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patient with a history of heparin‐induced thrombocytopenia, or an allergy to heparin, should not receive four‐factor PCC (Kcentra). However, patients can receive activated four‐factor PCC (FEIBA). Given his weight and elevated INR (INR > 6), the dose should be 50 units/kg, not to exceed 5000 units. For an INR 2–4, the dose should be 25 units/kg, not to exceed 2500 units; and for INR 4–6, the dose should be 35 units/kg, not to exceed 3500 units. While phytonadione (vitamin K) should be given intravenously (not orally ‐ Answer A), the onset is 6–12 hours, and would not rapidly reverse this patient’s severe supratherapeutic INR. Fresh frozen plasma requires large volumes, often has incomplete INR correction, has a risk of transfusion‐related reactions, and requires extended time to achieve hemostasis, and therefore would not be ideal for a hemodynamically unstable patient. While tranexamic acid, an antifibrinolytic agent, has been shown to be beneficial in trauma and obstetric hemorrhage in studies such as CRASH 2 and WOMAN trial, respectively, it should not be used for warfarin reversal.Answer: BDaley, MJ, Bauer, SR. Shock Syndromes II: hypovolemic, critical bleeding, and obstructive. 2019 ACCP Critical Care Pharmacy Preparatory Review and recertification Course. 2019

      7 Which of the following patients would be most appropriate for alvimopan?A 46‐year‐old man with hypertension and hyperlipidemia who is scheduled to undergo a laparoscopic colostomy reversal with colorectal anastomosis.A 63‐year‐old man with end‐stage renal disease on dialysis and diabetes who is scheduled to undergo a sigmoid resection for cancer.A 55‐year‐old woman with chronic back pain who is currently taking 15 mg morphine equivalents daily and is scheduled to have a laparoscopic gastric bypass.A 36‐year‐old woman who is postoperative day 4 following a small bowel resection secondary to a small bowel obstruction and has a persistent ileus.A 68‐year‐old man with COPD who is postoperative day 3 following a right hemicolectomy for cancer with end ileostomy and is now having 1500 mL/day output from his nasogastric tube.Alvimopan is a selective peripherally acting μ‐opioid receptor antagonist that specifically targets peripheral μ receptors in the GI tract. It is used to accelerate time to upper and lower gastrointestinal (GI) recovery following large or small bowel resection surgery in patients who undergo a primary anastomosis. Alvimopan blocks the adverse effects of opioids on the GI tract without affecting overall analgesia. It has been shown to reduce time to GI transit and subsequently reduce hospital time. Alvimopan is indicated for planned inpatient surgery in patients undergoing partial bowel resection with primary anastomosis. Ideal dosing is a single 12 mg capsule 30 minutes to 5 hours prior to surgery, and then subsequent twice daily dosing beginning on postoperative day 1, for a maximum of 7 days (15 doses) or until discharge. Patients must remain inpatient while taking alvimopan. Alvimopan is contraindicated in patients who have received therapeutic dosing of opioids for more than 7 days prior to surgery, have severe hepatic impairment, or end‐stage renal disease. It should not be used in patients with a small bowel obstruction or in those patients who will not undergo a primary anastomosis. Patient B is not a candidate due to end‐stage renal disease. Patient C is not a candidate due to chronic high‐dose opioid usage prior to surgery. Patient D is incorrect since she is postoperative from small bowel obstruction with a persistent ileus. Patient E is incorrect because he is postoperative, did not have a primary anastomosis, and is having high‐volume nasogastric tube output.Answer: ACurran MP, Robins GW, Scott LJ, et al. Alvimopan. Drugs. 2008; 68 (14):2011–9.Xu, LL, Zhou XQ, Yi PS, et al. Alvimopan combined with enhanced recovery strategy for managing postoperative ileus after open abdominal surgery: a systematic review and meta‐analysis. J Surg Res. 2016; 203 :211–221.Vaughan‐Shaw PG, Fecher IC, Harris S, et al. A meta‐analysis of the effectiveness of the opioid receptor antagonist alvimopan in reducing hospital length of stay and time of GI recovery in patients enrolled in a standardized accelerated recovery program after abdominal surgery. Diseases Colon and Rectum. 2012; 55 :611–620.

      8 Which one of the following definitions of pharmacokinetic and pharmacodynamic principles in the critically ill patient is correct?Aggressive fluid resuscitation will not alter the volume of distribution in morbidly obese patients.Metabolic clearance by the liver, mostly via the cytochrome P450 system, may be compromised in the critically ill patient by decreases in hepatic blood flow, intracellular oxygen tension, and cofactor availability.Gut wall edema, changes in gastric or intestinal blood flow, concurrent administration of enteral nutrition, and incomplete oral medication dissolution has no effect on drug absorption. The response to antibiotics that have time‐dependent killing pharmacodynamics would be improved by administering a higher dose of drug to increase the area under the inhibitory curve.Deceased in renal function decreases the half‐life of medications cleared via the kidney and result in accumulation of drugs or their metabolites.Critically ill patients have alterations in medication pharmacokinetics and pharmacodynamics. Pharmacokinetics characterizes what the body does to a drug—the absorption, distribution, metabolism, and elimination of the drug. Pharmacodynamics is what the drug does to the body and describes the relationship between the concentration of drug at the site of action and the clinical response observed. Many factors affect drug absorption, distribution, and clearance in the critically ill patient. Failure to recognize these variations may result in unpredictable serum concentrations that may lead to therapeutic failure or drug toxicity. Drug absorption is altered by gut wall edema and stasis, changes in gastric and intestinal blood flow, concurrent medications and therapies such as enteral nutrition, and incomplete disintegration or dissolution of oral medications (Answer C). The volume of distribution describes the relationship between the amount of drug in the body and concentration in the plasma. Fluid shifts, particularly after fluid resuscitation, and protein binding changes that occur during critical illness, alter drug distribution (Answer A). Plasma protein concentrations may change significantly during critical illness and may affect the volume of distribution by altering the amount of the active unbound or free drug. Metabolic clearance by the liver is the predominant route of drug detoxification and elimination. With hepatic dysfunction that may occur in the critically ill patient, drug clearance may be decreased secondary to reduced hepatic blood flow, decreased hepatocellular enzyme activity, or decreased bile flow. A common pathway for drug metabolism is the cytochrome P450 system (Answer B). Critical illness may compromise this system by decreasing hepatic blood flow, intracellular oxygen, or cofactor availability. Antibiotics are usually categorized as having either concentration‐dependent or time‐dependent killing. The activity of concentration‐dependent antibiotics increases as the peak serum concentrations of drug increase. Time‐dependent antibiotics kill at the same rate regardless of the peak serum concentration that is attained above the MIC (minimum inhibitory concentration). Thus, an increase in dose is not associated with improved AUIC (area under the inhibitory concentration curve). Instead, increasing dosing frequency would improve antibiotic killing (Answer D). Decreases in renal function will prolong the half‐life of drugs eliminated by the kidneys (Answer E).Answer: BVarghese JA, Robert JA, Lipman J . Pharmacokinetics and pharmacodynamics in critically ill patients. Curr Opinion Anesth. 2010; 23 (4):472–478.Devlin JW, Barletta JF . Principles of drug dosing in critically ill patients . In Critical Care Medicine Parrillo JE and Dellinger RP (eds), 3rd edn, Mosby, Philadelphia, PA, 2008; pp. 343–76.

      9 Which statement is true regarding andexanet alfa, the factor Xa inhibitor reversal agent?Reverses only direct‐acting oral anticoagulants (DOACs) and not low‐molecular‐weight heparin.There is concern for prothrombotic effects post‐administration.It is a monoclonal antibody that binds to factor Xa.It has a long half‐life and rarely requires redosing.Dosing is based on the anticoagulant and the time from last dose.Andexanet alfa is a modified factor Xa protein (not a monoclonal antibody ‐ Answer C) that directly binds to the factor Xa inhibitors in a 1:1 ratio to inactivate their anticoagulant response. Due to structural modifications, it does not have a direct prothrombotic effect (Answer B). Andexanet alpha reverses both direct‐ (DOACs) and indirect‐ (low‐molecular‐weight heparin) acting anticoagulants (Answer A). It has a short half‐life of 1 hour and the infusion runs over 2 hours. In theory, the 2‐hour time interval allows for a hemostatic plug to form and bleeding to stop. A rebound anticoagulation effect has yet to be found. In early studies, nearly 80% of patients had good or excellent hemostasis at 12 hours and did not require re‐administration of andexanet alpha (Answer D). Andexanet alpha administration is based on the half‐life of the anti‐Xa inhibitor as well as when it was last taken. See chart below for dosing:AnticoagulantLast dose<10 mg: low doseRivaroxaban>10 mg within 8 hours: high dose>10mg after 8 hours: low

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