Key words: Surgery: arthroscopy; anesthesia: orthopedic. Surgery, complications: cerebral edema; glycine intoxication; hyponatremia.
A 1.5% solution of glycine irrigating fluid is commonly used in urologic and gynecologic endoscopy and in arthroscopy. [1-3]However, intravascular absorption of this solution may cause cardiovascular, neurologic, visual disorders and water intoxication that can occasionally be fatal, generally because of cerebral edema. [2,4,5]Burkhart et al. reported that transient blindness occurred after a knee arthroscopy, and suggested that this may be due to glycine toxicity. We report a case of an unexplained death due to cerebral edema in a healthy patient who had undergone a shoulder arthroscopy. Because of our concerns regarding possible glycine toxicity, we then carried out a prospective examination of changes in serum glycine concentration in 22 patients during identical procedures.
A 40-yr-old woman who had suffered from chronic pain in her right shoulder for 3 yr was admitted for a shoulder arthroscopy. Preoperative physical examination and routine laboratory findings were normal (serum sodium: 141 mmol/l; potassium: 4.9 mmol/l; chloride: 104 mmol/l; protein: 75 g/l; and hematocrit: 41%). Preoperative medication with 0.5 mg atropine intramuscularly and 5 mg midazolam was given, and an interscalene block (35 ml 0.25% bupivacaine plus 1.5% lidocaine) was performed 1 h later. General anesthesia was induced 15 min later with 8 mg/kg thiopental and 0.1 mg fentanyl, followed by 0.5 mg/kg atracurium dibesylate to intubate the trachea. Anesthesia was maintained with 50% N sub 2 O in oxygen, 1% isoflurane, fentanyl, and atracurium dibesylate. The coracoacromial ligament was cut, and acromioplasty was performed during arthroscopy. A total of 18 l of 1.5% glycine solution was infused during the 90 min of the arthroscopy. The patient received an intravenous infusion of 500 ml of 10% glucose. The operative period was uneventful. Her recovery was slightly delayed, and she was transferred to the recovery room tracheally intubated and breathing spontaneously.
Tracheal extubation was performed 1 h, 15 min after the end of anesthesia. The patient complained of nausea. Her physical examination was unremarkable, with no evidence of cardiovascular instability or signs of altered consciousness. However, examination of her shoulder revealed a large increase in its volume. The patient was discharged from the recovery room after 4 h. She was awake, but remained nauseated and slightly sleepy. Thirty minutes later, her systolic blood pressure decreased for a few minutes to 70 mmHg and returned to 120 mmHg with 1,000 ml of Ringer's lactate. Her condition remained unchanged for 3 h. Seven and a half hours postoperatively, a nurse found her to have severe bradypnea and in a deep coma (Glasgow Coma Scale = 3). Her pupils were dilated and did not react to light.
The patient was transferred to the intensive care unit. At this time (8 h after intervention), her serum sodium concentration was 116 mmol/l, chloride 88 mmol/l, protein 48 g/l, osmolarity 269 mosm/l, and hematocrit 31%. A cerebral computed tomography scan showed severe diffuse cerebral edema, with both ventricles and basal cisterns collapsed. Intravenous infusion of hypertonic saline normalized the serum sodium concentration within 24 h. Serum glycine concentration was measured and found to be 1,360, 600, and 256 micro mol/l at 10, 20, and 24 h after arthroscopy. Finally, a cerebral angiography confirmed brain death diagnosis. The autopsy showed severe cerebral edema without any other abnormality.
Materials and Methods
Twenty-two patients (10 men and 12 women) were prospectively included during a 2-month period. The study was approved by the local ethics committee. All patients gave their informed consent according to the Helsinki II declaration. The inclusion criterion was a shoulder arthroscopy using a 1.5% glycine irrigating solution. Patients with hepatic and/or renal disease, abnormal preoperative values of serum sodium, glucose, urea, or measured plasma osmolarity were excluded.
Premedication was 5 mg intramuscular midazolam. General anesthesia was induced with 4-6 mg/kg thiopental combined with 0.1 mg fentanyl and 0.5 mg/kg atracurium dibesylate before intubation, and maintained with 50% N2O in oxygen, isoflurane, and fentanyl (6 patients). Two patients were given an interscalene block, and 14 patients were given a combination of local and general anesthesia. One thousand milliliters Ringer's lactate solution and 500 ml of 10% glucose were given intravenously during the procedure and 24 h after it. Glycine solution was infused with an arthropump or by gravity, without exceeding 80 mmHg.
The following data were collected: serum sodium, glucose, protein, hematocrit, measured plasma osmolarity, and serum glycine (ion exchange colorimetric detection using ninhydrin, amino acid analyzer Beckman 6300), ammonia, serine, alanine, glutamate, and glutamine. Samples were taken just before arthroscopy (0), postoperatively (PO), every 3 h for 12 h (3, 6, 9, 12), and at 18 h (18) and 24 h (24). The total volume of glycine solution infused was recorded. The principal vital signs that suggest vascular absorption of glycine (arterial pressure, arterial oxygen saturation, and heart rate) were monitored throughout surgery. The trachea was extubated in the operating room, and patients were transferred to the recovery room and then to their room, where heart rate, arterial blood pressure, Glasgow Coma Scale, visual disturbances, nausea, and vomiting were all monitored hourly for 12 h, then at 18 h and 24 h.
Analysis of variance for repeated measures was used to evaluate the changes in all the laboratory parameters. The relation between two parameters was assessed using a simple linear regression by the least square method. Data are reported as means +/- standard deviations (SD). A two-tailed P value less than 0.05 was considered statistically significant.
The principal demographic and surgical data are summarized in Table 1. The perioperative period was uneventful. Figure 1indicates that the serum glycine concentration increased immediately after arthroscopy to 2,088 micro mol/l (SD 2,299, range 395-11,100; P < 0.01), then returned to the baseline within 24 h. Hyperglycinemia occurred in each of the 22 patients. Serum sodium concentration decreased immediately after arthroscopy from 141 mmol/l (SD 2) to a minimum of 135 mmol/l (SD 3; P < 0.01) within 6 h (Figure 1). The plasma osmolarity changed in parallel with the serum sodium. Serum protein and hematocrit decreased significantly (P < 0.01) to a minimum at 12 h after arthroscopy. There were no changes in serum alanine, glutamate plus glutamine, or serum ammonia during the recording period. Serum serine concentration increased to 135 +/- 32 micro mol/l at 9 h after arthroscopy. The increase in serum glycine concentration was correlated with both the decrease in serum sodium (r = 0.92, P = 0.0001; Figure 2) and the total volume of glycine solution irrigated (r = 0.44, P = 0.0439; Figure 3).
Tracheal extubation was always possible in less than 45 min. Recovery was not delayed, and there were no particular events in the postoperative period, except that one patient had a mild obtundation (Glasgow Coma Scale = 13) and blurred vision during 9 h after surgery. This patient had the highest postoperative serum glycine concentration (11,100 micro mol/l).
A 1.5% glycine solution is used in a wide variety of procedures, including bladder, uterine, rectal, and renal procedures. [1,2,4,6]The intravascular absorption of this solution may be associated with neurologic, cardiovascular, renal, and visual disturbances. [1,2,4,7,8]Glycine toxicity has been suggested as the cause of transient blindness in a man after a knee arthroscopy. However, his serum glycine concentration was not measured. Our case report describes an abnormally increased serum glycine concentration that occurred after shoulder arthroscopy. The subsequent prospective study confirms that there is an intravascular absorption of glycine during shoulder arthroscopy. This absorption occurs in all patients, to a varying extent.
The way in which glycine solution causes toxicity remains to be debated. Some authors [1,4-11]believe it acts by inducing acute water intoxication. Intravascular absorption of this hypotonic solution results in hyponatremia and hemodilution, which may lead to cerebral edema. Our data are in agreement with these findings. Although there was no control group in our study, the hyponatremia of our patients could be explained by the intravascular absorption of glycine, because there was a relation between the decrease in serum sodium and the increase in serum glycine concentrations. Our patients also received only small volumes of isotonic solution during and after the procedure. The occurrence of neurologic signs without hyponatremia suggests that glycine also has direct toxic effects. [10,12-14]But, some authors believe that it also has indirect toxic effect via metabolites such as ammonia, [15-18]glyoxilic-glycolic acids, or serine. [13,19]
Hahn found that the threshold concentration of serum glycine toxicity was greater than 800 micro mol/l, but clinical signs consistent with a transurethral resection of the prostate syndrome are not always correlated with the serum glycine concentration. [18,20]They also depend on the severity of acute water intoxication, the occurrence of hypervolemia, and the capacity of the individual to metabolize glycine. Some of our asymptomatic patients had serum glycine concentrations exceeding 800 micro mol/l. We have no evidence that shoulder arthroscopy using glycine solution is always complicated by a transurethral resection of the prostate-like syndrome, but this may have been so for the patient described in the case report and for one of the patients that was part of the prospective study, because they had the neurologic signs and the highest serum glycine concentrations.
Because of the possible complications due to the intravascular absorption of glycine, we suggest that particular attention be paid to patients undergoing shoulder arthroscopy that involves using this solution. They should, at least, be closely clinically observed postoperatively. Because neurologic signs or changes in neurologic status are difficult to evaluate after general anesthesia, serum sodium concentration may be measured, because this parameter indirectly reflects the extent of intravascular glycine absorption. Hyperglycinemia also is correlated with the total volume of solution irrigated. Therefore, in agreement with others, [6,9,10]we recommend that this parameter be monitored. Hahn et al. suggested measuring the absorption of irrigant solution by adding a trace amount of ethanol to the solution, but more studies are needed before it can be used routinely.
Glycine solution is widely used during arthroscopy because it causes no intravascular hemolysis, does not conduct electricity allowing the use of an electrosurgical instrumentation, and provides good visibility for the surgeon. But, considering the potential risks of using this solution, particularly during procedures using large volumes, alternative irrigating solutions might be considered. [1,3,22]Saline or Ringer's lactate solutions are appropriate when diathermy is not necessary. Other alternatives might be sorbitol, glycerol, and mannitol solutions. Unlike glycine, these solutions have no direct toxic effects, but the absorption of large volumes may cause vascular overload with cardiac failure. [1,3]Therefore, whatever the nature of irrigating fluid, reducing the volume absorbed is crucial. To decrease fluid absorption, some precautions may be recommended: limit the pressure and the total volume of irrigation and avoid the outflow obstruction. 
With this study, we showed that glycine is absorbed intravascularly during shoulder arthroscopy. We recommend systematically monitoring the neurologic status of patients during the postoperative period and the total volume of irrigating solution.