A 52-year-old woman is admitted to the ICU, who is s/p orthotopic liver transplant 2 weeks ago, for septic shock requiring vasopressor support. Pertinent past medical history includes an unprovoked pulmonary embolism 3 months ago for which she takes apixaban 5 mg twice daily at home. Review of systems reveals normal renal function, active bowel sounds with two recent bowel movements, and a Glasgow Coma Score of 15. In the presence of distributive shock requiring vasopressor support, with regard to absorption, which scheduled medications would you be most concerned about?
Correct Answer: A
Critically ill patients receiving vasopressors may have reduced subcutaneous absorption of drugs. Presence of shock and/or use of vasopressors decrease peripheral tissue perfusion, resulting in impaired subcutaneous absorption. Studies evaluating low-molecular-weight heparins demonstrate lower antifactor Xa levels in critically ill patients receiving vasopressors when compared with critically ill patients not on vasopressors or those who are not critically ill. Sublingual absorption is not impaired in states of critical illness, and intravenous therapy always results in 100% bioavailability. Although blood is shunted to vital organs in states of hypotension and shock, the impact of splanchnic perfusion on drug absorption has not been well studied.
A 49-year-old man is admitted to the ICU for hemodynamic instability and ventilator weaning following surgery for a bowel perforation. His past medical history includes Crohn disease for which he takes adalimumab 40 mg once weekly. He was hospitalized 2 weeks ago for medical management of a bowel obstruction. He is started empirically on piperacillin/tazobactam and vancomycin, and 5 µg/min of norepinephrine to maintain a mean arterial pressure of at least 65 mm Hg. Over next 24 hours, the patient decompensates and is now requiring 37 µg/min of norepinephrine and 0.03 units/min of vasopressin to maintain a mean arterial pressure of 65 mm Hg, despite fluid resuscitation with 3 L of lactated ringers. He is currently anuric, is not responsive to fluids, and appears volume overloaded. Given his risk factors for multidrug-resistant organisms, his antibiotic regimen is broadened to meropenem, amikacin, daptomycin, and micafungin.
When determining dose of amikacin for this patient, what considerations should be made?
Correct Answer: C
Hydrophilic molecules, such as amikacin, generally remain in the plasma water volume. Capillary leak due to septic shock and exogenous volume administration will contribute to an increase in the volume of distribution. Studies evaluating aminoglycosides in states of critical illness report increases in the volume of distribution anywhere from 25% to 50%. Additionally, aminoglycosides are concentration-dependent agents that are most effective at concentrations 10 times the minimal inhibitory concentration of the offending pathogen. Therefore, the pharmacokinetic properties of the drug should lead the clinician to administering an increased dose. Although clearance of aminoglycosides will be decreased with impaired renal function, the initial dose should not be decreased because of the increased volume of distribution. Increasing the dosing frequency will increase the time above the minimal inhibitory concentration, but not result in target peak concentrations for some time. Amikacin is not protein bound, so will not be affected by decreased protein.
Which pathophysiological change seen in critically ill patients most frequently makes medication dosage adjustment necessary?
Correct Answer: B
Medications that undergo renal elimination generally have dosing recommendations based on GFR (glomerular filtration rate) estimated using the Cockroft-Gault formula. For renally eliminated medications, modifying dose regimens is essential in patients with acute or chronic kidney injury to prevent adverse drug events. Conversely, conditions such as sepsis, trauma, surgery, burns, and use of vasopressors can lead to an increase in renal blood flow, resulting in increased renal drug clearance. No empiric changes for augmented renal clearance are recommended by drug manufacturers. Although a decrease in plasma proteins can increase the free concentration of highly protein bound drugs, there are no empiric dosing changes that are recommended based on the degree of protein decrease. Similarly, although both enteral and subcutaneous absorption of medications is diminished in states of critical illness, no dosing adjustments exist for any medication empirically. Finally, there is no biomarker readily available in the clinical setting that can be used to determine the degree of liver impairment for the purposes of drug dosing. Although the Child-Pugh classification uses patient-specific data to assess severity of hepatic disease, its purpose was to predict mortality. Although some drug manufacturers include dosing adjustment recommendations based on Child-Pugh score, such recommendations are neither available for many drugs nor are they validated in critically ill patients.
Fentanyl, a drug with a high extraction ratio, will be most influenced by which critical illness–related metabolic abnormality?
The hepatic extraction ratio is the fraction of drug that is removed from the blood after one pass through the liver. Hepatic clearance of drugs with high extraction ratio (>0.7) primarily depends on liver blood flow and is less affected by changes in liver function (ie, intrinsic clearance or function hepatocytes). Conversely, hepatic clearance of drugs with low extraction ratio (<0.3) is more sensitive to changes in liver function. Protein binding can be an important determinant of a drug’s hepatic extraction ratio; however, changes to plasma protein binding are only relevant for drugs with high extraction ratios.
Phenytoin, a drug with a low extraction ratio, will be most influenced by which critical illness–related metabolic abnormality?
The hepatic extraction ratio is the fraction of drug that is removed from the blood after one pass through the liver. Hepatic clearance of drugs with low extraction ratio (<0.3) is more sensitive to changes in liver function (ie, intrinsic clearance or function hepatocytes). Conversely, hepatic clearance of drugs with high extraction ratio (>0.7) primarily depends on liver blood flow and is less affected by changes in liver function. Protein binding can be an important determinant of a drug’s hepatic extraction ratio; however, changes to plasma protein binding are only relevant for drugs with high extraction ratios.
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