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Sepsis in the Rural Setting: Early Recognition and Management

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1 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

2 No Disclosures

3 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

4 Outline Seriousness of sepsis
Difficulties with the diagnosis of sepsis Procalcitonin (PCT) Biomarker Kinetics Comparison to other biomarkers Application of PCT into sepsis management

5 Severe sepsis is costly and life-threatening
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

6 Determinants of mortality from sepsis
Early intervention is critical Appropriate antibiotic therapy within one hour of hypotension Resuscitation / re-establish perfusion within six hours

7 Duration of hypotension before initiation of appropriate ABX therapy is the critical determinant of survival in septic shock

8 Why do we struggle with the diagnosis of sepsis?

9 Relationship of SIRS, Sepsis, and Infection

10 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 > 12,000/mm3 < 4000/mm3 > 10% immature (band) forms

11 Making the Diagnosis Tachycardia – 718 possibilities Tachypnea possibilities Increased/Decreased Temperature – 1380 possibilities Increased/Decreased WBC – 350 possibilities 541 possible diagnoses with 2 or more of the criteria

12 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… ACCP: American College of Chest Physicians, SCCM SIRS Sepsis Severe Sepsis Septic Shock Bone RC, et al. Chest 1992 Jun;101(6):

13 Probability of a Sepsis Diagnosis
100% 0% Pretest situation: only clinical assessment is available Assessment of individual features and addition of PCT Post-test situation: Individually adjusted risk assessment > 90% PCT 2.0 40% PCT 0.3 < 10% Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis

14 What is Procalcitonin and its role in sepsis management?

15 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

16 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

17 Brunkhort FM et al., Intens. Care Med (1998) 24: 888-892
PCT Kinetics Time (Hours) Plasma Concentration 1 2 6 12 24 48 72 PCT The half life is 24 hours so when patients are on the appropriate abx therapy you should start to see a decline in PCT every 24 hours PCT kinetics provide important information on prognosis of sepsis patients. Highly specific induction due to bacterial infection. Rapid increase (more rapid compared to CRP). Levels increase 3-6 hours after bacterial challenge. Correlation to severity of disease; the higher the PCT level – the more severe is the patient‘s condition. Enormous magnitude of elevation that can be reached (up to 105 compared to healthy; other parameters: magnitude fold ) Half life of ~24 h Can be used also in patients with renal insufficiency. Easy to measure. Incubation time is 20 minutes. 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 17 Brunkhort FM et al., Intens. Care Med (1998) 24:

18 PCT values correlate directly with severity of bacterial load
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

19 PCT as a response to bacterial challenge
Elevated or rising PCT values Systemic response to bacterial infection Progressing infection 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

20 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 small-cell carcinoma and bronchial carcinoma Newborn < 48hr - increased PCT values (physiological peak) Abdominal surgeries: 2, kidney mild usually less than 2, heart less than 2, liver 2 to 10 Severe kidney disease rarely exceed 0.5ng/ml- some authors recommend an upper range of 1.5 instead of 0.5

21 Newborns less than 48 hours PCT measurements
Age (hours) PCT (ng/ml) 0 – 6 hours ≤ 2 6 – 12 hours ≤ 8 12 – 18 hours ≤15 18 – 30 hours ≤ 21 30 – 36 hours ≤ 15 36 – 42 hours 42 – 48 hours Chiesa et al., Council & Institute of Ped (1998) 45: 89-97

22 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: Rises in 4 to 6 hours Disadvantages: Non-specific No correlation to SOFA Scores, Slow Kinetics (peak 36-50h) Participates in the clearance of necrotic and apoptotic cells Enhances phagocytosis by macrophages Increase in 4-6 hrs Peak 36-50hrs The acute phase response develops in a wide range of acute and chronic inflammatory conditions like bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury or necrosis. These conditions cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver. Because there are a large number of disparate conditions that can increase CRP production, an elevated CRP level does not diagnose a specific disease. CRP binds to phosphocholine on microbes and damaged cells and enhances phagocytosis by macrophages. Thus, CRP participates in the clearance of necrotic and apoptotic cells. SOFA – sequential organ failure score Vingishi et al., J Clin Invest Apr ; 91(4): 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 Jan 9(1): 71-79

23 Interleukin-6 (IL-6) Pro-inflammatory cytokine (messenger protein)
Blood, monocytes, and endothelial cells Advantage Quick rise – one hour Decreases rapidly Disadvantage 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 Apr ; 91(4): 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 Jan 9(1): 71-79

24 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 Mueller/Marshall Another important biomarker that has specific relevance to distinguishing sepsis from septic shock and predicting the prognosis of the latter is the serum lactate level. For decades, serum lactate has been recognized and utilized as an indicator of tissue hypoxia, which has immediate relevance to the fundamental pathophysiologic difference between sepsis and septic shock. If, however, there is insufficient oxygen present in the mitochondria for the Krebs cycle to function, pyruvate accumulates in the cytoplasm and depletes the cell of mediators necessary for the continuation of glycolysis. To regenerate those mediators and continue glycolysis for what small amount of ATP it generates, pyruvate is converted to lactate that is then released into the bloodstream. This is known as anaerobic metabolism. Additionally, there are many clinical conditions, such as toxin ingestion or inborn errors of metabolism, which cause lactate production independent of tissue hypoxia. Under normal physiologic conditions, a small amount of lactate is produced, but almost all healthy tissues, and especially the liver, have the ability to convert lactate to pyruvate for use in cellular metabolism. This recycling of lactate to pyruvate itself is an energy and oxygen intensive process. Serum lactate levels rise when lactate production outstrips the body’s ability to metabolize it or when there is a decrement in that metabolic capacity, which is often seen in sepsis-associated multisystem organ failure. The overwhelming majority of research with serum lactate has been conducted in adults. The relevant pediatric investigations have been reviewed in detail with excellent discussions of the relevant physiology [46–50]. To summarize, it was first noted that serum lactate was increased in patients with sepsis and that this cohort was sicker and had increased mortality. Early on it was also observed that patients whose lactate levels decreased with therapy had better outcomes while those whose elevated levels persisted fared worse [51]. In these regards, the lactate level was used as a diagnostic, monitoring and prognostic biomarker. With the advent of this research, however, many other investigators demonstrated that lactate levels were not specific to tissue hypoxia, showing that lactate could be increased by adrenergic stimuli and lung injury independent of cellular hypoxia [46,52,53]. This challenged the fundamental premise that lactate distinguishes very well between states of adequate perfusion and poor oxygen delivery. Despite these findings, serum lactate provides valuable information about a patient’s physiologic status when considered in the context of other clinical signs and symptoms. To that end, the reduction of serum lactate is still advocated as a target for therapeutic interventions [54,55]. Even though we have discussed individual biomarkers in isolation except as compared with each other, a potentially more robust approach to the diagnosis of sepsis may be the combination of separate biomarkers into one panel so that multiple indicators of infection combine to improve specificity and sensitivity of the whole assay. Although little research has been conducted in pediatric sepsis using multiple markers in concert, the concept has been demonstrated by Kofoed et al. in adults [56]. In their study of patients presenting with SIRS suspected of having an infectious etiology, they used multiplex immunoassay measuring six markers to identify those with true bacterial infection. The AUC for the six marker panel was significantly greater than the AUCs of each individual constituent. Reduction of lactate is advocated as a target for therapeutic interventions (2C) Blomkalns AL 2007 Poeze M, et al. Crit Care Med 2005 Nov;33(11): Muller B, et al. Crit Care Med 2000 Apr;28(4):977-83

25 Diagnostic accuracy of PCT compared to other biomarkers used in sepsis

26 “BE”: UTI Case: Lactate Specificity
ABX Ceftriaxone Zosyn-Tobramycin Vancomycin BP 142/82 90/58 98/60

27 Case Presentations Application of PCT use for Sepsis and Antibiotic Management

28 HW CC/Hx/Presentation 73 Y/O female CC: dysuria, mental status changes, fever, nausea/vomiting 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 Medications 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

29 HW ED Treatment Plan: Dx of Sepsis due to UTI Admit to ICU Meropenem
Tobramycin Cystalloids and dopamine Note: at this time a PCT had not been ordered.

30 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 PCT ordered next am after admission. Patient received hydration through out the night.

31 HW Clinical Perles Considerations 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?

32 WR Temp 99.2 Pulse 80-90 WBC 13.1 SrCr 2.1 PCT 21 Plain Film
Labs/X-Ray/Plan 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 CC/Hx/Presentation 48 Y/O male Occupation: Lineman 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”

33 Initial Admission orders
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

34 Clindamycin 800 mg IV every 8 hours
WR Revised admission orders DC Doxycycline Clindamycin 800 mg IV every 8 hours Piperacillin/tazobactam grams IV every 6 hours

35 WR

36 WR – MRI Leg

37 WR – MRI Leg

38 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

39 ST Glargine insulin 32 units daily Regular insulin Sliding Scale
Medications 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 CC/Hx/Presentation 66 Y/O female 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

40 ST clinical course Admission – AM Plain film Scheduled MRI WBC 12.8
PCT 0.6 SrCr 1.8 Piperacillin/Tazobactam Vancomycin

41 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 Replaced Vancomycin with Linezolid

42 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

43 ST clinical course Day 3 - AM Day 3 - PM 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

44 ST Blood Culture #1 Culture Report
Organism 01 Escherichia coli (esccol) Antibiotics Ampicillin R Ampicillin/Sulbactam Ceftizoxime Gentamicin ESBL POS Cefoxitin Ceftazidime Ceftriaxone Cefepime Imipenem Meropenem Amikacin S Tobramycin Piperacillin/Tazobactam Levofloxacin Trimethoprim/Sulfamethox


46 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

47 GM Pulse Ox 82% RR 24 Prolonged expiration Rhonchi bilaterally A/P
CC/Hx 83 Y/O female Nursing home resident CC: SOB Worsening over 4 days COPD (Gold Stage III) Recent pneumonia hospitalization CHF HTN Fibromyalgia GERD AAA Repair 2 stents in 2012 Spine surgery X4 Presentation Pulse Ox 82% RR 24 Prolonged expiration Rhonchi bilaterally A/P Chest film WBC 3.2 Platelets 99,000 PCT 0.06 Temp 102.4 BP 143/87 Pulse 77 BNP 489

48 GM Pneumonia COPD exacerbation CHF exacerbation
Medications Ticagrelor 90mg bid Aspirin 81mg daily (was 325mg) 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) Hydrocodone/APAP 10mg qid Duloxetine 60mg daily Ipratropium/Albuterol qid Albuterol prn q 2 hours “Prednisone taper” Assessment/Plan Pneumonia Infiltrates Productive cough Signs of infection/inflammation COPD exacerbation CHF exacerbation Cefepime Vancomycin Methylpresnisolone Furosemide Peripheral smear

49 GM Admission Day 1 AM 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

50 Day 3 Methylprednisolone Admit Day 1 Day 2 Day 4 Day 5 Day 6 60mg q 6h
40mg daily


52 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

53 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 Sensitivity Specificity Lactate should be used primarily for evaluation of resuscitation efforts Educate staff

54 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 ICU admissions due to sepsis -64% Antibiotic exposure – sepsis related -45% GI related ADR’s (all reported) -40% Clostridium difficile infections -54%

55 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

56 Questions

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