BRIEF REPORT
Peritoneal lactate as a potential biomarker for predicting the need for reintervention after abdominal surgery Roberto Bini, MD, Giovanni Ferrari, MD, Franco Apra`, MD, Tiziana Viora, MD, Renzo Leli, MD, and Paolo Cotogni, MD, Torino, Italy
Early diagnosis of complications after abdominal surgery is crucial to improve outcomes. This study aimed to evaluate the use of the peritonealYserum lactate ratio and of peritoneal lactate levels applied alone for predicting the need for reintervention after abdominal surgery. METHODS: This prospective observational study included 88 patients who underwent abdominal surgery (48 emergency and 40 elective operations) and presented with fever, leukocytosis, late passage of flatus, and abdominal pain by the fourth postoperative day. The lactate levels were measured in the serum and peritoneal fluid. In total, 31 of 88 patients required reintervention. The receiver operator characteristic analysis was used to determine the best threshold value for the peritoneal-serum lactate ratio and for peritoneal lactate levels applied alone to identify patients who required reintervention. RESULTS: A peritoneal-serum lactate ratio greater than 4.5 (area under the curve, 0.865; 95% confidence interval, 0.773Y0.957; p G 0.001) and a peritoneal lactate value greater than 9.1 mmol/L (area under the curve, 0.834; 95% confidence interval, 0.735Y0.934; p G 0.0001) discriminated between patients who required reintervention with a sensitivity of 91.3%, a specificity of 81%, and a negative predictive value of 94.4% and a sensitivity of 81.9%, a specificity of 82%, and a positive predictive value of 89%, respectively. CONCLUSION: The results of our study support the hypothesis that the peritoneal-serum lactate ratio and the peritoneal lactate level applied alone could be safe, simple, inexpensive, noninvasive, and potentially valuable tools for the early identification of patients who require reintervention after elective or emergency abdominal surgery. (J Trauma Acute Care Surg. 2014;77: 376Y380. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Diagnostic study, level III. Prognostic study, level III. KEY WORDS: Relaparotomy; lactate; surgical complications. BACKGROUND:
B
oth elective and emergency surgery may give rise to intraabdominal fluid collection, anastomotic leakage, infarction, and other postoperative complications.1 Intra-abdominal sepsis caused by surgical complications is associated with a high mortality rate (950%) and high morbidity because of organ dysfunction.2,3 Early diagnosis of complications and subsequent emergency relaparotomy are necessary to treat intra-abdominal sepsis and hypoperfusion and are crucial to improve outcomes.4 Physical examination and laboratory data are often nonspecific, although great efforts have been made to identify reliable biomarkers for complications after major abdominal surgery.5Y7 Many surgical patients develop postoperative stress responses that include fever and leukocytosis. However, only one fourth of patients with fever develop complications, which Submitted: December 10, 2013, Revised: March 7, 2014, Accepted: March 10, 2014. From the Department of Surgery (R.B., T.V., R.L.), and High Dependency Unit (G.F., F.A.), Ospedale S. Giovanni Bosco; and Anesthesiology and Intensive Care (P.C.), Department of Medicine, S. Giovanni Battista Hospital, University of Turin, Torino, Italy. This study was presented as abstract at the XIII European Congress of Trauma and Emergency Surgery, 2012, in Basel, Switzerland. The authors certify that they have no affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript (e.g., employment, consultancies, stock ownership, and honoraria). Address for reprints: Roberto Bini, MD, Department of Surgery, Ospedale S. Giovanni Bosco, 10154, Torino, Italy; email: [email protected]. DOI: 10.1097/TA.0000000000000302
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are not necessarily related to the operation; furthermore, leukocytosis and anastomotic leaks are not closely correlated.5 Computed tomography (CT) is the preferred technique to examine patients who fail to progress after abdominal surgery.8 However, CT can identify only 47% of anastomotic leaks, and caution should be used when interpreting radiologic imaging of anastomoses because of a high false-negative rate.9 Even with multidetector CT, the capability to predict whether an intraabdominal fluid collection is infected based on imaging characteristics alone is limited; in fact, for determining the presence of infection, the average sensitivity and specificity were reported as 83.4% and 39.3%, respectively.10 Peritoneal inflammation can result in excess lactate production, which can be measured in peritoneal fluids.11,12 To the best of our knowledge, no studies have yet examined the correlation between peritoneal lactate levels and the detection of surgical complications. Our study aimed to assess the efficacy of the peritoneal-serum lactate ratio and of peritoneal lactate levels applied alone as biomarkers for predicting the need for reintervention after abdominal surgery.
PATIENTS AND METHODS This study was registered prospectively (ClinicalTrials.gov identifier: NCT01161849) and approved by the ethics committee of our hospital. Written informed consent was obtained from each patient. The study was conducted in accordance with the Declaration of Helsinki. J Trauma Acute Care Surg Volume 77, Number 2
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J Trauma Acute Care Surg Volume 77, Number 2
Bini et al.
TABLE 1. Characteristics of Study Population Emergency Surgery
Elective Surgery
No Reintervention
Reintervention
25 16/9 61.2 (24.2)
23 15/8 87.8 (10.4)*
No. patients Male/female POSSUM score, mean (SD) First intervention for Colorectal disease Gastric disease Pancreatic disease Biliary disease Bowel perforation Mesenteric ischemia Bowel obstruction Intra-abdominal sepsis Cholecystitis Gastrointestinal hemorrhage Complications Anastomotic leak Intra-abdominal abscess Biliary leak Hemorrhage Mesenteric ischemia
V V V V 12 (51%) 3 (11%) 7 (27%) 0 3 (11%) 0
No Reintervention
Total
8 4/4 67.4 (11.2)*
88 54/34
32 19/13 44.1 (17)
V V V V 7 (26%) 5 (21%) 5 (21%) 2 (10%) 1 (5%) 3 (16%)
V V V V V
Reintervention
19 7 2 4
(60%) (20%) (8%) (12%) V V V V V V
4 (50%) 0 2 (25%) 2 (25%) V V V V V V
V V V V V
9 6 1 2 5
2 4 2 V V
*p G 0.05.
Demographic data, underlying diseases, and surgical diagnoses were recorded on admission. The Physiologic and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM)13 score was recorded after surgery. Patients considered for inclusion were adults (aged between 18 years and 85 years) who had an abdominal drain placed by the operating surgeon and presented with all of the following symptoms by the fourth day following elective or emergency abdominal surgery: fever (i.e., 938.3-C), increased white blood cell count (i.e., 912,000/KL), late passage of flatus (i.e., 972 hours after surgery), and abdominal pain (Visual Analogue Scale score 9 3). The decision to place an abdominal drain was based on the personal experience of the senior surgeon in the operating room. The exclusion criteria were liver surgery, hepatic dysfunction (bilirubin Q 2 mg/dL), the presence of bile or blood in the abdominal drainage (which prevented sample collection), hemodynamic instability (i.e., systolic blood pressure G 90 mm Hg, mean arterial pressure G 70 mm Hg, or systolic blood pressure decrease 9 40 mm Hg), sepsis arising from an extra-abdominal infection site, and pregnancy. The postoperative complications were anastomotic and biliary leaks, intra-abdominal abscess, hemorrhage, and mesenteric ischemia. According to the definition of Dindo and Clavien,14 a ‘‘complication is considered any deviation from the ideal postoperative course that is not inherent in the procedure and does not comprise a failure to cure.’’ Reintervention was defined as the requirement for a surgical, endoscopic, or radiologic intervention. Blood and peritoneal samples were obtained once from patients when all of the abovementioned inclusion criteria appeared by the fourth day after the original operation.
Venous blood lactate and peritoneal lactateVcollected from the abdomen using an abdominal drain placed in the Douglas spaceVwere analyzed immediately after collection using an ABL700 blood gas analyzer (Radiometer, Copenhagen, Denmark). All of the patients included in the study underwent contrast-enhanced CT of the abdomen and subsequent evaluation by at least two senior surgeons before inclusion in the study population. The primary end point of this prospective observational study was the determination of peritoneal-serum lactate ratio cutoff values that could identify patients with surgical complications who required further intervention. The secondary end point was the correlation between peritoneal lactate levels applied alone and the presence of surgical complications. The data were analyzed using Epi Info statistical software (Centers for TABLE 2. Type of Interventions in Patients Required Reintervention Complications
n
Anastomotic leak Localized intra-abdominal abscess* Multiple intra-abdominal abscesses** Biliary leak
11 6 4 3
(12%) (7%) (5%) (3%)
Hemorrhage Mesenteric ischemia Total
2 (2%) 5 (6%) 31 (35%)
Interventions Relaparotomy Percutaneous drainage Relaparotomy 2 biliary stenting 1 percutaneous drainage Angioembolization Relaparotomy
*When there were no signs of generalized peritonitis. **With or without signs of generalized peritonitis.
* 2014 Lippincott Williams & Wilkins
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patients who required reintervention underwent surgical or nonsurgical intervention between the fourth and sixth postoperative days. Five of the 88 patients died of irreversible shock; all of the deaths occurred in patients who had previously undergone emergency surgery. The diagnostic performance of the peritoneal-serum lactate ratio was assessed using an ROC curve (Fig. 1). We observed that a ratio greater than 4.5 (area under the curve [AUC], 0.865; 95% confidence interval [CI], 0.773Y0.957; p G 0.001) discriminated between patients who required reintervention and those who did not, with a sensitivity of 91.3%, a specificity of 81%, a positive predictive value of 72.4%, a negative predictive value of 94.4%, and a positive likelihood ratio of 4.79 (Table 3). The peritoneal lactate levels applied alone were significantly higher in the reintervention group (p G 0.0001). The diagnostic performance of peritoneal lactate levels was assessed using an ROC curve (Fig. 2). We observed that a value greater than 9.1 mmol/L (AUC, 0.834; 95% CI, 0.735Y0.934) discriminated between patients who required reintervention and those who did not, with a sensitivity of 81.9%, a specificity of 82%, a positive predictive value of 89%, a negative predictive value of 71.4%, and a positive likelihood ratio of 4.8 (Table 3). Figure 1. Peritoneal-serum lactate ratio: ROC curve.
DISCUSSION Disease Control and Prevention, Atlanta, GA) and R version 2.14.1 (R Development Core Team, http://www.R-project.org). The results for the reintervention and no-intervention groups were evaluated using a two-tailed W2 test, an unpaired Student’s t test, or Fisher’s exact test, where appropriate. Comparisons of median values were performed using the Mann-Whitney U-test. The receiver operating characteristic (ROC) analysis was used to determine the best threshold value for the peritoneal-serum lactate ratio and for peritoneal lactate levels applied alone to differentiate between patients with and without surgical complications.
RESULTS This study was conducted from June to December 2012. In total, 88 patients were enrolled, with 40 patients undergoing elective surgery and 48 undergoing emergency laparotomy. The two groups were homogeneous with respect to age, American Society of Anesthesiologists score, sex, and type of surgery, but a significant difference was observed in the POSSUM score (p G 0.05) (Table 1). In total, 31 (35%) of 88 patients required reintervention because of various surgical complications, whereas the remaining 57 patients did not require additional therapy (Table 2). The
The aim of this study was to assess the efficacy of peritoneal lactate in predicting the need for reintervention after abdominal surgery. The main finding was that a peritoneal-serum lactate ratio greater than 4.5 and, when applied alone, a peritoneal lactate level greater than 9.1 mmol/L were both associated with the risk for reintervention. Diagnosing postoperative complications is challenging for surgeons, but the use of prophylactic abdominal drainage remains controversial among surgeons.15 Reintervention must be performed early after the diagnosis of surgical complications and before the onset of multiple-organ dysfunctions. Anastomotic leak is the most feared and serious complication after abdominal surgery because it is associated with increased morbidity and mortality, increased length of hospital stay, and higher costs;5 its incidence ranges from 2.9% to 15.3%, but at least one third of all mortalities after colorectal surgery are attributed to leaks, whereas hemorrhage and mesenteric ischemia are rare complications.16 In our study, no complication was predominant, with the same rates observed for anastomotic leak and intra-abdominal abscess. CT can diagnose mesenteric ischemia, fluid collection, abscess, and free air; however, the technique has low sensitivity/ specificity for detecting anastomotic leaks.8 Doeksen et al.17
TABLE 3. Prognostic Value of Peritoneal-Serum Lactate Ratio and Peritoneal Lactate Predictive Value for Reintervention Using ROC Analysis Variables Peritoneal-serum lactate ratio Peritoneal lactate, mmol/L
Cutoff Value
AUC (95% CI)
Sensitivity, %
Specificity, %
PPV, %
NPV, %
4.5 9.1
0.865 (0.773Y0.957) 0.834 (0.735Y0.934)
91.3 81.9
81 82
72.4 89
94.4 71.4
NPV, negative predictive value; PPV, positive predictive value.
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sepsis. DeLaurier et al.12 reported that the calculated difference between simultaneous peritoneal and serum lactate values is a helpful diagnostic index for patients in whom the diagnosis of acute abdomen is not otherwise obvious. Verdant et al.19 suggested that a persistently high lactate-pyruvate ratio assessed by intraperitoneal microdialysis should alert the clinician to the possibility of serious postoperative complications. Cini et al.20 recently described the measurement of several peritoneal drainage biomarkers for the early diagnosis of anastomotic leakage as promising, although the method is not yet sufficiently developed for clinical use. Decisions regarding whether and when to perform a reintervention in patients with postoperative complications are largely subjective and based on professional experience. As mentioned earlier, when used together, CT, scoring systems, and biomarkers may aid in this decision.
Limitations of the Study
Figure 2. Peritoneal lactate levels: ROC curve.
reported that negative diagnostic imaging results may contribute to delays in diagnosis and relaparotomies for anastomotic leakage; such delays were more than 2 days for two thirds of the patients. Paugam-Burtz et al.3 reported that a lack of daily improvement in an organ system failure score, such as the Goris or Sequential Organ Failure Assessment (SOFA) scale, may suggest persistent sepsis and support the need for new surgical exploration. We used the POSSUM score as the predictive score because it has been reported to correctly estimate the probability of surgical morbidity in most cases.13Y15 Indeed, in our study, the POSSUM score correctly identified the patients at greatest risk for reintervention. Biomarkers are promising tools for diagnosing surgical complications.6 Jansson et al.18 described the intraperitoneal cytokine response after major surgery and suggested that decreasing intraperitoneal cytokine levels are characteristic of a normal postoperative course. In patients undergoing emergency surgery, there is an additive effect of cytokine secretion from the underlying disease and the surgical procedure. Differences among patients may depend on variations in the magnitude of the surgical trauma. For example, the inflammatory response after rectal resection tends to be greater than that after a miscellaneous surgery.18 The balance between tumor necrosis factor > and interleukin 10 seems to predict the occurrence of postoperative complications.6 Under hypoxic conditions, cells produce serum lactate when energy metabolism becomes dependent on anaerobic glycolysis.19 Peritoneal changes that lead to an increased peritoneal lactate level may result from decreased mesenteric blood flow, as in cases of ischemia or bowel strangulation, or direct chemical aggression, as in cases of fecal, urinary, or biliary leakage.19 Reynaert et al.11 suggested that measuring serum and peritoneal lactate gradients may be useful to identify intra-abdominal
This study has several limitations. First, it was a singlecenter study. Moreover, the study was designed to be continuously performed over 6 months with an observational design, and no calculations were made regarding the number of subjects required. Second, a small number of patients were enrolled in the study. Third, the patients were not consecutively enrolled because the insertion of an abdominal drain was based exclusively on the clinical judgment of the surgical team. Finally, this techniqueVif used aloneVis nonspecific in identifying the type of complication (e.g., anastomotic leaks, mesenteric ischemia) because it simply identifies peritoneal irritation that requires reintervention. A multicenter randomized trial in a larger surgical population should be performed to determine the usefulness of peritoneal lactate as a biomarker for predicting the need for reintervention after abdominal surgery. The early diagnosis of postoperative complications and, consequently, the appropriate timing of reoperation are important issues to aid in reducing mortality in abdominal surgery. Our hypothesis was that measuring lactate from blood and peritoneal fluid will improve the diagnosis of postoperative complications. In conclusion, this study is the first report on the predictive value of the peritoneal-serum lactate ratio and that of the peritoneal lactate level applied alone for surgical complications requiring endoscopic or radiologic intervention or relaparotomy. Although this study has several limitations, our findings support the hypothesis that these biomarkers could be safe, simple, inexpensive, noninvasive, and potentially valuable tools for the early identification of patients who require an interventional procedure after elective or emergency abdominal surgery. AUTHORSHIP R.B., G.F., and P.C. drafted the manuscript and performed the analysis and interpretation of data. R.B., G.F., R.L., F.A., and T.V. acquired the data. R.B. and G.F. performed the statistical analysis. All authors contributed to the study concept and design and participated in the critical revision of the article.
DISCLOSURE The authors declare no conflicts of interest.
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REFERENCES 1. Healey MA, Shackford SR, Osler TM, Rogers FB, Burns E. Complications in surgical patients. Arch Surg. 2002;137:611Y618. 2. Hutchins RR, Gunning MP, Lucas DN, Allen-Mersh TG, Soni NC. Relaparotomy for suspected intraperitoneal sepsis after abdominal surgery. World J Surg. 2004;28:137Y141. 3. Paugam-Burtz C, Dupont H, Marmuse JP, Chosidow D, Malek L, Desmonts JM, Mantz J. Daily organ-system failure for diagnosis of persistent intra-abdominal sepsis after postoperative peritonitis. Intensive Care Med. 2002;28:594Y598. 4. Marshall JC, Maier RV, Jimenez M, Dellinger EP. Source control in the management of severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32(Suppl):513Y526. 5. Almeida AB, Faria G, Moreira H, Pinto-de-Sousa J, Correia-da-Silva P, Costa Maia J. Elevated serum C-reactive protein as a predictive factor for anastomotic leakage in colorectal surgery. Int J Surg. 2012;10:87Y91. 6. Dimopoulou I, Armaganidis A, Douka E, Mavrou I, Augustatou C, Kopterides P, Lyberopoulos P, Tzanela M, Orfanos SE, Pelekanou E, et al. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 are crucial mediators in post-operative systemic inflammatory response and determine the occurrence of complications after major abdominal surgery. Cytokine. 2007;37:55Y61. 7. Komen N, de Bruin RW, Kleinrensink GJ, Jeekel J, Lange JF. Anastomotic leakage, the search for a reliable biomarker. A review of the literature. Colorectal Dis. 2008;10:109Y105. 8. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein E, Baron EJ, O’Neill PJ, Chow AW, Dellinger EP, Eachempati SR, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133Y164. 9. Khoury W, Ben-Yehuda A, Ben-Haim M, Klausner JM, Szold O. Abdominal computed tomography for diagnosing postoperative lower gastrointestinal tract leaks. J Gastrointest Surg. 2009;13:1454Y1458.
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10. Allen BC, Barnhart H, Bashir M, Nieman C, Breault S, Jaffe TA. Diagnostic accuracy of intra-abdominal fluid collection characterization in the era of multidetector computed tomography. Am Surg. 2012;78:185Y189. 11. Reynaert MS, Bshouty ZH, Bertrand C, Cambier-Kremer C, Calteux N, Carlier M, Col J, Tre´mouroux J. Early diagnosis of peritoneal infection by simultaneous measurement of lactate concentration in peritoneal fluid and blood. Intensive Care Med. 1984;10:301Y304. 12. DeLaurier GA, Ivey RK, Johnson RH. Peritoneal fluid lactic acid and diagnostic dilemmas in acute abdominal disease. Am J Surg. 1994;167:302Y305. 13. Whiteley MS, Prytherch DR, Higgins B, Weaver PC, Prout WG. An evaluation of the POSSUM surgical scoring system. Brit J Surg. 1996;83: 812Y815. 14. Dindo D, Clavien PA. What is a surgical complication? World J Surg. 2008; 32:939Y941. 15. Petrowsky H, Demartines N, Rousson V, Clavien PA. Evidence-based value of prophylactic drainage in gastrointestinal surgery. a systematic review and meta-analyses. Ann Surg. 2004;240:1074Y1085. 16. Kirchhoff P, Clavien PA, Hahnloser D. Complications in colorectal surgery: risk factors and preventive strategies. Patient Saf Surg. 2010;4:5. 17. Doeksen A, Tanis PJ, Vrouenraets BC, Lanschot van JJ, Tets van WF. Factors determining delay in relaparotomy for anastomotic leakage after colorectal resection. World J Gastroenterol. 2007;13:3721Y3725. 18. Jansson K, Redler B, Truedsson L, Magnuson A, Matthiessen P, Andersson M, Norgren L. Intraperitoneal cytokine response after major surgery: higher postoperative intraperitoneal versus systemic cytokine levels suggest the gastrointestinal tract as the major source of the postoperative inflammatory reaction. Am J Surg. 2004;187:372Y377. 19. Verdant CL, Chierego M, De Moor V, Chamlou R, Creteur J, de Dieu Mutijima J, Loi P, Gelin M, Gullo A, Vincent JL, et al. Prediction of postoperative complications after urgent laparotomy by intraperitoneal microdialysis: a pilot study. Ann Surg. 2006;244:994Y1002. 20. Cini C, Wolthuis A, D’Hoore A. Peritoneal fluid cytokines and matrix metalloproteinases as early markers of anastomotic leakage in colorectal anastomosis: a literature review and meta-analysis. Colorectal Dis. 2013; 15:1070Y1077.
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Peritoneal lactate as a potential biomarker for predicting the need for reintervention after abdominal surgery Roberto Bini, MD, Giovanni Ferrari, MD, Franco Apra`, MD, Tiziana Viora, MD, Renzo Leli, MD, and Paolo Cotogni, MD, Torino, Italy
Early diagnosis of complications after abdominal surgery is crucial to improve outcomes. This study aimed to evaluate the use of the peritonealYserum lactate ratio and of peritoneal lactate levels applied alone for predicting the need for reintervention after abdominal surgery. METHODS: This prospective observational study included 88 patients who underwent abdominal surgery (48 emergency and 40 elective operations) and presented with fever, leukocytosis, late passage of flatus, and abdominal pain by the fourth postoperative day. The lactate levels were measured in the serum and peritoneal fluid. In total, 31 of 88 patients required reintervention. The receiver operator characteristic analysis was used to determine the best threshold value for the peritoneal-serum lactate ratio and for peritoneal lactate levels applied alone to identify patients who required reintervention. RESULTS: A peritoneal-serum lactate ratio greater than 4.5 (area under the curve, 0.865; 95% confidence interval, 0.773Y0.957; p G 0.001) and a peritoneal lactate value greater than 9.1 mmol/L (area under the curve, 0.834; 95% confidence interval, 0.735Y0.934; p G 0.0001) discriminated between patients who required reintervention with a sensitivity of 91.3%, a specificity of 81%, and a negative predictive value of 94.4% and a sensitivity of 81.9%, a specificity of 82%, and a positive predictive value of 89%, respectively. CONCLUSION: The results of our study support the hypothesis that the peritoneal-serum lactate ratio and the peritoneal lactate level applied alone could be safe, simple, inexpensive, noninvasive, and potentially valuable tools for the early identification of patients who require reintervention after elective or emergency abdominal surgery. (J Trauma Acute Care Surg. 2014;77: 376Y380. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Diagnostic study, level III. Prognostic study, level III. KEY WORDS: Relaparotomy; lactate; surgical complications. BACKGROUND:
B
oth elective and emergency surgery may give rise to intraabdominal fluid collection, anastomotic leakage, infarction, and other postoperative complications.1 Intra-abdominal sepsis caused by surgical complications is associated with a high mortality rate (950%) and high morbidity because of organ dysfunction.2,3 Early diagnosis of complications and subsequent emergency relaparotomy are necessary to treat intra-abdominal sepsis and hypoperfusion and are crucial to improve outcomes.4 Physical examination and laboratory data are often nonspecific, although great efforts have been made to identify reliable biomarkers for complications after major abdominal surgery.5Y7 Many surgical patients develop postoperative stress responses that include fever and leukocytosis. However, only one fourth of patients with fever develop complications, which Submitted: December 10, 2013, Revised: March 7, 2014, Accepted: March 10, 2014. From the Department of Surgery (R.B., T.V., R.L.), and High Dependency Unit (G.F., F.A.), Ospedale S. Giovanni Bosco; and Anesthesiology and Intensive Care (P.C.), Department of Medicine, S. Giovanni Battista Hospital, University of Turin, Torino, Italy. This study was presented as abstract at the XIII European Congress of Trauma and Emergency Surgery, 2012, in Basel, Switzerland. The authors certify that they have no affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript (e.g., employment, consultancies, stock ownership, and honoraria). Address for reprints: Roberto Bini, MD, Department of Surgery, Ospedale S. Giovanni Bosco, 10154, Torino, Italy; email: [email protected]. DOI: 10.1097/TA.0000000000000302
376
are not necessarily related to the operation; furthermore, leukocytosis and anastomotic leaks are not closely correlated.5 Computed tomography (CT) is the preferred technique to examine patients who fail to progress after abdominal surgery.8 However, CT can identify only 47% of anastomotic leaks, and caution should be used when interpreting radiologic imaging of anastomoses because of a high false-negative rate.9 Even with multidetector CT, the capability to predict whether an intraabdominal fluid collection is infected based on imaging characteristics alone is limited; in fact, for determining the presence of infection, the average sensitivity and specificity were reported as 83.4% and 39.3%, respectively.10 Peritoneal inflammation can result in excess lactate production, which can be measured in peritoneal fluids.11,12 To the best of our knowledge, no studies have yet examined the correlation between peritoneal lactate levels and the detection of surgical complications. Our study aimed to assess the efficacy of the peritoneal-serum lactate ratio and of peritoneal lactate levels applied alone as biomarkers for predicting the need for reintervention after abdominal surgery.
PATIENTS AND METHODS This study was registered prospectively (ClinicalTrials.gov identifier: NCT01161849) and approved by the ethics committee of our hospital. Written informed consent was obtained from each patient. The study was conducted in accordance with the Declaration of Helsinki. J Trauma Acute Care Surg Volume 77, Number 2
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Trauma Acute Care Surg Volume 77, Number 2
Bini et al.
TABLE 1. Characteristics of Study Population Emergency Surgery
Elective Surgery
No Reintervention
Reintervention
25 16/9 61.2 (24.2)
23 15/8 87.8 (10.4)*
No. patients Male/female POSSUM score, mean (SD) First intervention for Colorectal disease Gastric disease Pancreatic disease Biliary disease Bowel perforation Mesenteric ischemia Bowel obstruction Intra-abdominal sepsis Cholecystitis Gastrointestinal hemorrhage Complications Anastomotic leak Intra-abdominal abscess Biliary leak Hemorrhage Mesenteric ischemia
V V V V 12 (51%) 3 (11%) 7 (27%) 0 3 (11%) 0
No Reintervention
Total
8 4/4 67.4 (11.2)*
88 54/34
32 19/13 44.1 (17)
V V V V 7 (26%) 5 (21%) 5 (21%) 2 (10%) 1 (5%) 3 (16%)
V V V V V
Reintervention
19 7 2 4
(60%) (20%) (8%) (12%) V V V V V V
4 (50%) 0 2 (25%) 2 (25%) V V V V V V
V V V V V
9 6 1 2 5
2 4 2 V V
*p G 0.05.
Demographic data, underlying diseases, and surgical diagnoses were recorded on admission. The Physiologic and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM)13 score was recorded after surgery. Patients considered for inclusion were adults (aged between 18 years and 85 years) who had an abdominal drain placed by the operating surgeon and presented with all of the following symptoms by the fourth day following elective or emergency abdominal surgery: fever (i.e., 938.3-C), increased white blood cell count (i.e., 912,000/KL), late passage of flatus (i.e., 972 hours after surgery), and abdominal pain (Visual Analogue Scale score 9 3). The decision to place an abdominal drain was based on the personal experience of the senior surgeon in the operating room. The exclusion criteria were liver surgery, hepatic dysfunction (bilirubin Q 2 mg/dL), the presence of bile or blood in the abdominal drainage (which prevented sample collection), hemodynamic instability (i.e., systolic blood pressure G 90 mm Hg, mean arterial pressure G 70 mm Hg, or systolic blood pressure decrease 9 40 mm Hg), sepsis arising from an extra-abdominal infection site, and pregnancy. The postoperative complications were anastomotic and biliary leaks, intra-abdominal abscess, hemorrhage, and mesenteric ischemia. According to the definition of Dindo and Clavien,14 a ‘‘complication is considered any deviation from the ideal postoperative course that is not inherent in the procedure and does not comprise a failure to cure.’’ Reintervention was defined as the requirement for a surgical, endoscopic, or radiologic intervention. Blood and peritoneal samples were obtained once from patients when all of the abovementioned inclusion criteria appeared by the fourth day after the original operation.
Venous blood lactate and peritoneal lactateVcollected from the abdomen using an abdominal drain placed in the Douglas spaceVwere analyzed immediately after collection using an ABL700 blood gas analyzer (Radiometer, Copenhagen, Denmark). All of the patients included in the study underwent contrast-enhanced CT of the abdomen and subsequent evaluation by at least two senior surgeons before inclusion in the study population. The primary end point of this prospective observational study was the determination of peritoneal-serum lactate ratio cutoff values that could identify patients with surgical complications who required further intervention. The secondary end point was the correlation between peritoneal lactate levels applied alone and the presence of surgical complications. The data were analyzed using Epi Info statistical software (Centers for TABLE 2. Type of Interventions in Patients Required Reintervention Complications
n
Anastomotic leak Localized intra-abdominal abscess* Multiple intra-abdominal abscesses** Biliary leak
11 6 4 3
(12%) (7%) (5%) (3%)
Hemorrhage Mesenteric ischemia Total
2 (2%) 5 (6%) 31 (35%)
Interventions Relaparotomy Percutaneous drainage Relaparotomy 2 biliary stenting 1 percutaneous drainage Angioembolization Relaparotomy
*When there were no signs of generalized peritonitis. **With or without signs of generalized peritonitis.
* 2014 Lippincott Williams & Wilkins
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patients who required reintervention underwent surgical or nonsurgical intervention between the fourth and sixth postoperative days. Five of the 88 patients died of irreversible shock; all of the deaths occurred in patients who had previously undergone emergency surgery. The diagnostic performance of the peritoneal-serum lactate ratio was assessed using an ROC curve (Fig. 1). We observed that a ratio greater than 4.5 (area under the curve [AUC], 0.865; 95% confidence interval [CI], 0.773Y0.957; p G 0.001) discriminated between patients who required reintervention and those who did not, with a sensitivity of 91.3%, a specificity of 81%, a positive predictive value of 72.4%, a negative predictive value of 94.4%, and a positive likelihood ratio of 4.79 (Table 3). The peritoneal lactate levels applied alone were significantly higher in the reintervention group (p G 0.0001). The diagnostic performance of peritoneal lactate levels was assessed using an ROC curve (Fig. 2). We observed that a value greater than 9.1 mmol/L (AUC, 0.834; 95% CI, 0.735Y0.934) discriminated between patients who required reintervention and those who did not, with a sensitivity of 81.9%, a specificity of 82%, a positive predictive value of 89%, a negative predictive value of 71.4%, and a positive likelihood ratio of 4.8 (Table 3). Figure 1. Peritoneal-serum lactate ratio: ROC curve.
DISCUSSION Disease Control and Prevention, Atlanta, GA) and R version 2.14.1 (R Development Core Team, http://www.R-project.org). The results for the reintervention and no-intervention groups were evaluated using a two-tailed W2 test, an unpaired Student’s t test, or Fisher’s exact test, where appropriate. Comparisons of median values were performed using the Mann-Whitney U-test. The receiver operating characteristic (ROC) analysis was used to determine the best threshold value for the peritoneal-serum lactate ratio and for peritoneal lactate levels applied alone to differentiate between patients with and without surgical complications.
RESULTS This study was conducted from June to December 2012. In total, 88 patients were enrolled, with 40 patients undergoing elective surgery and 48 undergoing emergency laparotomy. The two groups were homogeneous with respect to age, American Society of Anesthesiologists score, sex, and type of surgery, but a significant difference was observed in the POSSUM score (p G 0.05) (Table 1). In total, 31 (35%) of 88 patients required reintervention because of various surgical complications, whereas the remaining 57 patients did not require additional therapy (Table 2). The
The aim of this study was to assess the efficacy of peritoneal lactate in predicting the need for reintervention after abdominal surgery. The main finding was that a peritoneal-serum lactate ratio greater than 4.5 and, when applied alone, a peritoneal lactate level greater than 9.1 mmol/L were both associated with the risk for reintervention. Diagnosing postoperative complications is challenging for surgeons, but the use of prophylactic abdominal drainage remains controversial among surgeons.15 Reintervention must be performed early after the diagnosis of surgical complications and before the onset of multiple-organ dysfunctions. Anastomotic leak is the most feared and serious complication after abdominal surgery because it is associated with increased morbidity and mortality, increased length of hospital stay, and higher costs;5 its incidence ranges from 2.9% to 15.3%, but at least one third of all mortalities after colorectal surgery are attributed to leaks, whereas hemorrhage and mesenteric ischemia are rare complications.16 In our study, no complication was predominant, with the same rates observed for anastomotic leak and intra-abdominal abscess. CT can diagnose mesenteric ischemia, fluid collection, abscess, and free air; however, the technique has low sensitivity/ specificity for detecting anastomotic leaks.8 Doeksen et al.17
TABLE 3. Prognostic Value of Peritoneal-Serum Lactate Ratio and Peritoneal Lactate Predictive Value for Reintervention Using ROC Analysis Variables Peritoneal-serum lactate ratio Peritoneal lactate, mmol/L
Cutoff Value
AUC (95% CI)
Sensitivity, %
Specificity, %
PPV, %
NPV, %
4.5 9.1
0.865 (0.773Y0.957) 0.834 (0.735Y0.934)
91.3 81.9
81 82
72.4 89
94.4 71.4
NPV, negative predictive value; PPV, positive predictive value.
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sepsis. DeLaurier et al.12 reported that the calculated difference between simultaneous peritoneal and serum lactate values is a helpful diagnostic index for patients in whom the diagnosis of acute abdomen is not otherwise obvious. Verdant et al.19 suggested that a persistently high lactate-pyruvate ratio assessed by intraperitoneal microdialysis should alert the clinician to the possibility of serious postoperative complications. Cini et al.20 recently described the measurement of several peritoneal drainage biomarkers for the early diagnosis of anastomotic leakage as promising, although the method is not yet sufficiently developed for clinical use. Decisions regarding whether and when to perform a reintervention in patients with postoperative complications are largely subjective and based on professional experience. As mentioned earlier, when used together, CT, scoring systems, and biomarkers may aid in this decision.
Limitations of the Study
Figure 2. Peritoneal lactate levels: ROC curve.
reported that negative diagnostic imaging results may contribute to delays in diagnosis and relaparotomies for anastomotic leakage; such delays were more than 2 days for two thirds of the patients. Paugam-Burtz et al.3 reported that a lack of daily improvement in an organ system failure score, such as the Goris or Sequential Organ Failure Assessment (SOFA) scale, may suggest persistent sepsis and support the need for new surgical exploration. We used the POSSUM score as the predictive score because it has been reported to correctly estimate the probability of surgical morbidity in most cases.13Y15 Indeed, in our study, the POSSUM score correctly identified the patients at greatest risk for reintervention. Biomarkers are promising tools for diagnosing surgical complications.6 Jansson et al.18 described the intraperitoneal cytokine response after major surgery and suggested that decreasing intraperitoneal cytokine levels are characteristic of a normal postoperative course. In patients undergoing emergency surgery, there is an additive effect of cytokine secretion from the underlying disease and the surgical procedure. Differences among patients may depend on variations in the magnitude of the surgical trauma. For example, the inflammatory response after rectal resection tends to be greater than that after a miscellaneous surgery.18 The balance between tumor necrosis factor > and interleukin 10 seems to predict the occurrence of postoperative complications.6 Under hypoxic conditions, cells produce serum lactate when energy metabolism becomes dependent on anaerobic glycolysis.19 Peritoneal changes that lead to an increased peritoneal lactate level may result from decreased mesenteric blood flow, as in cases of ischemia or bowel strangulation, or direct chemical aggression, as in cases of fecal, urinary, or biliary leakage.19 Reynaert et al.11 suggested that measuring serum and peritoneal lactate gradients may be useful to identify intra-abdominal
This study has several limitations. First, it was a singlecenter study. Moreover, the study was designed to be continuously performed over 6 months with an observational design, and no calculations were made regarding the number of subjects required. Second, a small number of patients were enrolled in the study. Third, the patients were not consecutively enrolled because the insertion of an abdominal drain was based exclusively on the clinical judgment of the surgical team. Finally, this techniqueVif used aloneVis nonspecific in identifying the type of complication (e.g., anastomotic leaks, mesenteric ischemia) because it simply identifies peritoneal irritation that requires reintervention. A multicenter randomized trial in a larger surgical population should be performed to determine the usefulness of peritoneal lactate as a biomarker for predicting the need for reintervention after abdominal surgery. The early diagnosis of postoperative complications and, consequently, the appropriate timing of reoperation are important issues to aid in reducing mortality in abdominal surgery. Our hypothesis was that measuring lactate from blood and peritoneal fluid will improve the diagnosis of postoperative complications. In conclusion, this study is the first report on the predictive value of the peritoneal-serum lactate ratio and that of the peritoneal lactate level applied alone for surgical complications requiring endoscopic or radiologic intervention or relaparotomy. Although this study has several limitations, our findings support the hypothesis that these biomarkers could be safe, simple, inexpensive, noninvasive, and potentially valuable tools for the early identification of patients who require an interventional procedure after elective or emergency abdominal surgery. AUTHORSHIP R.B., G.F., and P.C. drafted the manuscript and performed the analysis and interpretation of data. R.B., G.F., R.L., F.A., and T.V. acquired the data. R.B. and G.F. performed the statistical analysis. All authors contributed to the study concept and design and participated in the critical revision of the article.
DISCLOSURE The authors declare no conflicts of interest.
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