Procalcitonin is useful whereas C-reactive protein is not, to predict complications following coronary artery bypass surgery

BACKGROUND: The respective value of procalcitonin (PCT) and C-reactive protein (CRP) as markers of postoperative complications after coronary bypass surgery is unclear. Therefore, complications during one week after surgery were studied to evaluate the predictive role of PCT and CRP changes during the immediate postoperative period. METHODS: Thirty-two patients, in whom an uneventful immediate postoperative course was anticipated, were prospectively enrolled and followed-up to the 7th postoperative day. At the end of the follow-up, patients were divided into two groups. Group A were patients with an uncomplicated postoperative course and Group B were patients with a complicated postoperative course. RESULTS: Serum samples were drawn for PCT and CRP determination after induction of anesthesia (baseline), at the end of surgery and daily until postoperative day 2. Baseline serum PCT concentrations were 0.11 +/- 0.09 and 0.20 +/- 0.21 ng/mL in Groups A and B, respectively (NS). Serum PCT concentration increased compared with baseline in both groups during the first two days after surgery. The increase in serum PCT concentration was significantly greater in Group B than A patients (p < 0.0002). Considering a perioperative abnormal cut-off value of >0.5 ng/mL, there were none in Group A versus 57% in Group B (p < 0.0001). Baseline serum CRP concentrations were 1.44 +/- 1.30 and 1.58 +/- 1.35 ng/mL in Groups A and B, respectively (NS). After surgery, CRP increased significantly compared with baseline in both groups. When changes in time-varying variables were included in a logistic model, complications were predicted by changes (between baseline and end of surgery values) of PCT (coefficient = 9.410; t = 2.18) and heart rate (coefficient = 0.075; t = 1.57), whereas changes of CRP, white blood cells, mean blood and central venous pressures did not contribute statistically. The model constant was -4.827 (t = -2.43) and the ROC curve area was 0.8971. Thus, absolute PCT changes of 0.20, 0.40 and 0.60 ng/mL carry an approximate risk of 5, 26 and 69%, respectively, of postoperative complications in the time frame of this study. CONCLUSIONS: A postoperative serum PCT concentration of >0.5 ng/mL is highly suggestive of a postoperative complication. CRP changes do not contribute to predictive information.     

Usefulness of procalcitonin for diagnosis of infection in cardiac surgical patients

OBJECTIVE: To determine the value of procalcitonin (PCT) as a marker of postoperative infection after cardiac surgery. DESIGN: A prospective single institution three phase study. SETTING: University cardiac surgical intensive care unit (31 beds). PATIENTS: Phase 1: To determine the normal perioperative kinetics of PCT, 20 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass were included. Phase 2: To determine whether PCT may be useful for diagnosis of postoperative infection, 97 consecutive patients with suspected infection were included. Phase 3: To determine the ability of PCT to differentiate patients with septic shock from those with cardiogenic shock, 26 patients with postoperative circulatory failure were compared. MEASUREMENTS AND MAIN RESULTS: Phase 1: Serum samples were drawn for PCT determination after induction of anesthesia (baseline), at the end of surgery, and daily until postoperative day (POD) 8. Baseline serum PCT concentration was 0.17 +/- 0.08 ng/mL (mean +/- SD). Serum PCT increased after cardiac surgery with a peak on POD 1 (1.08 +/- 1.36). Serum PCT returned to normal range on POD 3 and remained stable thereafter. Phase 2: In patients with suspected infection, serum PCT was measured at the same time of C-reactive protein (CRP) and bacteriologic samples. Among the 97 included patients, 54 were infected with pneumonia (n = 17), bacteremia (n = 16), mediastinitis (n = 9), or septic shock (n = 12). In the 43 remaining patients, infection was excluded by microbiological examinations. In noninfected patients, serum PCT concentration was 0.41 +/- 0.36 ng/mL (range, 0.08-1.67 ng/mL). Serum PCT concentration was markedly higher in patients with septic shock (96.98 +/- 119.61 ng/mL). Moderate increase in serum PCT concentration occurred during pneumonia (4.85 +/-3.31 ng/mL) and bacteremia (3.57 +/- 2.98 ng/mL). Serum PCT concentration remained low during mediastinitis (0.80 +/- 0.58 ng/mL). Five patients with mediastinitis, two patients with bacteremia, and one patient with pneumonia had serum PCT concentrations of <1 ng/mL. These eight patients were administered antibiotics previously and serum PCT was measured during a therapeutic antibiotic window. For prediction of infection by PCT, the best cutoff value was 1 ng/mL, with sensitivity 85%, specificity 95%, positive predictive value 96%, and negative predictive value 84%. Serum CRP was high in all patients without intergroup difference. For prediction of infection by CRP, a value of 50 mg/L was sensitive (84%) but poorly specific (40%). Comparing the area under the receiver operating characteristic curves, PCT was better than CRP for diagnosis of postoperative sepsis (0.82 for PCT vs. 0.68 for CRP). Phase 3: Serum PCT concentration was significantly higher in patients with septic shock than in those with cardiogenic shock (96.98 +/- 119.61 ng/mL vs. 11.30 +/- 12.3 ng/mL). For discrimination between septic and cardiogenic shock, the best cutoff value was 10 ng/mL, with sensitivity of 100% and specificity of 62%. CONCLUSION: Cardiac surgery with cardiopulmonary bypass influences serum PCT concentration with a peak on POD 1. In the presence of fever, PCT is a reliable marker for diagnosis of infection after cardiac surgery, except in patients who previously received antibiotics. PCT was more relevant than CRP for diagnosis of postoperative infection. During a postoperative circulatory failure, a serum PCT concentration >10 ng/mL is highly indicative of a septic shock.     

Influence of prophylactic use of pentoxifylline on postoperative organ function in elderly cardiac surgery patients

OBJECTIVE: To study the effects of pretreatment with pentoxifylline before cardiac surgery on postoperative organ function in elderly patients (>80 yrs) undergoing cardiac surgery. DESIGN: Prospective, randomized, placebo-controlled study. SETTING: Two-day clinical investigation in an intensive care unit of a university-affiliated hospital. PATIENTS: Forty elderly patients (age >80 yrs) undergoing first-time elective aortocoronary bypass grafting. INTERVENTIONS: In 20 patients, pentoxifylline (loading bolus of 300 mg followed by a continuous infusion of 1.5 mg.kg-1.hr-1 until the second postoperative day) was given after induction of anesthesia; another 20 patients received saline solution as placebo. MEASUREMENTS AND MAIN RESULTS: Concentrations of soluble adhesion molecules (soluble E-selectin, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecules) were measured to assess endothelial function. Liver function was evaluated by monoethylglycinexylidide test and by measuring alpha-glutathione S-transferase plasma concentrations. Renal function was assessed by measuring serum creatinine and urine concentrations of alpha-1-microglobulin. Splanchnic perfusion was assessed by monitoring intramucosal pH by using continuous tonometry. All measurements were performed before pentoxifylline infusion (T0), at the end of surgery (T1), 5 hrs after surgery (T2), and at the morning of the first (T3) and second (T4) postoperative day. Postoperative concentrations of all measured soluble adhesion molecules were significantly higher in the nontreated controls than in the pentoxifylline-treated patients. Monoethylglycinexylidide serum concentrations were significantly lower and abnormal (<50 ng/mL) postoperatively only in the untreated control patients. alpha-Glutathione S-transferase increased in both groups with a significantly higher increase in the control group (from 3.2 +/- 1.2 to 24.1 +/- 4.2 ng/mL) than in the pentoxifylline-treated patients (from 3.8 +/- 1.9 to 11.5 +/- 2.1 ng/mL). Serum creatinine was unchanged in both groups, whereas alpha-1-microglobulin increased significantly more in the control group than in the pentoxifylline-treated group. Intramucosal pH remained almost unchanged in the pentoxifylline patients (>7.35) but decreased significantly in the control group (5 hrs after surgery, intramucosal pH 7.29 +/- 0.13). CONCLUSIONS: Pretreatment of patients aged >80 yrs undergoing cardiac surgery with pentoxifylline attenuated deterioration of endothelial, renal, and liver function as seen in an untreated control group. Splanchnic perfusion also appears to be improved in the pentoxifylline-treated group. Whether pretreatment with pentoxifylline will improve outcome in this patient population remains to be elucidated.     

Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6

OBJECTIVE: To evaluate whether plasma concentrations of procalcitonin (PCT), interleukin-6 (IL-6), protein complement 3a (C3a), leukocyte elastase (elastase), and the C-reactive protein (CRP) determined directly after the clinical onset of sepsis or systemic inflammatory response syndrome (SIRS) discriminate between patients suffering from sepsis or SIRS and predict the outcome of these patients. DESIGN: Prospective study. SETTING: Medical intensive care unit at a university hospital. PATIENTS: Twenty-two patients with sepsis and 11 patients with SIRS. MEASUREMENTS AND MAIN RESULTS: The plasma concentrations of PCT, C3a, and IL-6 obtained < or =8 hrs after clinical onset of sepsis or SIRS but not those of elastase or CRP were significantly higher in septic patients (PCT: median, 16.8 ng/mL, range, 0.9-351.2 ng/mL, p = .003; C3a: median, 807 ng/mL, range, 422-4788 ng/mL, p < .001; IL-6: median, 382 pg/mL, range, 5-1004 pg/mL, p = .009, all Mann-Whitney rank sum test) compared with patients suffering from SIRS (PCT: median, 3.0 ng/mL, range, 0.7-29.5 ng/mL; C3a: median, 409 ng/mL, range, 279566 ng/mL; IL-6: median, 98 pg/mL, range, 23-586 pg/mL). The power of PCT, C3a, and IL-6 to discriminate between septic and SIRS patients was determined in a receiver operating characteristic analysis. C3a was the best variable to differentiate between both populations with a maximal sensitivity of 86% and a specificity of 80%. An even better discrimination (i.e., a maximal sensitivity of 91% and a specificity of 80%) was achieved when PCT and C3a were combined in a "sepsis score." C3a concentrations also helped to predict the outcome of patients. Based on the sepsis score, a logistic regression model was developed that allows a convenient and reliable determination of the probability of an individual patient to suffer from sepsis or SIRS. CONCLUSIONS: Our data show that the determination of PCT, IL-6, and C3a is more reliable to differentiate between septic and SIRS patients than the variables CRP and elastase, routinely used at the intensive care unit. The determination of PCT and C3a plasma concentrations appears to be helpful for an early assessment of septic and SIRS patients in intensive care.     

Induction of systemic serum procalcitonin and cardiocirculatory reactions after isolated limb perfusion with recombinant human tumor necrosis factor-alpha and melphalan

OBJECTIVES: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP. SETTING: University surgical oncology division with an integrated eight-bed intensive care unit. PATIENTS: Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma. INTERVENTIONS: The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel. MEASUREMENTS AND MAIN RESULTS: PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes. CONCLUSIONS: Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.     

Procalcitonin release patterns in a baboon model of trauma and sepsis: relationship to cytokines and neopterin

OBJECTIVES: Procalcitonin (PCT) has been described as an early, discriminating marker of bacteria-associated sepsis in patients. However, little is known of its source and actions, in part because no appropriate animal models have been available. We tested the hypothesis that plasma PCT increases during various pathophysiological conditions, such as hemorrhagic shock and sepsis, which differ with regard to the degree of associated endotoxemia. We further hypothesized that in sepsis, PCT would be significantly different in survivors vs. nonsurvivors. DESIGN: Prospective, blinded analysis of previously collected plasma of experimental animals. SETTING: Independent nonprofit research laboratory in a trauma hospital and a contract research institute. SUBJECTS: A total of 22 male baboons (17.5-31 kg). INTERVENTIONS: Hemorrhagic-traumatic shock was induced by hemorrhage for up to 3 hrs, reperfusion with shed blood and infusion of cobra venom factor (n = 7). By using a similar experimental setup, severe hyperdynamic sepsis was induced (n = 15) by intravenous infusion of live Escherichia coli (2 x 10(9) colony-forming units/kg) over 2 hrs, followed by antibiotic therapy (gentamicin 4 mg/kg twice a day). MEASUREMENTS AND MAIN RESULTS: Plasma PCT at baseline was barely detectable, but levels increased significantly (p < .05) to 2+/-1.8 pg/mL 2 hrs after the start of reperfusion in the shock group, and to 987+/-230 pg/mL at 4 hrs after E. coli in the sepsis group. Levels were maximal between 6 and 32 hrs and had returned nearly to baseline levels at 72 hrs. Interleukin-6 levels paralleled the course of PCT measurements, whereas a significant increase in neopterin was seen at 24 hrs. PCT levels were approximately three times higher in the sepsis group than in the shock group, corresponding to endotoxin levels (at the end of hemorrhage, 286+/-144 pg/mL vs. 3576+/-979 pg/mL at the end of E. coli infusion; p = .003). PCT levels were significantly different at 24 hrs between survivors (2360+/-620 pg/mL) and nonsurvivors (4776+/-563 pg/mL) in the sepsis group (p = .032), as were interleukin-6 (1562+/-267 vs. 4903+/-608 pg/mL; p = .01) and neopterin/creatinine ratio (0.400+/-0.038 vs. 0.508+/-0.037; p = .032). CONCLUSIONS: PCT is detectable in the baboon as in humans, both in hemorrhagic shock and sepsis. PCT levels are significantly higher in sepsis than in hemorrhage, a finding that is probably related to the differences in endotoxin. The baboon can be used for the study of PCT kinetics in both models; PCT kinetics are clearly different from other markers of sepsis, either IL-6 or neopterin, in both models. There are significant differences between survivors and nonsurvivors in the sepsis model.     

Postoperative plasma concentrations of procalcitonin after different types of surgery

Objective: Procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations were measured after different types of surgery to analyze a possible postoperative induction of procalcitonin (PCT), which might interfere with the diagnosis of bacterial infection or sepsis by PCT. Design: PCT and CRP plasma levels as well as clinical symptoms of infection were prospectively registered preoperatively and 5 days postoperatively. Setting: University hospital, in-patient postoperative care. Patients: Hundred thirty patients were followed up; 117 patients with a normal postoperative course were statistically analyzed. Interventions: None. Measurements and results: PCT concentrations were moderately increased above the normal range in 32 % of patients after minor and aseptic surgery, in 59 % after cardiac and thoracic surgery, and in 95 % of patients after surgery of the intestine. In patients with an abnormal postoperative course, PCT was increased in 12 of 13 patients. CRP was increased in almost all patients. Conclusions: Postoperative induction of PCT largely depends on the type of surgery. Intestinal surgery and major operations more often increase PCT, whereas it is normal in the majority of patients after minor and primarily aseptic surgery. PCT can thus be used postoperatively for diagnostic means only when the range of PCT concentrations during the normal course of a certain type of surgery is considered and concentrations are followed up. Received: 20 October 1997 Accepted: 25 March 1998     

Dexamethasone reduces postoperative troponin levels in children undergoing cardiopulmonary bypass

OBJECTIVE: We previously demonstrated that dexamethasone treatment before cardiopulmonary bypass in children reduces the postoperative systemic inflammatory response. The purpose of this study was to test the hypothesis that dexamethasone administration before cardiopulmonary bypass in children correlates with a lesser degree of myocardial injury as measured by a decrease in cardiac troponin I release. DESIGN: A prospective, randomized, double-blind study. SETTING: The cardiac surgery operating room and intensive care unit of a pediatric referral hospital. SUBJECTS: Twenty-eight patients who underwent open-heart surgery for congenital heart defects. INTERVENTIONS: Patients received either placebo (group I, n = 13) or dexamethasone, 1 mg/kg iv (group II, n = 15), 1 hr before initiation of cardiopulmonary bypass. Plasma cardiac troponin I samples were obtained at three time points: immediately before study agent (sample 1), 10 mins after protamine sulfate administration after cardiopulmonary bypass (sample 2), and 24 hrs postoperatively (sample 3). MEASUREMENTS AND MAIN RESULTS: Mean cardiac troponin I levels (+/-sd) were significantly lower at sample time 3 in group II (dexamethasone; 33.4 +/- 20.0 ng/mL) vs. group I (control; 86.9 +/- 81.1) (p =.04). CONCLUSION: Dexamethasone administration before cardiopulmonary bypass in children resulted in a significant decrease in cardiac troponin I levels at 24 hrs postoperatively. We postulate that this may represent a decrease in myocardial injury, and, thus, a possible cardioprotective effect produced by dexamethasone.     

In vitro modulation of inducible nitric oxide synthase gene expression and nitric oxide synthesis by procalcitonin

OBJECTIVE: Serum procalcitonin (PCT) concentration was recently introduced as valuable diagnostic marker for systemic bacterial infection and sepsis. At present, the cellular sources and biological properties of PCT are unclear. During sepsis and septic shock, inducible nitric oxide synthase (iNOS) gene expression is stimulated followed by the release of large amounts of nitric oxide (NO). We investigated the possible association between PCT and iNOS gene expression in an in vitro cell culture model. DESIGN: Prospective, controlled in vitro cell culture study. SETTING: University research laboratories. INTERVENTIONS: Confluent rat vascular smooth muscle cells (VSMC) were incubated for 24 hrs and 48 hrs with PCT (1 ng/mL, 10 ng/mL, 100 ng/mL, 1,000 ng/mL, 5,000 ng/mL) alone or with the combination of tumor necrosis factor-alpha (TNF-alpha, 500 U/mL) plus interferon-gamma (IFN-gamma, 100 U/mL). iNOS gene expression was measured by qualitative as well as quantitative polymerase chain reaction analysis, NO release was estimated by the modified Griess method. MEASUREMENTS AND MAIN RESULTS: PCT in increasing concentrations had no effect on iNOS gene expression and nitrite/nitrate release for 24 hrs and 48 hrs, respectively. However, PCT ameliorated TNF-alpha/IFN-gamma-induced iNOS gene expression in a dose-dependent manner (maximal inhibition at PCT 100 ng/mL by -66% for 24 hrs and -80% for 48 hrs). This was accompanied by a significantly reduced release of nitrite/nitrate into the cell culture supernatant (maximal reduction at PCT 100 ng/mL by -56% and -45% for 24 hrs and 48 hrs, respectively). CONCLUSIONS: We conclude that recombinant PCT inhibits the iNOS-inducing effects of the proinflammatory cytokines TNF-alpha/ IFN-gamma in a dose-dependent manner. This might be a counter-regulatory mechanism directed against the large production of NO and the concomitant systemic hypotension in severe sepsis and septic shock.     

Detection of acute phase response and infection. The role of procalcitonin and C-reactive protein.

OBJECTIVE: Established parameters, e.g. C-reactive protein (CRP), do not differentiate specifically enough between patients developing an infection and those exhibiting an acute phase response following cardiac surgery. The objective of this prospective study was to investigate if procalcitonin (PCT) is more helpful than CRP. METHODS: During a 1-year period, seven out of 563 patients (1.2%) developed systemic infections (group A) after cardiac operations with cardiopulmonary bypass (CPB), and additional eight patients (1.4%) had local wound infections requiring surgical therapy (group B). Blood samples for PCT and CRP measurements were taken preoperatively, at the onset of infection (d1), as well as on the third day (d3), fifth day (d5), and seventh day (d7) following diagnosis of infection. Forty-four randomly selected patients undergoing cardiac surgery with CPB without clinical signs of infection, additional intensive care unit (ICU) management or additional antibiotic treatment served as control (group C) to assess the PCT and CRP contribution to acute phase response. PCT and CRP levels were measured preoperatively, on the first (d1), third (d3) and fifth day (d5) after operation. RESULTS: At the onset of infection, PCT levels (median interquartile range 25%-75%) increased significantly in group A as compared to baseline values (10.86 (3.28-15.13) ng/ml vs. 0.12 (0.08-0.21) ng/ml), and decreased during treatment to still significantly elevated values on d5 (0.56 (0.51-0.85) ng/ml). CRP levels were significantly elevated on all days investigated with no trend towards normalisation (d1: 164.5 (137-223) mg/l) vs. 1.95 (1.1-2.8) mg/l preoperatively, d5: 181.1 (134-189.6) mg/l. In group B, no increase in PCT levels, but a significant increase of CRP from d1 (165.9 (96.6-181.6) mg/l) vs. 3.7 (2-4.3) mg/l preoperatively) until d5 98 (92.8-226.2) mg/l was detected. In group C, postoperative PCT levels increased slightly but significantly in the absence of infection on d1 (0.46 (0.26-0.77) ng/ml vs. 0.13 (0.08-0.19) ng/ml preoperatively), and d3 (0.37 (0.2-0.65) ng/ml and reached baseline on d5 (0.24 (0.11-0.51) ng/ml)). CRP levels were significantly elevated as compared to baseline on all postoperative days investigated (baseline: 1.75 (0.6-2.9) mg/l, d1: 97.5 (74.5-120) mg/l), d3: 114 (83.05-168.5) mg/l, d5: 51.4 (27.4-99.8) mg/l)). PCT showed a significant correlation to CRP in group A (r =0.48, p < 0.001), a weak correlation in group C (r=0.27, p=0.002) and no correlation in group B. Intergroup comparison revealed a significant difference for PCT between all groups (A>C>B) and significantly higher CRP levels in group A vs. C and in group B vs. C. Thus, the pattern high PCT/high CRP appears to indicate a systemic infection, while low PCT/high CRP indicates either acute phase response or local wound problems, but no systemic infection. The cost for PCT measurements was 5.6-fold higher as compared to CRP. CONCLUSION: Due to the significant differences in the degree of increase, PCT appears to be useful in discriminating between acute phase response following cardiac surgery with CPB or local problems and systemic infections, with additional CRP-measurement increasing the specificity.     

Comparison of procalcitonin and C-reactive protein as markers of sepsis

OBJECTIVE: To compare the clinical informative value of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations in the detection of infection and sepsis and in the assessment of severity of sepsis. DESIGN: Prospective study. SETTING: Medicosurgical intensive care unit. PATIENTS: Seventy consecutive adult patients who were admitted to the intensive care unit for an expected stay >24 hrs. INTERVENTIONS: None. MEASUREMENTS: PCT and CRP plasma concentrations were measured daily during the intensive care unit stay. Each patient was examined daily for signs and symptoms of infection and was classified daily in one of the following four categories according to the American College of Chest Physicians/Society of Critical Care Medicine criteria: negative, systemic inflammatory response syndrome, localized infection, and sepsis group (sepsis, severe sepsis, or septic shock). The severity of sepsis-related organ failure was assessed by the sepsis-related organ failure assessment score. MAIN RESULTS: A total of 800 patient days were classified into the four categories. The median plasma PCT concentrations in noninfected (systemic inflammatory response syndrome) and localized-infection patient days were 0.4 and 1.4 ng/mL (p <.0001), respectively; the median CRP plasma concentrations were 79.9 and 85.3 mg/L (p =.08), respectively. The area under the receiver operating characteristic curve was 0.756 for PCT (95% confidence interval [CI], 0.675-0.836), compared with 0.580 for CRP (95% CI, 0.488-0.672) (p <.01). The median plasma PCT concentrations in nonseptic (systemic inflammatory response syndrome) and septic (sepsis, severe sepsis, or septic shock) patient days were 0.4 and 3.65 ng/mL (p <.0001), respectively, whereas those for CRP were 79.9 and 115.6 mg/L (p <.0001), respectively. The area under the receiver operating characteristic curve was 0.925 for PCT (95% CI, 0.899-0.952), compared with 0.677 for CRP (95% CI, 0.622-0.733) (p <.0001). The linear correlation between PCT plasma concentrations and the four categories was much stronger than in the case of CRP (Spearman's rho, 0.73 vs. 0.41; p <.05). A rise in sepsis-related organ failure assessment score was related to a higher median value of PCT but not CRP. CONCLUSION: PCT is a better marker of sepsis than CRP. The course of PCT shows a closer correlation than that of CRP with the severity of infection and organ dysfunction.     

Interleukin-10 and its role in clinical immunoparalysis following pediatric cardiac surgery

OBJECTIVE: A systemic insult is associated with subsequent hyporesponsiveness to endotoxin (as measured by ex vivo tumor necrosis factor [TNF]-alpha production) and an increased risk of late nosocomial infection in some patients. When combined with low monocyte surface major histocompatibility complex class II expression, this state of altered host defense is now commonly referred to as immunoparalysis. This study was undertaken to delineate the relationship between observed levels of the anti-inflammatory cytokine interleukin-10, common genetic polymorphisms that influence these levels, and the occurrence and severity of endotoxin hyporesponsiveness in children following elective cardiac surgery requiring cardiopulmonary bypass. DESIGN: A prospective observational clinical study. SETTING: A tertiary pediatric cardiac center. PATIENTS: Thirty-six infants and children <2 yrs of age undergoing elective cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We investigated the production of TNF-alpha, interleukin-6, interleukin-8, interleukin-1 receptor antagonist, and interleukin-10 in whole blood in response to lipopolysaccharide (Neisseria meningitides 10 ng/mL) in samples drawn before, during, and up to 48 hrs after surgery. Patients were genotyped for the -1082, -819, and -592 interleukin-10 promoter polymorphisms. Whole blood cytokine response to lipopolysaccharide was reduced postoperatively to 100 pg/mL) over the first 48 hrs were more likely to have an uncomplicated short stay (odds ratio 4.7, 95% confidence interval 1-22). CONCLUSIONS: Immediately following cardiac surgery, many children become relatively refractory to lipopolysaccharide stimulation. This immunoparalysis appears to be related in part to high circulating levels of interleukin-10 and places these patients at increased risk of postoperative complications. Interleukin-10 genotype may be a risk factor for immunoparalysis.     

Cardiac troponin I: its contribution to the diagnosis of perioperative myocardial infarction and various complications of cardiac surgery

OBJECTIVE: To study the value of assaying cardiac troponin I (cTnI) for the early diagnosis of perioperative myocardial infarction (PMI) and various complications of cardiac surgery. DESIGN: A prospective observational clinical study. SETTING: Biochemical laboratory, anesthesia, and cardiac surgery department of H?pital Broussais. PATIENTS: Two hundred and sixty consecutive patients undergoing cardiac surgery. INTERVENTIONS: All patients underwent coronary artery bypass grafting and/or valvular surgery under extracorporeal circulation. Per-operative and postoperative follow-up consisted of electrocardiogram, echocardiography (mainly by the transesophageal approach), and serial determinations of biochemical markers such as creatinine kinase-MB isoenzyme (CK-MB) and cTnI. PMI, new ST segment changes, and ventricular arrhythmias were considered postoperative adverse cardiac outcome. MEASUREMENTS AND MAIN RESULTS: CTnI was measured before cardiopulmonary bypass (T0) and 12 and 24 hrs after (T12, T24). CK-MB was measured on arrival in the intensive care unit and on the first postoperative day (D1). Patients were divided into three groups according to the type of surgery: coronary artery bypass graft (CABG), valvular surgery (VS), or both procedures. The plasma CK-MB and cTnI concentrations were high in all patients after extracorporeal circulation because of aortic clamping or cardioplegia. The CK-MB and cTnI values were higher in the VS group than in the CABG group. Values peaked at T12 and fell by T24, except when PMI occurred. Eight patients developed a PMI. Patients with PMI had significantly higher cTnI levels at T12 and T24, and higher CK-MB values at D1 than patients without PMI. Cutoff values of cTnI for diagnosing PMI were >19 microg/L at T12 with 100% sensitivity and 73% specificity, and >36 microg/L at T24, with 100% sensitivity and 93% specificity. Lower cTnI values were highly suggestive of the absence of PMI after CABG and/or VS. Other complications such as ST segment changes, ventricular arrhythmias and cardiac failure were indicated by high cTnI levels at T12 and T24. Myocardial protective measures were associated with a nonsignificant increase in cTnI values. CONCLUSIONS: CTnI is more sensitive and specific than CK-MB for diagnosing PMI and other forms of heart failure after cardiac surgery.     

Low-dose prostacyclin preserves renal function in high-risk patients after coronary bypass surgery

OBJECTIVE: Renal failure after bypass is still a threatening problem prolonging hospital care and reducing overall survival. The following pilot study was aimed to analyze whether perioperative low-dose prostacyclin infusion is able to preserve renal function in a selected group of patients who according to a poor cardiac function were stratified as high risk for the development of renal failure after bypass. DESIGN: Prospective randomized study. SETTING: Tertiary care university medical center. PATIENTS: Thirty-four patients scheduled for primary cardiac bypass surgery were included in the study (prostacyclin n = 17, control n = 17). Inclusion criteria were normal renal function before surgery and a cardiac ejection fraction <40%. INTERVENTIONS: Low-dose prostacyclin (2 ng/kg/min) was added to the standard anesthetic protocol. Infusion was started immediately before surgery and was continued for a maximum of 48 MEASUREMENTS AND MAIN RESULTS: Significant differences in the endogenous creatinine clearance were found between the prostacyclin and the control group. Whereas there was a significant drop in the creatinine clearance at 6 hrs after surgery in the control group with a prolonged recovery period, values in the prostacyclin group remained stable. Creatinine clearance before intervention was 100 +/- 22 mL/min in the control group and 91 +/- 22 mL/min in the prostacyclin group, values at 24 hr were 68 +/- 34 mL/min vs. 103 +/- 37 mL/min, respectively (p < .01). Significant findings in favor for the prostacyclin group were also found for urine output and the fractional excretion rate of sodium. CONCLUSION: This first pilot study indicates that low-dose prostacyclin may be of substantial value for preserving renal function in high-risk patients after coronary bypass surgery.     

Cardioprotective effects of acute normovolemic hemodilution in patients with severe aortic stenosis undergoing valve replacement

BACKGROUND: After acute normovolemic hemodilution (ANH), improvement of the rheologic conditions may contribute to optimize tissue oxygen delivery and attenuate ischemia-reperfusion injuries. It was hypothesized that ANH would confer additional cardioprotection in patients with ventricular hypertrophy undergoing open heart surgery. STUDY DESIGN AND METHODS: This study was a randomized controlled trial. Forty patients scheduled for elective aortic valve replacement were randomly assigned to a control group (standard care) or an ANH group (target hematocrit level of 28%). All patients were managed with standard myocardial preservation techniques (cold blood cardioplegia, anesthetic preconditioning). The outcome measures included the release of myocardial enzymes, perioperative hemodynamic changes, the need for pharmacologic cardiovascular support, and cardiac complications. RESULTS: In the ANH group, the postoperative release of troponin I (mean peak plasma concentrations, 1.7 ng/mL; 95% confidence interval, 1.4-2.1 ng/mL) and myocardial fraction of creatine kinase (22 U/L; range, 18-24 U/L) was significantly lower than in the control group (3.6 [range, 3.0-4.2] ng/mL and 45 [range, 39-51] U/L, respectively). In addition, requirement for inotropic support was significantly lower and fewer hemodiluted patients presented adverse cardiac events. After ANH, there was a significant decrease in heart rate (-11 +/- 6%) and rate-pressure product (-16 +/- 8%) until the aortic cross-clamping time and, at the end of surgery, the circulating levels of erythropoietin (EPO) were higher than in control patients (13.6 +/- 4.2 mUI/mL vs. 7.3 +/- 2.4 mUI/mL; p < 0.05). CONCLUSIONS: Besides conventional cardiac preservation techniques, preoperative ANH further attenuates myocardial injuries. Optimization of preischemic myocardial oxygen delivery and/or consumption and the postconditioning effects of endogenous EPO are potential mechanisms for ANH-induced cardioprotection.     

Serum concentrations of immune parameters during acute cardiogenic pulmonary edema.

OBJECTIVE: To evaluate the effect of acute cardiogenic pulmonary edema on the concentrations of immune parameters in serum. DESIGN: Prospective, controlled study. SETTING: Medical ICU. PATIENTS: Twenty-four consecutive patients with acute pulmonary edema who had significant clinical improvement within 30 mins and did not show any evidence of either tissue damage or infection. For comparison, 25 healthy, age-matched controls and 25 patients with mild chronic heart failure were also studied. INTERVENTIONS: Treatment with oxygen, nitrates, and loop diuretics. MEASUREMENTS: Lymphokines, acute-phase reactants, and cortisol concentrations were measured in serial serum and plasma samples. MAIN RESULTS: Serum concentrations of soluble CD-8 antigen (soluble CD-8) decreased from 928 +/- 124 (SEM) U/mL on admission to 712 +/- 112 and 579 +/- 67 U/mL after 2 and 6 hrs, respectively (p less than .05, p less than .01), and returned to baseline values within 48 hrs (853 +/- 109 U/mL). Concentrations of soluble interleukin-2 receptor increased from 721 +/- 71 to 1078 +/- 112 and 1226 +/- 128 U/mL 12 and 36 hrs, respectively, after admission (p less than .05, p less than .01). Plasma cortisol concentrations were markedly increased on admission (56.9 +/- 4.7 vs. 13.1 +/- 1.3 micrograms/dL after recovery, p less than .001). Increased cortisol concentrations coincided with the nadir of soluble CD-8. Tumor necrosis factor-alpha remained within normal limits in all patients. Neither acute-phase reactants nor angiotensin converting enzyme activity showed significant changes during the observation period. CONCLUSION: The present results indicate significant alterations in the serum concentrations of immune parameters as an effect of an uncomplicated acute cardiogenic pulmonary edema.     

Circulating leptin and the perioperative neuroendocrinological stress response after pediatric cardiac surgery.

OBJECTIVE: Leptin may be involved in the acute stress response, regulating inflammatory parameters of major importance after cardiopulmonary bypass (CPB) surgery. Critically ill patients demonstrated significant increases in leptin levels in response to stress-related cytokines (tumor necrosis factor, interleukin [IL]-1) and abolishment of the circadian rhythm of leptin secretion. We characterized the pattern of leptin secretion in the acute postoperative period in children undergoing cardiac surgery and compared the changes in leptin levels with concomitantly occurring changes in cortisol levels, IL-8, and clinical parameters. DESIGN: Investigative study. SETTING: University-affiliated tertiary care hospital. PARTICIPANTS AND INTERVENTIONS: Twenty-nine consecutive patients, aged 6 days to 15 yrs, operated upon for the correction of congenital heart defects were studied. Surgery in 20 patients (group 1) involved conventional CPB techniques, and 9 (group 2) underwent closed-heart surgery. The time courses of leptin, cortisol, and IL-8 levels were determined. Serial blood samples were collected preoperatively, on termination of CPB, and at six time points postoperatively. Plasma was recovered immediately, aliquoted, and frozen at -70 degrees C until use. MEASUREMENTS AND MAIN RESULTS: The leptin levels in group 1 decreased during CPB to 51% of baseline (p <.001), then gradually increased, reaching 120% of baseline levels at 12-18 hrs postoperatively (p <.001), returning to baseline levels at 24 hrs (p <.01). In patients undergoing closed-heart surgery (group 2), leptin levels displayed a pattern resembling the first group: they decreased during surgery to 71% of baseline levels (p =.002) and showed a tendency to return to baseline thereafter. All group 1 patients' cortisol levels increased significantly during the first hour of surgery, then decreased, returning to baseline levels at 18-24 hrs postoperatively. There was a significant negative correlation between leptin and cortisol levels (r = -2.8, p <.01). In group 2, cortisol levels increased during and after surgery, peaking 4 hrs postoperatively and decreasing thereafter. IL-8 levels determined in 15 group 1 patients increased significantly during CPB, peaked at the end of surgery, and then decreased but remained slightly elevated even at 48 hrs postoperatively. There was a significant correlation between cortisol and IL-8 levels (r = 2.55, p <.05). Children with leukocytosis, tachycardia, and hypotension had lower leptin levels and less variation over time as opposed to those with an uncomplicated course. CONCLUSIONS: CPB is associated with acute changes in circulating leptin levels. These changes parallel those in cortisol, demonstrating an inverse relationship between leptin and cortisol. Further studies of the prognostic and therapeutic roles of leptin after CPB should be investigated.     

Alfentanil reduces the febrile response to interleukin-2 in humans

OBJECTIVE: Manifestation of intraoperative fever is impaired by volatile anesthetics and muscle relaxants. Opioids are common anesthetic adjuvants and remain the dominant treatment for postoperative surgical pain and sedation of critically ill patients. The effect of opioids on normal thermoregulatory control is well established. However, the extent to which these drugs might inhibit fever remains unknown. Accordingly, we tested the hypothesis that relatively low plasma concentrations of the mu-receptor agonist alfentanil reduce fever magnitude. DESIGN: Prospective, randomized, crossover study. SETTING: Outcomes Research Laboratory, at the Department of Anesthesia and Perioperative Care, University of California, San Francisco. PATIENTS: Eight healthy male volunteers, aged 25-31 yrs, each studied on three separate days. INTERVENTION: Each volunteer was given an intravenous injection of 30 IU/g interleukin (IL)-2, followed 2 hrs later by 70 IU/g. One hour after the second dose, the volunteers were randomly assigned to three doses of alfentanil: a) none (control); b) a target plasma concentration of 100 ng/mL; and c) a target concentration of 200 ng/mL. Opioid administration continued for 5 hrs. METHODS AND MAIN RESULTS: Alfentanil significantly reduced the febrile response to pyrogen, decreasing integrated tympanic membrane temperatures from 7.5+/-2.2 degrees C x hr on the control day, to 4.9+/-1.5 degrees C x hr with 100 ng/mL alfentanil, and to 5.1+/-1.7 degrees C x hr with 200 ng/mL alfentanil (p = .011). Peak temperatures were also significantly reduced from 38.5+/-0.4 degrees C on the control day, to 38.0+/-0.4 degrees C on the 100 ng/mL-alfentanil day and 38.0+/-0.6 degrees C on the 200-ng/mL day (p = .019). Plasma cytokine concentrations increased after IL-2 administration, roughly in proportion to the elevation in core temperature. However, cytokine concentrations did not differ significantly among the treatment groups. CONCLUSION: Alfentanil significantly reduced the febrile response to IL-2 administration. However, the reduction was comparable at plasma concentrations near 100 and 200 ng/mL. These data indicate that concentrations of opioids commonly observed in critical care patients significantly inhibit the manifestation of fever.     

Mannose-binding lectin is involved in multiple organ dysfunction syndrome after cardiac surgery: effects of blood transfusions

BACKGROUND: Serum levels of mannose-binding lectin (MBL), a recognition molecule of the lectin pathway of complement, are highly variable, based on genetic variation. After cardiac surgery, extracorporeal circulation and ischemia-reperfusion injury initiate a systemic inflammatory response, which can evolve to multiple organ dysfunction syndrome (MODS). Preoperative transfusions of allogeneic white blood cells (WBCs) contribute to infectious and inflammatory complications. This study investigates the role of MBL in relation to blood transfusions and complications after cardiac surgery. STUDY DESIGN AND METHODS: In cardiac surgery patients who participated in a randomized trial comparing leukoreduced with buffy coat-depleted red blood cell (RBC) transfusions, circulating MBL was measured pre- and postoperatively by enzyme-linked immunosorbent assay (ELISA). Data were related to the incidence of complications and to the transfusions the patients received. RESULTS: Patients with high preoperative serum MBL levels (>400 ng/mL) show a significant (52 +/- 12%) decrease of serum MBL postoperatively, whereas patients with low serum MBL levels (< or =400 ng/mL) show a significant increase of serum MBL levels after surgery (140 +/- 106%), which was further enhanced by fresh-frozen plasma (FFP) transfusions. MBL levels were not associated with infections, sepsis, or death. Patients with MBL deficiency (MBL < or = 80 ng/mL) were protected against development of MODS (p = 0.016), whereas FFP transfusion abolished this protection (p = 0.048). CONCLUSION: Cardiac surgery is associated with MBL consumption, independent of the transfusion of allogeneic WBCs. Patients with MBL deficiency develop no MODS, unless they have been transfused with FFP, which is associated with MBL reconstitution. Therefore, sustained MBL deficiency may be a favorable status for patients undergoing cardiac surgery.     

Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients

OBJECTIVE: To compare procalcitonin (PCT) plasma levels of injured patients with the incidence and severity of systemic inflammatory response syndrome (SIRS), infection, and multiple organ dysfunction syndrome (MODS) and to assess the predictive value of PCT for these posttraumatic complications. DESIGN: Retrospective study comparing patients with mechanical trauma in terms of severity of injury, development of infectious complications, and organ dysfunctions. SETTING: Level I trauma center with emergency room, intensive care unit, and research laboratory. PATIENTS: Four hundred five injured patients with an Injury Severity Score of > or =9 points were enrolled in this study from January 1994 to February 1996. INTERVENTIONS: Blood samples were collected on the day of admission and on days 1, 3, 5, 7, 10, 14, and 21 thereafter. MEASUREMENTS AND MAIN RESULTS: We determined PCT serum levels using a specific immunoluminometric assay. We retrospectively evaluated the occurrence of SIRS, sepsis, and MODS using patients' charts. Mechanical trauma led to increased PCT plasma levels dependent on the severity of injury, with peak values on days 1 and 3 (p < .05) and a continuous decrease within 21 days after trauma. Patients who developed SIRS demonstrated a significant (p < .05) increase of peak PCT plasma levels compared with patients without SIRS. The highest PCT plasma concentrations early after injury were observed in patients with sepsis (6.9+/-2.5 ng/mL; day 1) or severe MODS (5.7+/-2.2 ng/mL; day 1) with a sustained increase (p < .05) for 14 days compared with patients with an uneventful posttraumatic course (1.1+/-0.2 ng/mL). Moreover, these increased PCT plasma levels during the first 3 days after trauma predicted (p < .0001; logistic regression analysis) severe SIRS, sepsis, and MODS. CONCLUSIONS: These data indicate that PCT represents a sensitive and predictive indicator of sepsis and severe MODS in injured patients. Routine analysis of PCT levels seems to aid early recognition of these posttraumatic complications. Thus, PCT may represent a useful marker to monitor the inflammatory status of injured patients at risk.