The anaesthetic potency of propofol in the rat is reduced by simultaneous intravenous administration of lignocaine.

Lignocaine added to the anaesthetic preparation Diprivan reduces propofol induced pain on injection. This effect is due to a drop in pH which decreases the content of propofol in the aqueous phase of the soya bean emulsion. This in turn changes the electrostatic forces in the emulsion and destabilization occurs. The effect of lignocaine on the anaesthetic potency of propofol was validated in a randomized blind study in the rat. The induction dose of 1% propofol mixed with 1% lignocaine (10 + 1) was significantly higher when compared with the induction dose of propofol 1% given after a separate injection of 1% lignocaine (9.4 +/- 5.5 vs. 5.6 +/- 5.2 mg; P < 0.05). The duration of sleep was shorter in rats injected with propofol 1% mixed with lignocaine 1% (10 + 1) compared with those given 1% lignocaine and 1% propofol in separate injections (160 +/- 181 vs. 375 +/- 202 s; P < 0.05). The anaesthetic potency of propofol was not significantly changed by the addition of either saline or hydrochloric acid. The anaesthesia inducing effect was not time-dependent. A similar lower potency was observed for a solution stored for 4 h compared with one freshly prepared, although sleeping time was longer (9.2 +/- 6.8 mg; 428 +/- 110 s) as compared with the 4 h mixture. The results indicate that lignocaine altered the propofol preparation. The reduced anaesthetic potency of propofol after addition of lignocaine is not due to the resultant drop in pH, which is known to occur.

Acidified propofol retains its anaesthetic potency after storage.

The reduction in propofol-induced pain on injection caused by the addition of lignocaine results mainly from a drop in pH, which reduces the concentration of propofol in the aqueous phase of the emulsion. It is not an effect of the local anaesthetic per se. Propofol emulsion mixed with lignocaine destabilizes within hours. We mixed 10 parts of propofol 1% emulsion with one part of 0.0064 M HCl or 0.013 M HCl, respectively. These mixtures were stored for 3 months and compared with a freshly prepared solution of propofol 1% emulsion and saline, in the same proportion, regarding their ability to induce anaesthesia in the rat. There was no significant difference in the amount of propofol required to induce anaesthesia, nor was there any difference in recovery time between the three groups.

Effect of lignocaine and pH on propofol-induced pain.

Propofol has the disadvantage of pain on injection. A higher partition of propofol in the aqueous phase of the preparation causes a higher incidence of pain on injection while addition of 1% lignocaine to propofol reduces pain. The low concentration of this local anaesthetic and the rapid pain relief observed indicates that mechanisms other than local anaesthesia are involved, that is change in pH. We performed a clinical study to investigate the influence of lignocaine and pH on pain during injection of 1% Diprivan. Ten parts of 1% Diprivan were mixed with one part of saline, 1% lignocaine or hydrochloric acid to achieve the same pH as that after addition of lignocaine. Diprivan 1% mixed with 1% lignocaine and with hydrochloric acid gave mean pain ratings (1-10) of 0.32 (SD 0.75) (n = 25) and 0.88 (1.30) (n = 24), respectively. These ratings were significantly lower than ratings after injection of a saline-Diprivan mixture (2.18 (2.06), n = 22). The pH of the 1% Diprivan formulation decreased after mixing with 1% lignocaine. The concentration of propofol in the aqueous phase was lower when 1% Diprivan was mixed with 1% lignocaine (0.376 g litre-1) or HCl (0.392 g litre-1) compared with 1% Diprivan and saline (0.476 g litre-1) mixed in the same proportion. Thus pH changes may modify propofol-induced pain on injection by a mechanism different from the effect of the local anaesthetic on the vascular endothelium. Our findings may explain why lignocaine mixed with propofol causes less pain than injection of lignocaine followed by propofol.

Large emphysematous bullae. Successful treatment with thoracoscopic technique using fibrin glue in poor-risk patients.

Five patients with poor lung function (FEV1, 0.8 to 1.0 L; MVV, 27 to 36 L/min) and large emphysematous bullae were operated on. Fibrin glue was introduced into the bullae through a thoracoscope. The results have been excellent and no serious perioperative or postoperative complications have occurred. The patients have all improved clinically and are very satisfied with the results. Postoperatively, FEV1 was between 1.0 and 1.2, and MVV was 30 to 52 L. The clinical improvement was, however, larger than these figures illustrate. Our preliminary experience using this technique suggests that it can be used in patients with very low lung function with a minimal risk. We propose that all patients with severe emphysema should be screened for bullous components because improvement might be possible by operation with this minimally traumatizing technique.

An alternative method of increasing PCO2 using apnoea and continuous positive airway pressure.

We have examined the use of continuous positive airway pressure (CPAP) and apnoeic oxygenation for restoration of spontaneous breathing at the end of anaesthesia after controlled ventilation. We studied 45 adult patients without a history of acute or chronic respiratory disturbances. Anaesthesia was induced with thiopentone or propofol and maintained with nitrous oxide and enflurane in oxygen. The patients were normocapnic during artificial ventilation. At the end of surgery, the lungs were ventilated for 5 min with oxygen and then given a CPAP of 8 cm H2O. Spontaneous ventilation was regained after a mean of 5 min and an arterial blood sample was obtained at the third breath. All patients were well oxygenated (PO2 mean 43.5 kPa, range 21-76 kPa) when spontaneous ventilation started. The pH was close to 7.28 in most cases (mean 7.28, range 7.21-7.32), and PCO2 varied in the range 6.6-9.9 kPa (mean 7.9 kPa). It is concluded that the method is safe with regard to oxygenation and acid-base balance.

Changes in cerebral perfusion after acute head injury: comparison of CT with Tc-99m HM-PAO SPECT.

Technetium-99m hexamethylpropyleneamine oxime (Tc-99m HM-PAO) was successfully used with single photon emission computed tomography (SPECT) on fourteen comatose patients who had acute head injuries. The SPECT scans were correlated with computed tomography (CT) scans obtained within 24 hours of the injury. Tc-99m HM-PAO SPECT was shown to have the following advantages: It reflected perfusion changes, was more sensitive than CT in demonstrating more lesions, and demonstrated lesions at an earlier stage than those demonstrated with CT. Different types of lesions, as evidenced by cerebral perfusion changes, have been described and categorized. The lesions that had a favorable prognosis could be separated from those with an unfavorable prognosis on the basis of the findings of Tc-99m HM-PAO SPECT.

Sympathetic outflow in man after anaesthesia of the glossopharyngeal and vagus nerves.

Bilateral lidocaine blocks of glossopharyngeal and vagus nerves in the neck were made in two healthy subjects to achieve deafferentation of arterial and cardiopulmonary baroreceptors. Microelectrode recordings of muscle nerve sympathetic activity (MSA) were made in one peroneal nerve; in one subject skin sympathetic activity (SSA) was recorded simultaneously in the other peroneal nerve. Following the nerve block in the neck there was a strong increase of MSA accompanied by temporary hypertension and tachycardia. The normal cardiac rhythmicity of MSA disappeared and the outflow appeared as bursts of impulses of variable duration occurring in a slow, irregular rhythm. Thus MSA became similar to SSA, but the activities never became synchronous. During the nerve block arousal stimuli evoked single bursts of MSA, a reflex response which normally occurs in SSA but not in MSA. It is concluded that (1) cardiac rhythmicity of MSA is due to baroreceptor influence; (2) a low level of MSA at rest depends on strong baroreceptor inhibition and not on a weak central drive; (3) central sympathetic outflows to skin and muscle are similar though not identical and the different characteristics normally observed are due to a large extent to different modulatory influences from afferent activity (presumably of baroreceptor origin) in glossopharyngeal and vagus nerves; and (4) baroreceptor deafferentation resulting in resting tachycardia and hypertension may explain sympathetic hyperactivity in the Guillain-Barré syndrome.

An anaesthetic lidocaine/prilocaine cream (EMLA) for epicutaneous application tested for cutting split skin grafts.

A 5% eutectic mixture of the two local anaesthetics lidocaine and prilocaine (EMLA, Astra Läkemedel AB) has been tested for application to the skin in the removal of split skin grafts. EMLA is an oil-in-water emulsion cream, containing 50 mg of active substances per ml (25 mg lidocaine, 25 mg prilocaine). The cream has been used on the donor sites of 146 patients and was applied a minimum of 1 h 30 min before surgery. 123 patients (84.3%) experienced adequate analgesia, feeling only the pressure of the dermatome or slight pain without objection to the skin graft being cut. 20 patients (13.7%) described the pain as being moderate, but the operation could be completed without further local or general anaesthesia. Three patients (2.0%) needed additional anaesthesia. Six patients complained of slight transient irritation immediately after application. After removal of the cream, erythema was present in 42 patients, pallor in 62 and oedema in 14. The concentrations of lidocaine and prilocaine in the blood were measured in 106 patients and did not exceed 1100 ng ml-1 for lidocaine and 200 ng ml-1 for prilocaine. There were no systemic side-effects.

Does geographical location influence inflow requirements of the Bain breathing system?

A review of publications from various countries, using the Bain system with a fresh gas flow of 70 ml kg-1 min-1 and controlled ventilation, show a range of mean PaCO2 values between 36 and 43 mmHg. It was suggested that these differences could be related to the geographic location of the patient population studied. Anaesthetists from seven institutions in West Germany, England, Sweden, the United States, Australia and Canada collaborated in a preliminary study designed to find out whether these differences could be reduplicated. In 142 patients under a standard anaesthesia with controlled ventilation, PaCO2 values were determined 30 min after the fresh gas flows had been set. For 70 ml kg-1 min-1 the mean PaCO2 values ranged from 33 to 40 mmHg; for 100 ml kg-1 min-1 from 28 to 35 mmHg. Compared to the mean PaCO2 values from Canada, the results from Australia and the USA were not different and all at the lower end of this range; Sweden, West Germany and England reported significantly higher PaCO2 values. In the absence of any other obvious explanation, we suggest that patients in England and Northern Europe could have a higher CO2 output under anaesthesia than North American or Australian patients.

Gas flow measurements with a gas dilution technique.

A new method for gas flow measurements, based on a gas dilution technique, is described. A known amount of fresh room air is injected as a tracer gas into a carrier gas stream. The downstream concentration profile of the tracer gas is recorded with a portable mass-spectrometer. The flow rate of the carrier gas is calculated from the area under the tracer gas curve as electronically integrated. The method was tested against precision spirometers, one of the rolling seal type and one of the fluidistor type. It was shown that any rapid gas analyser might be used for the analyses, either of the tracer gas or of the carrier gas. The applicability of this method during general anaesthesia and in other clinical situations is discussed.

New anaesthetic formulation for epicutaneous application tested for cutting split skin grafts.

Ane-Pad (A 2358, Astra Lakemedel AB), a new local anesthetic formulation for application to the skin has been tested in the removal of split skin grafts. Ane-Pad is a thin cotton pad, containing a solution of 10% ketocaine base in a solvent mixture of isopropanol, glycerol and water. The pad has been used on the donor sites of 173 patients with a minimum application time of 1 h before surgery. Eighteen patients complained of slight, transient irritation immediately after application. After removal of the pad erythema was present in 39 patients and oedema in eight. In 157 patients (90.8%) analgesia was adequate. Two patients (1.1%) needed additional anaesthesia. The concentration of ketocaine in the blood was measured in 101 patients and did not exceed 850 ng ml--1. Therewere no systemic side-effects.

Accumulation of substances with melanin affinity to the internal ear. Therapeutic or ototoxic mechanism?

The capacity of the melanin in the internal ear to accumulate and retain labelled lidocaine, bupivacaine and chlorpromazine after intravenous and intraperitoneal injection was examined by whole-body autoradiography. Both young pigmented hooded rats and albino rats were studied. In the pigmented rats chlorpromazine showed the greatest accumulation, which was more pronounced in the cochlea than in the vestibular portion. The other two substances were evenly distributed in the internal ear. After a single injection of chlorpromazine and of bupivacaine these substances were still bound to the melanin of the internal ear after 14 days, which was the longest survival time. Lidocaine, on the other hand, had disappeared after only 4 days. In albino animals there was very weak, transient uptake of chlorpromazine and bupivacaine, but not of lidocaine, in the internal ear. In studies in vitro on isolated bovine eye melanin there was considerably greater adsorption of chlorpromazine than of lidocaine and bupivacaine.

Melanin capacity to accumulate drugs in the internal ear. A study on lidocaine, bupivacaine and chlorpromazine.

The distribution and retention of labelled lidocaine, bupivacaine, and chlorpromazine to melanin in the internal ear after intravenous and intraperitoneal injection were examined by whole-body autoradiography. Both young pigmented hooded rats and albino rats were studied. In the pigmented rats chlorpromazine showed the greatest accumulation, which was more pronounced in the cochlea than in the vestibular portion. The other two substances were evenly distributed in the internal ear. After a single injection of chlorpromazine and of bupivacaine these substances were still bound to the melanin of the internal ear after 14 days, which was the longest survival time. Lidocaine, on the other hand, had disappeared after only 4 days. Strong uptake and retention of the three substances were observed in the eyes of pigmented animals. In albino animals there was very weak, transient uptake in the internal ear of chlorpromazine and bupivacaine, but not of lidocaine. In studies in vitro on isolated bovine eye melanin there was considerably greater adsorption of chlorpromazine than of lidocaine and bupivacaine. An uptake was noted in the human eye in experiments in vitro. Clinical tests revealed no acute or late damage to hearing or sight after large doses of lidocaine. The participation of melanin in different basal labyrinthine functions such as the energy transfer mechanism and the sound protective mechanism is discussed in the light of the results obtained. Further, the theory is put forward that the melanin affinity of certain substances can be of both therapeutic and ototoxic importance.

Accumulation of 14C-lidocaine in the inner ear. Preliminary clinical experience utilizing intravenous lidocaine in the treatment of severe tinnitus.

Clinical experience has demonstrated that intravenously administered local anaesthetics have a mitigating effect on severe tinnitus. In an attempt to gain some insight into the mechanism of this effect, autoradiography of the inner ear of young pigmented rats was performed after intravenous injection of 14C-lidocaine. Some accumulation of lidocaine was found in the modiolus, but almost none in the stria vascularis. A large accumulation was observed in other melanincontaining tissues, such as the hair follicles and uvea. The in vitro accumulation of 14C-labelled lidocaine adsorbed on melanin granules was low (12%) as compared with that of other drugs, such as kanamycin (89%) and chloroquine (85%). These autoradiographic results indicate that lidocaine has an effect upon the inner ear, in addition to its previously demonstrated effect on the CNS.

Central nervous system effects of local anaesthetic agents.

A review is given of an experimental study on cats where the influence of acid-base changes on central nervous system toxicity of local anaesthetic agents was studied. The conclusion of this study was that a respiratory acidosis increased the central nervous system toxicity of local anaesthetics and that the underlying metabolic conditions modified this increase. Thus a respiratory acidosis increased this toxicity more if it was based on a metabolic acidosis than on a metabolic alkalosis (Englesson, 1974; Englesson and Grevsten, 1974). An extended analysis is presented where automatic frequency analysis was performed on the e.e.g. recordings performed during the i.v. infusion of lignocaine, bupivacaine, L 134, HS 37 and its optical isomers. The preliminary results show that the electrical changes appearing in the e.e.g. from the start of the i.v. infusion until seizure activity were the same if this time interval was as short as 1 min or as long as 8 min. It also revealed remarkable individual differences between agents, for instance lignocaine displaying marked electrical changes already in the first third of this time period where bupivacaine showed no changes until shortly before seizures.