Procalcitonin in the Setting of Complicated Postoperative Course after Liver Transplantation

Procalcitonin in the Setting of Complicated Postoperative Course after Liver Transplantation A. Perrakis, S. Yedibela, V. Schellerer, W. Hohenberger, and V. Müller ABSTRACT Background. Orthotopic liver transplantation (OLT) is a treatment for end-stage liver disease. The shortage of available organs leads to the acceptance of marginal grafts, thereby increasing the risk of perioperative complications such as acute rejection, infection, and graft dysfunction Procalcitonin (PCT) has been shown to be a reliable marker for a complicated course after traumamatic injury as well as in the courses of systemic inflammatory response syndrome and sepsis. The aim of our study was to evaluate PCT as an early prognostic marker for the occurrence of complication during the postoperative course after OLT. Method. We analyzed PCT levels and clinical and paraclinical data of 32 patients who underwent 33 OLTs. The highest PCT was termed as peak-PCT. Patients were stratified into noncomplication and complication groups. Renal replacement therapy, respiratory insufficiency, postoperative bleeding, refractory ascites, pleural effusion, rejection, sepsis, and fatal outcome were defined as complications. A secondary stratification, using a peak-PCT of 5 ng/mL, was used to analyzed the risk of a complication. We also analyzed the course of PCT after OLT in each group. Results. The peak-PCT, which occurred between the first and third postoperative day in 30 patients, was followed by halving of the value every second day. Three subjects died because of sepsis. A constantly rising PCT or a secondary rise observed in 2 patients was associated with a fatal outcome. The noncomplication group included 18 patients, 8 of them showing a peakPCT ⬍5 ng/mL and 10 above. The complication group included 14 patients who underwent 15 transplantations; Only 1 displayed a peakPCT ⬍5 ng/mL. When the peak-PCT was ⬎5 ng/mL, the odds ratio of a complication was 11.2 (95% Confidence interval, 10.81–11.59; P ⬍ .025). However, not before the 7th postoperative day was the course of mean PCT levels significantly different between the complication and noncomplication groups. In transplant patients, an elevation of PCT was observed only in the presence of bacterial infection and not rejection or wound infection. PCT rose during respiratory failure and sepsis, but not renal replacement therapy, ascites, pleural effusion, rejection, or bleeding. Conclusion. PCT was a reliable marker. A decline was observed in 31 cases with subject, who both had fatal outcomes showing a constantly rising level. An initial high PCT indicated a poor prognosis; some members of the noncomplication group also had levels ⬎15 ng/mL. The patients in the complication group showed a higher mean PCT, which was significant at 7 days, most probably because of the high variation among levels. Still, a peak-PCT ⬎5 ng/mL showed an odds ratio of 11.2 for patients to experience a complication. xcellent 1- and 5-year survival rates have been achieved in orthotopic liver transplantation (OLT), but the gap between patients awaiting the procedure and available grafts has widened, leading to acceptance of marginal organs with a greater risk of perioperative complications, such as graft or multiorgan dysfunction and systemic infection, that increase morbidity and mortality. A systemic

E

From the Department of Surgery, University of ErlangenNuremberg, Erlangen, Germany. Address correspondence to Aristotelis Perrakis, MD, Department of Surgery, Krankenhausstr. 12 91054 Erlangen, Germany. E-mail: [email protected]

© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/–see front matter doi:10.1016/j.transproceed.2010.08.070

Transplantation Proceedings, 42, 4187– 4190 (2010)

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infection represents the most common risk factor for an impaired postoperative course associated with death. The early initiation of an antimicrobial therapy or the preemptive therapy in high-risk patients is critical for acceptable outcomes by preventing generalized sepsis and multiorgan dysfunction. Clinical signs of an infection (fever, hypothermia, tachycardia) are absent or nonspecific in most cases. Furthermore, commonly used biochemical markers, such as C-reactive protein (CRP) or leucocyte count, can not be considered to be optimal diagnostic markers. Procalcitonin (PCT) is a well established marker indicating a complication such as inflammation or sepsis among surgical patients.1 PCT rises 24 – 48 hours before and correlates better with the severity of sepsis and infection then CRP.1–3 However, the prognostic value of procalcitonin in liver transplant recipients, undergoing immunsuppression and showing severe comorbidities remains to be determined. Initially high PCT levels do not necessarily indicate a poor prognosis as do continuous or secondarily rising levels or elevations in the later postoperative course.2,4,5 In uncomplicated liver surgery cases, PCT peaks at 24 hours after the Pringle manuever with a half-life of 24 –30 hours.6 It has been reported that the liver has a primary role as the source of PCT production during endotoxin shock.7 In cirrhotic patients with impaired hepatic synthetic functions, PCT levels were not lower, displaying the same predictive power for infection as in patients without cirrhosis.8 PCT has been shown to increase among OLT patients with infections, but it fails to predict an acute rejection episode.9 Furthermore, PCT rises in all patients undergoing OLT owing to the perioperative distress. The aim of the present study was to evaluate, PCT as an early prognostic marker within 48 hours after OLT for subsequent postoperative complications. PATIENTS AND METHODS We included all 32 adult deceased donor liver transplant recipients who underwent 33 liver grafts from January 2005 through July 2007. The donor organ was always retrieved as part of a multiorgan donation. Either University of Wisconsin or histidine-tryptophan-Ketoglutarate solution was used for preservation. Liver transplantation was performed by using the piggyback technique in all patients. We performed a simultaneous portoarterial reperfusion in 31 subjects and only portal reperfusion in 1. All patients were treated with tacrolimus, starting 12 hours after transplantation at 0.1 mg/kg twice daily, and 500 mg methylprednisolone in the anhepatic phase. Eight patients received daclizumab (2 mg/kg) in the anhepatic phase followed by a second administration (1 mg/kg) at 5 days after transplantation. Mycophenolate mofetil (500 mg twice daily) treatment of 23 patients started 12 hours after transplantation. Ten patients were also treated with a tapering regime of corticosteroids. These patients were treated in our intensive care unit in the immediate postoperative phase. They received antimicrobial prophylaxis, consisting of antibacterial, antiviral, and antimycotic agents: pipril/sulbactame, aciclovir and posaconazole. Furthermore, high-risk patients recipients of a cytomegalovirus (CMV)– positive donor received preemptive antiviral treatment with ganciclovir/valganciclovir over a 6-week course. Clinical and paraclinical data were collected daily for the first 7 days after transplantation. Blood samples were collected once or twice a day until discharge.

PERRAKIS, YEDIBELA, SCHELLERER ET AL The standard laboratory workup included hematologic and biochemical parameters. The CMV status (viral load, pp65 antigen) was examined twice a week. X-Ray examinations of the chest and ultrasounds of the graft were performed daily. The procalcitonin levels were measured by an immunoluminometric LUMItest PCT kit (Brahms; Diagnostica, Berlin, Germany), which shows a detection range from 0.2 to 800.00 ng/mL and CRP by the Turbi-Quanti method (Behring, Marburg, Germany). Patients were stratified into a noncomplication group (A) and a complication group (B). Renal replacement therapy, respiratory insufficiency, hepatic artery thrombosis, ongoing coagulopathy, bleeding events requiring multiple transfusions or relaparotomy, refractory ascites or pleural effusion needing intervention, acute rejection episodes, sepsis, and fatal outcomes were defined as complications. The highest PCT level was termed the peak-PCT. Charts were reviewed for cold and warm ischemia time, glutamate oxalacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), bilirubin, creatinine, CRP, and donor age. Using a cutoff of peak-PCT at 5 ng/mL, we secondarily stratified patients into groups A1 and A2 and groups B1 and B2 (peak-PCT ⬍5 ng/mL vs ⬎5 ng/mL).

Statistics Data are shown as mean ⫾ SD. Student paired t test was used to compare the continuous data. The ␹2 test was performed for categoric data. Significance was stated at P ⬍ .05.

RESULTS

Thirty-two adult patients with end-stage liver disease underwent OLT. The median ICU stay was 10.3 days (range, 4–118 days). One acute rejection episode was registered. One patient needed retransplantation because of primary graft nonfunction. Five patients, who underwent 6 transplantations, died within 1 month, and 27 were alive at the end of the study. The mean survival time (range) was 15.6 months (2.1–28.8 months). In 29 patients the peak-PCT occurred within 48 hours after OLT. A rapidly rising PCT was observed in 2 patients associated with subsequent fatal outcomes. Among the 10 patients with peak-PCT values ⬍5 ng/mL, 9 displayed uneventful postoperative courses. PCT values ⬎5 ng/mL were observed among 22 patients with 23 OLT, including 12 with 13 OLT who suffered ⱖ1 complications. The odds ratio (OR) for a complicated course in the presence of an initial PCT ⬎5 ng/mL was calculated to be 11.7 (95% Confidence interval, 11.3–12.1; P ⬍ .025) with risk ratio of 5.65. The risk of renal failure requiring hemofiltration was independent of a PCT ⬎5 ng/mL (Table 2; OR 8.25; P ⬍ .04; ␹2 4.31). Patients with an initial PCT ⬎5 ng/mL showed a significantly higher PCT until the 5th postoperative day when was the course uneventful and not until the seventh postoperative day for those with a complication (Fig 1). Total bilirubin was significantly higher among patients with an initial PCT ⬎5 ng/mL until day 7, compared with patients with a PCT ⬍5 ng/mL (Fig 2). GOT was significantly higher on days 2 and 3 in these groups, but peak values for GOT and total bilirubin correlated significantly on univariate analysis (R ⬎ 0.399; P ⬍ .025). CRP did not show any significant difference between the groups. Ischemia times, which were not significantly differ-

PROCALCITONIN AFTER LIVER TRANSPLANTATION

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Table 1. PCT and Bilirubin Values in the Different Groups Substance

PCT, ng/mL

Bilirubin, mg/dL

Group

A A1 A2 B A A1 A2 B

POD 1

POD 2

POD 3

POD 4

POD 5

POD 6

POD 7

10.0 ⫾ 14.1 1.4 ⫾ 0.4 16.9 ⫾ 15.9 11.5 ⫾ 11.6 4.3 ⫾ 2.2 2.8 ⫾ 1.0 5.6 ⫾ 2.2 4.7 ⫾ 2.9

13.2 ⫾ 15.9 2.1 ⫾ 0.8 21.0 ⫾ 16.9 19.9 ⫾ 19.0 3.4 ⫾ 2.4 2.1 ⫾ 0.9 4.4 ⫾ 2.7 5.2 ⫾ 4.3

11.9 ⫾ 14.2 2.2 ⫾ 1.3 17.7 ⫾ 15.3 14.4 ⫾ 14.8 3.4 ⫾ 2.2 2.6 ⫾ 1.7 4.1 ⫾ 2.3 6.0 ⫾ 4.7

7.2 ⫾ 9.3 1.5 ⫾ 0.9 11.0 ⫾ 10.4 10.7 ⫾ 13.0 3.7 ⫾ 2.7 2.6 ⫾ 2.0 4.6 ⫾ 2.9 6.4 ⫾ 4.6

4.1 ⫾ 4.8 1.1 ⫾ 0.6 5.9 ⫾ 5.3 8.0 ⫾ 10.6 4.6 ⫾ 3.6 2.7 ⫾ 2.2 6.1 ⫾ 3.8 6.9 ⫾ 4.6

2.1 ⫾ 2.2 1.0 ⫾ 0.4 3.1 ⫾ 2.6 6.7 ⫾ 7.8 4.5 ⫾ 4.0 2.5 ⫾ 2.8 6.1 ⫾ 4.1 7.4 ⫾ 4.9

1.6 ⫾ 1.4 1.1 ⫾ 0.5 2.2 ⫾ 1.8 5.9 ⫾ 6.3 5.4 ⫾ 4.9 2.7 ⫾ 3.1 7.8 ⫾ 5.0 7.7 ⫾ 5.3

POD, postoperative day.

ent, did not influence the PCT level 467 min in group A versus 485 min in group B. Within the groups, there was no significant difference in cold or warm or entire ischemia time. The correlation coefficient for the impact of ischemia time on peak-PCT was highest for warm ischemia time, namely, 0.19. GOT, GPT, glutamate dehydrogenase and total bilirubin did not differ significantly between groups (Fig 2, Table 1). However, PCT started to become significantly lower among group A on day 7 after transplantation (Fig 1). The immunosuppression regimen was not significantly different regarding the occurrence of a complication or the occurrence of a peak-PCT of 5 ng/mL. DISCUSSION

PCT, a reliable marker for systemic inflammatory response syndrome and sepsis, rises with the severity of disease. A high initial PCT correlates with complications, including infection and sepsis as well as worse outcome.1,10,11 However, the peak value of PCT, usually occurring 2nd or 3rd postoperative day, was not an independent factor for a fatal outcome according to the present series. An initially high PCT has been described to not indicate a poor prognosis when followed by an adequate decline.1,12 The 9/10 patients with an initial PCT ⬍5 ng/mL displayed uneventful postoperative courses, whereas 13/23 with a value ⬎5 ng/mL experienced complications. They showed a significantly slower decline in PCT compared with those subjects with an initial PCT

⬍5 ng/mL. Our results confirmed for transplant patients the above-mentioned studies in the surgical population. We calculated the OR for experiencing a complication when the PCT was ⬎5 ng/mL within 48 hours after OLT to be 11.7, with a relative risk of 5.65 (P ⬍ .025). A rapidly rising PCT without a decline after the 3rd postoperative day was associated with a fatal outcome correlating with a bacterial or fungal infection. In contrast to earlier studies where an elevation of PCT was seen only in infectious complications,9 we also observed a greater number of noninfectious complications (Table 2) when the PCT was ⬎5 ng/mL. The high PCT did not predict the type or severity of the complication in general practice, but among transplant patients a further elevation was seen only in bacterial infections and not in rejection episodes or wound problems. We observed a rise of PCT in respiratory failure and sepsis, but not in renal dysfunction demanding renal replacement therapy, ascites, pleural effusion, acute rejection episodes, or bleeding, as reported by other authors.13 Our observation confirms the results of an earlier study.4 A rapid decline of PCT level was seen in 31 cases. On the contrary in 2 patients with a fatal outcome we observed a constantly rising level. This observation had been described before among nontransplant patients.14 –18 An initially high PCT has been described to not indicate a poor prognosis; course of PCT 25

§

Table 2. Complications After Liver Transplantation

Any complication Renal insufficiency Pulmonary insufficiency Bleeding/coagulopathy Pleural effusion Hepatic artery thrombosis Acute rejection episode Transplant dysfunction Sepsis

Odds Ratio

␹2 (Pearson)

P Value

14 12

11.7 8.25

6.18 4.31

0.013 0.038

7

3.12

1.08

PCT ng/ml

Complication

20

No. of Patients

§

*

§

15

* 10

§

*

*

5

9 7 1

4.80 3.12 1.05

2.16 1.08 0.45

*

0.299 0.141 0.299 0.503

*

§

* &

0 1

2

3

4

5

6

7

postopertative day

1

1.05

0.45

0.503

15

1.38

0.17

0.678

6

2.50

0.65

0.421

Subgroup A1

Subgroup A2

Group B

Fig 1. Postoperative course of PCT. *Statistical significance between subgroup A1 and group B. §Statistical significance between subgroups A1 and A2. &Statistical significance between groups A and B.

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PERRAKIS, YEDIBELA, SCHELLERER ET AL Course of total bilirubin

9 8

total bilirubin mg/dl

7 6 5

*

4

*

*

§

*

*

* §

§

* §

3 2 1 0 1

2

3

4

5

6

7

postoperative day Subgroup A1

Fig 2.

Subgroup A2

Group B

Postoperative course of total bilirubin.

patients in the noncomplication group also showed levels ⬎15 ng/mL. The complication group displayed a higher mean PCT, which became significant at the 7th day, most probably because of the large variation among the levels. It is generally accepted that cold and warm ischemia as well as reperfusion produce a proinflammatory response of impaired liver function.7 Owing to tissue damage which predisposes to generalized infection and postoperative sepsis. Nevertheless, we did not observe any correlation of PCT with ischemia time or reperfusion injury. In addition, elevated PCT values did not suggest a graft rejection process. PCT must not be regarded to be the only reliable diagnostic parameter.19 Postoperative complications after liver transplantation may result from multifactorial processes, which can not be monitored by only 1 marker. However, the value of and especially the trend after the peak value of PCT seem to be important diagnostic tools to detect serious infectious complications. An early diagnosis of a systemic infection is of great importance in the postoperative management of a liver transplant patient, because of the possibility of serious outcomes, such as a fatal septic shock.20,21 Therefore, the immediate initiation of proper antimicrobial therapy is the key to prevent mortality in the early postoperative phase. Our study revealed that patients experienced great benefit from prophylactic and preemptive antibacterial, antifungal, and antiviral therapy. The correlation between PCT levels and clinical course of respiratory, renal, and circulatory functions must be evaluated to detect early signs of sepsis. REFERENCES 1. Meisner M, Tschaikowsky K, Palmaers T, Schmidt J: Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS. Crit Care 3:45, 1999 2. Castelli GP, Pognani C, Meisner M, et al: Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care 8:R234, 2004

3. Arkader R, Troster EJ, Lopes MR, et al: Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome. Arch Dis Child 91:117, 2006 4. Kornberg A, Grube T, Wagner T, et al: Differentiated therapy with prostaglandin E1 (alprostadil) after orthotopic liver transplantation: the usefulness of procalcitonin (PCT) and hepatic artery resistive index (RI) for the evaluation of early graft function and clinical course. Clin Chem Lab Med 38:1177, 2000 5. Fazakas J, Gondos T, Varga M, et al: Analysis of systemic and regional procalcitonin serum levels during liver transplantation. Transpl Int 16:465, 2003 6. Kretzschmar M, Kruger A, Schirrmeister W: Procalcitonin following elective partial liver resection— origin from the liver? Acta Anaesthesiol Scand 45:1162, 2001 7. Meisner M, Müller V, Khakpour Z, et al: Induction of procalcitonin and proinflammatory cytokines in an anhepatic baboon endotoxin shock model. Shock 19:187, 2003 8. Bota DP, van Nuffelen M, Zakariah AN, Vincent JL: Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med 146:347, 2005 9. Kuse ER, Langefeld I, Jaeger K, Kulpmann WR: Procalcitonin in fever of unknown origin after liver transplantation: a variable to differentiate acute rejection from infection. Crit Care Med 28:555, 2000 10. Siassi M, Riese J, Steffensen R, et al: Mannan-binding lectin and procalcitonin measurement for prediction of postoperative infection. Crit Care 9:R483, 2005 11. Meisner M, Tschaikowsky K, Hutzler A, et al: Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med 24:680, 1998 12. Kunz D, Pross M, Konig W, et al: Diagnostic relevance of procalcitonin, IL-6 and cellular immune status in the early phase after liver transplantation. Transplant Proc 30:2398, 1998 13. van den Broek MAJ, Damnik SWMO, Winkens B, et al: Procalcitonin as a prognostic marker for infectious complications in liver transplant recipients in an intensive care unit. Liver Transpl 16:402, 2010 14. Assicot M, Gendrel D, Carsin H, et al: High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 341:515, 1993 15. Uzzan B, Cohen R, Nicolas P, et al: Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 34:1996, 2006 16. Tang BM, Eslick GD, Craig JC, et al: Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis 7:210, 2007 17. Simon L, Gauvin F, Amre DK, et al: Serum procalcitonin and c-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 39:206, 2004 18. Seligman R, Meisner M, Lisboa TC: Decreases in procalcitonin and C-reactive protein are strong predictors of survival in ventilator-associated pneumonia. Crit Care 10:R125, 2006 19. Cooper D, Sharples L, Cornelissen J, et al: Comparison between procalcitonin, serum amyloid A, and C-reactive protein as markers of serious bacterial and fungal infections after solid organ transplantation. Transplant Proc 33:1808, 2001 20. Prieto B, Llorente E, Gonzalez-Pinto I, et al: Plasma procalcitonin measured by time-resolved amplified cryptate emission (TRACE) in liver transplant patients. A prognosis marker of early infectious and non-infectious postoperative complications. Clin Chem Lab Med 46:660, 2008 21. Saner FH, Sotiropoulos GC, Radtke A, et al: Intensive care unit management of liver transplant patients: a formidable challenge for the intensivist. Transplant Proc 40:3206, 2008