Procalcitonin: Pearls and Pitfalls in Daily Practice Sarah K Harrison, PharmD, BCCCP Clinical Pearl Disclosures The author of this presentation has no disclosures concerning possible financial or personal relationship with commercial entities. 1 Objectives 1. Identify the utility of procalcitonin (PCT) in optimizing management of critically ill patients 2. Evaluate clinical patient scenarios that may impact utility of PCT 2 1
PCT in the Presence and Absence of Bacterial Infection Healthy Patients Bacterial Infection L Philippe et al. In Vitro and in Vivo Calcitonin I Gene Expression in Parenchymal Cells: A Novel Product of Human Adipose Tissue. Endocrinology 2003;144(12):5578 5584. R Konrad et al. Markers for Sepsis Diagnosis: What is Useful? Crit Care Clin 2006;22: 503 519. 3 PCT in the Presence and Absence of Bacterial Infection Healthy Patients Bacterial Infection L Philippe et al. In Vitro and in Vivo Calcitonin I Gene Expression in Parenchymal Cells: A Novel Product of Human Adipose Tissue. Endocrinology 2003;144(12):5578 5584. R Konrad et al. Markers for Sepsis Diagnosis: What is Useful? Crit Care Clin 2006;22: 503 519. 4 Comparison to Standard Markers of Infection Specificity Sensitivity Advantages Disadvantages PCT ++++ + Rapid induction Half life 24 hours Severity correlation C Reactive Protein (CRP) Low sensitivity for localized infections Expensive ++ ++ Inexpensive Low sensitivity Slow induction No correlation with severity Leukocytes + +++ High sensitivity Low specificity Temperature + ++++ High sensitivity Low specificity R Konrad et al. Markers for Sepsis Diagnosis: What is Useful? Crit Care Clin 2006;22: 503 519. 5 2
SAPS: Efficacy and Safety of Procalcitonin Guidance in Reducing the Duration of Antibiotic Treatment in Critically Ill Patients Multicenter, prospective, open label, RCT n= 1575 Inclusion Critically ill patients with suspected bacterial infections Exclusion Expected ICU stay < 24 hours Severe immunosuppression Intervention Endpoints Infections in which long term antibiotics were recommended PCT guided discontinuation of antibiotics vs. guideline recommended standard of care 1 Efficacy: Antibiotic consumption and duration of antibiotic treatment 1 Safety: Mortality at 28 days and 1 year E de Jong et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open label trial Lancet Infect Dis 2016 6 SAPS: Patient Population Procalcitonin (n=761) Control (n=785) Age (years) 65 65 Men (%) 61 60 Severity of illness (%) Sepsis or severe sepsis Septic shock Treatment in the first 24 hrs (%) Mechanical ventilation Inotrope or vasopressor Renal replacement Type of infection (%) Community acquired Hospital acquired ICU acquired 82 18 81 96 9 52 25 24 Pulmonary infection site (%) 65 64 81 19 80 96 11 51 24 25 E de Jong et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open label trial Lancet Infect Dis 2016 7 SAPS: PCT Algorithm PCT Level decreased by 80% of peak value Relative Stopping Threshold Recommend Discontinuation PCT 0.5 mcg/l Absolute Stopping Threshold Strongly Recommend Discontinuation E de Jong et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open label trial Lancet Infect Dis 2016 8 3
SAPS: Endpoints Antibiotic consumption (days) Daily defined doses in first 28 days Duration of treatment Mortality (%) 28 day mortality 1 year mortality Adverse events Reinfection Repeated course of antibiotics Time (days) between stop and antibiotic reinstitution Costs Total cumulative costs of antibiotics Median cumulative costs of antibiotics per patient Length of stay (days) ICU Hospital Procalcitonin (n=761) 7.5 (4 12.8) 5 (3 9) 149 (19.6%) 265 (34.8%) 38 (5) 175 (23) 4 (2 8) 150082 107 (51 229) 8.5 (5 17) 22 (13 39.3) Control (n=785) 9.3 (5 16.5) 7 (4 11) 196 (25%) 321 (40.9%) 23 (2.9) 173 (22) 4 (2 8) 181263 129 (66 273) 9 (4 17) 22 (12 40) p value < 0.0001 < 0.0001 0.0122 0.0158 0.0492 0.67 0.96 NA 0.0006 0.56 0.77 E de Jong et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open label trial Lancet Infect Dis 2016 9 Lessons Learned in Practice Obtaining a PCT: Who, when, and why? 1. Massive stress 2. Kidney disease 3. Algorithm adherence Potential Confounders Physiologic stress Massive stress (trauma, surgery, burns, pancreatitis) Prolonged, severe cardiogenic shock or organ perfusion abnormalities Non-bacterial cytokine activation Fungal infections Vasculitis and acute graft vs. host disease Chronic kidney disease (CKD) Dysregulated production Cytokine stimulating agents Paraneoplastic syndromes 11 4
Clinical Pearls for Massive Stress Response PCT may be falsely elevated within 24 hours of trauma or surgery Typically normalizes within 24-48 hours of inciting event unless ongoing shock PCT may remain falsely elevated for several days following cardiac arrest and throughout ongoing cardiogenic shock Negative predictive value maintained 12 Utility of PCT in Critically Ill Trauma Patients Single center, prospective, RCT n= 102 Inclusion Trauma team activation with direct admit to TICU Exclusion Pre existing renal failure TICU stay < 24 hours Comparison Group I: Systemic inflammatory response syndrome (SIRS) Group II: Sepsis Group III: Neither PCT Level PCT Level (mcg/l) SIRS (n=24) Sepsis (n=33) Neither (n= 23) p value 0.9 (0.2 1.5) 6.6 (2.7 10.5) 0.2 (0.1 0.4) <0.0001 JV Sakran et al. The utility of procalcitonin in critically ill trauma patients J Trauma Acute Care Surg. 2012;73: 413 418. 13 PCT to Guide Duration of Antibiotic Therapy in Surgical Intensive Care patients Single center, prospective, RCT n= 110 Inclusion SICU patients requiring antibiotic therapy based on confirmed or highly suspected bacterial infections and at least two concomitant SIRS criteria Intervention PCT guided discontinuation of antibiotics Discontinuation at < 1 mcg/ml or decrease to 25 35% of peak vs. guideline recommended standard of care Endpoints Control (n = 53) PCT Guided (n = 57) p value Intensive care (days) 17.7 ± 10.1 15.5 ± 12.5 0.046 Survival to hospital 39 42 > 0.05 discharge Length of antibiotic therapy (days) 7.9 ±0.5 5.9 ± 1.7 <0.001 M Hochreiter et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial Critical Care 2009, 13:R83. 14 5
PCT Levels Following Hypothermia After Cardiac Arrest Single center, retrospective, n= 34 Inclusion Therapeutic hypothermia after witnessed cardiac arrest Monitoring Daily PCT and CRP concentrations after induction of hypothermia Clinical diagnosis of infection: clinical evidence of infection and patients received antibiotics by the treating physicians P Schuets et al. Serum procalcitonin, C reactive protein, and white blood cell levels following hypothermia after cardiac arrest: a retrospective cohort study Eur J Clin Invest. 2010, 40(4): 376 381.. 15 Clinical Pearls for Patients with Renal Dysfunction Cytokine activation in CKD may increase baseline PCT levels Hemodialysis (HD) may eliminate some PCT Levels should be drawn before HD sessions PCT decline with infection resolution similar in severe CKD vs. normal renal function 16 Procalcitonin: Diagnostic Value in Systemic Infections in Chronic Kidney Disease or Renal Transplant Patients Single center, observational, n= 82 Inclusion Suspected infection Hemodialysis (n = 54) Renal transplant (n = 28) Comparison Group I: Confirmed infection Group II: Unconfirmed infection PCT Level Unconfirmed infection (n= 28) Confirmed infection (n= 54) pvalue PCT Level (mcg/l) 0.3 (0.1 0.5) 2.5 (0.9 5) <0.001 Sensitivity (%) Specificity (%) All HD Transplant All HD Transplant PCT > 0.5 mcg/l 93.1 97.7 78.6 79.2 70 85.7 PCT > 1.5 mcg/l 58.6 56.8 64.3 95.8 90 100 R Dumea et al. Procalcitonin: diagnostic value in systemic infections in chronic kidney disease or renal transplant patients Int Urol Nephrol 2014; 46:461 468. 17 6
Clinical Pearls in Algorithm Adherence Algorithm adherence has been reported as low as 47% Adherence issues in daily practice: Use to determine duration of therapy (PCT vs. standard of 7 days) Obtaining repeat PCT levels to trend L Bouadma et al. Use of procalcitonin to reduce patients exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial Lancet 2010; 375: 463 74. A Ammar et al. Compliance with Procalcitonin Algorithm Antibiotic Recommendations for Patients in Medical Intensive Care Unit Pharmacotherapy. 2016 doi:10.1002/phar.1887. 18 Guideline Recommendations Guideline Recommendation Level of Evidence Hospital Acquired Pneumonia/Ventilator Acquired Pneumonia (HAP/VAP) PCT levels plus clinical criteria to guide the discontinuation of antibiotic therapy, rather than clinical criteria alone Weak recommendation, low quality evidence Surviving Sepsis Campaign: Sepsis and Septic Shock PCT levels can be used to support shortening the duration of in sepsis patients PCT levels can be used to support the discontinuation of empiric antibiotics Weak recommendation, low quality evidence Weak recommendation, low quality evidence A Kalil etl al. Management of Adults With Hospital acquired and Ventilator associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society Clinical Infectious Diseases. 2016;63(5):e61 111. A Rhodes etl al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 Crit Care Med 2017; 3:00 00. 19 Algorithm for the Inpatient Use of Procalcitonin Presumed fungal, viral, or parasitic infections Penetrating trauma or cardiac surgery <24-48H prior No Will the PCT results impact antimicrobial therapy? Yes Day 1 of : Draw baseline PCT and start empiric antibiotics Day 3 of : Recheck PCT q48h after start to trend of PCT level Recommendation < 0.25 mcg/l Discontinuation strongly encouraged 0.25 0.49 mcg/l (or drop by > 80% at recheck) Discontinuation encouraged 0.5 mcg/l (and rising or not decreasing at recheck) Strongly recommend continuation of therapy consider escalation Empiric therapy is indicated in all patients with clinical suspicion of infection if withholding such therapy could have an adverse effect. If a PCT level is checked too early following the onset of infection (i.e. within 4h of onset), it may result in a falsely low level Consider continuing antibiotics that have been initiated in clinically unstable patients despite a PCT level that suggests discontinuation. Continue to trend PCT at least q48h to evaluate continued need for antibiotics. PCT may be elevated in pancreatitis, trauma or burns, ECMO, and surgery and elevated levels in these situations may not be an accurate reflection of the presence or absence of bacterial infection, however, the clinical significance of low levels should still hold. 7
Algorithm for the Inpatient Use of Procalcitonin Presumed fungal, viral, or parasitic infections Penetrating trauma or cardiac surgery <24-48H prior No Will the PCT Yes results impact? Day 1 of : Draw baseline PCT and start empiric antibiotics Day 3 of : Recheck PCT q48h after start to trend of PCT level Recommendation < 0.25 mcg/l Discontinuation strongly encouraged 0.25 0.49 mcg/l (or drop by > 80% at recheck) Discontinuation encouraged 0.5 mcg/l (and rising or not decreasing at recheck) Strongly recommend continuation of therapy consider escalation Empiric therapy is indicated in all patients with clinical suspicion of infection if withholding such therapy could have an adverse effect. If a PCT level is checked too early following the onset of infection (i.e. within 4h of onset), it may result in a falsely low level Consider continuing antibiotics that have been initiated in clinically unstable patients despite a PCT level that suggests discontinuation. Continue to trend PCT at least q48h to evaluate continued need for antibiotics. PCT may be elevated in pancreatitis, trauma or burns, ECMO, and surgery and elevated levels in these situations may not be an accurate reflection of the presence or absence of bacterial infection, however, the clinical significance of low levels should still hold. Algorithm for the Inpatient Use of Procalcitonin No Will the PCT results impact antimicrobial therapy? Yes Day 1 of : Draw Presumed fungal, viral, baseline or PCT parasitic and start empiric infections antibiotics Day 3 of : Recheck PCT q48h after start to trend Penetrating trauma or cardiac surgery <24- of PCT level Recommendation 48H prior < 0.25 mcg/l Discontinuation strongly encouraged 0.25 0.49 mcg/l (or drop by > 80% at recheck) Discontinuation encouraged 0.5 mcg/l (and rising or not decreasing at recheck) Strongly recommend continuation of therapy consider escalation Empiric therapy is indicated in all patients with clinical suspicion of infection if withholding such therapy could have an adverse effect. If a PCT level is checked too early following the onset of infection (i.e. within 4h of onset), it may result in a falsely low level Consider continuing antibiotics that have been initiated in clinically unstable patients despite a PCT level that suggests discontinuation. Continue to trend PCT at least q48h to evaluate continued need for antibiotics. PCT may be elevated in pancreatitis, trauma or burns, ECMO, and surgery and elevated levels in these situations may not be an accurate reflection of the presence or absence of bacterial infection, however, the clinical significance of low levels should still hold. Algorithm for the Inpatient Use of Procalcitonin Presumed fungal, viral, or parasitic infections Penetrating trauma or cardiac surgery <24-48H prior No Will the PCT results impact antimicrobial therapy? of PCT level Recommendation therapy: Recheck PCT q48h < 0.25 mcg/l Discontinuation strongly encouraged 0.25 0.49 mcg/l (or drop by > 80% at recheck) after Discontinuation start encouraged to trend 0.5 mcg/l (and rising or not decreasing at recheck) Strongly recommend continuation of therapy consider escalation Empiric therapy is indicated in all patients with clinical suspicion of infection if withholding such therapy could have an adverse effect. If a PCT level is checked too early following the onset of infection (i.e. within 4h of onset), it may result in a falsely low level Consider continuing antibiotics that have been initiated in clinically unstable patients despite a PCT level that suggests discontinuation. Continue to trend PCT at least q48h to evaluate continued need for antibiotics. PCT may be elevated in pancreatitis, trauma or burns, ECMO, and surgery and elevated levels in these situations may not be an accurate reflection of the presence or absence of bacterial infection, however, the clinical significance of low levels should still hold. Yes Day 1 of antimicrobial therapy: Draw baseline PCT and start empiric antibiotics Day 3 of antimicrobial 8
Algorithm for the Inpatient Use of Procalcitonin Presumed fungal, viral, or parasitic infections Penetrating trauma or cardiac surgery <24-48H prior No Will the PCT results impact antimicrobial therapy? Day 1 of : Draw baseline PCT and start empiric antibiotics Day 3 of : Recheck PCT q48h after start to trend of Empiric therapy is indicated in all patients with clinical suspicion of infection if withholding such therapy could have an adverse effect. If a PCT level is checked too early following the onset of infection PCT level(i.e. within 4h of onset), it may Recommendation result in a falsely low level < 0.25 mcg/l Consider continuing antibiotics Discontinuation that have strongly been encouraged initiated in clinically 0.25 0.49 mcg/l (or drop by > 80% at recheck) Discontinuation encouraged 0.5 mcg/l for (and antibiotics. rising or not decreasing at recheck) Strongly recommend continuation of therapy consider escalation Yes unstable patients despite a PCT level that suggests discontinuation. Continue to trend PCT at least q48h to evaluate continued need PCT may be elevated in pancreatitis, trauma or burns, ECMO, and surgery and elevated levels in these situations may not be an accurate reflection of the presence or absence of bacterial infection, however, the clinical significance of low levels should still hold. PCT Conclusions Highly sensitive and specific biomarker for bacterial infection, but must be utilized in conjunction with other indicators Should not be obtained unless it will help impact False elevation may occur in surgery, trauma, cardiac arrest, and during ongoing cardiogenic shock Sensitivity and specificity is maintained in CKD Procalcitonin: Pearls and Pitfalls in Daily Practice Sarah Harrison, PharmD, BCCCP Sarah.Harrison@BSWHealth.org 9