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Re: The devil is not only in the details.
- Anthony R Absalom, Vaithy Mani, Tom de Smet and Michel M.M.R.F. Struys (25 November 2009)
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The devil is not only in the details.
- Frank H Engbers, Nick Sutcliffe, Gavin Kenny, Stefan Schraag (3 November 2009)
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Anthony R Absalom University Medical Centre Groningen, Netherlands, Vaithy Mani, Tom de Smet and Michel M.M.R.F. Struys
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Dear Sir, We are pleased that our article has generated discussion and thank Dr. Engbers and colleagues for their constructive comments. We have sought clarification once more from the main manufacturers of ‘open TCI’systems on how their pumps deal with the calculation of the Schnider model elimination rate constant (k10) in morbidly obese patients, and based on this we agree that our figure 7 is not in keeping with the latest software versions implemented in these pumps. For the sake of clarity, we would like to explain the current situation in some detail. The Base Primea system (Fresenius-Kabi, Brezins, France) allows the user to input the actual patient parameters, but will not operate in TCI mode if the user enters a combination of height and total body weight (TBW) that yields a body mass index (BMI) >35 for females or a BMI >42 for male patients (personal communication, Mr. S. Ruton, Fresenius- Kabi). On the other hand, the Alaris Asena PK system (Carefusion, Basingstoke, UK) requires the user to first input the patient height and gender, and then will not allow the user to input a TBW value that generates a paradoxical LBM value based on the James equation1 (i.e. TBW and height combination that generate a LBM value that falls on the portion of the TBW vs. LBM curve with a negative slope) (personal communication, Mr. M. Richardson, Carefusion). The nett effect of these software solutions implemented in the currently available open TCI systems is to prevent the system microprocessors from applying paradoxical or absurd parameters. The heavy solid lines in figure 1(a) and l(b) indicate the range of TBW values within which both systems will operate for males and females respectively who are 160 cm or 190 cm tall, and the resulting k10 values with the Schnider model. The light continuous lines indicate the range of values for these heights, over which paradoxically decreasing LBM values would result in excessive k10 values if the Schnider model was implemented as published.2;3 Whether models are generated by formal mixed-effects modeling procedures or by more pragmatic methods, we agree with Engbers that it is dangerous to extrapolate a model beyond the boundaries of the important characteristics of the population from which it was developed. By observing the range of TBW values within which the systems will operate (indicated by the heavy solid lines in figure 1), the reader will notice that these software solutions also prevent the use of the Schnider model in morbidly obese patients whose characteristics are significantly different from those of the subjects from the studies from which the original Marsh and Schnider models were developed.2-4 We are aware of strategies that clinicians have developed to enable them to use open TCI systems with the Schnider model for TCI in morbidly obese patients. Although we do not recommend these practices, we feel that it is important to mention this issue, to illustrate the inherent and significant dangers. One option for clinicians who wish to use the Schnider model in morbidly obese patients is to input a ‘corrected’ TBW value – typically the user will input the maximum TBW value that the system will allow for a patient of that height (i.e. a falsely low TBW is used). As illustrated by the dotted lines in figures 1(a) and 1(b), the result of this strategy is that all morbidly obese patients of a given height and gender will be assigned the same TBW, LBM and k10 values, and all will thus receive the same amount of propofol for a given target concentration profile. By fixing k10 this strategy fixes the only Schnider model parameter that usually varies with weight (the only other parameters with co-variates are the fast re-distribution rate constants which vary with age). Thus anaesthetists who use the Schnider model in morbidly obese patients, should know that by inputting falsely low TBW values, they have generated a model where the infusion rates no longer scale according to the patient weight. Since propofol is a highly lipid-soluble agent, maintenance doses are likely to be related to total body weight. There is thus a real danger that with this strategy insufficient maintenance doses will be administered to morbidly obese patients. At present clinicians who wish to administer intravenous anaesthesia to morbidly obese patients are ‘between the devil and the deep blue sea’ (we promise not to re-invoke the satanic analogy!). Our personal view is that with current evidence and knowledge, the most prudent approach is to manually administer an induction bolus based on an estimate of lean body mass, and thereafter to administer a manually controlled infusion, carefully titrated to clinical effect. We have focused on obese patients, but there are several other groups who fall outside of the boundaries of the original research, such as the very young or old, and the critically ill, and in whom the utility of different models is uncertain. In his letter, Engbers has also touched on the issue of which model is best in ‘normal’ patients. The study of Glen and Servin5 which he mentions, is a valuable contribution, but cannot be regarded as conclusive evidence. A goal of the ‘WorldSIVA Open TCI’ initiative (www.opentci.org) is to attempt to answer precisely these sorts of questions, by harnessing the statistical benefits of combining data sets derived from different studies. A recent study resulting from this initiative, involving a very large dataset, has shown results at odds with those of Glen and Servin.6 There is clearly some way to go yet. Finally, we apologise for the error in figure 6. We were aware of it and have asked the editor to publish an erratum. A.R. Absalom V. Mani T. de Smet M.M.R.F Struys References 1. Research on obesity. London: Her Majesty's Stationary Office; 1976. 2. Schnider TW, Minto CF, Gambus PL, Andresen C, Goodale DB, Shafer SL et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiol 1998; 88(5):1170-1182. 3. Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB et al. The influence of age on propofol pharmacodynamics. Anesthesiol 1999; 90(6):1502-1516. 4. Gepts E, Camu F, Cockshott ID, Douglas EJ. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesthesia and Analgesia 1987; 66(12):1256-1263. 5. Glen JB, Servin F. Evaluation of the predictive performance of four pharmacokinetic models for propofol. Br J Anaesth 2009; 102(5):626-632. 6. Masui K, Upton RN, Doufas AG, Coetzee JF, Kazama T, Mortier EP et al. The Performance of Compartmental and Physiologically Based Recirculatory Pharmacokinetic Models for Propofol: A Comparison Using Bolus, Continuous, and Target-Controlled Infusion Data. Anesth Analg 2009; Oct 27. [Epub ahead of print](PMID: 19861357). Legend to Figure 1: Influence of total body weight and height on the k10 calculated by the Schnider model (males - figure 1a, females figure 1b) as implemented in the latest versions of commercially available ‘open TCI’ systems. The heavy black and blue lines indicate the range of TBW values within which the systems will operate for patients who heights are 160 and 190 cm respectively. The light black and blue lines indicate the k10 values which result from application of the original Schnider equation for k10 outside of the aforementioned ranges. Finally, the dotted lines indicate the k10 values that result if the systems use the maximum allowed TBW values, and fix the LBM at the maximum value, for patients whose heights are 160 and 190 cm. Conflict of Interest:None declared |
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Frank H Engbers, Anaesthesiologist Leiden University Medical Center, Nick Sutcliffe, Gavin Kenny, Stefan Schraag
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To the Editor. We congratulate the authors in their effort to address this complex topic and trying to explain the problems, controversies and differences that come with the current commercial Target Controlled infusion devices. There have been surprisingly few published papers about the differences between the pharmacokinetic models since they were introduced in so called open TCI systems several years ago(1). However, there is clearly confusion amongst anaesthetists since the introduction of multiple models for the delivery of propofol by TCI. That such confusion exists is confirmed by a recent paper from Enlund and an editorial in the EJA.(2,3) We feel that this current article only partially resolves this confusion and leaves other important points unaddressed. There are also some errors in the paper: -The x axis in figure 6 is wrongly labeled, it should be Wt and not time. -In the text, the authors suggest that the pumps compensate for the erroneous calculation of the Lean Body Mass for obese people by offering “a pragmatic solution”, fixing the LBM to the maximum while allowing the weight and length to increase (figure 7). We are unable to confirm this statement using the latest software version in commercial available infusion pumps. Dependent on the height of the patient the maximum weight is simply limited to the maximum Lean Body Mass. Therefore the graph in figure 7 should be changed as illustrated in figure 1 below. Note that now in the area above the maximum Lean Body Mass, the influence of the height of the patient is inverted. -Also figures 9 and 10 are confusing: the legend states that the solid line represents what the pumps are giving and the dotted line what would be administered if the systems ‘did not correct’ for the paradoxical decrease in LBM. In the range of the dotted line however there is no solid line and this corresponds with reality because the systems will not operate with parameters in this range and hence do not correct for any error. The second remark we want to make is more conceptual. There is no magic to pharmacokinetics: it predicts the right concentration and dose or it does not. In a recent publication(4) it has been shown, by measuring blood concentrations, that the Schnider model over-predicts the concentration and therefore under-predicts the dose in the initial (induction) phase. We agree with authors that it makes the Schnider model unsuitable for blood control TCI. When the model is used in effect site control, as advocated by the authors, the control modality is used for compensating the dose under- prediction of the model. The logical consequence of this is that it makes the information of the effect site concentration at induction useless as it will predict accomplishment of the effect concentration much faster than reality because the predicted high peak blood concentration(overpressure) in fact will not occur. This seems a high price to pay for the automatic adaptation to the age of the patient which is built into the Schnider model. We feel that this is a step backwards in the development of TCI. Lastly, after the excellent publication of one of the authors on the relationship between the keo and the mode of administration (bolus or infusion)(5), we challenge the use of the Time to Peak effect(TPE), which is based on a bolus, to ‘calibrate’ the keo for different pharmacokinetic models when used in Target controlled infusion mode. In our opinion the irregularity in the details are only signs of the hidden devil. Satan is the extrapolation of nonlinear model-effects outside the boundaries of the original, limited research data and the lack of appropriate validation of models, concepts and control modalities. 1 Barakat AR, Sutcliffe N, Schwab M. Effect site concentration during propofol TCI sedation: a comparison of sedation score with two pharmacokinetic models. Anaesthesia, 2007, 62, pages 661–666. 2 Enlund M. TCI : Target Controlled Infusion, or Totally Confused Infusion? Call for an Optimised Population Based Pharmacokinetic Model for Propofol. Upsala J Med Sci 113 (2): 161–170, 2008 3 Coetzee JF. Total intravenous anaesthesia to obese patients: largely guesswork? Eur J Anaesth. 2009;26:359-61. 4 Glen JB, Servin F. Evaluation of the predictive performance of four pharmacokinetic models for propofol. British Journal of Aaesthesia 102(5): 626-32(2009). 5 Struys MRF, Coppens MJ De Neve N Mortier EP Doufas AG, Van Bocxlaer JFP, Shaver SL.Influence of Administration Rate on Propofol Plasma–Effect Site Equilibration. Anesthesiology 2007; 107:386 –96 Figure 1 View Image The inverse relationship of k10 (and clearance) with LBM causes a non linear increase(solid line). If only LBM would be fixed on its maximum the increase becomes lineairly related to weight only, as suggested in the article(intermittend line).The pumps fix the weight at the maximum LBM, therefore with increasing weight there is no further change in k10 (dotted line). Conflict of Interest:None declared |
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