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
• seltamivir 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 11th

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) FiO2 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 11th

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 CO2: 27 GU SCr 194 eGFR 32 Troponin 7.51 (9th) 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 endotracheal suction Streptococcus penumoniae S- amoxicillin, levofloxacin, PenV, Trimeth/Sulfa R- Clindamycin, erythromycin, tetracycline Feb 8 Sputum endotracheal suction - Respiratory viral panel Influenza A virus subtype pandemic H1N1-2009 (confirmed on Feb 11)

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

• seltamivir.
• 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

• seltamivir.

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

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

• 18 pandemic H1N1 PCR positive patients

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

• utcomes 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
• seltamivir 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 BID (%) Oseltamivir 150mg BID (%) P- value Primary Endpoint: Negative for viral RNA 105/154 (68.2) (CI: 60.5-75) 115/159(72.3) (CI: 64.9-78.7) 0.42 Secondary endpoints Clinical Failure on day 5 (received 5 additional days of oseltamivir) 20/158(13) 16/161(9.9) 0.44 Mortality 9/161(5.6) (CI: 3-10) 12/164(7.3) (CI: 4.2-12.3) 0.54 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 BID (%) Oseltamivir 150mg BID (%) P-value # of patients with adverse event 27/161(16.8) 28/165(16.9) 0.96 Adverse event related to

• seltamivir

9 5

• Serious adverse

event related to

• seltamivir

1

• Sedyaningsih et al. BMJ 346(7911) 2013

Limitations

• South East Asian study (72% from Vietnam)
• Primary endpoint was a surrogate marker as opposed to a

clinical response

• Only 22.4% of patients presented within 3 days of illness

– Patients were enrolled after a median of 5 days after onset of illness

• Heterogenous population:

– Majority of patients were children (75.5%) – Patients infected with avian H5N1, H1N1-pdm09, and seasonal influenza – Only a small number of patients required immediate admission to intensive care (57 or 17.5%)

Limitations

• Study did not state what the specific adverse

events related to oseltamivir were

• Study states that 23% of enrolled patients

received oseltamivir before enrolment

– Did not explain if those patients were still receiving oseltamivir on enrolment or if they had received it in the past

Author’s Conclusions

“……..double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia”

Therapeutic Recommendation

• Discontinue Oseltamivir 150mg BID
• Oseltamivir 75mg OG BID x 2 more days to

complete a 5-day course

Justification

• Higher oseltamivir doses in patients with

uncomplicated or severe influenza have not been consistently shown to improve clinical or virological outcomes compared with the standard dose

Sedyaningsih et al. BMJ 346(7911) 2013

ICU Monitoring Plan

Efficacy Safety Normal vitals (temp <38.2) ↓ WBC, neutrophil ↓ FiO2, PEEP AC-> PS ventilator setting Extubation ↓cough Presence of vomiting, diarrhea

Follow-up

• Oseltamivir reduced to 75mg OG x 5 days
• Hydromorphone infusion increased to 2mg/hr
• Changed ASA 81mg EC to 80mg chewable
• Patient extubated on Feb 18th
• Patient moved to 4B on Feb 21st

Questions?