Controversies in Hospital Medicine: C. difficile, Pre-op Pulm & HIT

1. Controversies in Hospital Medicine: C. difficile, Pre-op Pulm & HIT Jeff Glasheen, MD Associate Professor of Medicine Director, Hospital Medicine Program University of Colorado Denver

2. Disclosures • Advisory Boards Sanofi-Aventis • Publishing Oakstone, Elsevier

3. Getting more Difficile How are mild and severe C. difficile treated?

4. What would you do next? A) Commence metronidazole orally B) Commence vancomycin orally C) Commence vancomycin and metronidazole orally D) Hold new antibiotics until culture/toxin return 64 yo female nearing discharge after 4 days of ceftriax/levo for severe CAP. Developed profuse watery diarrhea and new fever (38.7) + WBC (16k); abdomen benign. C. difficile culture and toxin assay are pending.

5. Old Dog… • Gram + organism • Anaerobe • Spore former • Hospital-acquired • Clindamycin-induced • ? increased LOS & cost • Nuisance diarrhea

6. New Tricks! • Epidemic strain • Increased incidence • Increased virulence • Increased mortality • Increased morbidity • Predilection for elderly • Increased resistance • Increased recurrences • Metronidazole failures • Community-acquired disease

7. Genetics Old Dog • tcdA/B encode toxins A/B • tcdC down-regulates A/B production • mutations result in loss of regulatory fx • cdtA and cdtB encode binary toxin x New Tricks!

8. Epidemic Strain • New virulent strain (B1/NAP1) • Produce binary toxin • cdtB = mediates cell surface binding and intracellular translocation • cdtA = disrupts actin filament; causes cell death • Deletion of tcdC • Forms 16x more Toxin A • Forms 23x more Toxin B • Increased antibiotic resistance • Especially quinolones • Previously uncommon strain of C. difficile • Variation in toxin genes;become more resistant to flouroquinolones and yields higher rates of outbreaks McDonald, NEJM 2005;353:2433-42

9. Increased Virulence • Complicated cases increased from 7.1% to 18.2% • 30-day mortality increased 4.7% to 13.8% Pepin, CMAJ 2004;171(5):466-72

10. Treatment failure & recurrence • Single hospital retrospective review • Quebec ’91-’04 • Proportion of pts switched to vanco or in which vanco was added due to disappointing results • 66/688 (9.6%) ’91-’02 • 112/435 (25.7%) ’03-’04 (p<.001) • 60-d probability of recurrence w/ metronidazole • 20.8% ’91-’02 • 47.2% ’03-’04 (p<.001) Pepin, Clin Infect Diseases 2005;40(11):1591-7

11. Is Vancomycin More Effective Than Metronidazole? • 1st prospective RCT of metro vs. vanco—172 patients • Metro 250mg PO qid vs. vanco 125mg PO qid • Stratified to mild or severe disease • Severe = ≥ 2 points • > 60 yo WBC > 15,000 • T > 38.3 Presence of pseudomebranous colitis (2 pts) • Alb < 2.5 mg/dl *p=.36 †P=.02 Recurrence rate 15% v. 14% Zar, CID 2007;45:302-307

12. Implications for Treatment • Mild-Moderate diseasemetronidazole is still 1st line • Mean diarrheal resolution of 3-4 d • Severe diseaseoral vancomycin • >60 yo, febrile, WBC > 15K, low alb, PMC • Ileus or fulminant CDAD • oral/PR vanco along with IV metro and surgery consult • Surgery • Shift toward earlier surgical intervention • ≥65 years, WBC ≥20k and/or lactate 2.2-4.9 meq/L • 14-day course or 1 week after stop prolonged antibx Lamontagne, Ann Surg. 2007 Feb;245(2):267-72

13. What would you do next? A) Commence metronidazole orally B) Commence vancomycin orally C) Commence vancomycin and metronidazole orally D) Hold new antibiotics until culture/toxin return 64 yo female nearing discharge after 4 days of ceftriax/levo for severe CAP. Developed profuse watery diarrhea and new fever (38.7) + WBC (16k); abdomen benign. C. difficile culture and toxin assay are pending.

14. Reducing the Risk What is the appropriate operative pulmonary evaluation?

15. What would you recommend to the surgeon? A) Recommend against surgery 2/2 high risk B) Order preop PFTs to assess pulmonary status C) Inspiratory muscle training prior to surgery D) Prophylactic steroids perioperatively 72 yo male ex-smoker with O2-dependent COPD awaiting L nephrectomy for early stage tumor. Can walk one mile slowly & go up two flights of stairs. Wheezing but VS are normal. Uses prn albuterol.

16. Post-operative Pulmonary Complications: Scope of the Problem • Pneumonia, atelectasis, bronchospasm, COPD exacerbation, respiratory failure (vent > 48 hr) • Common • Cardiac complications (MI, CHF, death) 2.5% • Pulmonary complications 2.7% • Morbid • 30-day mortality w/ resp failure26.5% v. 1.4% • Goal is prevention of PPC • Assess patient- & procedure-related factors Fleischmann, Am J Med 2003:115:515-520 Johnson, J Am Coll Surg 2007;204:1188-98

17. Patient Related Risk Factors • General Health • ASA classification >2 assd with 2-3x risk of PPC • Class 1 healthy Class 2 mild • Class 3 severe Class 4 severe threat to life • Class 5 moribund • Age • Age > 60 is significant risk factor • Increased risk from age or co-morbidities of age Warner, Anesthesiology 1996;85:460-467 ASA = American Society of Anesthesiologists

18. COPD 2x the risk of PPC 6x the risk if active symptoms Asthma If well controlled, no association w/ PPC1 Obesity No increase risk of PPC2-4 OSA 172 ptsPPC rate 9% v. 1%10 PHTN Case/control 62 ptsResp failure 21% v. 3%11 Tobacco Increase in PPC5,6 Quit > 8 wks prior to surgery4,7,8,9 Current smoker 33% PPC rate9 D/c 1-8 wks 57% PPC rate D/c > 8 wks 12% PPC rate (= nonsmokers) Patient Related Risk Factors 1Warner, Anesthesiology 1996;85:460-467 2Mitchell, Arch Surg 1998;133:194-198 3Barisione, Eur Respir J 1997;10:1301-1308 4Bluman, 1998;113:883-889 5Brooks-Brunn, Chest 1997;111:564-571 6Svensson, J Vasc Surg 1991;14:271-282 7Moller, Lancet 2002;359;114-117 8Nakagawa, Chest 2001;120:705-710 9Warner, Mayo 1989;64:609-616 10Hwang, Chest 2008;133:1128-1134 11Lai, Br J Anaesth 2007;99:184-90

19. Pulm eval different than cardiac eval Procedures more important than patient characteristics Procedure Related Risk Factors

20. Modifying the Risk: Preop PFTs • Do PFTs add to your clinical exam?1 • 2000 pts. OR for PPC • Abn Exam 5.8 • Abn CXR 3.2 • Abn Spirometry 1.0 • Does low FEV1 contraindicate surgery? • 89 patients, FEV1 < 50%2 • PPC 29%, Major PPC in 7% • Mortality 6%, (50% CABG; 1% in others) • PFT recommendations • Should not be used to deny surgery that is indicated • No role of routine PFTs in non-cardiac surgery 1Lawrence, Chest 1996;110:744-750 2Kroenke, Arch Intern Med 1992;152:967-971

21. Modifying the Risk: Preop IMT • RCT 279 CABG; high risk of PPC • FEV1 <80% predicted and • FEV1-FVC ratio < 70% predicted • Or 2 of following: • Age > 70, expectorant cough • DM, COPD, Tob, BMI > 27 • Preop inspir mm training (N=140) • Education, IS vs. resistance, forced exp technique • 20 min/d x 2 weeks • Usual care (N=139) • Preop instruct on DB & early mobilization Hulzebos, JAMA 2006;296:1851-7

22. Modifying the Risk: Post-op • Lung expansion works • Incentive spirometry • Deep breathing • Continuous positive airway pressure (CPAP) • Pts unable to do IS or DB • Meta-analysis 654 abd surgery pts • CPAP use OR: • PPC 0.66 (0.52-0.85) • Atelectasis 0.75 (0.58-0.97) • Pneumonia 0.33 (0.14-0.75) Ferreyra, Ann Surg 2008;247;617-26

23. What would you recommend to the orthopedic surgeon? A) Recommend against surgery 2/2 high risk B) Order preop PFTs to assess pulmonary status C) Inspiratory muscle training prior to surgery D) Prophylactic steroids perioperatively 72 yo male ex-smoker with h/o O2-dependent COPD awaiting CABG. Can walk one mile slowly & go up two flights of stairs. Wheezing but VS are normal. Uses prn albuterol. 72 yo male ex-smoker with O2-dependent COPD awaiting L nephrectomy for early stage tumor. Can walk one mile slowly & go up two flights of stairs. Wheezing but VS are normal. Uses prn albuterol. Don’t forget: Tobacco cessation IS/DB/CPAP

24. Never HIT patients How is HIT diagnosed and Treated?

25. What would you recommend to the surgeon? A) Continue outpatient dalteparin prophylaxis for 28 d B) Discontinue dalteparin, discharge home C) Discontinue dalteparin, start warfarin for 28 d, home D) Discontinue dalteparin, start direct thrombin inhibitor 51 yo male w/ DM, 6 days s/p L THR. Platelets drop 475210. No other sxs. Receiving dalteparin VTE prophylaxis. No other obvious cause of thrombocytopenia. Scheduled for discharge.

26. Characteristics of HIT 1 and 2 *Meta-analysis found incidence of 2.6% with UFH, 0.2% with LMWH prophylaxis Martel, Blood 2005 Oct 15;106(8):2710-5

27. Clinical diagnosis Laboratory confirmation ELISA Measure IgG ab presence High sensitivity High Neg Predictive Value Functional assays Serotonin release assay Heparin-ind platelet agg High specificity Often take a week Approach to HIT diagnosis: If intermediate/high pretest prob Treat for HIT Send ELISA If ELISA- Stop HIT treatment If ELISA+ Treat for HIT Confirm w/ platelet agg Diagnosis

28. Pre-test probability: 4 Ts • Thrombocytopenia • Platelet drop >50% + nadir >20k 2 points • Platelet drop 30-50% or nadir 10-19k 1 point • Platelet drop <30% or nadir <10k 0 points • Timing • Clear onset 5-10d after heparin onset, </=1d w/ hep w/in 30d 2 points • Less than clear onset 5-10d p hep, </=1d w/ hep use 30-100d 1 point • Less than 4 d w/o past hep use 0 points • Thrombosis • New clot 2 points • Progressive or recurrent clot 1 point • None 0 points • Other causes of thrombocytopenia • None 2 points • Possible 1 point • Definitive 0 points Limit ELISA to >/4 points If order ELISAtx HIT Lo, J Thromb Haemost. 2006 Apr;4(4):759-65

29. Treatment • HIT 1 • Discontinue heparin (or continue) • Platelets should rebound within 7 days • HIT 2 • Discontinue heparin (and LMWH) • Treat with non-heparin anticoagulants • Lepirudin*—Renally cleared • Agratroban*—Hepatically cleared • Bivalirudin†—↓doses safe combined hepatic/renal impairment • Fondaparinux‡—Renally cleared • Transition to warfarinstably anticoagulated, platelets > 150k • Overlap therapy for 5 days • Warfarin for 2-3 months if no clot, 3-6 months with clot *FDA approved for HIT treatment + prevention †FDA approved for HIT treatment/prev assd with PCI only ‡ Not FDA approved for HIT treatment or prevention

30. What would you recommend to the surgeon? A) Continue outpatient dalteparin prophylaxis for 28 d B) Discontinue dalteparin, discharge home C) Discontinue dalteparin, start warfarin for 28 d, home D) Discontinue dalteparin, start direct thrombin inhibitor 51 yo male w/ DM, 6 days s/p L THR. Platelets drop 475210. No other sxs. Receiving dalteparin VTE prophylaxis. No other obvious cause of thrombocytopenia. Scheduled for discharge.

31. Conclusions • C. difficile is changing • More common, virulent, recurrent • Metronidazole indicated for mild-moderate disease • Vancomycin for more severe disease • > 60 yo, WBC, fever, albumin, PMC • Operative pulmonary • Screen—procedure dictates most of the risk • Pre—smoking cess > 8 wks prior, IMT may be beneficial • Post—IS and DB • HIT • Common and morbid • Requires thoughtful testing • Switch to non-heparin anticoagulant + extended warfarin

33. Other therapies • Cholestyramine/Colestipol • No definitive studies; some data in relapes; binds vanco • Tolevamer • Toxin binding resin for C. diff. Not FDA approved • IVIG • Passive immunity; reports in relapse/severe expensive; no RCT • Rifaximin • Non-absorbable antibx; promising reports. Not approved • Probiotics • Insufficient evidence for probiotics in treatment/recurrence • Some recommend use with recurrence • Prevention—RCT 135 elderly hospitalized patients on antibiotics • Lactobacillus drink vs. protein shake bid for duration of antibx + 1 wk • CDAD rate 0% vs. 17% Hickson, BMJ 2007

34. Is Vancomycin More Effective Than Metronidazole? Initial Antibiotic Comp rate Metronidazole 13.1% Vancomycin 5.9% Pepin, CMAJ 2004;171(5):466-72

35. Patient Related Risk Factors • COPD • 2x the risk of PPC • 6x the risk if active symptoms • Asthma • If well controlled, no association w/ PPC1 • Obesity • No increase risk of PPC2-4 • OSA • 172 ptsPPC rate 9% v. 1%10 • InconclusiveNo role for screening • PHTN • Case/control 62 ptsResp failure 21% v. 3%11 • Tobacco • Increase in PPC5,6 • Quit > 8 wks prior to surgery4,7,8,9 • Current smoker 33% PPC rate9 • D/c 1-8 wks 57% PPC rate • D/c > 8 wks 12% PPC rate (= nonsmokers) 1Warner, Anesthesiology 1996;85:460-467 2Mitchell, Arch Surg 1998;133:194-198 3Barisione, Eur Respir J 1997;10:1301-1308 4Bluman, 1998;113:883-889 5Brooks-Brunn, Chest 1997;111:564-571 6Svensson, J Vasc Surg 1991;14:271-282 7Moller, Lancet 2002;359;114-117 8Nakagawa, Chest 2001;120:705-710 9Warner, Mayo 1989;64:609-616 10Hwang, Chest 2008;133:1128-1134 11Lai, Br J Anaesth 2007;99:184-90

36. HIT 1 Non-immune Heparin-induced platelet aggregation—spleen HIT 2 Immune Heparin induces platelet release of PF4 Heparin-PF4 complex is antigenicIgG antibody IgG-Hep/PF4 binds to plateletsaggregration AND binds to endotheliumCLOT Types of HIT

37. Double Entendre

38. C. difficile: Toxin-MediatedVirulence • Classically C. difficile formed two toxins • Toxin A and B • Adhere to receptors on colonocyte brush border  necrosis

39. Other things that might work… • Selective nasogastric use • Routine use in abd surg vs. symptomatic use • Increased PPCOR 1.45 (1.08-1.93) • Laparoscopic surgery • 19,156 bariatric surgery pts • Increased PPC w/ openOR 1.92 (1.54-2.38) • Post-op thoracic epidural analgesia • PPCs reduced by up to 50% Nelson, Cochrane 2007;July 18(3):CD004929 Weller, Ann Surg 2008;248:10-15 Liu, Anesth Analg 2007;104:689-702