The effect of ketamine pretreatment on propofol injection pain in 100 women
C. H. Tan Department of Anaesthesia, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Hong Kong, People's Republic of China
A controlled, randomised double-blind study was performed to compare the prior intravenous administration of ketamine 10 mg (1 ml) or 0.9% saline (1 ml) on propofol injection pain. One hundred patients of ASA status 1 or 2 presenting for gynaecological surgery were studied. Following an initial 5-ml bolus of propofol into a dorsal hand vein, 30 s after the treatment, 84% of the saline control patients experienced mild or severe pain compared to 26% of those who were given ketamine pretreatment (p < 0.05).
Propofol is a popular induction agent, especially for short cases, day surgery and when a laryngeal mask is to be used. Pain on injection occurs in 28–90% of patients and this may be severe [1, 2]. Various methods have been used to reduce this pain, including alfentanil [3, 4], metoclopramide and local anaesthetics [5, 6], addition of lignocaine to the propofol emulsion , pretreatment with intravenous lignocaine, preparation of skin before venepuncture with nitroglycerin ointment , chilling of the propofol to 4 °C , injection into large antecubital veins or into a freely flowing intravenous line [10, 11] and the dilution of the propofol emulsion with Intralipid .
Ketamine has been in clinical use for more than 30 years. Although unpleasant dreams and emergence reactions are associated with it, ketamine has some useful qualities, notably less marked cardiorespiratory depressant effects than other anaesthetic drugs [12, 13], and it has analgesic and local anaesthetic properties [14–16].
We conducted a prospective, randomised, double-blind trial in unpremedicated patients to determine if ketamine could reduce propofol injection pain in dorsal hand veins.
Ethics Committee approval was obtained and all patients gave informed consent. One hundred Chinese patients, ASA 1 or 2, aged 15–65 years, presenting for gynaecological surgery under general anaesthesia were randomly distributed into two groups. Patients with a history of allergy or fits, or who were taking sedative or analgesic medication were not studied. Pregnant women and those requiring a rapid sequence induction were similarly considered unsuitable for study.
Patients received either ketamine 10 mg in a total volume of 1 ml with 0.9% saline (n = 50; Group 1) or 1 ml 0.9% saline (n = 50; Group 2) 30 s before administration of propofol. All drugs were prepared at room temperature (21–23 °C) by a doctor not involved in induction of anaesthesia. Patients were unpremedicated.
On arrival in the operating theatre, a 20G cannula was inserted into a vein on the dorsum of the patient's hand. Lactated Ringers' solution was infused at the rate of 250 ml.h−1 using a volumetric pump. Arterial blood pressure was measured noninvasively and heart rate and peripheral oxygen saturation (SpO2) were recorded before injecting propofol and at 1, 2 and 3 min after.
Thirty seconds after intravenous injection of the test treatment, anaesthesia was induced with propofol 2.5 mg.kg−1. The first 5-ml bolus was given over 5 s; 15 s later, the patient was asked about the presence of injection pain. She was asked to grade this as ‘no pain’, ‘mild pain’ or ‘severe pain’ and these were then scored as 0, 1 or 2, respectively. Mild pain was defined as discomfort in the arm or hand, but was not a cause of distress and was acceptable to the patient. Severe pain was defined as grimacing or limb withdrawal and patients' comments; it was unacceptable to the patient. Both patient and anaesthetist were unaware of the nature of the test drug.
Following this, the injection of propofol continued at 1 ml.s−1 until anaesthesia was fully induced. Any excitation during induction and any recovery emergence reactions were noted. Once the patient was unconscious, a facemask was applied and the patient allowed to breathe nitrous oxide 60% and isoflurane 1.5% in oxygen either spontaneously or assisted. The duration of anaesthesia was recorded.
The results were analysed statistically using unpaired Student's t-tests and the Chi-squared test with the Yates correction when appropriate. Results were considered statistically significant when p < 0.05.
Patients' age, weight, ASA status and the duration of anaesthesia are presented in Table 1. There were no statistically significant differences between the groups.
Patient details and duration of anaesthesia. Values are mean (SD) where appropriate.
The incidence of pain was 26% in the ketamine group compared with 84% in the control group (p < 0.01). Severe and mild pain occurred in 14% and 12% respectively of those given ketamine compared to 36% and 48% in the control group (p < 0.05) (Table 2). The incidence of excitatory effects such as twitching, writhing and jerking was 6% in the ketamine group and 26% in the control group.
Number of patients with the pain scores shown after 5 ml intravenous propofol (1%) following the pretreatment shown. * p < 0.05 for intergroup differences. 0 = no pain; 1 = mild pain; 2 = severe pain.
There were no emergence reactions defined as dreams, hallucinations, delayed recovery and looking dissociated from surroundings in either treatment group. Hypotension, defined in our study as a fall of systolic blood pressure of greater than 20% of baseline value, occurred in 58% of the ketamine group compared to 60% of the control group. None of the patients experienced a heart rate of less than 50 beat.min−1 and none had an SpO2 < 94%.
The incidence of injection pain caused by propofol in 16% Cremophor EL is reported as 30–80% [17–20]. Reformulation of the drug as an aqueous emulsion in soya-bean oil to reduce the risk of anaphylactoid reactions has not had a corresponding effect on injection pain. This is reported to range from 30–70% in dorsal hand veins [21–23] to 0–30% in large, proximal veins [24–26]. The explanations for the pain include endothelial irritation, osmolality differences, unphysiological pH and the activation of pain mediators .
Many methods have been used to try to reduce the incidence of pain of propofol injection with variable success. Lignocaine, added to or given before injection of propofol, is widely employed. However, protection is not complete, with a failure rate of between 13% and 44% [28, 29]. Lignocaine (when premixed with propofol) acts as a stabiliser of the kinin cascade during the injection. Cooling the propofol to 4 °C reduces its injection pain possibly by delaying the activation of enzymatic cascade of pain mediators. Injecting into a large forearm vein also reduces the incidence of pain, probably by reducing contact between drug and endothelium. Diluting propofol with Intralipid and the application of EMLA cream to the skin before venepuncture have also been reported to reduce the incidence of propofol injection pain . Metoclopramide shares structural and physiochemical properties with lignocaine  and is a weak local anaesthetic . It has been shown to be as effective as lignocaine in reducing propofol injection pain . Opioids such as alfentanil may also reduce the incidence of pain, in the case of alfentanil from 84% to 36% .
The incidence of pain in our study using dorsal hand veins was reduced from 84% to 26% by ketamine pretreatment and this compares favourably with other methods. Our use of direct questioning to assess the severity of pain is thought to be more accurate than other methods of assessment .
Ketamine has been shown to have a local anaesthetic action when administered intravenously for regional anaesthesia and it also has an analgesic action when given intrathecally. The dose used by us is low (10 mg) (approximately 0.2 mg.kg−1 in our patients) and is much lower than the dose which one would choose if one wanted a central analgesic effect. It seems likely that the reduction in injection pain was the result of a peripheral action which attenuated the afferent pain pathway.
As a noncompetitive NMDA receptor antagonist, ketamine may activate NMDA receptors either in the vascular endothelium or in the central nervous system; this is another possible mechanism for our findings. It is possible that combinations of ketamine and propofol may have an additive hypnotic effect which diminishes pain sensation centrally . The optimum dosage and timing of ketamine pretreatment as a means of preventing propofol injection pain will require further investigation.
We thank the staff of the Department of Anaesthesia of Pamela Youde Nethersole Eastern Hospital for their help.