With the “how will he do that!” anticipation of a child about to see the magician pull the rabbit out of the hat, I read the article by Keidan et al.  1about the absence of tolerance to repeated doses of propofol in children undergoing repeated radiation therapy treatments. Tolerance in this setting has plenty of pharmacologic precedence and reinforces my clinical experience. I finished the article disappointed in the study design and unconvinced of its conclusion.

In their introduction, the authors hypothesize that tolerance should be manifested by a change in depth of sedation, as determined by the Bispectral Index (BIS), to a predetermined, “fixed” dose of propofol administered repeatedly over 6 weeks. Although the hypothesis makes sense, the methods rely on two flawed assumptions, namely that the propofol dose was fixed and that BIS is sufficiently sensitive and reactive to track depth of anesthesia in this clinical scenario. Any available pharmacokinetic modeling program*shows that the bolus plus constant infusion regimen the investigators used does not result in a fixed propofol concentration at the effect site but an ever-changing concentration. Using additional propofol doses at the clinicians’ discretion causes even greater swings in effect site concentrations. Radiation therapy treatments are of short duration and comprise no stimulation beyond airway manipulation, which did not occur in this study. Why did the investigators not titrate the propofol to a predetermined BIS range (40–50) using a target-controlled infusion, ie , flip propofol and BIS as the controlled and measured variables, respectively? (Ironically, they mention this reciprocal approach in the first paragraph of the Discussion.) Schmidt et al.  2and more recently Kreuer et al.  3have shown a good correlation between propofol at target-controlled infusion and BIS under steady state conditions. Hoymork et al. ,4however, could not confirm this and suggest the reason may be that the correlation may deteriorate during rapid variations and deep levels of anesthesia. BIS nadirs in the 20s and late recovery times around 17 min, with a short context-sensitive half-life agent such as propofol, suggest these patients were deeply anesthetized on induction and thus traversed many planes of anesthesia very rapidly. Titration to a lighter but adequate plane of anesthesia using a target-controlled infusion may place BIS in the linear portion of its relation to the pharmacodynamic effect of propofol at the effect site and will achieve better steady state effect site concentrations. Although BIS has been shown to reflect a concentration–effect relation between propofol and BIS at relatively stable levels, this has not been shown at the enormous variation in dose and BIS levels in this study, thus making the validity of the conclusions questionable.

Medical University of South Carolina, Charleston, South Carolina. overdykf@musc.edu

Keidan I, Perel A, Shabtai EL, Pfeffer RM: Children undergoing repeated exposures for radiation therapy do not develop tolerance to propofol. Anesthesiology 2004; 100:251–4
Schmidt G, Bischoff P, Standl T, Voigt M, Papavero L, Schulte am Esch J: Narcotrend, Bispectral Index, and classical electroencephalogram variables during emergence from propofol/remifentanil anesthesia. Anesth Analg 2002; 95:1324–30
Kreuer S, Wilhelm W, Grundmann U, Larsen R, Bruhn J: Narcotrend versus Bispectral Index as electroencephalogram measures of anesthetic drug effect during propofol anesthesia. Anesth Analg 2004; 98:692–7
Hoymork SC, Raeder J, Grimsmo B, Steen PA: Bispectral index, serum drug concentrations and emergence associated with individually adjusted target-controlled infusions of remifentanil and propofol for laparoscopic surgery. Br J Anaesth 2003; 91:773–80