Br.J. Anaesth. (1976), 48, 1187
REACTIONS TO INTRAVENOUS INJECTIONS OF DIAZEPAM H . SlEBKE, B . B . ELLERTSEN AND B . LlND SUMMARY
Local reactions during and after i.v. injection of two different formulations of diazepam were studied. Two-thirds of the patients felt pain during the injection. Verified or probable thrombophlebitis occurred with increasing frequency following operation, indicating a late onset. One month after discharge, 29% of those who had received diazepam in glycoferol-alcohol-benzoic acid complained of tender injection sites, compared with only 10% of the patients who received diazepam in cremophor EL. The difference is significant, indicating an influence of the solvent system.
other injection was given through the same needle, and no other infusions were given into the same arm. The arterial pressure was measured 2 min later. No other drugs were given during that period, but respiratory depression necessitated artificial ventilation in some patients. The induction sequence was continued with small doses of thiopentone, if required, and suxamethonium followed by tracheal intubation. Anaesthesia was maintained with halothane in nitrous oxide in oxygen, and an infusion of suxamethonium. The site of the injection was examined and reexamined on the 1st and on the 4th or 5th days after anaesthesia, and the presence or absence of tenderness, venous thickening, local erythema or oedema were recorded. One month after discharge from the hospital, each patient received a questionnaire, asking for the following information: Has your left arm been tender after the injection ? If yes: how large was the area of tenderness ? Have you been handicapped in your work because of the tenderness ? Have you consulted a doctor because of the discomfort this has caused you ? RESULTS
METHODS
The two formulations of Stesolid were used to induce anaesthesia in 120 patients undergoing gynaecological operations. Randomized 5-ml ampoules containing either mixture were given at an injection rate of 1 ml/min in the left forearm, through a 23-gauge needle. When the patient fell asleep, or the maximum induction dose of 3 mg/10 kg body weight (maximum 25 mg) was reached, the needle was withdrawn. No HARALD SlEBKE, M.D.; BJ0RG B. ELLERTSEN, M.D.; BJ0RN
LIND, M.D. ; Department of Anaesthesiology, University of Oslo, Akershus Central Hospital, N 1474 Nordbyhagen, Norway.
Fifty-six patients in the group who received the original formula and 58 who received the new formula answered the questionnaire. The results are shown in tables I, II and III. DISCUSSION
In both groups, pain during the injection was the rule rather than the exception. Two patients felt pain extending over the whole forearm. The frequency of tenderness increased equally in both groups from the 1st to the 4th or 5th day after anaesthesia. Venous thickening on the 4th or 5th day was always painful, suggesting thrombophlebitis. The
Downloaded from http://bja.oxfordjournals.org/ at Karolinska Institutet on July 15, 2015
Pain occurs frequently when diazepam is injected i.v. Langdon, Harlan and Bailey (1973) found that 3.5% of patients who received the drug developed thrombophlebitis at the site of injection. In some instances the effect was protracted, with marked discomfort. The frequency was reduced when the injections were given slowly into larger veins. The limited aqueous solubility of diazepam necessitates special solvents. Precipitation of diazepam occurs when the solution is diluted, either by mixing with a slow drip infusion or by injection into a vein at a low infusion rate. The possibility of precipitates causing thrombophlebitis was considered by Jusko, Gretch and Gassett (1973). Assuming that the solvent system is responsible for these complications, Dumex Ltd, Copenhagen, have produced an alternative formula of injectable diazepam. In this preparation (Stesolid), which is similar chemically to Valium (Roche), the original solvent system (glycoferol-alcohol-benzoic acid) is replaced by cremophor EL. In the following clinical study, the newer and older solutions were compared.
BRITISH JOURNAL OF ANAESTHESIA
1188
TABLE III. Answers to questionnaire 4 weeks after discharge
TABLE I. Reactions during the injection of two formulations of diazepam
Formulation
Formulation Original*
Pain
Yes No
No.
0/
38 17
69 31
Original New
No.
/o
Tender arm 37 21
64 36
Area of tenderness (cm)
Local erythema
—
1 54
2 98
2 55
— 4 96
No.
No.
16 40
29 71
52
1-4 5-10 10
6
10 90
16 7 5
Handicapped at work
difference of 9% and 4% between the original and new formulations, respectively, is not statistically significant. During the succeeding period, the frequency of tenderness increased in the group who received the original formulation, while in the other group the incidence decreased. The difference is significant (P
REACTIONS TO INTRAVENOUS INJECTIONS OF DIAZEPAM H . SlEBKE, B . B . ELLERTSEN AND B . LlND SUMMARY
Local reactions during and after i.v. injection of two different formulations of diazepam were studied. Two-thirds of the patients felt pain during the injection. Verified or probable thrombophlebitis occurred with increasing frequency following operation, indicating a late onset. One month after discharge, 29% of those who had received diazepam in glycoferol-alcohol-benzoic acid complained of tender injection sites, compared with only 10% of the patients who received diazepam in cremophor EL. The difference is significant, indicating an influence of the solvent system.
other injection was given through the same needle, and no other infusions were given into the same arm. The arterial pressure was measured 2 min later. No other drugs were given during that period, but respiratory depression necessitated artificial ventilation in some patients. The induction sequence was continued with small doses of thiopentone, if required, and suxamethonium followed by tracheal intubation. Anaesthesia was maintained with halothane in nitrous oxide in oxygen, and an infusion of suxamethonium. The site of the injection was examined and reexamined on the 1st and on the 4th or 5th days after anaesthesia, and the presence or absence of tenderness, venous thickening, local erythema or oedema were recorded. One month after discharge from the hospital, each patient received a questionnaire, asking for the following information: Has your left arm been tender after the injection ? If yes: how large was the area of tenderness ? Have you been handicapped in your work because of the tenderness ? Have you consulted a doctor because of the discomfort this has caused you ? RESULTS
METHODS
The two formulations of Stesolid were used to induce anaesthesia in 120 patients undergoing gynaecological operations. Randomized 5-ml ampoules containing either mixture were given at an injection rate of 1 ml/min in the left forearm, through a 23-gauge needle. When the patient fell asleep, or the maximum induction dose of 3 mg/10 kg body weight (maximum 25 mg) was reached, the needle was withdrawn. No HARALD SlEBKE, M.D.; BJ0RG B. ELLERTSEN, M.D.; BJ0RN
LIND, M.D. ; Department of Anaesthesiology, University of Oslo, Akershus Central Hospital, N 1474 Nordbyhagen, Norway.
Fifty-six patients in the group who received the original formula and 58 who received the new formula answered the questionnaire. The results are shown in tables I, II and III. DISCUSSION
In both groups, pain during the injection was the rule rather than the exception. Two patients felt pain extending over the whole forearm. The frequency of tenderness increased equally in both groups from the 1st to the 4th or 5th day after anaesthesia. Venous thickening on the 4th or 5th day was always painful, suggesting thrombophlebitis. The
Downloaded from http://bja.oxfordjournals.org/ at Karolinska Institutet on July 15, 2015
Pain occurs frequently when diazepam is injected i.v. Langdon, Harlan and Bailey (1973) found that 3.5% of patients who received the drug developed thrombophlebitis at the site of injection. In some instances the effect was protracted, with marked discomfort. The frequency was reduced when the injections were given slowly into larger veins. The limited aqueous solubility of diazepam necessitates special solvents. Precipitation of diazepam occurs when the solution is diluted, either by mixing with a slow drip infusion or by injection into a vein at a low infusion rate. The possibility of precipitates causing thrombophlebitis was considered by Jusko, Gretch and Gassett (1973). Assuming that the solvent system is responsible for these complications, Dumex Ltd, Copenhagen, have produced an alternative formula of injectable diazepam. In this preparation (Stesolid), which is similar chemically to Valium (Roche), the original solvent system (glycoferol-alcohol-benzoic acid) is replaced by cremophor EL. In the following clinical study, the newer and older solutions were compared.
BRITISH JOURNAL OF ANAESTHESIA
1188
TABLE III. Answers to questionnaire 4 weeks after discharge
TABLE I. Reactions during the injection of two formulations of diazepam
Formulation
Formulation Original*
Pain
Yes No
No.
0/
38 17
69 31
Original New
No.
/o
Tender arm 37 21
64 36
Area of tenderness (cm)
Local erythema
—
1 54
2 98
2 55
— 4 96
No.
No.
16 40
29 71
52
1-4 5-10 10
6
10 90
16 7 5
Handicapped at work
difference of 9% and 4% between the original and new formulations, respectively, is not statistically significant. During the succeeding period, the frequency of tenderness increased in the group who received the original formulation, while in the other group the incidence decreased. The difference is significant (P
