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. 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
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

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: Incidence and Mortality
Cases/100,000
Mortality
Deaths/Year
Sepsis is a common condition. In the US, the incidence of sepsis per 100,000 exceeds AIDS, breast cancer, and first myocardial infarctions. Concerted public awareness campaigns have emphasized the importance of coronary heart disease, AIDS, and breast cancer. Yet, as shown on this slide, the mortality of severe sepsis exceeds AIDS, breast cancer and is only slightly less that that of patients dying suddenly of an acute myocardial infarction. Severe sepsis shows a small peak in incidence in the very young (<1 year). The incidence then remains low until midlife when it begins to climb. As shown on this slide, both sepsis and severe sepsis are most problematic after the age of 50 years.
Angus DC, Linde-Zwirble WT, Lidicker J, et al. Incidence, cost and outcomes of severe sepsis in the United States. Crit Care Med 2001; In Press.
Angus DC, Linde-Zwirble WT, Lidicker J, et al. Incidence, cost and outcomes of severe sepsis in the United States. Crit Care Med 2001; American Heart Association Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association, 2000.
American Cancer Society. Cancer Statistics. Online edition, accessed 3/29/01.
Angus DC, et al. Crit Care Med. 2001; ACS.

6. 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
Adults, pediatrics, and newborn
Morbidity
Surgical rate is increasing
Clinical diagnosis remains challenging

7. Hospital mortality of severe sepsis patients with an ICU stay is 4 times that of other ICU patients.

8. Ventilator use in severe sepsis patients with an ICU stay is more than 15 times that of other patients.
sepsis.com

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

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

11. Cases of sepsis in the U.S. by pathogen
Martin S, et al, N Engl J med 248;16, April 17, 2003

12. Why do we struggle with the diagnosis of sepsis?

13. Relationship of SIRS, Sepsis, and Infection

14. 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

15. 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

16. 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):

17. 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

18. What is Procalcitonin and its role in sepsis management?

19. 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

20. 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

21. 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 6-12 hrs.
Peak values up to 1000 ng/ml
Half-life: ~ to 24 hours 21
Brunkhort FM et al., Intens. Care Med (1998) 24:

22. 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

23. 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-infectious etiology
Early phase of infection

24. 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

25. 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

26. 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

27. 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

28. 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
Poeze M, et al. Crit Care Med 2005 Nov;33(11):
Muller B, et al. Crit Care Med 2000 Apr;28(4):977-83

29. Diagnostic accuracy of PCT compared to other biomarkers used in sepsis

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

31. 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 96/52
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

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

33. 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
PCT ordered next am after admission. Patient received hydration through out the night.

34. 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 CC: Worsening right thigh and knee pain 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

35. Initial Admission ordersWR
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

36. 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

37. WR – MRI Leg

38. WR – MRI Leg

39. WR

40. 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
Hydrocodone/Acet 5mg/325mg prn q 4h for pain
CC/Hx/Presentation
66 Y/O female
Newly retired
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

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

42. 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

43. 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

44. 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

45. 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

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
MRSA positive in nares last two encounters
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
PCT 0.06
Platelets 99,000
Temp 102.4
BP 143/87
Pulse 77
BNP 489

48. GM Pneumonia COPD exacerbation CHF exacerbation
Medications
Ticagrelor 90mg bid
Pregabalin 75mg bid
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)
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 125mg IV q 6 hours
Day 1 AM
All meds same except:
DC Furosemide: BP 90/60’s & HR > 110

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

52. 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

53. 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%

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

55. Questions