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Haemolysis after etomidate: comparison of propylene glycol and lipid formulations
British Journal of Anaesthesia 1997; 79: 386–388
Haemolysis after etomidate: comparison of propylene glycol and lipid formulations
A. DOENICKE, M. F. ROIZEN, R. HOERNECKE, M. MAYER, P. OSTWALD AND J. FOSS
Summary We sought to determine if the solvent in the formulation of etomidate is responsible for haemolysis in patients. In a randomized, prospective, double-blind study of 49 patients undergoing otolaryngological surgery, patients received etomidate dissolved in propylene glycol or in lipid emulsion. Concentrations of free haemoglobin and haptoglobin were measured before and for up to 360 min after injection of etomidate. Free haemoglobin concentrations increased by 216.8 mg litre91 in patients who received the propylene glycol formulation and by 11.8 mg litre91 in the lipid emulsion group Correspondingly, reductions in (P艋0.0004). haptoglobin concentrations were significantly greater in the propylene glycol group (P艋0.002). We conclude that with respect to haemolysis, lipid emulsion is superior to propylene glycol as a solvent for etomidate. (Br. J. Anaesth. 1997; 79: 386–388). Key words Formulations, etomidate. Anaesthetics i.v., Complications, haemolysis. Blood, haemolysis.
etomidate.
We first suspected that etomidate formulated in propylene glycol causes haemolysis after observing a reddish discolouration of the sera of volunteers treated with etomidate dissolved in propylene glycol.1 We suspected that this reflected intravascular haemolysis caused by the high osmolality of etomidate (4965 mosmol litre91) dissolved in propylene glycol.2 In this study we attempted to confirm the hypothesis that etomidate dissolved in propylene glycol causes haemolysis and that this is not associated with a more physiological solvent (lipid emulsion). In lipid emulsion, etomidate has a near physiological osmolality of 400 mosmol litre91.
Methods and results After obtaining Institutional Review Board approval and informed consent, we studied 49 patients undergoing otolaryngological surgery, randomly allocated to receive etomidate in propylene glycol or in a lipid emulsion preparation
for induction of anaesthesia. On the evening before and 1 h before operation, each patient was premedicated with lormetazepam 2 mg orally. Patients were given fentanyl 2 g kg91 i.v. and atracurium 0.07 mg kg91 i.v. for induction for anaesthesia, followed 3 min later by etomidate 0.3 mg kg91 i.v. Patients in the propylene glycol group received Hypnomidate (Janssen, Neuss, Germany), etomidate 2 mg ml91 of an aqueous solution of 35 vol% propylene glycol. Patients in the lipid emulsion group received EtomidateLipuro (B. Braun, Melsungen, Germany), etomidate 2 mg ml91 of fat emulsion consisting of soy bean oil, medium-chain triglycerides, egg lecithin and glycerol. Neuromuscular block was produced with atracurium 0.5 mg kg91 i.v. before tracheal intubation. During induction with etomidate, patients’ lungs were ventilated with oxygen; subsequently, they were ventilated using a mask and 1–1.5% isoflurane in oxygen without nitrous oxide. After tracheal intubation, anaesthesia was maintained with 0.5–1.2% isoflurane and 65% nitrous oxide in oxygen. During operation, fentanyl i.v. was administered as needed. At the end of surgery, all patients were given droperidol 1.25–2.5 mg i.v. A second dose of etomidate was not given during anaesthesia. Patients also received an infusion of 1500 ml of a balanced electrolyte solution to reduce the dilution effect of blood sampling. To record and quantify haemolysis, free haemoglobin concentrations in plasma before and 5 min after administration of etomidate were measured by an antigen–antibody nephelometer test. As an additional measure of haemolysis, haptoglobin concentrations in serum were measured by enzyme immunoassay before and 120, 240 and 360 min after administration of etomidate. At each measurement time, packed cell volume (PCV) was
ALFRED DOENICKE*, MD, RAINER HOERNECKE, MD, MICHAEL MD, MD, PHILIPP OSTWALD, Institute for MAYER, Anaesthesiology, Ludwig-Maximilians University, Munich. MICHAEL F. ROIZEN, MD (Department of Anesthesia and Critical Care); JOSEPH FOSS, MD (Department of Anesthesia and Critical Care and the Committee on Clinical Pharmacology); University of Chicago, Chicago, IL, USA. Accepted for publication: April 8, 1997. *Address for correspondence: Institute for Anaesthesiology, Ludwig-Maximilians University of Munich, Pettenkoferstr. 8a, 80336 Munich, Germany.
Propylene glycol solvent causes haemolysis
397
Table 1 Comparison of serum free haemoglobin (mg litre91) and serum haptoglobin (g litre91) concentrations in the two groups. Serum haptoglobin concentration are corrected for changes in packed cell volume. Values are (mean (SEM))
Time of measurement Free haemoglobin Baseline 5 min Haptoglobin Baseline 120 min 240 min 360 min
Etomidate in propylene glycol (n:24)
P value compared with baseline
Etomidate in lipid emulsion (n:25)
P value compared with baseline
P value between groups
42.2 (9.3) 259.0 (15.1)
0.0004
42.3 (9.3) 54.1 (5.7)
0.289
0.996 0.0004
0.0004 0.0004 0.0004
0.950 0.042 0.003 0.002
1.78 (0.15) 1.10 (0.13) 0.85 (0.11) 0.84 (0.11)
0.0004 0.0004 0.0004
also measured, and correction in haptoglobin concentrations was made for the dilution effect. The t test for non-paired samples and covariance analysis was used for statistical analysis with P艋0.05 considered statistically significant. The two groups did not differ in age, height, weight, sex distribution, duration of procedure or dose of etomidate received. PCV values did not differ between groups. Mean free haemoglobin concentrations after etomidate in propylene glycol increased significantly from 42.2 (SEM 9.3) mg litre91 at baseline to 259 (15.1) mg litre91 min later (P艋0.0004) and in the lipid emulsion group from 42.3 (9.3) to 54.1 (5.7) mg litre91 (P:0.289) (table 1). Between-group differences were significant 5 min after administration of etomidate (P艋0.0004). Serum haptoglobin concentrations decreased significantly compared with baseline in both groups after administration of etomidate. The reduction in free haptoglobin after etomidate in propylene glycol was significantly greater after 240 and 360 min (P艋0.003 and P艋0.002, respectively) (table 1).
Comment Several adverse effects caused by propylene glycol have been described: hypotension, pain on injection, lactic acidosis and pulmonary hypertension.1 3–5 In our study, a single injection of etomidate 0.3 mg kg91 dissolved in propylene glycol increased free haemoglobin (514%) and decreased serum haptoglobin (52.8%) concentrations significantly, indicating intravascular haemolysis. Free haemoglobin is bound within a few minutes by haptoglobin, forming a haptoglobin– haemoglobin complex. The half-life of haptoglobin is 3–4 days compared with that of the haptoglobin– haemoglobin complex of only 8 min. If intravascular free haemoglobin increases, haptoglobin concentration decreases, which is a measurable sign of haemolysis. Haemolysis and cell lysis associated with an induction dose of etomidate dissolved in propylene glycol may not cause detectable renal injury in healthy individuals. However, several other drugs are also dissolved in propylene glycol such as lorazepam (osmolality 12800 mosmol litre91) and
1.79 (0.13) 1.47 (0.13) 1.36 (0.12) 1.39 (0.13)
nitroglycerin (osmolality 4550 mosmol litre91).2 Combined use of drugs dissolved in propylene glycol may increase the likelihood and severity of haemolysis. If etomidate dissolved in propylene glycol or other drugs with similar formulations are injected repeatedly after short intervals, or if they are used in combination, circulating haptoglobin may be depleted completely. Under such circumstances free haemoglobin from haemolysis may exceed binding capacity and exert toxic effects.6 Intraoperative autotransfusion in patients who have received etomidate dissolved in propylene glycol also makes haemolysis problematic. It has been shown that infusion of packed red cells, especially from autotransfusion, decreases haptoglobin concentrations.7 In fact, haptoglobin was undetectable in seven of 47 patients after autotransfusion. Etomidate is a desirable induction agent for older, less healthy patients because it does not effect cardiovascular stability. These patients often undergo procedures (total hip replacement or vascular surgery) that use autotransfusion. In such patients, the combined effects of etomidate in propylene glycol and autotransfusion may decrease haptoglobin concentrations. We speculate that those likely to be affected include patients with other risk factors, such as impaired renal function or patients in shock who need high re-transfusion volumes. Our results are consistent with the hypothesis that propylene glycol is a less safe vehicle than lipid emulsion for etomidate. Side effects associated with propylene glycol may be toxic for some patients.
Acknowledgements The study was supported by the Institute for Anaesthesiology, Ludwig-Maximilians University, Munich, Germany and the Department of Anesthesia and Critical Care, University of Chicago, IL, USA.
References 1. Doenicke A, Roizen MF, Nebauer AE, Kugler A, Hoernecke R, Beger-Hintzen H. A comparison of two formulations for etomidate, 2-hydroxpropyl-beta-cyclodextrin (HPCD) and propylene glycol. Anesthesia and Analgesia 1994; 79: 933–938.
388 2. Doenicke A, Nebauer AE, Hoernecke R, Mayer M, Roizen MF. Osmolalities of propylene glycol-containing drug formulations for parenteral use. Should propylene glycol be used as a solvent? Anesthesia and Analgesia 1992; 75: 431–435. 3. Bedichek E, Kirschbaum B. A case of propylene glycol toxic reaction associated with etomidate infusion. Archives of Internal Medicine 1991; 151: 297–298. 4. Demey HE, Daelemars RA, Verpooten GA, De Broe ME, Van Campenhout CM, Lakiere FV, Schepens PJ, Bossaert LL. Propylene glycol induced side effects during intravenous nitroglycerin therapy. Intensive Care Medicine 1988; 14: 221–226.
British Journal of Anaesthesia 5. Levy ML, Aranda M, Zelman V, Glannotta SL. Propylene glycol toxicity following continuous etomidate infusion for the control of refractory cerebral edema. Neurosurgery 1995; 37: 363–369. 6. Goldfinger D. Acute hemolytic transfusion reactions—a fresh look at pathogenesis and considerations regarding therapy. Transfusion 1977; 17: 85–98. 7. Henn A, Hoffmann R, Müller HAG. Haptoglobin determination in patients serum after intraoperative autotransfusion with Haemonetics Cell-Saver III. Haemolysis and intraoperative autotransfusion. Anaesthesist 1988; 37: 741–745.
Haemolysis after etomidate: comparison of propylene glycol and lipid formulations
A. DOENICKE, M. F. ROIZEN, R. HOERNECKE, M. MAYER, P. OSTWALD AND J. FOSS
Summary We sought to determine if the solvent in the formulation of etomidate is responsible for haemolysis in patients. In a randomized, prospective, double-blind study of 49 patients undergoing otolaryngological surgery, patients received etomidate dissolved in propylene glycol or in lipid emulsion. Concentrations of free haemoglobin and haptoglobin were measured before and for up to 360 min after injection of etomidate. Free haemoglobin concentrations increased by 216.8 mg litre91 in patients who received the propylene glycol formulation and by 11.8 mg litre91 in the lipid emulsion group Correspondingly, reductions in (P艋0.0004). haptoglobin concentrations were significantly greater in the propylene glycol group (P艋0.002). We conclude that with respect to haemolysis, lipid emulsion is superior to propylene glycol as a solvent for etomidate. (Br. J. Anaesth. 1997; 79: 386–388). Key words Formulations, etomidate. Anaesthetics i.v., Complications, haemolysis. Blood, haemolysis.
etomidate.
We first suspected that etomidate formulated in propylene glycol causes haemolysis after observing a reddish discolouration of the sera of volunteers treated with etomidate dissolved in propylene glycol.1 We suspected that this reflected intravascular haemolysis caused by the high osmolality of etomidate (4965 mosmol litre91) dissolved in propylene glycol.2 In this study we attempted to confirm the hypothesis that etomidate dissolved in propylene glycol causes haemolysis and that this is not associated with a more physiological solvent (lipid emulsion). In lipid emulsion, etomidate has a near physiological osmolality of 400 mosmol litre91.
Methods and results After obtaining Institutional Review Board approval and informed consent, we studied 49 patients undergoing otolaryngological surgery, randomly allocated to receive etomidate in propylene glycol or in a lipid emulsion preparation
for induction of anaesthesia. On the evening before and 1 h before operation, each patient was premedicated with lormetazepam 2 mg orally. Patients were given fentanyl 2 g kg91 i.v. and atracurium 0.07 mg kg91 i.v. for induction for anaesthesia, followed 3 min later by etomidate 0.3 mg kg91 i.v. Patients in the propylene glycol group received Hypnomidate (Janssen, Neuss, Germany), etomidate 2 mg ml91 of an aqueous solution of 35 vol% propylene glycol. Patients in the lipid emulsion group received EtomidateLipuro (B. Braun, Melsungen, Germany), etomidate 2 mg ml91 of fat emulsion consisting of soy bean oil, medium-chain triglycerides, egg lecithin and glycerol. Neuromuscular block was produced with atracurium 0.5 mg kg91 i.v. before tracheal intubation. During induction with etomidate, patients’ lungs were ventilated with oxygen; subsequently, they were ventilated using a mask and 1–1.5% isoflurane in oxygen without nitrous oxide. After tracheal intubation, anaesthesia was maintained with 0.5–1.2% isoflurane and 65% nitrous oxide in oxygen. During operation, fentanyl i.v. was administered as needed. At the end of surgery, all patients were given droperidol 1.25–2.5 mg i.v. A second dose of etomidate was not given during anaesthesia. Patients also received an infusion of 1500 ml of a balanced electrolyte solution to reduce the dilution effect of blood sampling. To record and quantify haemolysis, free haemoglobin concentrations in plasma before and 5 min after administration of etomidate were measured by an antigen–antibody nephelometer test. As an additional measure of haemolysis, haptoglobin concentrations in serum were measured by enzyme immunoassay before and 120, 240 and 360 min after administration of etomidate. At each measurement time, packed cell volume (PCV) was
ALFRED DOENICKE*, MD, RAINER HOERNECKE, MD, MICHAEL MD, MD, PHILIPP OSTWALD, Institute for MAYER, Anaesthesiology, Ludwig-Maximilians University, Munich. MICHAEL F. ROIZEN, MD (Department of Anesthesia and Critical Care); JOSEPH FOSS, MD (Department of Anesthesia and Critical Care and the Committee on Clinical Pharmacology); University of Chicago, Chicago, IL, USA. Accepted for publication: April 8, 1997. *Address for correspondence: Institute for Anaesthesiology, Ludwig-Maximilians University of Munich, Pettenkoferstr. 8a, 80336 Munich, Germany.
Propylene glycol solvent causes haemolysis
397
Table 1 Comparison of serum free haemoglobin (mg litre91) and serum haptoglobin (g litre91) concentrations in the two groups. Serum haptoglobin concentration are corrected for changes in packed cell volume. Values are (mean (SEM))
Time of measurement Free haemoglobin Baseline 5 min Haptoglobin Baseline 120 min 240 min 360 min
Etomidate in propylene glycol (n:24)
P value compared with baseline
Etomidate in lipid emulsion (n:25)
P value compared with baseline
P value between groups
42.2 (9.3) 259.0 (15.1)
0.0004
42.3 (9.3) 54.1 (5.7)
0.289
0.996 0.0004
0.0004 0.0004 0.0004
0.950 0.042 0.003 0.002
1.78 (0.15) 1.10 (0.13) 0.85 (0.11) 0.84 (0.11)
0.0004 0.0004 0.0004
also measured, and correction in haptoglobin concentrations was made for the dilution effect. The t test for non-paired samples and covariance analysis was used for statistical analysis with P艋0.05 considered statistically significant. The two groups did not differ in age, height, weight, sex distribution, duration of procedure or dose of etomidate received. PCV values did not differ between groups. Mean free haemoglobin concentrations after etomidate in propylene glycol increased significantly from 42.2 (SEM 9.3) mg litre91 at baseline to 259 (15.1) mg litre91 min later (P艋0.0004) and in the lipid emulsion group from 42.3 (9.3) to 54.1 (5.7) mg litre91 (P:0.289) (table 1). Between-group differences were significant 5 min after administration of etomidate (P艋0.0004). Serum haptoglobin concentrations decreased significantly compared with baseline in both groups after administration of etomidate. The reduction in free haptoglobin after etomidate in propylene glycol was significantly greater after 240 and 360 min (P艋0.003 and P艋0.002, respectively) (table 1).
Comment Several adverse effects caused by propylene glycol have been described: hypotension, pain on injection, lactic acidosis and pulmonary hypertension.1 3–5 In our study, a single injection of etomidate 0.3 mg kg91 dissolved in propylene glycol increased free haemoglobin (514%) and decreased serum haptoglobin (52.8%) concentrations significantly, indicating intravascular haemolysis. Free haemoglobin is bound within a few minutes by haptoglobin, forming a haptoglobin– haemoglobin complex. The half-life of haptoglobin is 3–4 days compared with that of the haptoglobin– haemoglobin complex of only 8 min. If intravascular free haemoglobin increases, haptoglobin concentration decreases, which is a measurable sign of haemolysis. Haemolysis and cell lysis associated with an induction dose of etomidate dissolved in propylene glycol may not cause detectable renal injury in healthy individuals. However, several other drugs are also dissolved in propylene glycol such as lorazepam (osmolality 12800 mosmol litre91) and
1.79 (0.13) 1.47 (0.13) 1.36 (0.12) 1.39 (0.13)
nitroglycerin (osmolality 4550 mosmol litre91).2 Combined use of drugs dissolved in propylene glycol may increase the likelihood and severity of haemolysis. If etomidate dissolved in propylene glycol or other drugs with similar formulations are injected repeatedly after short intervals, or if they are used in combination, circulating haptoglobin may be depleted completely. Under such circumstances free haemoglobin from haemolysis may exceed binding capacity and exert toxic effects.6 Intraoperative autotransfusion in patients who have received etomidate dissolved in propylene glycol also makes haemolysis problematic. It has been shown that infusion of packed red cells, especially from autotransfusion, decreases haptoglobin concentrations.7 In fact, haptoglobin was undetectable in seven of 47 patients after autotransfusion. Etomidate is a desirable induction agent for older, less healthy patients because it does not effect cardiovascular stability. These patients often undergo procedures (total hip replacement or vascular surgery) that use autotransfusion. In such patients, the combined effects of etomidate in propylene glycol and autotransfusion may decrease haptoglobin concentrations. We speculate that those likely to be affected include patients with other risk factors, such as impaired renal function or patients in shock who need high re-transfusion volumes. Our results are consistent with the hypothesis that propylene glycol is a less safe vehicle than lipid emulsion for etomidate. Side effects associated with propylene glycol may be toxic for some patients.
Acknowledgements The study was supported by the Institute for Anaesthesiology, Ludwig-Maximilians University, Munich, Germany and the Department of Anesthesia and Critical Care, University of Chicago, IL, USA.
References 1. Doenicke A, Roizen MF, Nebauer AE, Kugler A, Hoernecke R, Beger-Hintzen H. A comparison of two formulations for etomidate, 2-hydroxpropyl-beta-cyclodextrin (HPCD) and propylene glycol. Anesthesia and Analgesia 1994; 79: 933–938.
388 2. Doenicke A, Nebauer AE, Hoernecke R, Mayer M, Roizen MF. Osmolalities of propylene glycol-containing drug formulations for parenteral use. Should propylene glycol be used as a solvent? Anesthesia and Analgesia 1992; 75: 431–435. 3. Bedichek E, Kirschbaum B. A case of propylene glycol toxic reaction associated with etomidate infusion. Archives of Internal Medicine 1991; 151: 297–298. 4. Demey HE, Daelemars RA, Verpooten GA, De Broe ME, Van Campenhout CM, Lakiere FV, Schepens PJ, Bossaert LL. Propylene glycol induced side effects during intravenous nitroglycerin therapy. Intensive Care Medicine 1988; 14: 221–226.
British Journal of Anaesthesia 5. Levy ML, Aranda M, Zelman V, Glannotta SL. Propylene glycol toxicity following continuous etomidate infusion for the control of refractory cerebral edema. Neurosurgery 1995; 37: 363–369. 6. Goldfinger D. Acute hemolytic transfusion reactions—a fresh look at pathogenesis and considerations regarding therapy. Transfusion 1977; 17: 85–98. 7. Henn A, Hoffmann R, Müller HAG. Haptoglobin determination in patients serum after intraoperative autotransfusion with Haemonetics Cell-Saver III. Haemolysis and intraoperative autotransfusion. Anaesthesist 1988; 37: 741–745.