Effects of Obesity on Anesthetic Agents

Hendrikus JM Lemmens and Jerry Ingrande

Introduction

Morbid obesity can alter pharmacokinetics (PK) and pharmacodynamics (PD) of anesthetic agents.

Factors that can affect the PK and PD of anesthetic agents are:

  1. Increased cardiac output (CO)
  2. Increased lean body weight (LBW)
  3. Increased fat mass
  4. Increased extra cellular fluid volume
  5. Liver and kidney abnormalities
  6. Increased splanchnic blood flow
  7. Changes in plasma protein concentration and the binding of drugs to plasma proteins.

Dosing scalars

Doses of drugs are individualized (scaled) according to a measure of body weight or size and a patient’s condition. A dosing scalar should not only take into account changes in body composition that occur with obesity but also body-composition factors as age and gender.

  1. Total body weight (TBW): Dosing recommendations in package inserts, which are based upon kilograms of TBW, are valid for normal weight patients of varying sizes. However, in MO patients, adipose tissue and lean body mass do not increase proportionally (Figure 1). Instead, fat tissue increases proportionally with TBW, but the percentage of lean body tissue per kg of TBW decreases. These changes alter a drug’s distribution and require that obese patients’ doses be individualized accordingly to other dosing scalars.
  2. Ideal Body weight (IBW): IBW describes the ideal weight associated with maximum life expectancy for a given height and body frame. Although IBW differentiates genders, it has two chief disadvantages: it indicates all patients of the same height should receive the same dose, and it does not take into account the changes in body composition associated with obesity. Therefore, IBW and %IBW (the ratio of TBW to IBW) are illogical dosing scalars for an obese patient.
  3. Body mass Index (BMI): The ratio of TBW to height in meters squared is the standard metric used to classify obesity. However, because BMI cannot differentiate between fat and muscle mass, patients with a large muscle mass would receive the same dose as those with a large fat mass.
  4. Body surface area (BSA): BSA is the gold-standard metric used to determine dosing of chemotherapeutic agents. Equations to calculate BSA contain TBW and height and are derived from regression on anatomic measurements. Body surface area is a disadvantageous scalar for dosing obese patients, because it fails to consider gender or to distinguish between fat and muscle mass.
  5. Adjusted Body weight (ABW): ABW was intended to normalize (correct) the increased volume of distribution in obese patients. To calculate ABW, some fixed proportion of the excess weight is added to the patient’s IBW. Since physicochemical properties and distribution volumes of drugs differ, ABW should be determined for each drug.
  6. Predicted normal weight (PNW): PNW of the obese patient is the sum of lean body weight and predicted normal fat mass. Its application as a dosing scalar in the obese patient is unclear.
  7. Lean Body Weight (LBW): LBW is TBW minus body fat weight. When TBW increases, LBW also increases taking into account changes in body composition associated with obesity depending on TBW, height and gender. Lean body weight is also significantly correlated with CO, an important factor of the early distribution kinetics. Almost all metabolic activity in the body occurs in the lean tissues, and clearance increases linearly with LBW. Therefore, LBW as a dosing scalar is valid across all body compositions. However, few PK studies in obese patients have considered this scalar, presumably because formulas to accurately estimate LBW, especially in obese patients have been problematic. Janmahasatian derived LBW equations for patients ranging between 40 and 220 kg. These LBW equations have accurate predictive properties. Figure 2 shows the relation between TBW and LBW for a wide range of patients. This data can be used to easily approximate LBW.

Anesthetic Agents

Hypnotics

Thiopental: The increased CO associated with morbid obesity significantly affects thiopental induction dose requirements in the obese. After a thiopental induction dose of 250 mg peak arterial concentration is 60% lower in a 100% overweight patient (BMI ~42 kg/m2) than in a lean patient. Thiopental dose adjusted according to LBW results in the same peak plasma concentration as dose adjusted according to CO. These data suggest dosing thiopental in the morbidly obese on the basis of either the higher CO or increased LBW. Although this dose adjustment will result in similar peak plasma concentrations, the increased CO and LBW will result in more rapid redistribution from the brain and a faster awakening time should be anticipated.

Propofol: MO patients in whom anesthesia was induced with a fast propofol infusion based on LBW required similar doses of propofol and had similar times to loss of consciousness compared to non-obese control patients given a propofol infusion based on TBW. Just like thiopental, the increased CO and LBW will result in a faster awakening time.

Opioids

Opioids should be carefully titrated according to individual patient need. For fentanyl, sufentanil, alfentanil and remifentanil LBW dosing will result in plasma concentrations similar to those in normal weight subjects when dosed according to TBW.

Inhaled anesthetics

Because isoflurane is more lipophilic than either desflurane or sevoflurane, desflurane and sevoflurane have been marketed as the anesthetics of choice for obese patients when fast recovery from anesthesia is desired. However, obese and non-obese patients responded to commands equally rapidly (7 min) after 0.6 MAC isoflurane administrations for procedures lasting 2–4 hours. Blood flow per kg fat tissue decreases with increasing obesity. Also, the time constants (the time to reach 63% of equilibrium) for equilibrium of isoflurane or desflurane with fat are 2110 and 1350 min respectively. The decreased fat perfusion and the long time constants will minimize the effect of increased fat tissue mass when isoflurane is used in routine clinical practice. Indeed, during routine surgical procedures the effect of BMI on isoflurane uptake was small and clinically insignificant.

Muscle Relaxants

The depolarizing muscle relaxant succinylcholine has rapid onset and short duration of action, properties ideal for MO patients because hemoglobin desaturation occurs rapidly after apnea, and intubation of the trachea must be accomplished quickly. When succinylcholine administration is based upon 1 mg kg-1 TBW, rather than upon 1 mg kg-1 LBW or IBW, a more profound neuromuscular block and better intubating conditions are achieved. With the availability of the neuromuscular reversal agent sugammadex, a fast-acting, non-depolarizing muscle relaxant such as rocuronium will become a safe alternative to succinylcholine. With sugammadex, reversal will be obtained immediately, effectively controlling time of paralysis.

Non-depolarizing muscle relaxants such as rocuronium are only weakly or moderately lipophilic. Rocuronium administered to MO patients on the basis of both TBW and IBW results in duration of action more than double when dosed on TBW. In subjects receiving TBW-based 0.1 mg kg−1 vecuronium obese took 60% longer to recover from neuromuscular blockade than did normal weight subjects. For atracurium when dosed based on TBW a prolonged duration of action in obese patients has been demonstrated as well. Therefore it is recommended basing non-depolarizing muscle relaxants in the MO on IBW. Even so, because the reported recovery times for rocuronium and all other muscle relaxants are highly variable in obese patients, careful monitoring of the degree of neuromuscular blockade is recommended.

Reversal Agents

Neostigmine: When vecuronium dosage is based on TBW and reversed with neostigmine, 0.04 mg kg−1, at 25% recovery of twitch height, time to a train-of-four (TOF) ratio of 0.7 (inadequate reversal) is similar between normal weight and obese patients (3.8–4.8 min). However, recovery time to a TOF ratio of 0.9 (adequate reversal) is four times slower in the obese patient (25.9 min) than in the normal weight patient (6.9 min). Atracurium administered to obese patients based on TBW, is equally rapid reversed to a TOF ratio of 0.7 by neostigmine, 0.07 mg kg−1, when compared to normal weight patients. Neostigmine has a ceiling effect – higher doses only result in a faster onset of effect. Neostigmine’s reversal effect appears within 1–2 min; its maximum effect occurs within 6–10 min. If, at the peak, the antagonistic effect of neostigmine complete reversal is not obtained, further recovery is slow and further depend on the balance between spontaneous recovery and the waning reversal effect of neostigmine. The recommended dose is 0.04–0.08 mg kg−1, not to exceed a total dose of 5 mg.

Sugammadex: Sugammadex is a new, selective, relaxant-binding agent designed to bind and encapsulate rocuronium and vecuronium with very high affinity. Sugammadex’s binding decreases the concentration of neuromuscular blocking agent at the nicotinic receptor, resulting in reversal of neuromuscular blockade. The bound complex is excreted by the kidneys at a rate equal to that of glomerular filtration. Unlike neostigmine, sugammadex has no effect at the receptor level, and no hemodynamic or other side effects. After sugammadex is administered, it distributes rapidly in a small distribution volume equal to the extracellular fluid volume. Sugammadex can reverse profound neuromuscular blockade. For example, after an intubating dose of rocuronium has been administered, sugammadex 16 mg kg−1 can provide immediate reversal; a dose of sugammadex 2–4 mg kg−1 can reverse an incomplete block. The dose-response relationship of sugammadex in the obese patient has not yet been investigated.

Figure 1. Schematic of TBW, fat weight and LBW at different BMI’s in a standard height male. LBW and fat weight was derived from the equations of Janmahasatian et al. (Janmahasatian S, Duffull SB, Ash S et al. Quantification of lean bodyweight. Clin Pharmacokinet 2005; 44:1051-65.)

Figure 2. Estimated lean body weight for females and males. Estimates are derived from the equations of Janmahasatian.