Morbidly obese (MO) patients pose significant challenges to anesthesiologists. Many researchers have described the effects of obesity on metabolic, cardiovascular, and pulmonary function, and have documented the increased risk of anesthesia in these subjects.1,2 However, few studies have considered the effects of excess weight on the clinical pharmacology of anesthetic drugs. Obese subjects have both an increased amount of fat and lean body weight (LBW) compared with non-obese subjects of similar age, height, and gender.3 Although LBW increases by 20% to 40%, fat mass per kilogram total body weight (TBW) increases to a greater extent, resulting in a decrease in LBW per kilogram body weight.3 These changes markedly affect the apparent volume of distribution of some drugs in obese patients. Additionally, increases in cardiac output (CO), total blood volume, and changes in regional blood flow may affect peak plasma concentration, clearance, and elimination half-life of many anesthetics.2–4
In current anesthetic practice, propofol is the most frequently used induction drug for obese subjects even though the appropriate induction dosing scalar has not been determined. Both TBW and a corrected formula based on ideal body weight (IBW) have been proposed as appropriate scalars for the induction dose of propofol in MO subjects.5,6 LBW has also been proposed as the optimal scalar for induction with propofol; however, that study did not involve obese subjects.7 Given this controversy, we proposed to determine the appropriate dosing scalar among TBW, LBW, and IBW for the induction dose of propofol in MO subjects. We hypothesized that LBW would be a more appropriate dosing scalar than TBW for MO subjects.
This study was approved by the Human Subjects Review Board at Stanford University School of Medicine and was conducted in the operating suites at Stanford University Medical Center. Written informed consent was obtained from 90 subjects between July 2008 and February 2009. All 90 subjects were ASA physical status I, II, or III, between the ages of 18 and 65 years, and were scheduled for elective procedures under general anesthesia. Of these 90 subjects, 60 were MO (body mass index [BMI] ≥40 kg/m2). These 60 subjects were randomized by sealed envelope into 2 groups of 30, each to receive a propofol infusion (100 mg · kg−1 · h−1) for induction of general anesthesia based on either TBW (n = 30) or LBW (n = 30). The dose regimen of 100 mg · kg−1 · h−1 was chosen because this would minimize the total induction dose necessary to induce loss of consciousness (LOC) by reducing the amount of residual dose in the central compartment that has yet to equilibrate into the effect site.8 All MO subjects underwent elective bariatric, general, orthopedic, plastic, gynecologic, or ear, nose, throat surgery. Thirty patients in the control arm (BMI ≤25 kg/m2) received a propofol infusion (100 mg · kg−1 · h−1) for induction of general anesthesia based on TBW. Subjects in the control arm underwent elective general, orthopedic, plastic, gynecologic, or ear, nose, throat surgery.
Subjects were excluded from study if they had any evidence of cardiopulmonary disease, hepatic disease, or renal dysfunction. Additionally, subjects with extreme anxiety, or whose preoperative medication regimen included benzodiazepines, opioids, or any prescribed or over-the-counter sleep medications, were excluded. Subjects with a history of difficult tracheal intubation, scheduled to undergo elective awake fiberoptic tracheal intubation, or scheduled to receive preoperative regional blockade were also excluded.
After written informed consent was obtained, each subject was weighed on a Tanita® TBF-310 body impedance scale (Tanita Corp., Tokyo, Japan). The Tanita TBF-310 body impedance scale has been validated against dual energy radiograph absorptiometry.9 The scale is accurate up to a maximum weight of 600 lb (272 kg).
An 18- or 20-gauge peripheral IV catheter connected to a T-piece tubing was placed in the subject's left or right forearm. Each subject was brought to the operating suite without premedication and allowed to position himself or herself on the operating table. All MO subjects were positioned in the “ramped” position to achieve horizontal alignment between the external auditory meatus and sternal notch, as described by Collins et al.10 While in the operating room, standard ASA monitors were applied. Noninvasive bioimpedance CO data were gathered before anesthetic induction, using a NICCOMO™ CO analyzer (medis-de, Ilmenau, Germany). A Syringe Infusion Pump 22® (Harvard Apparatus, Holliston, MA) was used for propofol administration.
Each subject was instructed to lie on the table in a quiet operating suite devoid of distraction. Each subject was asked to hold a 20-mL saline-filled syringe between their thumb and index finger in the hand opposite the IV and instructed not to drop that syringe. Each MO subject was randomized to receive propofol via infusion (100 mg · kg−1 · h−1) based on TBW (n = 30) or LBW (n = 30). Each control subject received a propofol infusion (100 mg · kg−1 · h−1) based on TBW (n = 30). After breathing oxygen for 3 minutes via the facemask, the propofol infusion was started. LOC was determined when the subject dropped the weighted syringe. The propofol infusion was stopped once LOC was achieved. After syringe drop, the subject was asked to open his or her eyes and move his or her toes. Confirmation of LOC was achieved if there was a negative response to both cues. After LOC, the airway was secured at the discretion of the anesthesiologist (in each of the MO subjects, the trachea was intubated, whereas in the control subjects, either tracheal intubation or a laryngeal mask airway was used). All MO subjects were given a standardized dose of fentanyl (150 μg, IV) and succinylcholine (1 mg/kg, IV TBW) before tracheal intubation. Cricoid pressure was applied to all MO subjects before LOC and was maintained until tracheal intubation.
Total propofol induction dose required to achieve LOC (defined by syringe drop), time to LOC, hemodynamic variables (heart rate, arterial blood pressure), and CO were recorded. Post hoc calculations including total propofol dose per kilogram TBW, LBW, and IBW were performed. IBW was determined by the formula IBW = (22 · height [m]2).11 This formula was extrapolated from the BMI equation BMI = (weight [kg]/height [m]2) with 22 defined as the ideal BMI. After completion of the surgery, subjects were brought to the postoperative recovery unit and interviewed 30 to 60 minutes after emergence to determine whether perioperative awareness had occurred.
Before beginning this study, a power analysis indicated that 3 groups of 30 subjects would be required to achieve a statistical power of 0.8 at an α level of 0.05 and a standard deviation of 0.5 mg/kg to detect a difference in dosing of approximately 0.2 mg/kg. Sample means were tested for normality using the Kolmogorov-Smirnov test, and then compared using analysis of variance followed by the Tukey test for multiple group comparisons. The relation between dose and weight-based scalars was determined by linear regression analysis. All statistical analyses were performed using S-PLUS for Windows version 6.2 (Insightful, Seattle, WA).
Ninety subjects (30 control subjects, 60 MO subjects) were enrolled in this study. All enrolled patients completed the study. There were no differences in demographic variables among the 3 groups with the exception of BMI, TBW, and LBW, which were significantly less in the control group (Table 1).
The propofol dose at the time of LOC was larger in the MO group receiving propofol based on TBW versus MO subjects receiving propofol based on LBW (244.7 vs 183.3 mg; P = 0.0002). Dose per kilogram LBW in the MO group given propofol based on LBW was similar to dose per kilogram TBW in the control group (2.76 vs 2.57 mg/kg; Table 2).
Time to LOC was shorter in the MO group who received propofol based on TBW compared with control subjects and MO subjects receiving propofol based on LBW (65, 86, and 94 seconds, respectively; P = 0.0001).
Preinduction CO was similar between the 2 MO groups (9.38 vs 8.30 L/min), and both were significantly greater than CO in the control group (Table 2).
Dose was significantly related to LBW and TBW in all 3 groups (Fig. 1). In the control group, the relationship between LBW and dose was stronger than the relationship between TBW and dose (R2 = 0.58 vs 0.49). MO subjects given propofol based on LBW also showed a stronger relationship between LBW and dose versus TBW and dose (R2 = 0.74 vs 0.65). The relationship between IBW and dose was also significant in all 3 groups; however, this relationship was the weakest compared with LBW and TBW (Fig. 1).
Preinduction CO was positively related to total propofol induction dose in all subjects (Fig. 2). There was a significant relationship between dose and CO in MO subjects given propofol based on LBW (Fig. 2).
No subject experienced any significant surgical or anesthetic complications. Postinduction hypotension was defined as a 40% decrease in baseline mean arterial blood pressure within 5 minutes of propofol infusion. Three subjects in the control group, 5 in the MO group given a propofol dose based on LBW, and 9 MO subjects given a propofol dose based on TBW experienced postinduction hypotension. These results were not significant. Subjects experiencing postinduction hypotension were treated with vasoactive drugs (ephedrine, phenylephrine), and fluid boluses to return their mean arterial blood pressure to preinduction baseline. There were no other side effects during anesthetic induction. No subject reported intraoperative awareness or recall upon questioning during the postoperative interview.
Induction of anesthesia in the MO population can be complicated because of the reduction of safe apneic time and the possibility of gastroesophageal reflux.12 Therefore, a rapid sequence induction has been advocated when inducing general anesthesia for this patient population. Propofol, which has been used for the induction and maintenance of general anesthesia in the MO population for many years, is often given as a bolus per kilogram TBW. This allows for a rapid LOC, but may predispose the patient to untoward side effects such as hypotension. The optimal weight-based dosing scalar for a propofol induction bolus dose in the MO patient population that would allow for fast induction times with minimal side effects has not been established.
Bolus dose recommendations are generally made on the basis of TBW, a valid approach for non-obese subjects of varying sizes. However, in MO subjects, LBW does not increase to the same proportion as the increase in adipose tissue.13 The volume of fat tissue increases proportionally with TBW and BMI. The absolute value of LBW increases in MO subjects; however, the percentage of lean body tissue relative to TBW actually decreases. In addition, increased CO and stroke volume are proportionately greater in the individual whose increased size is due to increased lean tissue rather than adipose tissue.14 Because blood flow to fat is much smaller than that to lean tissue (viscera, brain, heart, etc.), increasing the propofol dose based on TBW will result in an increased propofol concentration in blood perfusing these tissues and, as a consequence, presumably increased cardiovascular effects such as hypotension and myocardial depression.15,16 Because these changes in body composition and distribution of blood flow alter a drug's distribution, patients who are obese need doses individualized according to other dosing scalars.
Despite evidence supporting TBW for use during propofol maintenance dosing,5,17 reports describing the appropriate anesthetic induction dosing scalar are conflicting, with both TBW5 and an IBW-based scalar6 proposed as acceptable regimens. A dosing scalar for the MO patient should account for relevant changes in body composition and blood flow that occur with obesity. In addition, LBW is positively related to CO,14 an important factor of the early distribution kinetics,4,15,16 suggesting the importance of LBW not only for determining maintenance dosing but also for determining initial loading and induction doses. We recognize the limitations of using LBW in the clinical setting, because very few individuals present with an actual measurement of their LBW. When an actual measurement of LBW is unavailable, we suggest using the formula described by Janmahasatian et al.13 for determining LBW:
LBW values obtained using this formula show in general a good agreement with the results obtained by direct measurement using the Tanita TBF-310 body impedance scale (Fig. 3).
When compared with control subjects receiving a propofol induction dose based on TBW, MO subjects receiving a propofol induction based on LBW require similar doses (mg/kg) of propofol and have similar times to reach LOC, suggesting the relevance of LBW as a more accurate dosing scalar in MO subjects. We demonstrated a significant relationship between LBW and propofol induction dose in all 3 groups (Fig. 1). Although there is also a significant relationship between TBW and propofol induction dose in all 3 groups, this relationship is weaker in both the control subjects and MO subjects dosed by LBW (Fig. 1). These results are not surprising, because CO is predominantly distributed to lean rather than adipose tissue.14
A positive relationship between propofol induction dose and preinduction CO was present in all groups. However, there was a significant relationship between dose and CO only in the MO group given propofol based on LBW and the patients of all groups combined (Fig. 2).
Comparing multiple infusion rates, Kazama et al.8 demonstrated a significant relationship among the rate of propofol infusion, time to LOC, and propofol induction dose. In addition, postinduction hypotension was also related to infusion rate.8 In our study, MO subjects in whom propofol was infused based on TBW achieved LOC significantly faster than MO subjects given an infusion based on LBW. Our results are in agreement with Kazama et al. and suggest that a TBW dosing scalar may result in overdosing of propofol. An overdose would result in a larger plasma concentration, faster time to LOC, and possibly a greater degree of hypotension and a prolonged time to awakening compared with subjects who receive a propofol dose based on LBW. We cannot explain why there was no significant difference in the degree of postinduction hypotension between MO subjects given propofol based on TBW in our study, other than that the lack of difference was possibly due to a type II error. Previous studies have demonstrated a positive relationship between hypotension and speed of propofol administration.8,18,19
In the present study, we used a standard infusion rate (100 mg · kg−1 · h−1) using 2 weight-based scalars (TBW and LBW) to characterize the differences in dose requirement and time to LOC in MO subjects. Despite the fact that in most clinical settings propofol is given as a bolus rather than infusion to induce anesthesia, an infusion method for propofol administration was chosen for several reasons. First, a bolus dose would call for standardization of the dose per kilogram TBW or LBW. This standardization would not allow for accurate assessment of the clinical end point: time required to reach LOC. Additionally, it would be impossible to accurately measure the dose required to reach LOC. Second, the association between speed of propofol administration and the dose administered with hypotension has been documented.8,18,19 Given the extremes of weight of subjects enrolled in this study, bolus administration on a per kilogram TBW or LBW would likely result in a larger degree of hypotension than what we had otherwise encountered. Third, high rates of propofol administration have been shown to result in higher propofol dose requirements for induction.8 High infusion rates can result in rapid deposition of drug into the central compartment. Given the lag time of drug equilibration between the effect site and the central compartment, rapid administration results in a depot formation of drug in the central compartment described in previous studies as a residual dose.8 Kazama et al.8 described the effective induction dose as the total induction dose minus this residual dose. We speculate that a bolus injection would falsely overestimate the effective induction dose by failing to account for the residual dose in the central compartment yet to distribute to the effect site and other tissue.
One of the limitations of this study is the fact that multiple infusion rates were used. Higher infusion rates would result in larger doses administered and faster times to induction. Previous studies have examined the effect of infusion rate on the pharmacokinetics and pharmacodynamics of propofol.20,21 Both of these studies found that infusion rate had no effect on propofol pharmacodynamics. The models described for the various infusion rates used were appropriately described with one keo. According to the keo model, the rate of equilibration between the plasma and effect site is independent of infusion rate.
In conclusion, MO subjects in whom anesthesia was induced with a propofol infusion based on LBW required similar doses of propofol and had similar times to LOC compared with non-obese control subjects given a propofol infusion based on TBW. Although TBW has been shown to be an appropriate weight-based dosing scalar for maintenance of anesthesia in MO subjects,5 we conclude that for induction of anesthesia in MO subjects, LBW is the most appropriate weight-based scalar. However, the impact of the changes in body composition and the increased CO associated with obesity on other important issues such as awakening time after an induction dose are unclear from the results of this study. A high-resolution pharmacokinetic/pharmacodynamic study is necessary to accurately determine the effect of obesity on the relationship among propofol dose, plasma concentration, and drug effect.
JI helped design and conduct the study, analyze the data, and write the manuscript. This author is responsible for archiving the study files. JBB helped conduct the study and write the manuscript. HJML helped design and conduct the study, analyze the data, and write the manuscript. All authors have seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
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