgery when the glycine absorption exceeded 1000 to 1500 mL was respected, according to the guidelines of the College and the American Association of Gynecologic Laparoscopists.10,19,20 To minimize biases, gynecologists were not aware of the intraoperative calculated glycine absorption until it reached 500 mL. At this point, surgeons had to know the evolution of glycine absorption because of higher risks of complications and the potential need for discontinuation. The operative time was defined as the time between introduction of the resectoscope and its final withdrawal. Endometrial strips were sent for histologic evaluation. At their arrival in the recovery room, postoperative blood samples, including hemoglobin and serum sodium analyses, were obtained from patients.

The following data were collected for every patient using a standardized form: age, body mass index, ASA physical status, medical history, pre- and postoperative diagnostics, operative time, glycine absorption, and total medication and hydration used. Intraoperative and postoperative complications were also recorded. On postoperative day 1, a phone interview was conducted by 2 independent nurses to ensure patients' recovery using the 8-item Short Form Health Survey (SF-8) standardized questionnaire.21 Patients' satisfaction with their anesthesia was evaluated by the following “yes” or “no” question: “If you had to undergo the same surgery, would you choose the same type of anesthesia?”

Patients' data were analyzed in their initial randomization group using the intention-to-treat method. The primary outcome was the median absorption of glycine (10th–90th percentile). Secondary outcomes included absorption of glycine between 500 and 1000 mL and >1000 mL, incidence of premature discontinuation of surgery because of excessive absorption, change in serum sodium, incidence of severe postoperative hyponatremia (<125 mmol/L),22 and patient satisfaction with the type of anesthesia and quality of life at 24 hours (SF-8 questionnaire). Based on our previous study,14 an optimal sample size of 93 patients was calculated to obtain a difference of 100% (from 150 to 300 mL, standard deviation of 250 mL) between groups, considering a β error of 20%, an α error of 5%, and a 5% loss to follow-up. Nonparametric analyses (Mann-Whitney U test, χ2, and Fisher exact test) were used to compare the 2 groups except for the SF-8 results for which means were compared with the Student t test. Statistical analyses were done using SPSS Statistics 17.0 software (SPSS, Inc., Chicago, IL). Statistical significance was accepted at P < 0.05.

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RESULTS

Of 142 eligible patients, 95 agreed to participate and were randomized: 51 patients in the general anesthesia group and 44 patients in the local anesthesia with IV sedation group (Fig. 1). Demographic, clinical, and surgical characteristics were comparable between the 2 groups (Tables 1 and 2). In the general anesthesia group, 21 women (41%) were tracheally intubated and 30 women (59%) had a laryngeal mask for airway management. Thirty-three women of this group (65%) received rocuronium and 39 (76%) received prophylaxis for nausea and vomiting because they met ≥2 of the Apfel criteria (female sex, nonsmoker, and history of motion sickness). In the second group, sedation was performed using midazolam (median [10th–90th percentile]: 2.5 mg [1.5–4.8 mg]), sufentanil (15 μg [10–20 μg]), and propofol (123 mg [0–237 mg]). There were no significant differences between the 2 arms in terms of operative time (15 minutes [7–49 minutes] vs 16 minutes [8–43 minutes]) or amount of NaCl administered IV (500 mL [400–900 mL] vs 500 mL [300–750 mL]).

Figure 1

Figure 1

Table 1

Table 1

Table 2

Table 2

We found a significant difference in the primary outcome between the 2 groups. Median glycine absorption was 480 mL (10th–90th percentile: 76–1300 mL) for patients who underwent general anesthesia and 253 mL (10th–90th percentile: 70–728 mL) for patients who underwent local anesthesia with sedation (P = 0.01) (Table 2). The median difference between the 2 groups was 228 mL (95% confidence interval [CI]: 60–395 mL). Moreover, compared with local anesthesia with sedation, general anesthesia was associated with a more rapid rate of glycine absorption in the 500- to 1000-mL (27% vs 14%) and >1000-mL categories (20% vs 4%) (P = 0.009) for a global rate of glycine absorption >500 mL of 47% with general anesthesia compared with 18% with local anesthesia and sedation (Fig. 2). These findings were also confirmed by a greater change in serum sodium (2 vs 0.5 mEq/L; P < 0.001) and a larger decrease in serum sodium ≥10 mEq/L (8% vs 0%; P = 0.005) in the general anesthesia group (Table 2). A similar effect of anesthesia was also found in both subgroups used for our stratification: the median absorption was approximately 1.7 times more with general anesthesia (premenopausal: 565 vs 335 mL, P = 0.03, with a median difference of 230 mL [95% CI: 201–259 mL]; postmenopausal: 310 vs 175 mL, P = 0.13, with a median difference of 135 mL [95% CI: −55 to 325 mL]).

Figure 2

Figure 2

None of the women had severe excessive intravascular volume, defined as an intraoperative glycine absorption ≥1500 mL. However, 6 procedures had to be discontinued because of excessive glycine absorption: 4 cases in the general anesthesia group and 2 cases in the local anesthesia with sedation group (P = 0.68; difference of 4% [95% CI: −5.65% to 13.65%]). One of these patients had severe hyponatremia (115 mEq/L) in the recovery room. Her surgery was uneventfully performed under general anesthesia and 1200 mL glycine absorption was reported. She was admitted into the intensive care unit for close monitoring. Hyponatremia was slowly corrected with diuretics and normal saline infusion. This severe hyponatremia did not lead to more severe complications and the patient left the hospital on postoperative day 1. Otherwise, no major complication occurred in our trial. Only 2 patients (5%) under local anesthesia with sedation required general anesthesia because of discomfort and excessive anxiety.

The phone interview evaluating patients' quality of life on postoperative day 1 (SF-8 questionnaire) and patients' satisfaction rate showed no difference between the 2 groups (Table 3). The difference in the rate of dissatisfaction was 5.26% (95% CI: −4.96% to 15.48%).

Table 3

Table 3

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DISCUSSION

In operative hysteroscopy, local anesthesia with IV sedation is associated with significantly decreased intraoperative glycine absorption including a smaller proportion of patients with absorption >500 mL or >1000 mL compared with general anesthesia. In addition to greater absorption of glycine, patients who underwent general anesthesia were more likely to experience a larger change in serum sodium. These results are in agreement with our previous retrospective study of a cohort of 282 patients.14 In that study, we reported that local anesthesia with sedation was associated with significantly decreased intraoperative glycine absorption (median absorption was 145 mL [10th–90th percentile: 0–963 mL] for general anesthesia and 35 mL [10th–90th percentile: 0–389 mL] for local anesthesia) and less absorption >500 mL compared with general anesthesia (absorption of 500–1000 mL [4.2% vs 13.4%] and of 1000–1500 mL [3.6% vs 9.8%] [P = 0.002]). Although the median glycine absorption slightly differs between the 2 studies, the tendency of general anesthesia to cause higher absorption is found again. The greater fluid absorption observed in this randomized controlled trial may be explained by a stricter protocol on calculation of the fluid absorption, the larger proportion of patients who had myomas, and the use of a vacuum to recuperate glycine loss on the floor. The impact of the type of anesthesia on glycine absorption in operative hysteroscopy has also been described by Goldenberg et al.13 in a randomized controlled trial of 24 patients. They reported significantly less glycine absorption in patients under general rather than epidural anesthesia (380.8 ± 158.2 mL vs 648.3 ± 157.1 mL; P < 0.0005).13

In hysteroscopic surgery, fluid management is critical for intraoperative safety because the excessive absorption of distension medium can lead to several complications.5 Dilutional hyponatremia and cerebral edema have been described with glycine absorption as low as 500 mL.2,23 Moreover, because excessive glycine absorption has been reported to occur in as many as 6% of women undergoing endometrial resection,2 it is essential that more measures be taken to minimize its incidence. The present study focused on the impact of anesthesia on the absorption of glycine.

Several hypotheses can be raised to explain this difference. We believe that inhaled anesthetics used in general anesthesia have a predominant effect on the absorption of glycine. In fact, inhaled anesthetics relax arteriolar muscles, thus inducing an important vasodilatation that can lead to increased absorption of glycine.24 Intravasation of distension fluid is then easily made from the uterine cavity through the extensively truncated and dilated uterine vessels. This hypothesis could also explain the results of previous studies on glycine absorption in neuraxial anesthesia13,14 that both reported a greater absorption of glycine under neuraxial anesthesia. We hypothesize that in neuraxial anesthesia, sympathectomy induces a larger pelvic vasodilatation than with inhaled anesthetics, thus enhancing absorption.

Our study is limited by the fact that the patients and surgeons were not blinded to the anesthesia group. However, median surgery duration was comparable in both groups, and the surgeon remained blinded to the amount of glycine absorption until it had reached 500 mL. Another limitation pertains to the measurement of glycine absorption: in fact, it represents the infused glycine 1.5% solution minus the volume of recuperated solution that could be influenced by loss and by additional fluid recuperated (blood). Nevertheless, all efforts were made to minimize these intrinsic measurement biases that were the same in both arms. Furthermore, our study was underpowered to detect a difference in the rate of discontinued surgery or severe hyponatremia, i.e., 2 ultimate complications of excessive glycine absorption. However, we believe that our primary and other secondary outcomes are clinically important and provide a good estimate of the potential difference for such complications between the 2 types of anesthesia. Other immediate complications associated with operative hysteroscopy include uterine perforation and operative hemorrhage.2,20 Although frequently reported, the latter complications did not occur among women enrolled in our study. The lack of these complications may also have been attributable in part to the limited size of our sample and the surgical experience of our gynecologists.

An additional advantage of local anesthesia with sedation is that the patient is awake and able to communicate, thus serving as a subjective monitor for physical well-being. Thereby, the patient may alert physicians of early symptoms of hyponatremia and excessive intravascular volume, which could in turn prevent more severe complications.22 The anesthesiologist must be aware that these early symptoms of excessive intravascular volume may indeed be masked under general anesthesia or under very deep sedation.22 Furthermore, early recognition of the signs and symptoms associated with hyponatremia is crucial during operative hysteroscopy because female patients, especially in reproductive ages, are at greater risk for developing significant neurologic sequelae after severe hyponatremia.25 Finally, local anesthesia with IV sedation is well tolerated for operative hysteroscopy14,26 and this has been confirmed in our study with a conversion rate to general anesthesia of only 5%.

We conclude that local anesthesia with sedation is associated with decreased absorption of glycine during operative hysteroscopy. Thus, regional anesthesia with sedation should be considered for patients presenting for an operative hysteroscopy and resection when glycine is used as the distending solution.

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DISCLOSURES

Name: Marie-Eve Bergeron, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Marie-Eve Bergeron has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: Marie-Eve Bergeron reported no conflicts of interest.

Name: Pascale Ouellet, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Pascale Ouellet has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Pascale Ouellet reported no conflicts of interest.

Name: Philippe Laberge, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Philippe Laberge has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Philippe Laberge reported no conflicts of interest.

Name: Caroline Rhéaume, MD.

Contribution: This author helped design the study and conduct the study.

Attestation: Caroline Rhéaume has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Caroline Rhéaume reported no conflicts of interest.

Name: Maxime Cote, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Maxime Cote has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Maxime Cote reported no conflicts of interest.

Name: Daniel Lapointe, MD.

Contributions: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Daniel Lapointe has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Daniel Lapointe reported no conflicts of interest.

Name: Madeleine Lemyre, MD.

Contributions: This author helped design the study and conduct the study.

Attestation: Madeleine Lemyre has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Madeleine Lemyre received honoraria from Ethicon Endosurgical, received honoraria from Wyeth, received honoraria from Bayer, received honoraria from Merck, and received honoraria from Schering Speaker.

Name: Emmanuel Bujold, MD, MSc.

Contributions: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Emmanuel Bujold has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Emmanuel Bujold reported no conflicts of interest.

Name: Christine Beaudet, MD.

Contributions: This author helped design the study and conduct the study.

Attestation: Christine Beaudet has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Christine Beaudet reported no conflicts of interest.

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ACKNOWLEDGMENTS

The authors thank the Canadian Institutes for Health Research for the Clinician-Scientist Award and Jeanne et Jean-Louis Lévesque Perinatal Research Chair that support Dr. Emmanuel Bujold. The authors also thank Ms. Josée Mailhot and Ms. Francine Dufour for their advice and their help in patient recruitment and Ms. Stéphanie Roberge and Belkacem Abdous for their contribution to statistical analysis.

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