Drug dosing for the patient living with obesity

Drug dosing in the obese

• Dependent on the properties of the drug
• Fat-soluble drugs
  • Larger volume of distribution (more adipose tissue)
  • Accumulate in the peripheral compartments
  • Especially in the context of long infusions
• Water-soluble drugs
  • Relatively smaller increases in the volume of distribution
  • Dosing recommendations should reflect body composition changes in the obese that are relevant for each specific drug
• Paucity of information available on drug adjustments available
• Society of Bariatric Anaesthesia Guidelines provides recommendations on drug dosing and what size descriptor to use
• To add to the confusion the size descriptor required to predict the initial or loading dose may not be the same as that required to predict the maintenance dose

Size descriptor: Total Body Weight (TBW)

• Most commonly used for drug dosing
• Inaccurate as volumes and clearances do not increase proportionally with body weight in a linear manner.
  • Clearance of a drug increases in a non-linear manner with weight
  • This increases the risk of overdose
• Allometric models using TBW have been successfully used to describe size-related non-linear changes in clearance, volumes and drug half-life
• Allometry is the study of changes in the characteristics in relation to body size
• The use of allometric scaling to determine pharmacokinetic parameters in obese individuals from data obtained from non-obese is sparse
• TCI pumps are not available worldwide and a simpler method is required for manual TIVA

Size descriptor: Ideal body weight (IBW)

• This is probably the best way to derive a “normal” body weight.
• Can be derived using the BMI equation when the patient’s height is known and the ideal BMI is used

Size descriptor: Lean body weight (LBW)

• LBW is the difference between TBW and fat mass
• Having adipose tissue is normal so this will under predict weight
• In non-obese this is usually 70% – 90% of TBW.
• In obese this ratio is altered due to excess fat
• James equation used in the Schnider and Minto model to calculate LBW leads to a paradoxical decrease in severe obesity – 70kg 175cm LBW= 56.5 kg – 280kg 175cm = -20 kg (negative value!)

Size descriptor: Fat-free mass (FFM)

• Alternative to LBW but also underpredicts weight
• Obese patients, if mobile, often have a lot of muscle
• Predicted from sex, height and body weight.
• Formula developed in adults but has been described for children as young as three years

Size descriptor: Adjusted Body Weight (ABW)

• Practical and simple
• ABW = IBW + Correction Factor X (TBW- IBW)
• Correction Factor (CF) based on the physical properties of the drug – Fat-soluble drugs require a higher CF (CF = 0.4) – Fat-insoluble drugs can be assigned a CF of 0

Propofol:

• High lipid solubility
• High volume of distribution
• Rapid clearance
• Allometric models using TBW are more accurate than alternatives
  • Eleveld: uses allometry and TBW to scale volumes and clearances
  • Derived from 30 previously published studies
  • Appropriate for use in the general population
  • NONMEM (NONlinear Mixed Effects Modeling)
  • Anaesthetic drugs were explored as co-variates
  • The predictive performance was measured across young children, adults, elderly, high BMI individuals and in simulated TCI applications
• Population-based models
  • Cortinez used data from only morbidly obese patients (BMI >35 kg.m−2)
    • Linear scaling of all parameters using TBW because it is designed specifically for the obese
  • Marsh and Schnider models are available in open TCI pumps but perform poorly in patients living with obesity
    • High BMI patients were not included in the population studies from which the models were derived – Lean body weight formulae in TCI pumps are inconsistent at extremes of size – Some practitioners target a lower plasma effect-site concentration using the TCI pump to circumvent this problem – We recommend inputting ABW and a correction factor of 0.4 in morbidly obese patients and using the Marsh model
• TCI in obese children is more uncertain than in adults
• The allometric TBW relationships included in the Eleveld models should be expected to perform better than the linear TBW relationships present in the Kataria model
• Manual propofol infusion
  • ABW (suggested correction factor of 0.4) can be used instead of TBW and proceed with the usual formula Bristol manual infusion regime is an example which purports to produce a blood propofol concentration of 3 μg.ml−1
    • Loading dose of 1 mg/kg followed by an immediate infusion of
    • 10 mg/kg/hour for 10 minutes
    • 8 mg/kg/hour for the next 10 minutes
    • 6 mg/kg/hour thereafter
  • TBW to achieve propofol effect-site concentrations within 3 to 4 μg.ml−1 in a typical obese patient
    • Loading dose of 1.5 mg/kg followed by an immediate infusion of
    • 120 mcg/kg/minute for 10 minutes
    • 100 mcg/kg/minute for the next 10 minutes
    • 80 mcg/kg/minute thereafter

Remifentanil

• Low lipid solubility
• Low volume of distribution
• Rapid clearance (metabolised by plasma esterases) which is organ independent
• An infusion based on IBW and adjusted according to clinical response is a good option to administer remifentanil in obese patients
• As BMI increases infusion rates in mcg/kg/minutes decrease in order to maintain the same plasma concentration
• Remifentanil infusions based on TBW in obese subjects results in supra-therapeutic plasma concentrations and increases the risk of adverse side effects
• Population based TCI infusion
  • Minto model did not incorporate obese individuals in their study population
  • Parameters: V1, V2, & clearance, are scaled with LBW
  • LBW is calculated with the same equation that is used by Schnider for propofol and is not appropriate for the morbidly obese (James equation)
  • Decreasing clearance for the morbidly obese
  • The use of the Minto model with ABW (CF = 0.4) results in slightly higher infusion rates than those predicted by the Kim model (PK model for remifentanil dosing calculations in adult obese patients)

Dexmedetomidine

• Popular adjunct in TIVA
• Lowers opioid and anaesthesia requirements
• Relatively low lipid solubility, volume of distribution and clearance in comparison to propofol
• If TBW is used infusions produce higher concentrations of the drug in obese compared to non-obese patients
• Overestimates increases in volumes and clearances
• Lower infusion rates should be used for mcg/kg/hr intra-operative maintenance
• Base your infusion on IBW

Ketamine

• Use ideal body weight for dosing

Muscle relaxants

• Polar & hydrophilic drugs
  • Limited distribution in excess body fat
  • Obese patients can have a lot of muscle
• SOBA guidelines recommend
  • LBW for non-depolarising muscle relaxants
    • However, we think this may underdose in obese patients who are mobile as they have more muscle than calculated from LBW
  • TBW for depolarising muscle relaxants (Suxamethonium)
    • Increase in pseudocholinesterase & extracellular fluid
• Based on individual PK studies the following recommendations have been made
  • Atracurium (Varin et al)
    • Dose calculated on TBW
    • No difference in elimination half-life, volume of distribution at steady state and total clearance in obese vs non obese
    • No difference between the 2 groups in the time of recovery from neuromuscular blockade despite higher concentration in obese patients
  • Vecuronium (Schwartz et al)
    • Dose calculated on IBW
    • No difference in elimination half-life, volume of distribution at steady state and total clearance in obese vs non obese
  • Rocuronium (Puhringe et al)
    • Infusion rates decreased
    • Volume of distribution at steady state and clearance is decreased with longer elimination half life in obese vs non obese