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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 No 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 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 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 • Newborn, pediatric, adults, aged • Morbidity • Surgical sepsis rate is increasing • Clinical diagnosis remains challenging 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 12 to 24 hours • Peak values up to 1000 ng/ml • Half-life: ~ to 24 hours Brunkhort FM et al., Intens. Care Med (1998) 24: 888-892 17 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-bacterial 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 Case Presentations Application of PCT use for Sepsis and Antibiotic Management HW S/P laparoscopic cholecystectomy: 4 days post procedural complication r/o Temp 103.4 RR 19 BP 86/52 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 Tobramycin 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 tobramycin Start piperacillin/tazobactam Moved to Med-Surg Cx: Proteus mirabilis sensitive to 1st generation cephalosporins and resistant to quinolones (day2) • Changed to cephalexin HW Clinical Perles • • • • • • Patient met SIRS criteria SIRS criteria complicated by medications? SIRS criteria clouded by volume depletion? Baseline PCT Process to ensure PCT draw Establish a process - Order sets Considerations • Assumed sepsis prompting aggressive response • ICU admission? • Vasopressor? WR CC: Worsening right thigh and knee pain Five scratches on leg, 2 -3 cm in length from thorns/briars Pain is not proportional to visual presentation Started 24 hours ago Complains area is “pulsing” Patient states: “Some swelling in last 18 hours” 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 Occupation: Lineman 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 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 1 @ 1200 6.6 ED @ 1130 Day 1 @ 0800 Day 1 @ 1200 4.8 5.6 Lactic Acid PCT WBC 600 16 14 500 12 400 10 300 8 6 200 4 100 0 PCT 2 ED @ 1130 Day 1 @ 0530 Day 1 @ 0800 Day 1 @ 1200 21 330 444 550 0 WBC ED @ 1120 Day 1 @ 0530 Day 1 @ 0800 13.1 13 13.4 WR – MRI Leg WR – MRI Leg WR Clinical Perles: Continued Procalcitonin escalation despite suspected adequate Abx • Clinical presentation mismatch to seriousness of illness • A significant elevation in PCT is always a cause for concern • Resistant organism • Abscess • Need for surgical intervention • Other source/site of infection ST 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 “Aleve” 440mg prn bid on “most days” Hydrocodone/Acet 5mg/325mg prn q 4h for pain Medications CC: pain, tenderness, and fever with recurrent cellulitis of left great toe and shin just superior to ankle 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 • Lactate 2.1 • 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 • Worsened hemo-dynamically: increased LVP rate • 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 ST Clinical Perles • Understanding PCT principles will allow effective monitoring and shorten time to intervene > requires through education efforts • Reducing intervention time can preempt more serious disease progression • PCT is effective in monitoring and managing antibiotic therapy 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 WBC 3.2 CHF Platelets 99,000 HTN PCT 0.06 Fibromyalgia Temp 102.4 GERD BP 143/87 AAA Repair Pulse 77 2 stents in 2012 BNP 489 Spine surgery X4 Presentation Nursing home resident CC/Hx 83 Y/O female GM Pregabalin 75mg bid Carvedilol 6.25mg bid Atorvastatin 40mg daily Amiodarone 100mg daily Enalapril 20mg bid 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 Aspirin 81mg daily (was 325mg) Medications Ticagrelor 90mg bid GM Admission • • • • Cefepime 1gm q 8 hours Vancomycin dose adjusted Furosemide 40mg IV q 12 hours Methylprednisolone 60mg IV q 6 hours Day 1 AM • All meds same except: • DC Furosemide: BP 90/60’s & HR > 110 WBC 30 28.2 25 24.6 22.8 20 18.1 16.3 15 10.8 10 5 3.2 0 Admission Admit Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 1 Day 2 Day 3 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 6 5.9 5.6 4 3.1 2 1.4 0 Admission Day 1 Day 2 Day 3 Day 4 0.8 Day 5 0.4 Day 6 WBC 30 Lactate 6 28.2 25 5 24.6 22.8 20 4 18.1 16.3 15 3 10.8 10 5 5.7 2 2 2 1 3.2 0.5 0 0 Admission Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Admission PCT 14 12.8 12 10 8 6 5.9 5.6 4 3.1 2 1.4 0 Admission Day 1 Day 2 Day 3 Day 4 0.8 Day 5 0.4 Day 6 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 GM Clinical Perles • WBC may be a poor biomarker affected by immune state, diseases, and steroids • When LOS permits, use PCT follow up algorithms to stop antibiotic therapy sooner • Decrease ABX exposure • Selection for resistance • Adverse event reduction 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