the Treatment of Critically Ill Patients with Severe Influenza - PowerPoint PPT Presentation

Oseltamivir Dosing Controversies in the Treatment of Critically Ill Patients with Severe Influenza Soomi Hwang, Manish Khullar B.Sc.(Pharm). Interior Health Pharmacy Residents Critical Care Rotation February 27, 2014

Learning Objectives • Describe the mechanism of action and pharmacokinetic properties of oseltamivir • List antiviral options for patients with influenza • Describe the current evidence for using oseltamivir 150mg BID over 75mg BID on its efficacy and safety in patients in critically ill patients

Our Patient on Admission ID 49 y/o male, admitted to ICU on Feb 8 Ht: 178cm Wt: 95kg CC/RFA Came to ER with SOB, dyspnea and O2sat 68% on Feb 8/ Hypoxemic respiratory failure HPI Shortness of breath x 1 week Allergies NKDA Social History 1 pack/day smoker Recovering from chronic alcoholism Previous IV drug user (heroin, hydromorphone) Lives alone

Our Patient Past Medical History Medications Prior to Admission Chronic pain/ opioid dependency Methadone 150mg daily (Witness once a week) Personality disorder Sertraline 200mg daily Insomnia Trazodone 50mg 1-2 tabs HS

Review of Systems- Feb 11 th Vitals T: 37.7 BP: ~125/55 MAP: 90 HR: ~90 RR: 20/28 SaO2: 97% CNS GCS 6 / RASS -4 (target 0) / delirium UTA HEENT - RESP Ventilator: assisted control (AC) FiO 2 0.45/ PEEP 10(↓) cm of water Productive cough, large yellow sputum, crackles Reduced A/E bilaterally CVS Sinus rhythm/ S1S2 GI OG in situ GU Foley catheter MSK/DERM Warm, rash on back Mild generalized edema

Labs – Feb 11 th Heme WBC: 10.6 H Hgb: 101 L MCV: 87.0 Plt: 156 Neut: 9.96 H Lytes Na: 144 K: 4.0 Cl: 109 CO 2 : 27 GU SCr 194 eGFR 32 7.51 (9 th ) Troponin ABG 7.28 / 53 /76/25 SaO2 97% Respiratory acidosis

Investigations • Diagnostics Date Test Findings Feb 8 Chest X-Ray Airspace disease within both lungs Impression: Diffuse bronchopneumonia Feb 8 ECHO (TTE) Normal LV size and wall thickness; LVEF ~30-40% No significant structural valve abnormalities Feb 11 Chest X-Ray Extensive airspace disease in both lungs

Investigations • Microbiology Date Source Findings Feb 8 Blood venipuncture Streptococcus pneumoniae S- ceftriaxone, levofloxacin, penV, penG, vancomycin Feb 8 Sputum Streptococcus penumoniae endotracheal S- amoxicillin, levofloxacin, PenV, Trimeth/Sulfa suction R- Clindamycin, erythromycin, tetracycline Feb 8 Sputum Influenza A virus subtype pandemic H1N1-2009 endotracheal (confirmed on Feb 11) suction - Respiratory viral panel

Course in Hospital • Feb 8: Admitted to ICU for respiratory failure and sepsis – Vancomycin 1250mg IV q8h – Azithromycin 500mg IV daily – Ceftriaxone 2g daily – Oseltamivir 150mg BID • Feb 9: vancomycin and azithromycin discontinued • Feb 8-9: Patient required deep sedation and paralysis for ventilation and oxygenation

Our Patient – Feb 11 Medical Problems Medications Methadone withdrawal/pain Hydromorphone infusion 1mg/hr Hydromorphone 1-2mg IV q1h prn Acetaminophen 1000mg PO q6h prn Physiologic sedation Propofol infusion 80mg/hr Midazolam 2-5mg IV q5m prn Influenza A Oseltamivir 150mg PO q12h (day 4) Pneumonia Ceftriaxone 2g IV daily (day 4) Bronchspasm Salbutamol 6-12 puffs q4h + prn Ipratropium 4-8 puffs q4h Respiratory acidosis - Increased troponin Metoprolol 25mg PO BID ASA 81mg PO daily Renal insufficiency/AKI - DVT prophylaxis Heparin 5000 units SC q12h Electrolyte replacement KCl, MgSO4, CaCl, PO4 prn (ICU protocol)

Prioritized List of DRPs • Patient is at risk of experiencing an adverse event with no added benefit secondary to receiving a higher than recommended dose of oseltamivir. • Patient is at risk of experiencing opioid withdrawal symptoms secondary to receiving a low dose of hydromorphone infusion compared to his long-term methadone dose.

DRP Focus • Patient is at risk of experiencing an adverse event with no added benefit secondary to receiving a higher than recommended dose of oseltamivir .

Treatment Options for Influenza • Oseltamivir 75mg PO BID x 5 days • Zanamivir 10mg inhaled BID x 5 days – Restricted for patients unresponsive to other antivirals • Amantadine x 5 days – Influenza A only – <64 y/o: 100mg PO BID – >64 y/o: 100mg PO daily • Best if started within 48 hrs of symptom onset • Peramivir- not available in Canada/NDA accepted by FDA – Open label trial in 2013 showed that peramivir 300mg IV BID or 600mg IV daily was associated with decreased viral shedding and clinical improvement in 127 patients with influenza

Viable Options for Our Patient • Adult with moderate, progressive, severe or complicated illness – initiate antiviral therapy Oseltamivir 75mg po BID for 5-10 days – if not responding, zanamivir 10mg inhaled BID Appendix B. Algorithm for oseltamivir and zanamivir treatment of moderate, progressive, severe or complicated influenza in adults. AMMI Canada. 2013

How Does Oseltamivir Work? flipper.diff.org

Properties of Oseltamivir • A- well absorbed • D- Vd: 23-26L • M- 90% hepatic metabolism to oseltamivir carboxylate • E- excreted in urine • Side effects: n/v/d, abdominal pain, epistaxis • No dose adjustment for obese patients required

Goals of Therapy • Reduce mortality • Reduce duration of ICU stay and hospital stay • Reduce duration of infection • Minimize complications of influenza • Reduce signs and symptoms of influenza • Normalize surrogate markers – WBC, neutrophils • Prevent adverse events

Abstract Viral Clearance with Standard or Triple Dose Oseltamivir Therapy in Critically Ill Patients with Pandemic (H1N1) 2009 Influenza

Kumar et al, 2013 D Double blind, randomized control of influenza 2009-2011 at 25 Canadian sites P N=56 patients randomized 18 pandemic H1N1 PCR-positive patients I/C Oseltamivir 225mg BID vs 75mg BID O Primary endpoint: • Complete viral clearance on day 5 of therapy Secondary endpoint: • 30 day ICU and hospital survival • Duration of mechanical ventilation

Results • 18 pandemic H1N1 PCR positive patients Oseltamivir 75mg Oseltamivir 225mg P-value BID BID Negative PCR by 1/9 (11%) 7/9 (78%) 0.015 day 5 Secondary No significant differences among the groups endpoints

Author’s Conclusions • “Triple therapy of patients with severe pandemic (H1N1) influenza A infections is associated with more rapid viral clearance” • “…as more rapid clearance of pathogens has been associated with improved clinical outcomes in other infectious syndromes, this study provides a rationale for high dose therapy…”

Okay, then!

Clinical Question • In a critically ill patient with influenza A, is oseltamivir 150mg BID x 5 days more effective than oseltamivir 75mg BID x 5 days at reducing mortality, time to extubation and duration of hospitalization without increasing the risk of adverse events?

Literature Review • Resources: – Embase 1980-2013, Medline 1946-present • Search Terms: – (oseltamivir or tamiflu) – (critical care or critically ill or critical illness or ICU or mechanical ventilat* or intensive care or respiratory failure) – influenza • limit to randomized controlled trial • 1 RCT found

Oseltamivir 150mg vs 75mg D Prospective, multicenter, double blind, randomized trial 2007-2010 in 13 hospitals in South East Asia P Inclusion: • Age > 1 year, respiratory illness with duration of symptoms < 10 days, laboratory confirmed influenza • Either Positive result for H5N1 or • Severe influenza: admission to the hospital and one of the following: -New infiltrate on chest x-ray -Tachypnea (RR > 30 for ages > 12) -Dyspnea -Hypoxia (SaO2 < 92% on room air) Exclusion: Pregnancy, women actively breastfeeding, delay >72 hours before treatment, CrCl < 10mL/minute Baseline: N= 326 (246 children, 80 adults), 80% infected with influenza A, 16% influenza B, 4% false positives, 57 patients admitted to ICU (34 required mechanical ventilation; 25 had ARDS) I/C Oseltamivir 150mg BID vs Oseltamivir 75mg BID x 5 days O Primary Endpoint : proportion of all patients with no detectable viral RNA on day 5 Secondary Endpoints: mortality, mechanical ventilation, time in ICU Sedyaningsih et al. BMJ 346(7911) 2013

Results: Efficacy Oseltamivir 75 mg Oseltamivir 150mg P- value BID (%) BID (%) Primary Endpoint: 105/154 (68.2) 115/159(72.3) 0.42 Negative for viral RNA (CI: 60.5-75) (CI: 64.9-78.7) Secondary endpoints Clinical Failure on day 5 20/158(13) 16/161(9.9) 0.44 (received 5 additional days of oseltamivir) Mortality 9/161(5.6) 12/164(7.3) 0.54 (CI: 3-10) (CI: 4.2-12.3) Time in ICU 5 days 4.5 days 0.66 Time on ventilation 8 days 2.5 days 0.58 Sedyaningsih et al. BMJ 346(7911) 2013

Results: Safety Oseltamivir 75 mg Oseltamivir 150mg P-value BID (%) BID (%) # of patients with 27/161(16.8) 28/165(16.9) 0.96 adverse event Adverse event 9 5 - related to oseltamivir Serious adverse 1 0 - event related to oseltamivir Sedyaningsih et al. BMJ 346(7911) 2013