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Sepsis in the Rural Setting: Early Recognition and Management Mike Broyles, BSPharm, PD, PharmD Director of Pharmacy and Laboratory Services Five Rivers Medical Center Pocahontas, AR Disclosures Objectives Understand the definitions and differing clinical presentations of SIRS, Sepsis, Severe Sepsis and Septic shock as defined by SCCM/ACCP Discuss the role of biomarkers, clinical presentation, and other laboratory tests used in the evaluation of patients with suspected Sepsis Use case studies to recognize how procalcitonin, other biomarkers, and clinical exam can assist in early recognition, risk stratification, and management of patients with suspected and confirmed Sepsis Outline Seriousness of sepsis Difficulties with the diagnosis of sepsis Procalcitonin (PCT) • Biomarker • Kinetics Comparison to other biomarkers Application of PCT into sepsis management Severe Sepsis: Incidence and Mortality Incidence Mortality 300 Deaths/Year 250 Cases/100,000 200 150 100 50 0 AIDS Breast Cancer 1st MI Severe Sepsis Angus DC, et al. Crit Care Med. 2001; ACS. Severe sepsis is costly and lifethreatening • Strikes more than 750,000 people each year in the United States • Mortality remains greater than 30% (1 person every 2.5 minutes) • Mortality rate has not improved in the last 20 years • Adults, pediatrics, and newborn • Morbidity • Surgical rate is increasing • Clinical diagnosis remains challenging Hospital mortality of severe sepsis patients with an ICU stay is 4 times that of other ICU patients. ICU Mortality Rate % 30% 25% 20% 15% 10% 5% 0% ICU Mortality Rate % Severe sepsis 28% All other patients 7% Ventilator use in severe sepsis patients with an ICU stay is more than 15 times that of other patients. ICU Ventilator Use % 35% 30% 25% 20% 15% 10% 5% 0% ICU Ventilator Use % Severe Sepsis 31% All other patients 2% sepsis.com Determinants of mortality from sepsis • Early intervention is critical • Appropriate antibiotic therapy within one hour of hypotension • Resuscitation / re-establish perfusion within six hours Duration of hypotension before initiation of appropriate ABX therapy is the critical determinant of survival in septic shock Why do we struggle with the diagnosis of sepsis? Relationship of SIRS, Sepsis, and Infection SIRS Criteria: Two or more of the following • Temperature > 100.4F (38C) or < 96.8F (36C) • Heart rate > 90 beats/minute • Respiratory rate > 20 breaths/minute or PaCO2 < 32 mm Hg • WBC o > 12,000/mm3 o < 4000/mm3 o > 10% immature (band) forms Making the Diagnosis • Tachycardia – 718 possibilities • Tachypnea - 371 possibilities • Increased/Decreased Temperature – 1380 possibilities • Increased/Decreased WBC – 350 possibilities 541 possible diagnoses with 2 or more of the criteria www.diagnosispro.com Sepsis: ACCP/SCCM Definitions • Sepsis is SIRS plus a known or suspected infection. • Severe Sepsis is sepsis associated with organ dysfunction, hypoperfusion, or hypotension. • Septic Shock is sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities. • May include • Lactic acidosis • Oliguria • An Acute alteration in mental status • Others… SIRS Sepsis Severe Sepsis Septic Shock Bone RC, et al. Chest 1992 Jun;101(6):1644-55. Probability of a Sepsis Diagnosis 100% 100% 100% > 90% PCT 2.0 40% PCT 0.3 < 10% 0% 0% 0% Pretest situation: only clinical assessment is available Assessment of individual features and addition of PCT Post-test situation: Individually adjusted risk assessment Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis What is Procalcitonin and its role in sepsis management? Procalcitonin • • • • PCT is an immunologically active protein PCT is induced in systemic inflammatory reactions Bacterial infections induce PCT PCT induction is generally in direction proportion to the bacterial insult to the body • Viral infections, autoimmune diseases, transplant rejections, and allergic reactions generally do not induce PCT • PCT is therefore an “indirect marker” of a bacterial infection: PCT a measurement of the body’s inflammatory response to the bacteria Highly specific induction – Produced all tissue Calcitonin: Source of production in healthy people Healthy Sepsis PCT: Source of Production in Septic Patients In relevant bacterial infection, PCT is produced and released into circulation from the entire body Müller B. et al., JCEM 2001 Plasma Concentration PCT Kinetics PCT 1 2 6 12 Time (Hours) 24 48 72 • Rapid kinetics: detectable 3 hours after infection has begun, with a peak after 6-12 hrs. • Peak values up to 1000 ng/ml • Half-life: ~ to 24 hours Brunkhort FM et al., Intens. Care Med (1998) 24: 888-892 21 PCT values correlate directly with severity of bacterial load 2 ng/ml 0.5 ng/ml 0.05 ng/ml Healthy Individuals • • Local Infections Systemic Infections (Sepsis) Severe Sepsis Septic Shock In critically ill patients, PCT levels elevate in correlation to the severity of bacterial infection Integrating PCT in sepsis management can lead to improved patient outcomes PCT as a response to bacterial challenge Elevated or rising PCT values • Systemic response to bacterial infection o Progressing infection o Immune system is overwhelmed • Risk of significant disease progression Low PCT values in presence of clinical presentation • Self-limiting infection • Non-infectious etiology • Early phase of infection Procalcitonin release in the absence of infection • Primary inflammation syndrome following trauma: multiple trauma, extensive burns, major surgery (abdominal and transplant) • Severe pancreatitis or severe liver damage (1) • Prolonged circulatory failure: IE severe multiple organ dysfunction syndrome (MODS) (1.4) • Medullary C-cell cancers of the thyroid, pulmonary smallcell carcinoma and bronchial carcinoma • Newborn < 48hr - increased PCT values (physiological peak) Newborns less than 48 hours PCT measurements Age (hours) 0 – 6 hours 6 – 12 hours 12 – 18 hours 18 – 30 hours 30 – 36 hours 36 – 42 hours 42 – 48 hours PCT (ng/ml) ≤2 ≤8 ≤15 ≤ 21 ≤ 15 ≤8 ≤2 Chiesa et al., Council & Institute of Ped (1998) 45: 89-97 C-Reactive Protein (CRP) • Acute Phase Reactant synthesized by the liver • Secretion triggered by cytokine (IL-6, IL-1, TNF-α) • Produced in response to acute & chronic inflammation • • • • • • • • Bacterial, Viral, Fungal Rheumatic Inflammatory diseases Malignancy Tissue Injury, Necrosis Steroid Treatment Liver Failure Obesity • Advantages: o Rises in 4 to 6 hours • Disadvantages: o Non-specific o No correlation to SOFA Scores, o Slow Kinetics (peak 36-50h) Vingishi et al., J Clin Invest. 1993 Apr ; 91(4): 1351-7 Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1 Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79 Interleukin-6 (IL-6) • Pro-inflammatory cytokine (messenger protein) • Blood, monocytes, and endothelial cells • Advantage o Quick rise – one hour o Decreases rapidly • Disadvantage o o o o Any inflammatory process can increase IL-6 Affected in immune-compromised patients Sample must be cooled and spun immediately Containers must be free of endotoxins since IL-6 can be formed by decomposed leukocytes in the blood sample Vingishi et al., J Clin Invest. 1993 Apr ; 91(4): 1351-7 Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1 Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79 Lactate Lactate (lactic acid) is produced due to inadequate tissue perfusion – a defining parameter of late sepsis. • Advantage • Rapid turn-around • Readily available • Reliable marker of perfusion and prognosis • Disadvantage • Late elevation in course of sepsis • Non-specific Reduction of lactate is advocated as a target for therapeutic interventions (2C) Blomkalns AL www.emcreg.org 2007 Poeze M, et al. Crit Care Med 2005 Nov;33(11):2494-500 Muller B, et al. Crit Care Med 2000 Apr;28(4):977-83 Diagnostic accuracy of PCT compared to other biomarkers used in sepsis “BE”: UTI Case: Lactate Specificity 5 PCT 4.5 Lactate 4.3 4 Troponin 3.5 3 2.7 2.5 2 ABX Ceftriaxone Zosyn-Tobramycin Vancomycin 1.5 1.51 1 BP 142/82 90/58 98/60 0.5 0 0.05 0.05 0.05 HW S/P laparoscopic cholecystectomy: 4 days post procedural complication r/o Temp 103.4 RR 19 BP 96/52 HR 95 WBC 28.4 w/4 bands SrCr 1.6 w/ BUN 38 Mini-cath UA • Nitrite positive • 4+ bacteria Amlodipine 10mg daily Benazepril 20mg daily Propranolol LA 160mg daily HCTZ 25mg daily Aspirin 81 mg daily Furosemide 40mg prn daily for leg edema Oxybutynin 5mg bid Alprazolam 0.5mg tid Dicyclomine 10mg prn tid for irritable bowel Meloxicam 15mg daily Zolpidem 5mg hs Medications CC: dysuria, mental status changes, fever, nausea/vomiting CC/Hx/Presentation 73 Y/O female HW ED Treatment Plan: Dx of Sepsis due to UTI • • • • Admit to ICU Meropenem Vancomycin Cystalloids and dopamine HW • • • • • • • • • Hospitalist orders PCT in ICU after admission PCT 0.25 ng/ml Fluid bolus and continued rehydration DC dopamine DC merpenem DC vancomycin Start piperacillin/tazobactam Moved to Med-Surg Cx: Proteus mirabilis sensitive to 1st generation cephalosporins and resistant to quinolones (day2) • Changed cephalexin WR Pain is not proportional to visual presentation Complains area is “pulsing” Started 24 hours ago Occupation: Lineman Five scratches on leg from thorns/briars “Swelling is worse last 18 hours” Medical Hx: HTN in last three years Temp 99.2 Pulse 80-90 WBC 13.1 SrCr 2.1 PCT 21 Plain Film US: Subcutaneous edema suggesting cellulitis, but no localized collections MRI: Myositis involving vastus lateralis muscle with overlying cellulitis. Most likely etiologies from infection or trauma Surgery consult Antibiotics Labs/X-Ray/Plan CC: Worsening right thigh and knee pain CC/Hx/Presentation 48 Y/O male WR ED orders • Clindamycin 300 IV once • Doxycycline 100 mg IV once Initial Admission orders • Clindamycin 300 mg IV every 6 hours • Doxycycline 100 mg IV every 12 hours WR Revised admission orders • DC Doxycycline • Clindamycin 800 mg IV every 8 hours • Piperacillin/tazobactam 3.375 grams IV every 6 hours WR – MRI Leg WR – MRI Leg WR SrCr Lactic Acid 7 6 6 5 5 4 4 3 3 2 2 1 1 0 ED @ 1130 SrCr Day 1 @ 0530 2.1 5.1 0 Day 2 @ 1200 6.6 ED @ 1130 Day 1 @ 0800 Day 1 @ 1200 4.8 5.6 Lactic Acid WBC PCT 16 600 14 500 12 400 10 300 8 6 200 4 100 0 PCT 2 ED @ 1130 21 Day 1 @ 0530 330 Day 1 @ 0900 444 Day 1 @ 1200 550 0 WBC ED @ 1120 Day 1 @ 0530 Day 1 @ 0900 13.1 13 13.4 ST CC: pain, tenderness, and fever with recurrent cellulitis of left great toe and shin just superior to ankle Second day of recurrent infection that had “resolved” two weeks ago Adult onset insulin dependent diabetic Neuropathy in legs/feet Mild CHF HTN Glargine insulin 32 units daily Regular insulin Sliding Scale Sitagliptin 100mg daily Lisinopril 20mg bid Furosemide 20mg bid Carvedilol 25mg bid Gabapentin 400mg tid Pregabalin 150mg bid Alprazolam 0.5mg prn tid Hydrocodone/Acet 5mg/325mg prn q 4h for pain Medications Newly retired CC/Hx/Presentation 66 Y/O female ST clinical course Admission – AM • • • • • • • Plain film Scheduled MRI WBC 12.8 PCT 0.6 SrCr 1.8 Piperacillin/Tazobactam Vancomycin ST clinical course Day 1 - AM • WBC 14.4 • PCT 16 • SrCr 1.7 • Replace Piperacillin/Tazobactam with Meropenem Day 1 - PM • WBC 16.8 • PCT 26 • Lactate 2.1 • Replaced Vancomycin with Linezolid ST clinical course Day 2 - AM • WBC 24.8 • PCT 77 • Lactate 4.4 • SrCr 2.4 • Continued to worsen hemodynamically • Added Tobramycin 7mg/kg Day 2 - PM • PCT 64 • Lactate 2.2 ST clinical course Day 3 - AM • WBC 22.0 • PCT 39 • Lactate 1.9 • Blood Cx: gram stain gram negative rods Day 3 - PM • First blood Cx and sensitivity completed • Escherichia coli: CRE ST Blood Culture #1 Culture Report Organism 01 Escherichia coli (esccol) Antibiotics Ampicillin R Ampicillin/Sulbactam R Ceftizoxime R Gentamicin R ESBL POS Cefoxitin R Ceftazidime R Ceftriaxone R Cefepime R Imipenem R Meropenem R Amikacin S Tobramycin S Piperacillin/Tazobactam R Levofloxacin R Trimethoprim/Sulfamethox R WBC SrCr 30 3 25 2.5 20 2 15 1.5 10 1 5 0.5 0 Admissi Day 1 on AM WBC 12.8 14.4 Day 1 PM Day 2 AM Day 3 AM Day 4 AM Day 5 AM 16.8 24.8 22 18.5 11.2 0 Admissi on Day 1 AM Day 2 AM Day 3 AM Day 4 AM Day 5 AM 1.8 1.7 2.4 2.2 2 1.9 SrCr PCT 90 80 70 60 50 40 30 20 10 0 PCT Admis Day 1 sion AM 0.6 16 Lactic Acid Day 1 PM Day 2 AM Day 2 PM Day 3 AM Day 4 AM Day 5 AM 26 77 64 39 16 7 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Lactic Acid Day 1 PM Day 2 AM Day 2 PM Day 3 AM 2.1 4.4 2.4 1.9 Day 4 AM Day 5 AM GM CC: SOB Worsening over 4 days COPD (Gold Stage III) Recent pneumonia hospitalization Pulse Ox 82% RR 24 Prolonged expiration Rhonchi bilaterally A/P Chest film CHF WBC 3.2 HTN PCT 0.06 MRSA positive in nares last two encounters Platelets 99,000 Fibromyalgia GERD AAA Repair 2 stents in 2012 Spine surgery X4 Temp 102.4 BP 143/87 Pulse 77 BNP 489 Presentation Nursing home resident CC/Hx 83 Y/O female GM Carvedilol 6.25mg bid Atorvastatin 40mg daily Amiodarone 100mg daily Enalapril 20mg bid Aspirin 81mg daily (was 325mg) Mirtazapine 15mg hs Furosemide 40mg daily (doubled last 4 days) Pneumonia • Infiltrates • Productive cough • Signs of infection/inflammation COPD exacerbation CHF exacerbation Cefepime Vancomycin Methylpresnisolone Hydrocodone/APAP 10mg qid Furosemide Duloxetine 60mg daily Peripheral smear Ipratropium/Albuterol qid Albuterol prn q 2 hours “Prednisone taper” Assessment/Plan Pregabalin 75mg bid Medications Ticagrelor 90mg bid GM Admission • • • • Cefepime 1gm q 8 hours Vancomycin dose adjusted Furosemide 40mg IV q 12 hours Methylprednisolone 125mg IV q 6 hours Day 1 AM • All meds same except: • DC Furosemide: BP 90/60’s & HR > 110 WBC 30 25 24.6 20.1 20 16.3 15 12.8 10 5 3.2 10.8 4.3 0 Admission Admit Day 1 Day 2 Day 1 Day 3 Day 4 Day 3 Day 2 Day 5 Day 6 Day 4 Day 5 Day 6 40mg q 8h 40mg q12h 40mg daily Methylprednisolone 60mg q 6h 60mg q 6h 40mg q 6h 40mg q 8h PCT 14 12.8 12 10 8 5.9 6 4 3.1 2 0 0.06 Admission Day 1 Day 2 Day 3 1.4 Day 4 0.8 Day 5 0.4 Day 6 WBC Lactate 30 6 25 5 24.6 20 4 20.1 16.3 15 12.8 3.2 3 10.8 2 10 5 0 PCT 14 12.8 10 8 6 5.9 4 3.1 2 0 1.4 0.06 2 1 4.3 0 12 5.7 0.8 0.4 0.5 Keys to Success: Early Recognition and Treatment • Process in place to avoid loopholes and achieve consistency • Protocol or Order Sets • Appropriate biomarkers with clinical presentation o Sensitivity o Specificity • Lactate should be used primarily for evaluation of resuscitation efforts • Educate staff Five Rivers Medical Center Outcomes Comparison: Control Vs. Procalcitonin Date range 3 years Case Mix: 40% coded to an ID related diagnosis Sepsis related LOS -50% Sepsis related drugs costs -50% ICU admissions due to sepsis Antibiotic exposure – sepsis related GI related ADR’s (all reported) -64% -45% -40% Clostridium difficile infections -54% Summary The most important indications for PCT levels • Diagnosis of sepsis, severe sepsis, and septic shock • Differential diagnosis of clinically relevant bacterial infections and sepsis • Evaluation of the severity of a bacterial infection and systemic inflammatory reactions • Monitoring of the course of treatment of patients with sepsis • Evaluation of progression and control of antibiotic treatment Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis Questions