In Reply:—

We wish to thank Dr. Eger for his interest in our work and we appreciate the chance to respond to his comments. However, we disagree with his observations about our work. 1Dr. Eger raised three issues. We would like to respond in reverse order to his comments. First, the concentrations of propofol with and without metabisulfite were diluted with normal saline to 5 mg/ml to facilitate the infusions. However, Dr. Eger seems to misunderstand that the metabisulfite that was in the commercially available propofol was also diluted. Therefore, the same ratio of propofol to metabisulfite in the infusion was maintained. Thus, there was no “lesser propofol concentration [to] affect the balance of the effect of the metabisulfite and the propofol on bronchoconstriction.” Also, the fact that the same concentration of metabisulfite alone as that delivered in the propofol with metabisulfite solution enhanced both the vagal nerve stimulation and the direct smooth muscle–induced bronchoconstriction supports our findings that the metabisulfite attenuated the response of propofol to prevent bronchoconstriction.

We also disagree with Dr. Eger's calculations of clinically relevant dose. The infusion rates were 0.06, 0.2, and 0.6 ml/min for propofol with and without metabisulfite. For propofol, we calculated the molar concentrations from our continuous infusion into the bronchial circulation to be 8.4 × 10−5, 2.8 × 10−4, and 8.4 × 10−4m, respectively. As pointed out in our Discussion section, these doses are within the range of clinical relevance as demonstrated by other investigators studying the effects of propofol in a sheep model for induction of anesthesia. 2Using a continuous infusion, Ludbrook et al .2observed concentrations of propofol in the brain of the sheep as measured by the area under the curve of 73.7 ± 15.2, 54 ± 4.4, and 67.7 ± 11.9 μg · min−1· ml−1, concentrations comparable to those calculated by Dr. Eger of our concentrations. Furthermore, there are clearly species and even strain differences in anesthetic potency as demonstrated by Dr. Eger himself 3,4and others. 5Thus, the anesthetic dose in sheep does not necessarily equate to the same anesthetic dose in humans. Dr. Eger does raise an extremely important point that requires clarification. He compares the doses we used to blunt airway responsiveness to those that cause loss of consciousness or failure to respond to commands. The dose required for loss of consciousness or failure to respond to commands should not be assumed to be adequate anesthesia for procedures, especially for bronchoprotection. The minimum dose to cause loss of consciousness would most likely be inadequate anesthesia for tracheal intubation in a healthy individual and particularly in an asthmatic patient. Clearly, instrumentation of the airway of an inadequately anesthetized asthmatic patient can have catastrophic consequences.

Finally, a “small effect” is a relative term. We believe that our observed difference of 30% in prevention of bronchoconstriction between propofol without and with metabisulfite is not an inconsequential effect. It is clearly statistically significant and would likely be clinically relevant. Although this is an animal model of airway responsiveness, an equivalent prevention of a 30% decrease in airway resistance in an anesthetized asthmatic patient may be the difference between being able to ventilate the patient or not. We continue to believe that propofol is an excellent drug for the prevention of bronchoconstriction and that the preservative used for propofol can have a significant effect on its ability to attenuate bronchoconstriction.

Brown RH, Greenberg RS, Wagner EM: Efficacy of propofol to prevent bronchoconstriction: Effects of preservative. A nesthesiology 2001; 94: 851–5
Ludbrook GL, Upton RN, Grant C, Martinez A: The effect of rate on administration on brain concentrations of propofol in sheep. Anesth Analg 1998; 86: 1301–6
Sonner JM, Gong D, Eger EI, Laster MJ: Naturally occurring variability in anesthetic potency among inbred mouse strains. Anesth Analg 2000; 91: 720–6
Hitt BA, Mazze RI, Stevens WC, White A, Eger EI: Species, strain, sex and individual differences in enflurane metabolism. Br J Anaesth 1975; 47: 1157–61
Mahmood I: Interspecies scaling of inhalational anesthetic potency minimum alveolar concentration (MAC): Application of a correction factor for the prediction of MAC in humans. Am J Ther 2001; 8: 135–47