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The Journal of Heart and Lung Transplantation, Vol 33, No 11, November 2014
grateful for the assistance of Patrick Markey, Peter Macdonald, Anne Keogh, Eugene Kotlyar, Emily Granger and Phillip Spratt in the care of these patients and for allowing the study to be performed. C.S.H. has received research funding and travel support unrelated to the current project from HeartWare, Inc. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
Appendix A. Supporting Information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/ j.healun.2014.08.011.
Can procalcitonin differentiate infection from systemic inflammatory reaction in patients on extracorporeal membrane oxygenation? Daizo Tanaka, MD, Harrison T. Pitcher, MD, Nicholas C. Cavarocchi, MD, and Hitoshi Hirose, MD From the Division of Cardiothoracic Surgery, Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
It is difficult for clinicians to differentiate an infectious process from systemic inflammatory syndromes in patients on extracorporeal membranous oxygenation (ECMO) using standard laboratory tests. False information triggers the clinician to initiate unwarranted or prolonged antibiotics, procedures and/or diagnostic investigations. Furthermore, it is especially important to strictly rule out any infections when the patient is planned for heart transplant or implantation of a long-term circulatory assist device. Procalcitonin (PCT), a biomarker of systemic infection, has been reported to be more specific than conventional markers such as white blood cell (WBC) counts or C-reactive protein.1 The effectiveness of the PCT assay has been described in many studies, especially for those of lower respiratory infection and sepsis.2,3 However, its value in adult patients on ECMO is still unclear. We have developed a PCT-based algorithm to manage patients suspected of having infection and evaluated its effectiveness in patients on ECMO (Figure 1). PCT was assayed as part of a clinical work-up for suspected infection. This algorithm was utilized on all ECMO patients with clinical signs of infection (trigger events), including: fever; elevated WBC counts; infiltration on chest X-ray suggestive of infection; positive urinalysis or culture; increasing vasopressor requirement; and/or other signs of sepsis/shock. Although empirical broad-spectrum antibiotics (vancomycin
References 1. Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29(4 Suppl):S1-39. 2. Schima H, Boehm H, Huber L, et al. Automatic system for noninvasive blood pressure determination in rotary pump recipients. Artif Organs 2004;28:451-7. 3. Martina JR, Westerhof BE, de Jonge N, et al. Noninvasive arterial blood pressure waveforms in patients with continuous-flow left ventricular assist devices. ASAIO J 2014;60:154-61. 4. Lanier GM, Orlanes K, Hayashi Y, et al. Validity and reliability of a novel slow cuff-deflation system for noninvasive blood pressure monitoring in patients with continuous-flow left ventricular assist device. Circ Heart Fail 2013;6:1005-12. 5. Bennett MK, Roberts CA, Dordunoo D, Shah A, Russell SD. Ideal methodology to assess systemic blood pressure in patients with continuousflow left ventricular assist devices. J Heart Lung Transplant 2010;29:593-4.
and piperacillin/tazobactam) were started when patients were suspected of infection after all cultures were sent, initial point-of-care PCT levels were utilized to further guide management. If PCT values were Z2 ng/ml, the result was considered positive and empirical broad-spectrum antibiotics were continued while pending cultures. If no source of infection was identified but PCT was 42 ng/ml, antibiotics and further work-up were continued. If PCT was o2 ng/ml and clinical improvement was recognized, antibiotics were discontinued within 24 to 48 hours. With no clinical improvement, treatment and further work-up were continued regardless of PCT value. Follow-up PCT assays were done but only initial PCT levels were evaluated in this study. Diagnosis of infection was based on clinical diagnosis concomitant with positive culture results. Data were accumulated retrospectively for patients on ECMO from January 2012 to June 2013, as approved by the internal review board. Patients with prolonged systemic malperfusion were excluded from this study. Continuous valuables were compared with Student’s t-test and categorical variables were compared with chi-square test or Fisher’s exact test as appropriate. The receiver operating characteristic (ROC) curve was plotted between PCT value and presence of documented infection, and its area under the curve (AUC) was calculated. The sensitivity, specificity and predictive values of PCT were determined by ROC curve analysis to determine the best threshold to diagnose infection. During this study period, there were 41 patients placed on ECMO, with a total of 21 episodes of suspected infection identified in 20 patients. Table 1 presents the demographics of patients with documented infection and with suspected infection (without documented infection). Ten patients had documented infection based on clinical diagnosis and positive cultures (5 sepsis, 4 pneumonia, 1 abscess). There were no significant demographic differences between the groups with documented infection and suspected infection. Procalcitonin values (expressed as mean ⫾ standard deviation) of patients with and without documented infection were 23.4 ⫾ 31.8 ng/ml and 1.78 ⫾ 1.74 ng/ml,
Research Correspondence
1187
Figure 1 Algorithmic PCT protocol for suspected infection in patients on ECMO. PCT, procalcitonin; CBC, complete blood cell count; WBC, white blood cell.
respectively (p ¼ 0.07). WBC counts were 15.7 ⫾ 4.6 B/liter and 12.7 ⫾ 5.5 B/liter, respectively (p ¼ 0.22). When the cut-off of PCT was set to 2 ng/ml, PCT was able to predict infection with sensitivity of 90% (9 of 10) and specificity of 82% (9 of 11), with a positive predictive value of 82% (9 of 11) and negative predictive value of 90% (9 of 10). All patients in the true positive group, defined as having both Table 1
positive PCT and subsequent positive culture findings consistent with clinical diagnosis (documented infection), were treated with antibiotics appropriately. Eighty-nine percent (8 of 9) of patients in the true negative group, defined as having negative PCT levels and with infection ruled out (suspected infection), avoided unnecessary treatment (defined as continuing antibiotics for 424 to 48 hours
Demographics of Patients With Documented Infection and Suspected Infection (Without Documented Infection)
Number of cases Age (years old) Male Body mass index Type of infection Sepsis Pneumonia Soft tissue infection Procalcitonin (ng/ml) Temperature (1F) White blood cell count (B/liter)
Documented infection
Suspected infection
p-value
10 55.9 ⫾ 14.4 8 (80%) 31.8 ⫾ 6.0
11 57.5 ⫾ 13.5 7 (64%) 30.2 ⫾ 10.0
0.82 0.29 0.68
5 4 1 23.4 ⫾ 31.8 99.1 ⫾ 1.9 15.7 ⫾ 4.6
1.78 ⫾ 1.74 99.2 ⫾ 1.3 12.7 ⫾ 5.5
0.07 0.92 0.22
Data expressed as mean ⫾ standard deviation or number (%).
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The Journal of Heart and Lung Transplantation, Vol 33, No 11, November 2014
Figure 2 Receiver operating characteristic (ROC) analysis between procalcitonin (PCT) value and infection (solid line) and the ROC between white blood cell (WBC) count and infection (dotted line). The area under the curve (AUC) was 0.873 (95% confidence interval [CI] 0.610 to 0.968). The AUC of the ROC between WBC count and infection was 0.700 (95% CI 0.400 to 0.891). Cut-off values are given for PCT (1.0, 2.0 and 3.0 ng/ml).
and further advanced diagnostic tests). The area under the ROC curve of PCT (0.873; 95% confidence interval [CI] 0.610-0.968; po0.01), was significantly better than that of the non-discrimination curve (0.873; 95% confidence WBC (0.700; 95% CI 0.400-0.891, p ¼ 0.20) validating PCT as a reliable marker to diagnose infection (Figure 2). The effectiveness of the PCT assay for diagnosis of infection has been described in multiple studies.2,3 However, reports of utilization of the PCT assay in adult patients on ECMO are very limited and we identified only one relevant study. Marina et al conducted a case-control investigation and concluded that PCT was effective in patients on veno-arterial ECMO but not veno-venous ECMO.4 In our study, we identified similar PCT sensitivity but improved specificity with a similar PCT cut-off of 2 ng/ml (1.89 ng/ml in Marina’s study). The possible explanation for better specificity in our study is that we excluded PCT assays after prolonged systemic malperfusion. Although PCT is more specific than other markers, it is known that PCT can be elevated after significant systemic injuries. For these patients, a single PCT assay was not reliable for diagnosis of infection; however, the trending PCT value was beneficial because it is known to correlate with the severity of infection.5,6
In our protocol, the cut-off for PCT was initially set to 2 ng/ml because it signaled strong suspicion for sepsis.6 This cut-off value is simple and it turned out to be the best cut-off for various infections, including sepsis, pneumonia and abscess, in patients on ECMO. Utilizing our protocol, all patients with documented infection were treated with antibiotics and the majority of patients with suspected infection avoided unnecessary treatment. Furthermore, the cut-off of 2 ng/ml was able to exclude infection with a very high negative predictive value of 90%, suggesting its usefulness for ruling out infection in patients about to undergo heart transplantation or implantation of a long-term circulatory assist device. A limitation of this study includes its retrospective study design, relatively small sample size and diagnosis of infection. The diagnosis of infection was based on a clinical diagnosis concomitant with positive culture results. However, cultures may not be highly sensitive for certain infections and accuracy of a clinical diagnosis depends on a number of factors. In conclusion, PCT is an effective test for differentiating infection from inflammation in patients on ECMO utilizing PCT Z2 ng/ml as indicative for diagnosis of infection. With this protocol, use of empirical antibiotics can be minimized.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Gendrel D, Bohuon C. Procalcitonin, a marker of bacterial infection. Infection 1997;25:133-4. 2. Schuetz P, Chiappa V, Briel M, et al. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171:1322-31. 3. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. 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. 4. Pieri M, Greco T, De Bonis M, et al. Diagnosis of infection in patients undergoing extracorporeal membrane oxygenation: a case-control study. J Thorac Cardiovasc Surg 2012;143:1411-6. 5. Assicot M, Gendrel D, Carsin H, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341: 515-8. 6. Brunkhorst FM, Wegscheider K, Forycki ZF, et al. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 2000;26(suppl):S148-52.
The Journal of Heart and Lung Transplantation, Vol 33, No 11, November 2014
grateful for the assistance of Patrick Markey, Peter Macdonald, Anne Keogh, Eugene Kotlyar, Emily Granger and Phillip Spratt in the care of these patients and for allowing the study to be performed. C.S.H. has received research funding and travel support unrelated to the current project from HeartWare, Inc. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
Appendix A. Supporting Information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/ j.healun.2014.08.011.
Can procalcitonin differentiate infection from systemic inflammatory reaction in patients on extracorporeal membrane oxygenation? Daizo Tanaka, MD, Harrison T. Pitcher, MD, Nicholas C. Cavarocchi, MD, and Hitoshi Hirose, MD From the Division of Cardiothoracic Surgery, Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
It is difficult for clinicians to differentiate an infectious process from systemic inflammatory syndromes in patients on extracorporeal membranous oxygenation (ECMO) using standard laboratory tests. False information triggers the clinician to initiate unwarranted or prolonged antibiotics, procedures and/or diagnostic investigations. Furthermore, it is especially important to strictly rule out any infections when the patient is planned for heart transplant or implantation of a long-term circulatory assist device. Procalcitonin (PCT), a biomarker of systemic infection, has been reported to be more specific than conventional markers such as white blood cell (WBC) counts or C-reactive protein.1 The effectiveness of the PCT assay has been described in many studies, especially for those of lower respiratory infection and sepsis.2,3 However, its value in adult patients on ECMO is still unclear. We have developed a PCT-based algorithm to manage patients suspected of having infection and evaluated its effectiveness in patients on ECMO (Figure 1). PCT was assayed as part of a clinical work-up for suspected infection. This algorithm was utilized on all ECMO patients with clinical signs of infection (trigger events), including: fever; elevated WBC counts; infiltration on chest X-ray suggestive of infection; positive urinalysis or culture; increasing vasopressor requirement; and/or other signs of sepsis/shock. Although empirical broad-spectrum antibiotics (vancomycin
References 1. Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29(4 Suppl):S1-39. 2. Schima H, Boehm H, Huber L, et al. Automatic system for noninvasive blood pressure determination in rotary pump recipients. Artif Organs 2004;28:451-7. 3. Martina JR, Westerhof BE, de Jonge N, et al. Noninvasive arterial blood pressure waveforms in patients with continuous-flow left ventricular assist devices. ASAIO J 2014;60:154-61. 4. Lanier GM, Orlanes K, Hayashi Y, et al. Validity and reliability of a novel slow cuff-deflation system for noninvasive blood pressure monitoring in patients with continuous-flow left ventricular assist device. Circ Heart Fail 2013;6:1005-12. 5. Bennett MK, Roberts CA, Dordunoo D, Shah A, Russell SD. Ideal methodology to assess systemic blood pressure in patients with continuousflow left ventricular assist devices. J Heart Lung Transplant 2010;29:593-4.
and piperacillin/tazobactam) were started when patients were suspected of infection after all cultures were sent, initial point-of-care PCT levels were utilized to further guide management. If PCT values were Z2 ng/ml, the result was considered positive and empirical broad-spectrum antibiotics were continued while pending cultures. If no source of infection was identified but PCT was 42 ng/ml, antibiotics and further work-up were continued. If PCT was o2 ng/ml and clinical improvement was recognized, antibiotics were discontinued within 24 to 48 hours. With no clinical improvement, treatment and further work-up were continued regardless of PCT value. Follow-up PCT assays were done but only initial PCT levels were evaluated in this study. Diagnosis of infection was based on clinical diagnosis concomitant with positive culture results. Data were accumulated retrospectively for patients on ECMO from January 2012 to June 2013, as approved by the internal review board. Patients with prolonged systemic malperfusion were excluded from this study. Continuous valuables were compared with Student’s t-test and categorical variables were compared with chi-square test or Fisher’s exact test as appropriate. The receiver operating characteristic (ROC) curve was plotted between PCT value and presence of documented infection, and its area under the curve (AUC) was calculated. The sensitivity, specificity and predictive values of PCT were determined by ROC curve analysis to determine the best threshold to diagnose infection. During this study period, there were 41 patients placed on ECMO, with a total of 21 episodes of suspected infection identified in 20 patients. Table 1 presents the demographics of patients with documented infection and with suspected infection (without documented infection). Ten patients had documented infection based on clinical diagnosis and positive cultures (5 sepsis, 4 pneumonia, 1 abscess). There were no significant demographic differences between the groups with documented infection and suspected infection. Procalcitonin values (expressed as mean ⫾ standard deviation) of patients with and without documented infection were 23.4 ⫾ 31.8 ng/ml and 1.78 ⫾ 1.74 ng/ml,
Research Correspondence
1187
Figure 1 Algorithmic PCT protocol for suspected infection in patients on ECMO. PCT, procalcitonin; CBC, complete blood cell count; WBC, white blood cell.
respectively (p ¼ 0.07). WBC counts were 15.7 ⫾ 4.6 B/liter and 12.7 ⫾ 5.5 B/liter, respectively (p ¼ 0.22). When the cut-off of PCT was set to 2 ng/ml, PCT was able to predict infection with sensitivity of 90% (9 of 10) and specificity of 82% (9 of 11), with a positive predictive value of 82% (9 of 11) and negative predictive value of 90% (9 of 10). All patients in the true positive group, defined as having both Table 1
positive PCT and subsequent positive culture findings consistent with clinical diagnosis (documented infection), were treated with antibiotics appropriately. Eighty-nine percent (8 of 9) of patients in the true negative group, defined as having negative PCT levels and with infection ruled out (suspected infection), avoided unnecessary treatment (defined as continuing antibiotics for 424 to 48 hours
Demographics of Patients With Documented Infection and Suspected Infection (Without Documented Infection)
Number of cases Age (years old) Male Body mass index Type of infection Sepsis Pneumonia Soft tissue infection Procalcitonin (ng/ml) Temperature (1F) White blood cell count (B/liter)
Documented infection
Suspected infection
p-value
10 55.9 ⫾ 14.4 8 (80%) 31.8 ⫾ 6.0
11 57.5 ⫾ 13.5 7 (64%) 30.2 ⫾ 10.0
0.82 0.29 0.68
5 4 1 23.4 ⫾ 31.8 99.1 ⫾ 1.9 15.7 ⫾ 4.6
1.78 ⫾ 1.74 99.2 ⫾ 1.3 12.7 ⫾ 5.5
0.07 0.92 0.22
Data expressed as mean ⫾ standard deviation or number (%).
1188
The Journal of Heart and Lung Transplantation, Vol 33, No 11, November 2014
Figure 2 Receiver operating characteristic (ROC) analysis between procalcitonin (PCT) value and infection (solid line) and the ROC between white blood cell (WBC) count and infection (dotted line). The area under the curve (AUC) was 0.873 (95% confidence interval [CI] 0.610 to 0.968). The AUC of the ROC between WBC count and infection was 0.700 (95% CI 0.400 to 0.891). Cut-off values are given for PCT (1.0, 2.0 and 3.0 ng/ml).
and further advanced diagnostic tests). The area under the ROC curve of PCT (0.873; 95% confidence interval [CI] 0.610-0.968; po0.01), was significantly better than that of the non-discrimination curve (0.873; 95% confidence WBC (0.700; 95% CI 0.400-0.891, p ¼ 0.20) validating PCT as a reliable marker to diagnose infection (Figure 2). The effectiveness of the PCT assay for diagnosis of infection has been described in multiple studies.2,3 However, reports of utilization of the PCT assay in adult patients on ECMO are very limited and we identified only one relevant study. Marina et al conducted a case-control investigation and concluded that PCT was effective in patients on veno-arterial ECMO but not veno-venous ECMO.4 In our study, we identified similar PCT sensitivity but improved specificity with a similar PCT cut-off of 2 ng/ml (1.89 ng/ml in Marina’s study). The possible explanation for better specificity in our study is that we excluded PCT assays after prolonged systemic malperfusion. Although PCT is more specific than other markers, it is known that PCT can be elevated after significant systemic injuries. For these patients, a single PCT assay was not reliable for diagnosis of infection; however, the trending PCT value was beneficial because it is known to correlate with the severity of infection.5,6
In our protocol, the cut-off for PCT was initially set to 2 ng/ml because it signaled strong suspicion for sepsis.6 This cut-off value is simple and it turned out to be the best cut-off for various infections, including sepsis, pneumonia and abscess, in patients on ECMO. Utilizing our protocol, all patients with documented infection were treated with antibiotics and the majority of patients with suspected infection avoided unnecessary treatment. Furthermore, the cut-off of 2 ng/ml was able to exclude infection with a very high negative predictive value of 90%, suggesting its usefulness for ruling out infection in patients about to undergo heart transplantation or implantation of a long-term circulatory assist device. A limitation of this study includes its retrospective study design, relatively small sample size and diagnosis of infection. The diagnosis of infection was based on a clinical diagnosis concomitant with positive culture results. However, cultures may not be highly sensitive for certain infections and accuracy of a clinical diagnosis depends on a number of factors. In conclusion, PCT is an effective test for differentiating infection from inflammation in patients on ECMO utilizing PCT Z2 ng/ml as indicative for diagnosis of infection. With this protocol, use of empirical antibiotics can be minimized.
Disclosure statement The authors have no conflicts of interest to disclose.
References 1. Gendrel D, Bohuon C. Procalcitonin, a marker of bacterial infection. Infection 1997;25:133-4. 2. Schuetz P, Chiappa V, Briel M, et al. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171:1322-31. 3. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. 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. 4. Pieri M, Greco T, De Bonis M, et al. Diagnosis of infection in patients undergoing extracorporeal membrane oxygenation: a case-control study. J Thorac Cardiovasc Surg 2012;143:1411-6. 5. Assicot M, Gendrel D, Carsin H, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341: 515-8. 6. Brunkhorst FM, Wegscheider K, Forycki ZF, et al. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 2000;26(suppl):S148-52.
