7/31/2020 FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Contact Information Drew Silverman, PharmD Pharmacotherapy Specialist in Abdominal Transplantation Tampa General Hospital Critical Keys to Managing the [email protected] Transplant Patient in the ICU 813-844-7210 th FSHPDrew Silverman,54 Annual Pharm.D; Meeting Pharmacotherapy Specialist in Abdominal Transplantation; Tampa General Hospital August 7-9, 2020 References: 12 FSHP 54th Annual Meeting – August 7-9, 2020 Disclosure Kidney = 358 • I have (or an immediate family member has) a vested Kidney-Pancreas = 10 Liver = 145 interest in or affiliation with any corporate organization Heart = 36 offering financial support or grant monies for this Lung = 34 continuing education activity or with any organization that Total = 584 has a specific interest in the therapeutic areas under Tampa General Hospital Solid Organ Transplants Calendar Year 2019 discussion as follows: Consultant: Veloxis Pharmaceuticals Speaker with honorarium: Veloxis Pharmaceuticals, Novartis Pharmaceuticals 34 FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Disease Specific Considerations Outline in the Transplant Patient Objectives • Kidney Transplant 1. Understand the interplay of common diseases seen in critically ill • Recurrent disease transplant patients • Acute Kidney Injury 2. Design a management strategy for treating rejection in the critically ill • Drug clearance patient • Electrolyte disturbances 3. Describe tools for monitoring and assessment of the critically ill transplant • Hyperkalemia, Hypervolemic Hyponatremia, metabolic acidosis patients • Liver Transplantation 4. Recognize the pharmacokinetic and pharmacodynamic interactions • Biliary issues between immunosuppressive agents and medications used to manage the • Drug clearance – immunosuppression, decreased biliary transport critically ill transplant patient • Hepatocyte damage 5. Discuss alternative routes of administration for immunosuppressive agents • Drug metabolism in the NPO patient • Decreased tacrolimus clearance by up to 66% • Increase tacrolimus half-life 3-fold References: References: 56 1 7/31/2020 FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Disease Specific Considerations mTORs – Interstitial in the Transplant Patient Lung Disease • Heart Transplantation • Mechanism: Autoimmune response vs. delayed type hypersensitivity? • Decreased EF • No correlation with dose or duration of time therapy • Decreased clearance of high extraction drugs • Diagnosis of exclusion • Cyclosporine, tacrolimus • AKI • Complications • Electrolyte disturbances • • Hyperkalemia, Hyponatremia Interstitial pneumonitis & organizing pneumonia • Lung Transplantation • Intubated patients need alternative routes of administration • Clinical consideration • Intravenous • Consider mTOR‐I induced interstitial lung disease when patient presents with • Mycophenolic acid unexplained respiratory symptoms • Cyclosporine • R/O all other causes of interstitial lung disease • Steroids • Opportunistic Infections • Tacrolimus- very nephrotoxic • TROLI, Pulmonary interstitial hemorrhage • Sublingual route • Withdrawal of mTOR‐I is therapeutic References: References: Chajed et al. Respiration. 2006;73:367‐374. 78 FSHP 54th Annual Meeting – August 7-9, 2020 New Onset Diabetes after NODAT Pharmacologic Management Transplant (NODAT) Risk Factors Class Drug Renal Adjustments Comments Exenatide CrCl<30‐ Avoid use GLP‐1 receptor Liraglutide **Severe renal impairment‐ use with •Cardiovascular benefit agonists Dulaglutide caution •GI ADRs common Albiglutide Semaglutide No dosage adjustment necessary eGFR<45‐ use not recommended •Cardiovascular benefit Canagliflozin & eGFR <30‐ use CI •Reduced efficacy and increased Empagliflozin SGLT2 inhibitors risk of ADRs in renal impairment eGFR<60‐ use not recommended •Increased risk of dehydration and Dapagliflozin eGFR <30‐ use CI GU infections Sitagliptin CrCl<50‐ by 50%, <25‐ by 75% •May have beta cell preservation Saxagliptin CrCl<50‐ by 50% DDP‐4 inhibitor •Low risk of hypoglycemia Alogliptin CrCl<60‐ by 50%, <30‐ by 75% •Minimal reduction in A1c Linagliptin None • by 25‐50% when NPO All insulin No specific adjustments, but cleared Insulin •Increased clearance with good products renally graft function (post‐txp) References: Endocrino Metab Clin N Am 35 (2007) 873-890 910 FSHP 54th Annual Meeting – August 7-9, 2020 Oral Antidiabetic Agents in Transplant Post‐Transplant Hypertension Class Drug Renal Adjustments Comments • Incidence: 50‐90% eGFR 30‐45: not recommended for initiation of therapy • Etiology: • eGFR falls to <45 during therapy, consider •Rarely used: risk lactic • Native‐kidney mediated Biguanides Metformin benefits/risks of continuing therapy or dose acidosis, GI side effects • Donor‐kidney mediated reduction (eg, 50% reduction or 50% of maximal dose) • Renal artery stenosis eGFR <30: use CI • Drug‐induced Glipizide No specific recs • Steroids‐ Overstimulation of mineralocorticoid receptorsleads to sodium and water retention 2nd generation Glimepiride Use with caution •Risk of hypoglycemia • Calcineurin inhibitors (cyclo>tacrolimus)‐ Vasoconstriction of the afferent renal arterioles and intrarenal vessels sulfonylureas Glyburide CrCl<60: use CI due to endothelin release • Chronic allograft dysfunction Alpha‐glucosidase Acarbose Not recommended SCr>2 mg/dL or CrCl <25 •GI side effects • inhibitors Miglitol CrCl<25: Not been studied Goal BP • JNC8: <140/90 mmHg Renal impairment: Not been studies/use with Repaglinide •Minor substrate of • 2017 ACC/AHA: <130/80 mmHg Meglitinide Analog caution Nateglinide CYP3A4 • KDOQI/KDIGO goal: <130/80 mmHg • Acceptable to have higher BP in immediate post‐transplant period to ensure adequate renal •Heart failure Pioglitazone allograft perfusion (<150s/90s) Thiazolidinediones None •Peripheral edema Rosiglitazone •Bone fractures References: 1. Campistol et al Nephrol Dial Transplant 2004;19(3):64‐66 2. Najeed et al Int J Cardiol 2011;152:4‐6 3. Fernando Transplantation 2015;99:1016‐1022 11 12 2 7/31/2020 FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Treatment of Post‐Transplant Managing Hemodynamics Hypertension in the Transplant Patient • Calcium channel blockers (CCBs) • Volume • Dihydropyridine (amlodipine, nifedipine) • Significant DDI with nicardipine and non‐dihydropyridine CCBs with CNIs & mTORs (Potent • Albumin is key in liver transplant patients. Especially when serum albumin is less CYP‐3A4 inhibitor) than 2.5 or less than 3 with significant interstitial fluid volume. • Verapamil > diltiazem • Safe intravenous choice is clevidipine. • Avoid rapid sodium shifts in liver transplant patients. • Agent of choice for CNI induced HTN: counteracts vaso‐constrictive effects of CNIs • 6meq/24hrs. Above that increases risk of central pontine myelinolysis • ADR: edema, constipation Hetastarch contraindicated in liver transplant- bleeding risks • ACEI/ARBs • Not used within first 1‐3 months after kidney transplant • Pressors • May be beneficial in renal protective effects (insufficient literature) • ADR: hyperkalemia, anemia, elevations in SCr • Vasopressin • Beta blockers • Norepinephrine • Useful post MI, high CAD risk, SV tachycardia • Dopamine • ADR: hyperkalemia, glucose intolerance References: 1. Fernando Transplantation 2015;99:1016‐1022 2. Dobrowolski et al Neth J Med 2014;72(5):258‐263 References: 13 14 FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Management of Arrythmias Management of Arrythmias • Sinus tachycardia • Dofetilide, Flecainide • Fix underlying cause. Hypotension, anemia, pain, fever, etc. • Significant issues with renal function • Beta-blockers • Watch hypomagnesemia and hyperkalemia • Metoprolol DOC Ventricular arrhythmias • Calcium-channel blockers • Fix underlying cause • Diltiazem DOC • Drugs that increase QTc • Atrial fibrillation • Tacrolimus, cyclosporine • Fix underlying cause • Azole antifungals • Fluid overload, hypovolemia, check central line placement • Macrolide antibiotics • Antipsychotics • Rate control first • Anti-depressants • Rhythm control • Correct hypomagnesemia • Amiodarone • Infuse IV magnesium at 2 grams iv x 1 then 1gram over 2 hours, and repeat as needed. • Significant drug interaction with most immunosuppression • Risk vs. benefit of diuresis with loops. • Hepatotoxin, pulmonary toxin. • Add amiloride where possible. (watch serum potassium) References: References: 15 16 FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Sedation and Agitation Sedation and Agitation in the ICU in the ICU Anti-psychotics • Propofol • Benefits- short acting. Easy titration. Short half-life even in significant liver disease • Haloperidol • Risks- myoclonic movements. No pain relief • Lowers seizure threshold. Higher risk with liver transplant patients • Benzodiazepines • Tacrolimus, history of alcoholic liver disease, hepatic encephalopathy, hypocholesterolemia, and • Lorazepam hypomagnesemia all risk factors • Benefits- can lower seizure risk. May help in treatment of akithesias. Safe to use in liver failure. • QTc prolongation • Risks- can induce psychosis. Half-life 6-8 hours with normal kidney function. No pain relief • Tacrolimus, hypomagnesemia, azole antifungals, antidepressants, all risk factors • Midazolam • Benefits- quicker onset than lorazepam. Half-life 4-6 hours with normal liver function • Akathisia