Procalcitonin Guided Antibiotic Management for the Post-operative Open Heart Surgery Patient Daizo Tanaka, MD; Shinya Unai, MD; Harrison T. Pitcher, MD Nicholas Cavarocchi, MD; James T. Diehl, MD; Hitoshi Hirose, MD Division of Cardiothoracic Surgery, Department of Surgery Thomas Jefferson University Hospital

Diagnosis of infection in postop cardiac surgery patients Systemic inflammation after cardiac surgery makes diagnosis of infection difficult. Surgical trauma Cardiopulmonary bypass Prat C, Ricart P, Ruyra X, Domínguez J, Morillas J, Blanco S, Tomasa T, Torres T, Cámara L, Molinos S, Ausina V. Serum concentrations of Procalcitonin after cardiac surgery. J Card Surg 2008; 23:627-32. Aouifi A, Piriou V, Blanc P, Bouvier H, Bastien O, Chiari P, Rousson R, Evans R, Lehot JJ. Effect of cardiopulmonary bypass on serum Procalcitonin and C-reactive protein concentrations. Br J Anaesth 1999; 83:602-7. Conventional signs and markers of infection (fever, WBC count, CRP etc.) are inaccurate.

Procalcitonin (PCT) More specific for infection than conventional markers Aouifi A, Piriou V, Blanc P, Bouvier H, Bastien O, Chiari P, Rousson R, Evans R, Lehot JJ. Effect of cardiopulmonary bypass on serum Procalcitonin and C-reactive protein concentrations. Br J Anaesth 1999; 83:602-7. Valuable for diagnosis of community-acquired pneumonia, urinary tract infection and sepsis Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum Procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341:515-8. Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, Müller B. Effect of Procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomized, single-blinded intervention trial. Lancet 2004;363:600-7. Only limited reports for postop cardiac surgery patients

Study design Algorithm to manage postop patients suspected of infection Retrospective study from Jan 2012 to Jan 2013 Postop cardiac surgery patients tested for PCT Exclusion PCT value on POD1 prolonged systemic malperfusion immunosuppression

Algorithm TREGGER EVENT Increased WBC count Fever >101.4 Infiltration on chest x-ray Positive urinalysis or culture Increasing vasopressor requirement Signs of sepsis/shock NO Continue standard of care Yes Study confirmation of source Cultures: blood, urine, sputum Duplex ultrasound Laboratory tests (Labs) Start broad-spectrum antibiotics Initial Procalcitonin (PCT) level Trend PCT levels Treat per standard of care

Treat per standard of care Initial Procalcitonin (PCT) level Trend PCT Treat per standard of care Initial Procalcitonin (PCT) level PCT < 2ng/ml PCT ≥ 2ng/ml Positive PCT with Source confirmation Trend PCT Continue antibiotics Follow-up cultures Trend PCT Continue antibiotics Follow-up cultures Worsening clinical picture PCT < 2ng/ml Increasing/positive PCT No clinical improvement Positive PCT No source identified Clinical improvement Trend PCT Continue antibiotics CT chest/abdomen/pelvis Consider repeat cultures Discontinue antibiotics No additional imaging Positive PCT Source not identified on imaging Negative PCT No clinical improvement Positive PCT Source identified on imaging Trend PCT Continue antibiotics False negative PCT Restart antibiotics Improving clinical picture Trend PCT Treat per standard of care (consider operation) False positive PCT Discontinue antibiotics

Characteristics of patients   With infection Without infection P value Number 16 17 - Age (years old) 55.5 ± 13.1 61.2 ± 15.3 0.37 Male 14 (88%) 13 (76%) Body mass index 28.3 ± 7.4 29.3 ± 6.2 0.68 Procedure CABG 2 5 Valve 8 Other 9 4 PCT (ng/ml) 16.4 ± 26.5 4.1 ± 10.2 0.11 Temperature (F) 99.4 ± 1.6 100.1 ± 1.5 0.27 WBC count (B/L) 16.8 ± 9.0 13.1 ± 5.3 0.18

Sensitivity, specificity, predictive values with different cut-off of PCT value Cut-off (ng/ml) Sensitivity (%) Specificity (%) PPV (%) NPV (%) 2.0 81 82 1.5 88 1.0 94 77 79 93

Receiver operating characteristics 1.0 ng/ml PCT 1.5 ng/ml WBC 2.0 ng/ml   Area under curve PCT 0.864 (0.658 – 0.955) WBC 0.605 (0.399 – 0.779) P 0.03 Sensitivity Specificity

True positive PCT All 15 true positive patients (PCT≥2ng/nl, +infection) were treated with ABX. 10/15 patients: PCT was trended until <2ng/ml 3 patients: ABX continued (2 mediastinitis and 1 sepsis after AVR) 7 patients: ABX discontinued, no recurrence

True negative PCT 12/14 true negative patients (PCT<2ng/ml, – infection) had empiric ABX discontinued by 72 hours. 12/14 patients: ABX discontinued

False positive/negative PCT Only one case with PCT<1ng/ml and +infection; mediastinitis (contained sternal abscess) PCT values have been reported to be low in case of contained infection and abscess, and it could be the limitation of the PCT assay. Aouifi A, Piriou V, Bastien O, Blanc P, Bouvier H, Evans R, Célard M, Vandenesch F, Rousson R, Lehot JJ. Usefulness of Procalcitonin for diagnosis of infection in cardiac surgical patients. Crit Care Med 2000;28:3171-6. 3 cases of false positives (PCT≥2ng/ml and –infection); no positive culture was obtained Trending of PCT level was effective in following up severity of infection.

Conclusion PCT assays incorporated in the algorithm was able to predict infection with excellent sensitivity and specificity. PCT value of 1 to 2ng/ml would be the best cut-off to diagnose infection. can vary depending on timing and other condition This PCT based algorithm potentially reduces hospital cost and length of stay.