Critical Care

David E. Zimmerman

Pharmacokinetic Considerations in Obese Intensive Care Unit Patients

Patients in the intensive care unit (ICU) represent some of the most complicated and vulnerable patients seen in practice. Unfortunately, there is a lack of strong evidence for dosing obese ICU patients. Reasons for this include a high variance among the types of patients and disease states commonly seen in the ICU, difficulty in performing clinical pharmacokinetic (PK) studies in this population, or simple exclusion from clinical trials. Prevalence of these disease states depends on the type of ICU setting: medical, surgical, cardiac, trauma, burn, neurological, or combined units. This chapter will focus on reviewing the available evidence for dosing of medications in the obese critically ill patient.

PK parameters can be altered (or not altered) in any of these patients. Absorption can be affected by surgical procedures involving resection or manipulation of the gastrointestinal (GI) tract, decreased perfusion due to splanchnic constriction, inflammation, or simply a patient who is made nothing per oral for an extended period of time.¹ The volume of distribution (V_d) can be altered by changes in protein binding, patients aggressively volume resuscitated in septic shock, or in patients that are fluid overloaded.¹ The primary mechanisms of clearance (Cl) and elimination for the majority of medications rely on renal and hepatic function. Patients with septic shock can develop multiorgan failure in the form of acute or acute-on-chronic kidney injury as well as hepatic injury. These changes in end-organ function result in a decline in the ability to metabolize and eliminate medications. Given the state of chronic inflammation in obese patients with excess interleukins, tumor necrosis factor alpha, and other cytokines released by adipose tissue, alterations in the inflammatory response during sepsis are also thought to occur.²

Considerations for Obese ICU Patients

Risk of Complications

All patients in the ICU are at risk for infections, thromboembolism, or medication errors that could lead to iatrogenic injury. Outcomes specific to obese patients are not widely available. A review of seven studies showed mixed results for the impact of obesity on sepsis mortality.² The differences in the methods and statistical analysis of the seven trials did not allow the authors to make true comparisons. Three studies showed no difference in mortality; one study showed an increase in mortality; and three studies found reduced mortality.² Obesity has been shown to increase the risk of nosocomial infections, antibiotic treatment failure, pressure ulcers, and risk for acute respiratory distress syndrome development.^2-4

Challenges from an Informatics Perspective

Technology is becoming more and more complex in the healthcare industry. Many institutions are moving or have moved toward electronic health records, computer physician order-entry (CPOE) software, and smart infusion pumps. With this increasing complexity, there is a risk for input errors regarding weight-based drugs. Patients’ height and weight are stored in the CPOE system, which can be used to prepopulate medication doses for electronic orders to make calculations easier for prescribers. This may lead prescribers to dose off of total body weight (TBW) when an adjusted body weight or ideal body weight (IBW) would be more appropriate. Another example is in smart pumps where the “brain” is programmed for a weight for the channel that infuses the medication. If another infusion is added, which requires an additional channel, the brain will automatically use the already programmed weight. If one medication is based on TBW dosing and the other is based on IBW, then medication errors could potentially occur. It is important to realize the complexity of the technology to prevent medication errors from occurring in the obese ICU patient by implementing training and guardrails.

Vasopressors and Inotropes

Few published data exist on vasopressors and inotropes used in obese patients. All of these agents, except for vasopressin, are weight-based infusions, have short half-lives, and are titrated to goal blood pressure (BP) targets. It is unclear at this point which weight would have the best correlation with therapeutic success, and thus no formal recommendation can be made.⁵ Careful monitoring of hemodynamics based on the patient’s clinical response should be implemented, similarly to normal-weight individuals.

Helpful Tips

•Make sure to always remind healthcare professionals to assess for extravasation.

Summary

•No formal recommendations can be made based on the lack of evidence.

•Consistent weights should be used, and doses should be titrated based on clinical response.

Antihypertensives

Antihypertensives commonly used in the critical care patient include beta-blockers, calcium channel blockers (CCBs), and vasodilators. Beta-blockers can be classified based on their selectivity for beta-1, intrinsic sympathomimetic activity, and activity at alpha-receptors. These agents also differ in their lipophilicity and protein binding, which would lead one to expect different responses in obese patients.

Beta-Blockers

Labetalol

Labetalol is a nonselective beta-blocker that has a high hepatic extraction ratio (meaning a large proportion of labetalol is metabolized when it passes through the liver) and is noteworthy for its antagonistic effect on beta-receptors and alpha-1 receptors.⁶ A single intravenous (IV) dose of 0.99 mg/kg based on IBW was given to nine obese and nine normal body weight volunteers.⁷ There was no statistical difference with overall Cl or half-life.⁷ Total V_d was significantly greater in the obese group, but no difference was seen after correcting for TBW. Similar decreases in BP and heart rate (HR) were seen in both groups.

Atenolol

Atenolol is a rather hydrophilic, beta-1 selective-blocker that is excreted via the kidneys primarily as the parent compound.⁸ A crossover study compared the effects of atenolol 100 mg orally or propranolol 80 mg orally among three groups of patients: lean patients, obese patients without hypercholesteremia, and obese patients with hypercholesteremia.⁸ For atenolol, there were statistically significant decreases in concentration, Cl, and area under the curve (AUC) in both obese groups compared to lean subjects. The pharmacodynamic effects were similar among the three groups though, and no significant correlation was seen between the plasma levels and hemodynamic effects. Similar results regarding a lack of pharmacodynamics changes were found in another study of atenolol that assessed single and chronic administration of atenolol.⁹ Contrary to the first study, this second study did not find any PK differences in obese patients.

Propranolol

Propranolol is a nonselective beta-blocker that is lipophilic and highly protein-bound to alpha-1 acid glycoprotein (AAG). In the aforementioned crossover study with atenolol, there were no significant differences in propranolol pharmacokinetics or pharmacodynamics seen among the three patient groups.⁸ A study by Cheymol and colleagues investigated a single dose of propranolol 8 mg IV in obese and nonobese patients.¹⁰ The AUC was significantly increased by 47%, and V_d and Cl were significantly lower in obese patients, even after correction for TBW. Because both the V_d and Cl were reduced by similar amounts, the half-life did not significantly change. Similar results were seen in a single-arm, follow-up study.¹¹ In a different study, Bowman and colleagues compared propranolol 10 mg intravenously or 40 mg orally in six obese and six normal body weight subjects.¹² No difference was seen in total Cl, but it was significantly different when adjusted for weight. The V_d results contradicted the previously discussed trials by finding a larger V_d, resulting in a longer half-life in the obese subjects compared to lean subjects. A fourth study investigated propranolol, labetalol, and nebivolol in obese and nonobese subjects.⁷ No statistical difference in Cl, V_d, half-life, or pharmacodynamics parameters were found between obese and nonobese subjects following a single IV dose of 0.108 mg/kg based on IBW.

Nebivolol

Nebivolol is a lipophilic molecule and a beta-1 selective antagonist. Cheymol and colleagues studied a single IV dose of 0.073 mg/kg based on IBW in nine obese and nine nonobese volunteers.¹³ The V_d and Cl were found to be significantly higher, but once corrected for TBW there was no difference in the V_d. There do not appear to be major differences in distribution of nebivolol in obese and normal-weight patients. Most importantly from a pharmacodynamics standpoint, nebivolol had similar reductions in HR and BP in both groups.

Sotalol

Sotalol is noteworthy more so for its effect on potassium channels and use as an antiarrhythmic in addition to its effect on beta-receptors. From a PK standpoint, it is a hydrophilic molecule with limited protein binding and is predominantly excreted unchanged in the urine.¹¹ In the previously discussed study by Poirier et al., sotalol 1.064 mg/kg IV based on IBW was given to six obese patients and compared to previous PK parameters.¹¹ There was no significant difference in V_d, Cl, or half-life between the obese group and historical comparators.

Metoprolol

Metoprolol is a beta-1 selective, lipophilic molecule that undergoes hepatic metabolism.⁹ In the previously mentioned study by Galletti and colleagues, metoprolol succinate 200 mg/day had calculated PK parameters that exhibited a higher V_d when corrected for TBW, higher Cl, lower peak concentration, but no change in half-life when compared to historical normal- weight patients.⁹ The clinical relevance on its PD effects was not compared and remains unclear.

Esmolol

Esmolol is a beta-1 selective blocker that is used for the treatment of supraventricular arrhythmias, cardiac surgery in the pre- and postoperative setting, and hypertensive emergencies. It is administered via a weight-based IV infusion—with or without a bolus—due to its short duration of action and titrated to effect. It is metabolized by red blood cell esterases and does not need dose adjustments in patients with renal or hepatic dysfunction.¹⁴ No studies exist that investigate the effect of obesity on esmolol. With a short onset of activity of ~2 minutes, it would be reasonable to dose esmolol based on IBW and give supplemental doses as needed for goal clinical effect.

Helpful Tips

•Remember, beta-blockers can mask many of the symptoms of hypoglycemia.

Summary

•It is unclear if obesity plays a large role on the PK of many beta-blockers. Although PK parameters were different in some studies, there was no difference in the PD parameters.

•Based on the available evidence, patients should be started at conventional doses. Clinical targets and patient hemodynamics should drive dose titrations.

Calcium Channel Blockers

CCBs are separated into the nondihydropyridines and dihydropyridines. The dihydropyridines primarily inhibit L-type calcium channels in smooth muscle leading to an overall reduction in peripheral vascular resistance and decrease in BP.¹⁵ The nondihydropyridines additionally decrease atrioventricular (AV)-nodal conduction and are used in the treatment of various arrhythmias.

Nondihydropyridines

Verapamil— Verapamil is a nondihydropyridine CCB that is highly protein bound, undergoes hepatic metabolism, and is dependent on hepatic blood flow due to a high extraction ratio.¹⁵ In a study by Abernethy and colleagues, verapamil 0.15 mg/kg (max 25 mg) was given to 12 obese subjects, defined as >130% of IBW, and 11 normal body weight patients.¹⁶ The half-life was 2.8 times longer in the obese patient group due to an unchanged Cl and a 2.4 times increase in the V_d. No change was seen in the plasma protein binding between the two groups of patients. Similar decreases in BP were seen between the two groups; however, there was less reflex tachycardia and less impairment of the AV node in the obese patient group. The authors recommended a loading dose be based on TBW due to the increase in V_d, but maintenance dosing may reflect dosing for normal-weight individuals. However, this study was only a single-dose study and may be difficult to extrapolate to maintenance dosing.

Diltiazem—Diltiazem is another nondihydropyridine available for oral or IV use. Diltiazem is 70% to 80% protein bound and undergoes hepatic metabolism via the cytochrome P450 (CYP) system.¹⁵ Diltiazem can be given orally, as an IV bolus, or continuous IV infusion depending on the indication for use. No published data exist on its use in obese patients. The package labeling suggests TBW be used when calculating the initial IV bolus doses of 0.25 to 0.35 mg/kg (20 to 25 mg in the average patient) for the treatment of arrhythmias.¹⁷ Given the concern for hemodynamic compromise, it would be reasonable to dose diltiazem based on IBW or an adjusted weight with additional doses given as needed. The continuous infusion is not weight based and thus should be infused at a rate of 5 to 15 mg/hr and titrated to goal clinical effect.

Dihydropyridines

Nifedipine—Nifedipine is a dihydropyridine that undergoes hepatic oxidation and hydrolysis.¹⁵ It is available only via oral formulation, and thus its use is limited in the critical care setting. No published reports exist of its use in obese patients. Dosing should be based on conventional use and titrated to clinical effect.

Nicardipine—Nicardipine is another dihydropyridine CCB that is available in both oral and IV formulations. It is highly protein bound and metabolized in the liver.¹⁸ No published literature exists for obese patients. The IV infusion is not weight-based and should be initiated at normal doses and titrated to goal BP.

Clevidipine—Clevidipine is a third-generation dihydropyridine CCB that stands out as it is formulated in a 20% lipid emulsion, similar to propofol. It has an onset of action of 2 to 3 minutes, a high Cl rate due to its metabolism by blood and tissue esterases with a terminal phase half-life of 10 to 15 minutes, and a V_d similar to intravascular volume.¹⁹ Safety data have been published for infusions up to 72 hours but unfortunately not specifically in obese patients.²⁰ Similar to nicardipine, the infusion for clevidipine is not weight-based and should be initiated at a normal rate and titrated to goal effect.

Helpful Tips

•Nicardipine and clevidipine should not be used in patients with advanced aortic stenosis due to the secondary effect of reduced afterload leading to a reduction in myocardial oxygen delivery.

Summary

•Evidence shows TBW should be used for initial dosing of verapamil and subsequent doses based on conventional dosing. It would be reasonable, however, to use IBW or an adjusted weight followed by subsequent doses in patients with tenuous hemodynamics.

•Normal dosing should be used for diltiazem and the dihydropyridines.

Vasodilators

Nitroglycerin

Nitroglycerin is a vasodilator that is used in acute coronary syndrome, flash pulmonary edema, and surgical procedures, among other indications. Only one animal study was found investigating the effect of obesity on nitroglycerin. Nitroglycerin 10 mcg/minutes IV infusion was given to three different groups of rats, one group being obese Zucker rats.²¹ No difference was seen in dose-response curves or concentration levels, concluding at least in a rat model that obesity does not have a significant effect on the PK and PD of nitroglycerin.

Sodium Nitroprusside

Sodium nitroprusside is an arterial and venous vasodilator that is available for IV use in treatment of hypertensive emergency and acute decompensated heart failure.²² Currently, no studies exist that investigate its use in obese patients. Given its short half-life, practitioners can initiate infusions, based on IBW or an adjusted body weight, and titrate the infusion rate accordingly.

Hydralazine

The exact mechanism of hydralazine has not been fully elucidated. Its early PK studies were affected by poor selectivity of assays, leading to various bioavailability and V_d values being reported.²³ Hydralazine undergoes acetylation in the liver, which is affected by rapid or slow acetylator genotypes.²³ Currently, no literature exists regarding obese patients; therefore, conventional doses should be used and titrated to goal BP.

Helpful Tips

•Sodium nitroprusside is metabolized to cyanide and then to thiocyanate, which can accumulate and lead to toxicity in prolonged use in patients with renal dysfunction.

Summary

•There is a lack of clear evidence in which weight to use for vasodilators in obese patients.

•Conservative dosing may be used, and quick titration to clinical effect would most likely be the best option.

Antiarrhythmics

Procainamide

Procainamide is a Vaughan-Williams Class IA antiarrhythmic that is available only for IV use for the cessation of ventricular and atrial arrhythmias. Procainamide is 10% to 15% protein bound and undergoes equal hepatic and renal metabolism.²⁴ Its hepatic metabolism is a Phase II acetylation, in which it is converted to an active metabolite, N-acetylprocainamide (NAPA).

A single, 300-mg IV infusion of procainamide over 1 hour was compared in seven obese and seven normal body weight patients.²⁵ Uncorrected V_d and corrected V_d based on IBW showed no difference between the two groups, while correction for TBW showed a significantly smaller V_d in the obese patient group compared to the control group.²⁵ Similar V_d and total Cl of procainamide and NAPA between the two groups suggest loading and maintenance doses should be based on IBW. If needed, additional doses can always be administered based on clinical response.

Amiodarone

Amiodarone is classified as a Vaughan-Williams Class III antiarrhythmic but noted to have properties of all the classes. From a PK standpoint, amiodarone is lipophilic and highly protein bound (>95% protein bound) leading to a relatively large V_d.²⁶ Amiodarone undergoes extensive hepatic metabolism by CYP3A4 and has an active metabolite, N-desethylamiodarone.²⁷ It is predominantly excreted in the bile and urine. In normal body weight subjects, the elimination half-life with single doses is estimated to be 18 to 36 hours, but the terminal half-life increases to 20 to 60 days for chronic therapy.²⁶

There is only one study by Fukuchi and colleagues that investigated the effect of overweight (not obese) patients and total body fat in 23 patients on oral amiodarone.²⁸ The patients were classified according to their body fat and obesity status. BMI, age, and daily amiodarone dose were shown to influence Cl. A 22.3% reduction in Cl was seen when the BMI was >25 kg/m² and a 47% reduction in Cl was seen in patients 65 years or older. Given the reduction in Cl with BMI and age, special care should be taken when dosing elderly obese patients as they are at the highest risk for having a reduced Cl. A limitation is the classification of obese as a BMI ≥25 kg/m². In fact, the group that was classified as obese based on both BMI and body fat had an average BMI of 27.7 kg/m² and would be classified as overweight by the WHO categorization.

Digoxin

Digoxin is a cardiac glycoside that is used in the treatment of heart failure and atrial arrhythmias.²⁹

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