Eight Things to Do Differently Tomorrow. Learning Objec-ves. The Benefits of 3000 Common Medical Treatments

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1 Eight Things to Do Differently Tomorrow Evidence Based Answers to Common Clinical Questions in Hospitalist Practice Chad R. Stickrath, MD October 10 th, 2014 Learning Objec-ves Understand the (new) evidence behind eight common clinical ques8ons faced by hospitalists Consider making changes to our prac8ce based on this evidence No Disclosures The Benefits of 3000 Common Medical Treatments BMJ s Clinical Evidence Website, accessed 8/25/2014 hnp://clinicalevidence.bmj.com.hsl- ezproxy.ucdenver.edu/ceweb/about/ knowledge.jsp

2 Topic Selec-on Most Common Diagnoses ShiV in Evidence Category Alters Daily Prac8ce Sources: ACP Journalwise ACP Journal club The Hospitalist In the Literature Choosing Wisely Manual Journal Surveillance Case #1 A 83 year- old male with COPD (no baseline O2 requirement) presents with dyspnea, new cough, and pleuri8c chest pain. In the ED, his O 2 sats are 83% on RA, jvp is normal, breath sounds are distant. Ddimer is 750µg/L. Chest x- ray is hyperexpanded, without infiltrate. Which would be the LEAST appropriate next step? 1) Check CT pulmonary angiogram 2) Start bronchodilators 3) Ini8ate steroids 4) Check procalcitonin level CTPEs are Frequently Ordered, Rarely Posi-ve for PE 2.7 million chest CT angiograms in the US per year (Berrington de Gonzales, Arch Intern Med 2009;169) Pulmonary Nega-ve Embolism 10% 9% Incidentalomas No Follow- up 24% Incidentalomas Requiring Follow- up 24% Other Explanatory Symptoms 33% (Hall, Arch Intern Med 2009;169) 2,700 excess cancers/year from CTPEs (Berrington de Gonzales, Arch Intern Med 2009;169)

3 Can We Safely Reduce Number of CTPEs Ordered? Mul8- center, prospec8ve ED pa8ents with clinical suspicion of PE Diagnos8c strategy: Clinical probability (Geneva or Wells) Age adjusted ddimer for low/intermediate Age < 50 years Nega8ve Ddimer < 500 µg/l Age > 50 years Nega8ve Ddimer < Age x 10 3 month follow- up phone calls We Can Avoid CTPEs by U-lizing Age- adjusted D- dimer Tomorrow I Will Implement the Age- adjusted Ddimer to avoid unnecessary CT pulmonary angiograms Society of Nuclear Medicine and Molecular Imaging (SNMMI) Recommenda)on: Avoid using a CT angiogram to diagnose pulmonary embolism (PE) in young women with a normal chest radiograph; consider a radionuclide lung (V/Q) study instead.

4 Case #1 A 83 year- old male with COPD (no baseline O2 requirement) presents with dyspnea, new cough, and pleuri8c chest pain. In the ED, his O 2 sats are 83% on RA, jvp is normal, breath sounds are distant. Ddimer is 750µg/L. Chest x- ray is hyperexpanded, without infiltrate. Which would be the LEAST appropriate next step? 1) Check CT pulmonary angiogram 2) Start bronchodilators 3) Ini8ate steroids 4) Check procalcitonin level Case #2 A 73 year- old male with a remote history of oropharyngeal cancer s/p chemotherapy and radia8on, complicated by severe peripheral neuropathy presents with a red, hot, malodorous foot ulcer that is draining pus. On arrival to ED, BP 85/40, HR 130. Labs reveal WBC of 18, HCT 27, crea8nine of 3.0. Which measure will be essen8al to ini8ate? 1) Placement of central venous catheter 2) CVP and ScvO2 monitoring 3) Aggressive crystalloid resuscita8on 4) Transfusion of PRBCs 5) All of the above Sepsis is Increasingly Prevalent and Early Aggressive Assessment and Treatment is Life- saving > 750,000 cases/yr severe sepsis/shock in US (Angus, Crit Care Med 2001;29) Early goal- directed therapy reduced mortality 47% 31% in Rivers, N Engl J Med 2001 EGDT requires special invasive ScvO2 monitors, possible ionotropes, & transfusions

5 Is Strict Adherence to EGDT Required to Reproduce the Benefits ( Do I need a con-nuous ScvO2 monitor )? Prospec8ve, randomized, mul8site Pa8ents with early sep8c shock Compared: EGDT protocol Protocol- based standard therapy Usual care Protocol EGDT EGDT Protocol- based Usual Care 1341 pa8ents par8cipated

6 Tomorrow I Will Avoid con8nuous ScvO 2 monitoring, dobutamine, and transfusions in the early management of severe sepsis Case #2 A 73 year- old male with a remote history of oropharyngeal cancer s/p chemotherapy and radia8on, complicated by severe peripheral neuropathy presents with a red, hot, malodorous foot ulcer that is draining pus. On arrival to ED, BP 85/40, HR 130. Labs reveal WBC of 18, HCT 27, crea8nine of 3.0. Which measure will be essen8al to ini8ate? 1) Placement of central venous catheter 2) CVP and ScvO2 monitoring 3) Aggressive crystalloid resuscita8on 4) Transfusion of PRBCs 5) All of the above Case #2 Con-nued AVer aggressive volume resuscita8on and pressor therapy based on shock index, ini8a8on of vancomycin and piperacillin- tazobactam, and extensive sov 8ssue debridement, pa8ent is much improved. MRI reveals no osteomyeli8s and wound cultures return with MRSA at that 8me. What is the most appropriate next step? 1) Finish 7 day course of IV vancomycin and piperacillin- tazobactam 2) Discon8nue Piperacillin- tazobactam, finish 7 days of vancomycin 3) Complete 6 weeks of vancomycin and piperacillin- tazobactam 4) Rotate an8bio8cs to oral cephalexin to complete 14 days of an8bio8cs

7 Early & Broad An-bio-c Management in Sepsis is Crucial An8bio8c management in sepsis, should be: TIMELY APPROPRIATE Hospital Morality (Ferrer R, Crit Care Med 2014;doi ) (Kumar A, Chest 2009;136) Should An-bio-cs Be Narrowed? Prospec8ve, observa8onal study 40 bed M/S ICU in Europe Pa8ents admined with severe sepsis/sep8c shock An-bio-cs in Sepsis Should Be Narrowed

8 Tomorrow I Will Narrow an8bio8cs in pa8ents recovering from severe sepsis when culture data is available Case #2 Con-nued AVer aggressive volume resuscita8on and pressor therapy based on shock index, ini8a8on of vancomycin and piperacillin- tazobactam, and extensive sov 8ssue debridement, pa8ent is much improved. MRI reveals no osteomyeli8s and wound cultures return with MRSA at that 8me. What is the most appropriate next step? 1) Finish 7 day course of IV vancomycin and piperacillin- tazobactam 2) Discon8nue Piperacillin- tazobactam, finish 7 days of vancomycin 3) Complete 6 weeks of vancomycin and piperacillin- tazobactam 4) Rotate an8bio8cs to oral cephalexin to complete 14 days of an8bio8cs Case #3 An 87 year old male with end- stage pancrea8c cancer is admined to the hospital for increasing fa8gue, abdominal pain, and nausea. AVer confirming further spread of his malignancy and achieving pain relief, the pa8ent elects to focus on comfort care and would like to pursue placement with hospice care. The family does not want to discon8nue his IV fluids. Which poten8al symptoms is most likely to benefit from ongoing fluid administra8on? 1) Delirium 2) Nausea 3) Fa8gue 4) Well- being

9 Care for Pa-ents with End- Stage Cancer Ocen Centers on Trea-ng Symptoms Most pa8ents decrease their oral intake Dehydra8on can cause, or aggravate fa8gue, myoclonus, and delirium Typically, receive parental hydra8on in the hospital Bruera E, J Clin Onc 2013;31 Dalal S, Curr Opin Supprt Palliat Care 2009;3 Do Pa-ents with End- Stage Cancer Benefit from Parenteral Hydra-on? Randomized, placebo- controlled mul8site End- stage cancer pa8ents receiving hospice care Parenteral hydra8on (1 liter/ day) vs. placebo Hydra-on Not Superior to Placebo for Symptoms 120 Pa8ents Individual symptoms No difference: pain, fa8gue, nausea, depression, appe8te, well- being, myoclonus Trend toward improvement with hydra8on: delirium

10 Tomorrow I Will Reassure pa8ents and families that parenteral hydra8on is not essen8al for symptom relief in end- stage cancer pa8ents. Case #3 An 87 year old male with end- stage pancrea8c cancer is admined to the hospital for increasing fa8gue, abdominal pain, and nausea. AVer confirming further spread of his malignancy and achieving pain relief, the pa8ent elects to focus on comfort care and would like to pursue placement with hospice care. The family does not want to discon8nue his IV fluids. Which poten8al symptoms is most likely to benefit from ongoing fluid administra8on? 1) Delirium 2) Nausea 3) Fa8gue 4) Well- being Case #4 A 43 year- old male with diabetes and hypertension is admined to the inpa8ent psychiatry unit for severe depression. Psychiatry has called you for new SOB, cough hypoxemia with WBC 15 and RML infiltrate on chest x- ray. What is the best treatment choice? 1) Transfer the pa8ent to medicine for IV cevriaxone and azithromycin 2) Transfer the pa8ent to medicine for IV vancomycin, piperacillin- tazobactam, and moxifloxacin 3) Start oral moxifloxacin on the psychiatry unit 4) Start oral linezolid on the psychiatry unit

11 Healthcare- Associated Pneumonia is a Heterogenous Disease IDSA defines HCAP as including recent contact: Nursing homes, Dialysis centers, Hospital admissions (Maruyama T, Clin Infect Dis 2013;57) (Brito V, Curr Opin Infect Dis 2009;22) Do All Pa-ents Admieed with HCAP Need Broad Spectrum An-bio-cs? Prospec8ve, mul8- site study in Japan Separated pa8ents: MDR risk factors: immune suppression, hospitaliza8on < 90 days, poor func8onal status, an8bio8cs w/i 60 days Treated based on MDR risk factors 0 1! CAP therapy 2! HCAP therapy Low risk HCAP CAP 445 pa8ents, 321 with HCAP Established diagnosis: 68% of HCAP pa8ents 30- day Mortality

12 Tomorrow I Will Risk stra8fy HCAP pa8ents Treat low MDR risk pa8ents with CAP agents Case #4 A 43 year- old male with diabetes and hypertension is admined to the inpa8ent psychiatry unit for severe depression. Psychiatry has called you for new SOB, cough hypoxemia with WBC 15 and RML infiltrate on chest x- ray. What is the best treatment choice? 1) Transfer the pa8ent to medicine for IV cevriaxone and azithromycin 2) Transfer the pa8ent to medicine for IV vancomycin, piperacillin- tazobactam, and moxifloxacin 3) Start oral moxifloxacin on the psychiatry unit 4) Start oral linezolid on the psychiatry unit Case #5 A 69 year- old male with alcoholic cirrhosis and BPH is admined with confusion and increasing somnolence. Exam reveals afebrile, confused and sleepy male with BP 92/58, notable asterixis, s8gmata of chronic liver disease. Urinanalysis reveals > 50 WBCs, + nitrite and large leukocyte esterase; paracentesis is not consistent with infec8on. In addi8on to trea8ng his UTI, which therapy is most efficacious (and safest) for trea8ng his hepa8c encephalopathy? 1) Lactulose 8trated to 2-3 sov BMs per day 2) Neomycin three 8mes daily 3) Rifaximin twice daily 4) Lactulose for 2-3 BMs per day + Rifaximin twice daily

13 Hepa-c Encephalopathy is a Serious, but Reversible Disorder Hepa8c Encephalopathy (HE) occurs: 30 40% of cirrho8cs 10 50% of TIPS pa8ents Survival aver first episode HE: 1- year! 42% 3- year! 23% (Sharma B, Am J Gastroentrol 2013;108) Lactulose likely bener than placebo at reversing HE, but no effect on mortality (Als- Nielsen B, BMJ 2004;328) Rifaximin at least as effec8ve and safer than other agents (Eltawil K, World J Gastroenterol 2012;18) How Efficacious is the Combina-on of Rifaximin and Lactulose for HE? Prospec8ve, double blind RCT Pa8ents with cirrhosis admined with HE Lactulose vs. Lactulose + Rifaximin (400mg TID) Lactulose + Rifaximin Superior 120 pa8ents Complete reversal of HE within 10 days: Lactulose! 44% Lactulose + Rifaximin! 78% Excess deaths d/t sepsis, not GIB, or HRS

14 Tomorrow I Will U8lize Lactulose + Rifaximin for acute hepa8c encephalopathy Case #5 A 69 year- old male with alcoholic cirrhosis and BPH is admined with confusion and increasing somnolence. Exam reveals afebrile, confused and sleepy male with BP 92/58, notable asterixis, s8gmata of chronic liver disease. Urinanalysis reveals > 50 WBCs, + nitrite and large leukocyte esterase; paracentesis is not consistent with infec8on. In addi8on to trea8ng his UTI, which therapy is most efficacious (and safest) for trea8ng his hepa8c encephalopathy? 1) Lactulose 8trated to 2-3 sov BMs per day 2) Neomycin three 8mes daily 3) Rifaximin twice daily 4) Lactulose for 2-3 BMs per day + Rifaximin twice daily Case #6 A 71 year- old male with DM and COPD presents with cough, respiratory distress, and severe hypoxemia. He is found to have diffuse bilateral pulmonary infiltrates and is intubated in the ED. He is started on an8bio8cs, seda8on, and mechanical ven8la8on. Although he stabilizes over the first 12 hours, he remains severely hypoxemic. Which strategy will NOT posi8vely impact survival for this pa8ent? 1) Lung protec8ve ven8la8on 2) Restric8ve fluid strategy 3) Prone ven8la8on 4) High frequency oscilla8ng ven8la8on

15 ARDS Strategies Improving, But Mortality S-ll High ARMA 12: High 8dal volumes ARMA 6: Low 8dal volumes FACCT: Conserva8ve fluid ALTA + OMEGA: Recent all strategies (Wilson J, J Hosp Med 2014;7) Is There Anything We Can Do to Further Improve ARDS Outcomes? Prospec8ve, mul8- site RCT in Europe Pa8ents with severe ARDS (P:F < 150 mm Hg, FiO2 0.6, PEEP 5 cm water) Prone vs. Supine Stabiliza8on period of hours Randomized to prone! 16 hours of prone/day Proning Significantly Improves ARDS Survival 474 pa8ents

16 Tomorrow I Will Use prone ven8la8on in pa8ents admined with severe ARDS Case #6 A 71 year- old male with DM and COPD presents with cough, respiratory distress, and severe hypoxemia. He is found to have diffuse bilateral pulmonary infiltrates and is intubated in the ED. He is started on an8bio8cs, seda8on, and lung protec8ve ven8la8on. Although he stabilizes over the first 12 hours, he remains severely hypoxemic. Which strategy will NOT posi8vely impact survival for this pa8ent? 1) Lung protec8ve ven8la8on 2) Restric8ve fluid strategy 3) Prone ven8la8on 4) High frequency oscilla8ng ven8la8on Case #7 An 81 year- old male with atrial fibrilla8on and CAD suffers an MVA on his return from family vaca8on in the mountains and presents with sleepiness and headache. INR is 6.5 and imaging is below. The ED physicians are tending to his airway and breathing and neurosurgery is on the way to evaluate. Which treatment will be the most efficient and effec8ve for reversing his an8coagula8on? 1) Vitamin K 2) Fresh Frozen Plasma 3) Prothrombin Complex Concentrate 4) Factor VII infusion

17 Serious Bleeding in An-coagulated Pa-ents is Frequent > 22 million prescrip8ons for Vitamin K antagonists (VKAs) wrinen per year in US Major hemorrhage: % of pa8ents annually > 42,000 hospitaliza8ons annually for bleeding and supratherapeu8c INRs What is the Most Effec-ve Emergent An-coagula-on Reversal? Prospec8ve, randomized trials in US INR 2, acute major bleeding Comparing 4F- PCC vs. FFP PCC is Beeer than FFP 202 pa8ents Good or Excellent Hemosta8c Efficacy 4F - PCC FFP Significant? 72% 65% NS INR 1.3 at 0.5 hours 62% 10% Yes Treatment related AEs 10% 21% Yes *Related deaths vs. 5 overall

18 Tomorrow I Will Use prothrombin complex concentrate (instead of FFP) when emergently reversing supratherapeu8c INR Case #7 An 81 year- old male with atrial fibrilla8on and CAD suffers an MVA on his return from family vaca8on in the mountains and presents with sleepiness and headache. INR is 6.5 and imaging is below. The ED physicians are tending to his airway and breathing and neurosurgery is on the way to evaluate. Which treatment will be the most efficient and effec8ve for reversing his an8coagula8on? 1) Vitamin K 2) Fresh Frozen Plasma 3) Prothrombin Complex Concentrate 4) Factor VII infusion Summary Employ the age- adjusted Ddimer Use IVF, an8bio8cs, pressors, Not ScvO 2 monitoring, iontropes, and prbcs for sepsis Narrow an8bio8cs in severe sepsis

19 Summary Don t feel compelled to give IVF for comfort to end- stage cancer pa8ents Treat low MDR- risk HCAP pa8ents for CAP Summary Combine lactulose and rifaximin for HE reversal U8lize prone ven8la8on in severe ARDS Give prothrombin complex concentrate (PCC) for emergent VKA associated, supratherapeu8c INR reversal Jeff Glasheen Acknowledgements VA Hospitalist Colleagues Mel Anderson Bob Burke Kate Jennings Kris8n StraNon Cliff Zwillich Eric Young Melanie S8ckrath

20 References 1. Hall WB, et al., The prevalence of clinically relevant incidental findings on chest computed tomographic angiograms ordered to diagnose pulmonary embolism. Arch intern med 2009; Berrington de Gonzalez A, et al., Projected cancer risks from computed tomographic scans performed in the United States in Arch Intern med 2009; Righini M, et al., Age- adjusted D- dimer cutoff levels to rule out pulmonary embolism. JAMA 2014; Yealy DM, et al., A randomized trial of protocol- based care for early sep8c shock. N Engl J Med 2014; Kumar A, et al., Ini8a8on of inappropriate an8microbial therapy results in a fivefold reduc8on of survival in human sep8c shock. Chest 2009; Ferrer R, et al., Empiric an8bio8c treamtent reduces mortality in severe sepsis and sep8c shock from the first hour: results from a guideline- based performance improvement program. Crit Care Med 2014; Garnacho- Montero J, et al., De- escala8on of empirical therapy is associated with lower mortality in pa8ents with severe sepsis and sep8c shock. Intensive Care Med 2014; Breura E, et al., Parenteral hydra8on in pa8ents with advanced cancer: a mul8- center, double- blind, placebo- controlled randomized trial. J Clin Oncol 2013; Brito V, Niederman S, Healthcare- associate pneumonia is a heterogenous disease, and all pa8ents do not need the same broad- spectrum an8bio8c therapy as complex nosocomial pneumonia. Curr Opin Infect Dis 2009; Maruyama T, et al., A new strategy for healthcare- associated pneumonia: a 2- year prospec8ve mul8center cohort study using risk factors for mul8drug- resistant pathogens to select in8al empiric therapy. Clin Infect Dis 2013; Sharma BC, et al., A randomized, double- blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepa8c encephalopathy. Am J Gastroenterol 2013; Guerin C, et al., Prone posi8oning in severe acute respiratory distress syndrome. N Engl J Med 2013;368; Sarode R, et al., Efficacy and safety of a 4- factor prothrombin complex concentrate in pa8ents on vitamin K antagonists presen8ng with major bleeding: a randomized, plasma- controlled, phase IIIb study. Circula8on 2013;128.