Solvent for etomidate may cause pain and adverse effects

British Journal of Anaesthesia 83 (3): 464–6 (1999)

Solvent for etomidate may cause pain and adverse effects A. W. Doenicke1*, M. F. Roizen2, R. Hoernecke1, W. Lorenz3 and P. Ostwald1 1Institute

for Anaesthesiology, Ludwig-Maximilians University, Innenstadtkliniken, Pettenkoferstr. 8a, D-80336 Mu¨nchen, Germany. 2Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA. 3Institute for Theoretical Surgery, Philipps University, Marburg, Germany *Corresponding author We tested the hypothesis that the solvent for etomidate was a factor in the incidence of pain and other side effects after injection, and that these were associated with histamine release. Nine of 10 volunteers who received etomidate in a propylene glycol formulation reported moderate to severe pain on injection; only one of 10 subjects who received a lipid emulsion formulation reported mild pain (P,0.05). The incidence of venous sequelae in the injected vein over the next 8 days was 50% in the propylene glycol group and 0% in the lipid emulsion group (P,0.05). In one volunteer in the propylene group, there was a 13-fold increase in histamine concentrations and in one subject a four-fold increase. In the lipid emulsion group, no volunteer had an increase in histamine concentrations .1 ng ml–1. We conclude that etomidate formulated in propylene glycol may cause direct injury to vascular endothelium resulting in pain and venous sequelae, whereas etomidate in lipid emulsion does not. There was no relationship between pain or venous sequelae and histamine release. Br J Anaesth 1999; 83: 464–6 Keywords: anaesthetics i.v., etomidate; formulations, etomidate; histamine; pain, injection Accepted for publication: April 12, 1999

Rapid administration of drugs formulated in propylene glycol is associated with pain on injection and inflammation, which in turn is associated with phlebitis and thrombosis.1 2 Etomidate is a poorly water-soluble drug which can be formulated in propylene glycol, lipid emulsions, polyethylene glycol or phosphate buffers. Originally formulated in a phosphate buffer, etomidate was not associated with histamine release.3 In 1977, because phosphate-buffered etomidate was unstable for long-term storage, etomidate was re-formulated in a 35% propylene glycol solution. In the past 10 yr, lipid emulsions have become available as solvents for poorly water soluble drugs. We sought to determine if the side effects of pain and/or venous sequelae after etomidate were caused by release of histamine as a result of the hyperosmolality or other properties of the solvent.

Methods and results After obtaining approval from the Institutional Review Board and written informed consent, we studied 20 healthy volunteers (12 males; ASA I; aged 21–27 yr) allocated randomly to receive etomidate in propylene glycol (Hypnomidate®, marketed as Amidate® in the USA, JanssenCilag, Neuss, Germany) or in a mixture of soybean oil and medium-chain triglycerides (LCT/MCT) (Etomidate®, Lipuro, B. Braun Melsungen, Melsungen, Germany). After

insertion of an i.v. catheter into a dorsal vein of the hand, etomidate 0.3 mg kg–1 in one of the two formulations was injected as a bolus over 30 s. Volunteers and observers were blinded to the formulation. Before, 3 and 5 min after injection of etomidate, blood was obtained from the antecubital vein of the ipsilateral arm and assayed for histamine concentrations. Plasma concentrations of histamine were measured using a fluorometric–enzymatic method.4 This assay has a lower limit of detection of 20 pg ml–1 and a coefficient of variation of 13% at low plasma concentrations and 9% at high plasma concentrations. None of the drug formulations used interfered with the fluorometric assay at concentrations up to 10–3 mol ml–1. Heart rate was measured by the ECG (Siemens Sirecust 300). Arterial pressure (systolic, diastolic) was recorded non-invasively (Dinamap 1846SX, Critikon) every 1 min after induction of anaesthesia. Changes in arterial pressure and heart rate were considered significant if they deviated by 20% from baseline values. Observers assessed each subject for 18 signs and symptoms of histamine release, including sensation of heat, tightness of the chest, flush, erythema, coughing, stuffy nose, tachycardia, hypotension, hypertension, pulsation at the temples, nausea, metallic taste, salivation, headache, outbreak of sweating, ‘wet eyes’, head congestion or wheals. Subjects were also assessed for pain before, during and

© British Journal of Anaesthesia

Propylene glycol and histamine release

Table 1 Histamine concentrations and adverse effects in volunteers after injection (p.a.) of etomidate. * 05No pain on injection; 105intolerable pain. Histamine p.a.5Highest histamine plasma concentration of the two measurements, 3 and 5 min after injection of etomidate. ∆Histamine5calculated change in histamine plasma concentration from baseline to p.a. Subject No.

Flush

Erythema

Phlebitis

Thrombosis

Pain score 0–10*

Histamine base (ng ml–1)

Histamine p.a. ∆Histamine (ng ml–1)

Etomidate lipid emulsion group 1 2 8 9 10 11 16 17 18 19

X X

X X

X

n510 Min. Max. Median

6

1

X

X

0

0

0 0 0 0 0 3 0 0 0 0

0.25 0.36 0.30 0.15 0.03 0.04 0.24 0.28 0.30 0.43

1.06 0.48 0.24 0.21 0.04 0.09 0.42 0.52 0.73 0.51

0.81 0.12 –0.06 0.06 0.01 0.05 0.18 0.24 0.43 0.08

1 0 3

10 0.03 0.43 0.27

10 0.04 1.06 0.45

10 –0.06 0.81 0.10

7 6 0 5 9 7 8 9 7 8

0.37 0.74 0.33 0.28 0.27 0.27 0.25 0.27 0.28 0.33

0.42 2.48 0.49 0.56 0.75 3.66 0.43 0.37 0.12 0.42

0.05 1.74 0.16 0.28 0.48 3.39 0.18 0.10 –0.16 0.09

9 0 9 7

10 0.25 0.74 0.28

10 0.12 3.66 0.46

10 –0.16 3.39 0.17

Etomidate propylene glycol group 3 4 5 6 7 12 13 14 15 20

X X X

n510 Min. Max. Median

8

X X X X X

X X

X X X

X X X

3

4

1

after recovery from these symptoms. Pain was assessed on a visual analogue scale (05no pain, 105intolerable pain). On each day for 8 days after injection, observers examined the subjects for signs of venous sequelae. Pearson’s chi-square one-way analysis of variance and the Mann–Whitney U test were used for comparisons within and between groups. For comparison of histamine release, the number of volunteers with an increase in histamine .1 ng ml–1 was compared. Differences were considered statistically significant at the 5% level (P,0.05). Nine of 10 volunteers who received etomidate formulated in propylene glycol reported moderate to severe pain on injection (Table 1) whereas one of 10 volunteers who received etomidate formulated in lipid emulsion reported mild pain on injection (P,0.05). The incidence of venous sequelae in the injected vein was 50% in the propylene glycol group and 0% in the lipid emulsion group (P,0.05) (Table 1). Thrombosis in one female volunteer in the propylene glycol group required local treatment for several weeks. There was no correlation between histamine release and pain or venous sequelae (Table 1). Plasma concentrations of histamine increased significantly in two subjects in the propylene glycol group, from 0.74 to 2.48 ng ml–1 (No. 4) and from 0.27 to

3.66 ng ml–1 (No. 12), respectively. These increased concentrations in the same two subjects were associated with urticaria, cough, throat irritation and colicky pain in the abdomen in one subject (No. 12), and flushing and cough in the other (No. 4). In one other subject (No. 7) who received the propylene glycol formulation, and in two (Nos 1 and 18) who received the lipid emulsion, plasma concentrations of histamine increased moderately and were associated with pain and flush (No. 7) or with flush and/or erythema (Nos 1 and 18) (Table 1). Haemodynamic state was stable after injection of the preparations, even in the two subjects with significant increases in histamine concentration. Plasma samples collected from the propylene glycol group were red for 20 min after injection, indicating haemolysis.5 Plasma from the lipid emulsion group was tinged white (like the lipid emulsion) at 3 min but was clear after 5 min.

Comment Etomidate was formulated originally as a sulphate in a phosphate buffer with a pH of 3.3 and an osmolality of 270 mosmol kg–1 and was not associated with histamine release.3 When formulated in 35% propylene glycol, etomid-

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ate has an osmolality of 4900 mosmol kg–1.6 We postulated that the high osmolality of the etomidate formulation was the cause of pain on injection, histamine release and phlebitis, conditions that are often associated. Replacement of propylene glycol by lipid emulsion significantly reduced the occurrence of pain on injection, venous sequelae2 and haemolysis5 after injection of etomidate. However, in this study, increases in histamine concentrations were not associated with pain or venous sequelae. The more than 13-fold increase in histamine concentration observed in one volunteer (No. 12) was not associated with haemodynamic deterioration. The absence of hypotension may be explained by the only brief presence of histamine in the circulation.7 The small amount of histamine released from destroyed blood and tissue cells is not sustained by the cascade mechanism of mediators and does not therefore produce haemodynamic sequelae.7 Histamine release and pain on injection or venous sequelae are probably not associated because the mechanisms responsible for these events are different. Perhaps the mechanisms that produce vessel inflammation and pain also differ. The hyperosmolality of the propylene glycol formulation may cause direct injury to vascular endothelium,8 resulting in local physical damage and release of histamine into the circulation. Pain and venous sequelae reported in this and previous studies1 2 can be attributed to stimulation of pain receptors and irritation of the vascular tissue.8 Lack of association of

histamine release with pain or venous sequelae implies that the mechanisms producing these effects may be different.

References

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1 Zacharias M, Clarke RS, Dundee JW, Johnson SB. Venous sequelae following etomidate. Br J Anaesth 1979; 51: 779–83 2 Doenicke A, Kugler A, Vollmann N, Suttmann H, Taeger K. Etomidate using a new solubilizer. Experimental clinical studies on venous tolerance and bioavailability. Anaesthesist 1990; 39: 475–80 3 Doenicke A, Lorenz W, Beigl R, et al. Histamine release after intravenous application of short-acting hypnotics. A comparison of etomidate, Althesin (CT1341) and propanidid. Br J Anaesth 1973; 45: 1097–104 4 Lorenz W, Neugebauer E. Current techniques of histamine determination: fluorometric assays. In: Uvna¨s B, eds. Handbook of Experimental Pharmacology. New York: Springer, 1990; 385–93 5 Doenicke A, Roizen MF, Hoernecke R, Mayer M, Ostwald P, Foss J. Haemolysis after etomidate: comparison of propylene glycol and lipid formulations. Br J Anaesth 1997; 79: 386–8 6 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? Anesth Analg 1992; 75: 431–5 7 Watkins J. Allergic and pseudoallergic mechanisms in anesthesia. Int Anesthesiol Clin 1985; 23: 17–40 8 Ruo W, Shay J, Attele A, Doenicke A, Moss J. Propylene glycol damages vascular smooth muscle and endothelium. Anesthesiology 1992; 77S: A1096