2000 - Calcitonin Precursors Are Reliable Markers of Sepsis in A Medical Intensive Care Unit (CritCare)

Ovid: Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit.
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Critical Care Medicine Nmero: Volume 28(4), April 2000, pp 977-983 Copyright: 2000 Lippincott Williams & Wilkins, Inc. Tipo de publicacin: [Clinical Investigations] ISSN: 0090-3493 Registro: 00003246-200004000-00011 Palabras clave: calcitonin, infection, sepsis, inflammation, critical illness, acute disease, protein precursors, diagnosis, differential diagnosis, biological markers, antibiotics [Clinical Investigations]
Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit
Mller, Beat MD; Becker, Kenneth L. MD, PhD; Schchinger, Hartmut MD; Rickenbacher, Peter R. MD; Huber, Peter R. PhD; Zimmerli, Werner MD; Ritz, Rudolf MD
Informacin sobre el autor

From the Divisions of Medical Intensive Care (Drs. Mller, Schchinger, Rickenbacker, and Ritz) and Infectious Diseases (Dr. Zimmerli), and the Department of Internal Medicine, Hormone Laboratory, Department of Chemical Pathology (Dr. Huber), University Hospitals, Basel, Switzerland, and the Division of Endocrinology, and the Department of Medicine, the Veterans Affairs Medical Center and George Washington University, Washington, DC (Dr. Becker). Supported, in part, by funds from the Division of Medical Intensive Care, University Hospitals, Basel, Switzerland. We are indebted to the Brahms Company, Berlin, Germany, for providing some of the kit material. Address requests for reprints to: Beat Mller; MD, Division of Endocrinology, Diabetology, and Metabolism, Dept. of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail: happymiller@bigfoot.com
Abstract
Objective: The diagnosis of infection in critically ill patients is challenging because traditional markers of infection are often misleading. For example, serum concentrations of calcitonin pre-cursors are increased in patients with infections. However, their predictive accuracy for the diagnosis of sepsis in unselected patients in a medical intensive care unit (ICU) is unknown. Therefore, we compared the usefulness of serum concentrations of calcitonin precursors, C-reactive protein, interleukin-6, and lactate for the diagnosis of sepsis in consecutive patients suffering from a broad range of diseases with an anticipated stay of >= 24 hrs in a medical ICU. Design: Prospective cohort study. Setting: Medical intensive care unit in a university medical center. Patients: 101 consecutive critically ill patients. Intervention: None. Measurements and Main Results: Blood samples were collected at various time points during the course of the disease. Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock were diagnosed according to standardized criteria, and patients were reclassified daily without prior knowledge of the serum concentrations of calcitonin precursors or interleukin-6. At admission, 99% of the patients had systemic inflammatory response syndrome, 53% had sepsis, and 5% developed sepsis during their stay in the ICU. Calcitonin precursors, C-reactive protein, interleukin-6, and lactate levels increased with the severity of infection (p < .01, one-way analysis of variance). In a receiver operating characteristic curve analysis, calcitonin precursors were found to be the most reliable laboratory variable for the diagnosis of sepsis as compared with C-reactive protein, interleukin-6, and lactate (p < .01, for each comparison). Calcitonin precursor concentrations of > 1 ng/mL had sensitivity of 89% and specificity of 94% for the diagnosis of sepsis. High serum concentrations of calcitonin precursors were associated with poor prognosis (p = .01). Conclusions: In a medical ICU, serum calcitonin precursor concentrations are more sensitive and are specific markers of sepsis as compared with serum C-reactive protein, interleukin-6, and lactate levels.
Sepsis is a common cause of morbidity and mortality, particularly in elderly, immunocompromised, and critically ill patients (1-3). Indeed, sepsis is the most common cause of death in medical intensive care units (ICU) (4-6). Despite the use of new treatment modalities, the mortality rate of sepsis remains high, often because of delayed diagnosis and treatment (7, 8). Importantly, when appropriate antibiotic therapy is administered early in the course of the disease, the occurrence of septic shock is reduced by half (9, 10).
Critically ill patients often manifest a systemic inflammatory response syndrome (SIRS) independently of an infection (11). The clinical signs of infection and routine laboratory tests are not specific and are sometimes misleading. The lack of specific early markers of infection might be responsible in part for withholding, delaying, or
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misleading. The lack of specific early markers of infection might be responsible in part for withholding, delaying, or overutilizing antimicrobial treatment in critically ill patients (7). Moreover, the misuse of antimicrobial agents has contributed to the emergence of multiresistant microorganisms (12, 13), and this has become a major problem in ICUs (14). In view of this diagnostic and therapeutic dilemma, an unequivocal test for the differential diagnosis of infection and sepsis would be useful.
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Calcitonin, a 32-amino-acid amidated hormone, is initially biosynthesized as a precursor, named preprocalcitonin (15). This protein is processed into several calcitonin precursors (Figure 1). In adults and children, infection and sepsis have been found to be associated with increased serum levels of calcitonin precursors (16-23). These concentrations were shown to be positively correlated with a subsequent mortality rate (20). However, the reliability of calcitonin precursor concentrations as diagnostic markers of sepsis in an unselected population of critically ill patients in a medical ICU is unknown.
Figure 1. Schematic diagram of the human calcitonin precursors. Segments of the calcitonin precursors, detectable by the assay used in this study, are striped. No evidence was found for the presence of preprocalcitonin in normal or septic serum. To validate the previously reported elevated calcitonin precursor levels in a well-defined cohort of patients, we compared the usefulness of serum concentrations of calcitonin precursors, C-reactive protein, interleukin-6, and lactate for the diagnosis of sepsis in a medical ICU in nonselected patients suffering from a broad range of diseases.
MATERIALS AND METHODS

Study Subjects. We studied 101 consecutive patients with an anticipated stay of >= 24 hrs who had been admitted for intensive treatment to the medical ICU of the University Hospitals, Basel, Switzerland, between September 1996 and June 1997. Informed consent was obtained before enrollment from conscious patients. For unconscious patients, the consent was obtained from patient next of kin. The study protocol was approved by the local ethical committee of the University Hospitals.
Study Design. Systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock was diagnosed according to standardized criteria (11). In the present study, we report the data collected at admission (during the first 24 hrs), on day 2, and on the day of discharge from the ICU, or on the day of death. At those time points, the patients were either very sick or had stabilized and were ready for discharge to a medical ward. Thus, a very high percentage (at admission, 99%) of patients were fulfilling two or more criteria for SIRS. Therefore, at the time points investigated, all patients found to have an infection were also fulfilling two or more criteria of SIRS and were, therefore, classified as septic. A patient could be classified one day as septic, and, after treatment, as having
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therefore, classified as septic. A patient could be classified one day as septic, and, after treatment, as having infection without SIRS. Because the clinical spectrum of SIRS to septic shock is a fluid continuum that can progress very rapidly, the patients were classified at the time of blood collection. No patient showed signs of infection at admission or on day 2 with fewer than two criteria of SIRS. However, this constellation occurred in two patients with resolving pneumonia under antibiotic therapy on the day of discharge to the medical ward. As expected, these patients showed declining, yet still elevated, calcitonin precursor levels in the absence of SIRS (1.2 ng/mL and 3.4 ng/mL, respectively). Because the focus of this study was on sepsis, we excluded these two time points from analysis because they did not fit in any of the defined categories.
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The clinical investigation and classification were carried out without knowledge of the test results for calcitonin precursors or interleukin-6, which were analyzed as batch analyses after the end of the study. Additionally, all remainders of daily routine morning blood samples were collected, and the results of these routine blood analyses (complete blood count, serum chemistry, blood gas analyses, and C-reactive protein) were also recorded.
Definitions. The following terms were used in the study. Systemic inflammatory response syndrome (SIRS) with no signs of infection, is characterized by the presence of at least two of the following four clinical criteria: a) fever or hypothermia (temperature > 100.4F [>38C] or <96.8F [<36C]); b) tachycardia (>90 beats/min); c) tachypnea (>20 breaths/min or PaCO2 <4.3 kPa [32 mm Hg] or the need for mechanical ventilatory support); and d) an altered white blood cell count of >12,000 cells/L, <4,000 cells/L, or the presence of >10% band forms, respectively. Sepsis is defined as SIRS with an infection (11). Infection was diagnosed by textbook standard criteria (24), or in case of uncertainty, by one of the authors who is an infectious disease specialist (WZ). Severe sepsis is defined as the presence of sepsis and at least one of the following manifestations of inadequate organ perfusion or function: a) hypoxemia (PaO2 of <10 kPa [<75 mm Hg]); b) metabolic acidosis (pH of <7.30); c) oliguria (output of <30 mL/hr); d) lactic acidosis (serum lactate level of >2 mmol/L); or e) an acute alteration in mental status without sedation (a reduction by >=3 points from baseline value in the Glasgow coma score). Septic shock is defined as the presence of sepsis accompanied by a sustained decrease in systolic blood pressure (<90 mm Hg, or a drop of 40 mm Hg from baseline systolic blood pressure) despite fluid resuscitation and the need for vasoactive amines to maintain adequate blood pressure. Severity of disease was estimated by the Acute Physiology and Chronic Health Evaluation II (25, 26), calculated by means of deviation of 12 physiologic variables from normal plus correction for age and different chronic illnesses (27).
Laboratory Measurements. For rapidity of determination, in the present study we chose to use a commercially available immunoluminometric assay to measure calcitonin precursors (LUMItest PCT; Brahms Diagnostica, Berlin, Germany). Two monoclonal antibodies bind at sites within two peptides: calcitonin and the calcitonin carboxypeptide I (Figure 1). Therefore, several calcitonin precursors are detected by this assay, procalcitonin, the conjoined calcitonin:calcitonin carboxypeptide-I, and perhaps, other yet uncharacterized peptides (28, 29). This immunoluminometric assay requires 20-50 L of plasma or serum and can be completed within 3 hrs. Interassay and intra-assay variations at low and high concentrations were <8% and <7%, respectively. The assay has the disadvantage of insensitivity, with a detection limit of ~0.3-0.5 ng/mL. A sensitive radioimmunoassay for calcitonin precursors has been developed that detects aminoprocalcitonin and the intact procalcitonin molecule (30-32). This assay, which was not available at the time the current study was commenced, has the advantage of a sensitivity of 0.004 ng/mL and detects values in nearly all normal persons. For elevated values, the calcitonin precursor levels obtained were similar with both assays (n = 275, r2 = .94, p < .01 by Spearman's rank-correlation test). Recent literature (16-23) refers to measurement of procalcitonin. However, this is incorrect, because none of the presently available assays measure the procalcitonin molecule exclusively (Figure 1). The commercially available two-site assay that we used for this study measures both procalcitonin and the conjoined calcitonin: calcitonin-carboxypeptide I. The more sensitive radioimmunoassay we developed uses an antibody to the amino portion of the prohormone. It detects both the intact procalcitonin and the free aminoprocalcitonin. We have shown (32) that in sepsis, several calcitonin precursors may be increased (intact procalcitonin, free aminoprocalcitonin, calcitonin-carboxypeptide-I, and the conjoined calcitonin:calcitonin-carboxypeptide I). Importantly, the extent to which any specific calcitonin precursor is increased, relative to the other peptides in hypercalcitonemic patients, varies. We have shown (32) that in the presence of sepsis, the levels of calcitonin-carboxypeptide I and aminoprocalcitonin may be even higher than procalcitonin values. For exactness of terminology, we have, therefore, chosen the term calcitonin precursors to indicate, globally, the immunoreactive material detected by these assays.
C-reactive protein was measured by an enzyme immunoassay (EMIT C-reactive protein assay; E. Merck Diagnostica, Zrich, Switzerland); a value of > 10 mg/L was considered to be abnormally elevated. Lactate concentrations were measured enzymatically (Du Pont, Wilmington, DE) (reference range 1.1-2.0 mmol/L). Serum IL6 concentrations were measured with a commercially available quantitative sandwich enzyme immunoassay (CLB; Pelikine Compact, Amsterdam, Netherlands) with a limit of detection at 0.6 pg/mL.
Statistical Analysis. Data in the text are shown as mean SD, and in the figures as SEM. Logarithmic transformation was applied to reduce skewness and normalize the distribution of data, if indicated by Shapiro-Wilk's W test. Two-group comparison (survivors vs. nonsurvivors) of normally distributed data were performed by Student's t-test. For multigroup comparisons, one-way analysis of variance was applied, with least square difference for post hoc comparison. For data not normally distributed, the Mann-Whitney U test was used if only two groups were compared, and the Kruskal-Wallis one-way analysis of variance was used if more than two groups were being
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compared, and the Kruskal-Wallis one-way analysis of variance was used if more than two groups were being compared. Predictive accuracy, the ability of a test to discriminate diseased patients from normal patients, was assessed by measuring the 95% confidence interval of the area under a receiver-operating-characteristic curve (33, 34). Levels that were nondetectable were assigned a value equal to the lower limit of detection for the assay. All testing was two-tailed, and a p of <.05 was considered statistically significant (35).
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RESULTS
Descriptive Characteristics of Patients. The median age of the 101 patients (55 men and 46 women) included in this study was 59 yrs (range, 23-86 yrs) and the mean Acute Physiology and Chronic Health Evaluation II score at admission was 22 8 points. The median length of stay in the ICU was 4 days (range, 0.2-60 days) with a mortality rate of 23%. The principal diagnoses of all patients are summarized in Table 1. In 70% of the 101 patients, antimicrobial therapy was administered during the ICU stay, whereas an infection was diagnosed in 58% of the patients (in 53 patients at admission; five additional patients developed sepsis during their stay in the medical ICU). The principal site of infection was the lung (Table 2). In 38 (66%) of the 58 patients with sepsis, the etiological microorganism was identified and 14 patients (24%) had bacteremia.
Table 1. Clinical diagnoses of the patients
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Table 2. Site of infection and microbiology Patients fulfilling more than two SIRS criteria were as follows: 99% of 101 patients at admission, 96% of 74 patients on day 2, and 68% of 95 patients on the day of discharge or death. Patients who were discharged or died on day 2 were classified into the latter group. The following percentages of patients were classified as having sepsis, severe sepsis, or septic shock: 53% at admission, 60% on day 2, and 36% on the day of discharge or death.
Laboratory Data. For the time points presented in this study, patients could be categorized into the following five groups: patients with neither signs of infection nor SIRS were classified as having no infection and no SIRS; patients fulfilling two or more criteria for SIRS without infection were classified as having SIRS; and patients with infection were classified as having sepsis, severe sepsis, or septic shock as defined above. Figure 2 illustrates the higher variability of serum interleukin-6 concentrations as compared with calcitonin precursor measurements in critically ill patients with different severities of disease and infection during their stay at the medical ICU. In the absence of infection, serum calcitonin precursor concentrations were not significantly elevated in patients with SIRS as compared with patients with no SIRS. Serum calcitonin precursor concentrations were significantly elevated only in patients with sepsis, severe sepsis, or septic shock, as compared with uninfected patients with or without SIRS (p < .01 for each comparison). In patients with sepsis, severe sepsis, or septic shock, serum concentrations of calcitonin precursors and C-reactive protein were higher in those with microbiologically documented bacterial infection as compared with those with no bacterial growth (36.9 60.5 vs. 6.6 8.9 ng/mL and 252 139 vs. 140 105 mg/L, respectively, p < .01), whereas Acute Physiology and Chronic Health Evaluation II score, interleukin-6, and lactate concentrations were not significantly different between the groups (23.3 10.6 vs. 21.0 10.7 points, 797 1804 vs. 483 1327 pg/mL and 3.6 6.1 vs. 3.4 4.8 mmol/L, respectively).
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Figure 2. Serum interleukin-6 and calcitonin precursor concentrations in critically ill patients. Interleukin-6 and calcitonin precursors measurements from the day of admission (n = 101) are represented by circles, from day 2 (n = 74) by squares, and from the day of discharge or death (n = 97) by triangles. p values of the logarithmic data (p < .01) were calculated by one-way analysis of variance. Logarithmic data describe the rise of serum concentrations of interleukin-6 and calcitonin precursors with increased severity of disease and infection. Statistical results were similar for data analyzed by time point or were combined. Diamonds represent mean, boxes SEM, and whiskers 1.96 SEM of the combined data (total n = 272). SIRS denotes systemic inflammatory response syndrome. Other terms used are defined in the Materials and Methods section. Serum calcitonin precursor concentrations were higher in septic patients who died than in those who survived (33.5 55.1 vs. 17.4 41.4 ng/mL, p = .01). The diagnostic reliability of serum calcitonin precursors compared with interleukin-6, C-reactive protein, and lactate concentrations was evaluated by using receiver operating characteristic curve analysis (Figure 3). Calcitonin precursors were found to be the most reliable markers for the diagnosis of sepsis at all time points investigated (p = .01).
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Figure 3. Receiver-operating-curve analysis of serum calcitonin precursors (solid circles) vs. interleukin-6 (solid triangles), C-reactive protein (open circles), and lactate (open trianlgles) concentrations. Values are shown for all time points (n = 272; 101 values at admission, 74 values on day 2, and 97 values on day of discharge or death) for the diagnoses of sepsis, severe sepsis, or septic shock. Table 3 summarizes the predictive accuracy of the laboratory variables for the specific diagnoses of sepsis, severe sepsis, or septic shock. With a cutoff value of 1 ng/mL, serum concentrations of calcitonin precursors were found to be the most discriminatory laboratory variable as compared with interleukin-6, C-reactive protein, and lactate values.
Table 3. Evaluation of laboratory parameters for the diagnosis of sepsis in a medical intensive care unit (%)
DISCUSSION
The recognition of sepsis in critically ill patients is difficult because no single variable of inflammation allows the establishment of the diagnosis (36). In this study of unselected but well-defined patients in a medical ICU, serum calcitonin precursor concentrations were shown to be the most reliable markers for the diagnosis of sepsis; furthermore, higher serum concentrations were associated with poorer prognosis.
The population of the present study was representative of patients admitted to a medical ICU (3, 37). It included a broad range of unselected medical patients with severe illnesses, unlike prior studies focusing on selected subpopulations, and excluding patients without infection or sepsis. The relatively high rate of negative culture results found in this study illustrates a common diagnostic dilemma for the clinician in a medical ICU, namely, many patients have been treated before admission, thus making the identification of a pathogenic microorganism often impossible (38). Hence, there is no gold standard to accurately diagnose sepsis, and all definitions and classifications are limited (39). To accurately validate signs and symptoms of infection, we applied standardized textbook definitions (24) and the expertise of a board-certified, infectious disease specialist (WZ).
Serum calcitonin precursor and interleukin-6 concentrations were determined in a blinded fashion and, therefore, did not influence the clinical evaluation of the patients. In contrast, the interpretation of C-reactive protein and lactate might be biased because their serum concentrations were known at the time of clinical investigation and classification. The reliability of interleukin-6, C-reactive protein, and lactate was mainly limited by the high variability of the test results in the different subgroups, thus reducing their usefulness as diagnostic markers in individual patients. These traditional markers reflect the nonspecific response of the organism to various stimuli, all resulting in a relatively common systemic inflammatory response, present in most critically ill patients (40, 41). In addition, only approximately half of the patients with septic syndrome have shown elevated cytokine levels (42, 43). Reported results of different cytokine-studies are contradictory. For example, very high concentrations of cytokines were reported (44) in patients with a rapid onset of septic shock; however, this could not be confirmed in another trial (45). The conflicting results in the literature, and the high variance found in the present study, might be explained by a sudden, transient, rather than sustained, cytokine release attributable to down-regulating mechanisms. Consequently, the levels of cytokines diminish despite ongoing infection and, therefore, are not reliable markers for the course of an infection (46). Another disadvantage is the bioinstability of some cytokines, such as tumor necrosis factor-[alpha], requiring immediate refrigeration and involving a fastidious, time-consuming determination. In contrast, calcitonin precursors are stable in vitro (47), and their analysis is rapid and easily performed.
The origin, metabolic pathway, and mediators responsible for the marked increase of calcitonin precursors
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The origin, metabolic pathway, and mediators responsible for the marked increase of calcitonin precursors during sepsis are enigmatic. These peptides are found in low concentrations in sera of normal persons, and several of these are variably increased in systemic inflammation, infection, and sepsis (31). Whether or not bacterial infection has been found, increased serum calcitonin precursor levels occur in pancreatitis (48, 49), chemical pneumonitis (50), burns (51, 52), and heat stroke (53). In addition, some parasitic infections such as malaria (54) or fungal infections (55), can substantially increase serum calcitonin precursor levels. Also, viral infections occasionally manifest moderately elevated calcitonin precursor concentrations (56). Whatever the initiating provocative insult may be, markedly severe systemic inflammation, per se, may manifest increased serum levels of calcitonin precursors. Additional studies are required to determine whether the increased serum calcitonin precursor levels of such apparently non-bacterial insults are a manifestation of translocation to the blood stream of bacterial products from the gut (57). The calcitonin precursor assay we used is reliable for the diagnosis of sepsis in a medical ICU. However, it does not detect the hypercalcitonemia of incipient and mild degrees of systemic inflammation or infection. Toward this goal, an alternative assay has been developed (31, 52).
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The administration of the calcitonin prohormone, procalcitonin, to septic hamsters with peritonitis markedly decreases their survival. Furthermore, treatment with procalcitonin-reactive antiserum increased survival of hamsters with experimental sepsis (58). These observations indicate that the procalcitonin molecule is a potentially harmful mediator involved in the response to sepsis. Whether treatment with antiserum reactive with this prohormone is able to improve the prognosis of sepsis in humans remains to be clarified in future studies.
In summary, this study suggests that the measurement of calcitonin precursors is a reliable and important marker for the diagnosis of sepsis in a medical ICU. The early diagnosis of sepsis might facilitate rapid initiation of antimicrobial and other appropriate treatment, thus potentially improving the unfavorable prognosis of sepsis and septic shock.
ACKNOWLEDGMENT
We are indebted to the staff of the medical ICU and of the laboratory of pathologic chemistry, University Hospitals, Basel, Switzerland. We thank M. A. Viollier, Th. Witschi, R. H. Snider, R. Landmann, J. Hoch, and M. Fischer for their help.
REFERENCES
1. Parillo JE, Parker MM, Natanson C, et al: Septic shock: Advances in the understanding of pathogenesis, cardiovascular dysfunctions, and therapy. Ann Intern Med 1990; 113: 227-242 [Context Link]
2. Tran DD, Groeneveld BJ, van der Meulen J, et al: Age, chronic disease, sepsis, organ system failure, and mortality in a medical intensive care unit. Crit Care Med 1990; 18:474-479 Solicitud de Documentos Texto Completo BVSSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
3. Brun-Buisson C, Doyon F, Carlet J, et al: Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. JAMA 1995; 274:968-974 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos Open Access [Context Link]
4. Manship L, McMillin RD, Brown JJ: The influence of sepsis and multisystem organ failure on mortality in the surgical intensive care unit. Am Surg 1984; 50:94-101 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
5. Niederman MS, Fein AM: Sepsis syndrome, the adult respiratory distress syndrome, and nosocomial pneumonia: A common clinical sequence. Clin Chest Med 1990; 11:633-650 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
6. Lowry SF: Sepsis and its complications: Clinical definitions and therapeutic prospects. Crit Care Med 1994; 22:S1S2 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
7. Executive Summary of an American College of Chest Physicians, National Institute of Allergy and Infectious Disease, and National Heart, Lung, and Blood Institute Workshop: From the bench to the bedside: The future of sepsis research. Chest 1997; 111:744-753 [Context Link]
Pgina 8 de 12
20/01/13 23:51
8. Warren HS: Strategies for the treatment of sepsis. N Engl J Med 1997; 336:952-953 Texto Completo BV-SSPA Texto Completo Recursos de Internet Enlaces Bibliograficos [Context Link]
9. Bryant RE, Hood AF, Hood CE, et al: Factors affecting mortality of gram-negative bacteremia. Arch Intern Med 1971; 127:120-128 [Context Link]
10. Bryan CS, Reynold KL, Brenner ER: Analysis of 1186 episodes of gram-negative bacteremia in non-university hospitals: The effects of antimicrobial therapy. Rev Infect Dis 1983; 5:629-638 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
11. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864-874 [Context Link]
12. Schwartz B, Bell DM, Hughes JM: Preventing the emergence of antimicrobial resistance. A call for action by clinicians, public health officials, and patients. JAMA 1997; 278:944-945 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos Open Access [Context Link]
13. Cohen FL, Tartasky D: Microbial resistance to drug therapy: A review. Am J Infect Control 1997; 25:51-64 [Context Link]
14. Lingnau W, Allerberger F: Control of an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) by hygienic measures in a general intensive care unit. Infection 1994; 22:135-139 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet [Context Link]
15. Becker KL, Nyln ES, Cohen R, et al: Calcitonin gene family of peptides. In: Principles and Practice of Endocrinology and Metabolism. Becker KL (Ed). Second Edition. Philadelphia, JB Lippincott, 1995, pp 474-483 [Context Link]
16. Mallet E, Lanse X, Devaux AM, et al: Hypercalcitoninaemia in fulminant meningococcaemia in children. Lancet 1983; i:294 [Context Link]
17. Chesney RW, McCarron DM, Haddad JG, et al: Pathogenic mechanisms of the hypocalcemia of the staphylococcal toxic-shock syndrome. J Lab Clin Med 1983; 101:576-585 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
18. Becker KL, Silva OL, Snider RH, et al: The pathophysiology of pulmonary calcitonin. In: The Endocrine Lung in Health and Disease. Becker KL, Gazdar AF (Eds). Philadelphia, WB Saunders, 1984, pp 277-279 [Context Link]
19. Assicot M, Gendrel D, Carsin H, et al: High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993; 341:515-518 Texto Completo BV-SSPA Texto Completo Recursos de Internet Enlaces Bibliograficos [Context Link]
20. Lind L, Bucht E, Ljunghall S: Pronounced elevation in circulating calcitonin in critical care patients is related to the severity of illness and survival. Intensive Care Med 1995; 21:63-66 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
21. Gendrel D, Assicot M, Raymond J, et al: Procalcitonin as a marker for the early diagnosis of neonatal infection. J Pediatr 1996; 128:570-573 Texto Completo BV-SSPA Texto Completo Recursos de Internet Enlaces Bibliograficos [Context Link]
22. de Werra I, Jaccard C, Corradin SB: Cytokines, nitrite/nitrate, soluble tumor necrosis factor receptors, and procalcitonin concentrations: Comparisons in patients with septic shock, cardiogenic shock, and bacterial pneumonia. Crit Care Med 1997; 25:607-613 [Context Link]
Pgina 9 de 12
20/01/13 23:51
23. Grard Y, Hober D, Assicot M, et al: Procalcitonin as a marker of bacterial sepsis in patients infected with HIV-1. J Infect 1997; 35:41-46 Texto Completo BV-SSPA Texto Completo Recursos de Internet Enlaces Bibliograficos [Context Link]
24. Young LS: Sepsis syndrome. In: Principles and Practice of Infectious Diseases. Mandell GL, Bennett JE, Dolin R (Eds). Fourth Edition. New York, NY, Churchill Livingston, 1995, pp 690-705 [Context Link]
25. Knaus WA, Draper EA, Wagner DP, et al: APACHE II: A severity of disease classification system. Crit Care Med 1985; 13:818-829 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
26. Wagner DP, Knaus WA, Harrell FE, et al: Daily prognostic estimates for critically ill adults in intensive care units: Results from a prospective, multicenter, inception cohort analysis. Crit Care Med 1994; 22:1359-1372 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
27. Castella X, Artigas A, Bion J, et al: A comparison of severity of illness scoring systems for intensive care unit patients: Results of a multicenter, multinational study. Crit Care Med 1995; 23:1327-1335 Texto Completo BV-SSPA Texto Completo OVID Recursos de Internet Enlaces Bibliograficos [Context Link]
28. Ghillani PP, Mott P, Troalen F, et al: Identification and measurement of calcitonin precursors in serum of patients with malignant diseases. Cancer Res 1989; 49:6845-6851 Solicitud de Documentos Texto Completo BVSSPA Recursos de Internet Enlaces Bibliograficos Open Access [Context Link]
29. Becker KL, Nylen ES, Cohen R, et al: Calcitonin: Structure, molecular biology, and actions. In: Principles of Bone Biology. Bilezikian JP, Raisz LG, Rodan GA (Eds). New York, Academic Press, 1996, pp 471-494 [Context Link]
30. Nylen ES, Jeng J, Jordan MH, et al: Late pulmonary sequela following burns: Persistence of hyperprocalcitonemia using a 1-57 amino acid N-terminal flanking peptide assay. Respir Med 1995; 89:41-46 [Context Link]
31. Whang KT, Steinwald PM, White JC, et al: Serum calcitonin precursors in sepsis and systemic inflammation. J Clin Endocrinol Metab 1998; 83:3296-3301 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos Open Access [Context Link]
32. Snider RH, Nylen ES, Becker KL: Procalcitonin and its component peptides in systemic inflammation: Immunochemical characterization. J Invest Med 1997; 45:552-560 Solicitud de Documentos Texto Completo BVSSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
33. Zweig MH, Campbel G: Receiver-operating characteristic (ROC) plots: A fundamental evaluation tool in clinical medicine. Clin Chem 1993; 39:561-577. [Erratum published in Clin Chem 1993; 39:1589] [Context Link]
34. Griner PF, Mayewski RJ, Mushlin AI, et al: Selection and interpretation of diagnostic tests and procedures. Ann Intern Med 1981; 94:555-600 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet [Context Link]
35. Altman DG: Practical statistics for medical research. First Edition. London, Chapman & Hall, 1991 [Context Link]
36. Fassbender K, Pargger H, Mller W, et al: Interleukin-6 and acute-phase protein concentrations in surgical intensive care unit patients: Diagnostic signs in nosocomial infections. Crit Care Med 1993; 21:1175-1180 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
37. Rangel-Frausto MS, Pittet D, Costigan M, et al: The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 1995; 273:117-123 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos Open Access [Context Link]
38. van Dissel JT, van Langevelde P, Westendorp RGJ, et al: Anti-inflammatory cytokine profile and mortality in
Pgina 10 de 12
20/01/13 23:51
febrile patients. Lancet 1998; 351:950-953 Texto Completo BV-SSPA Texto Completo Recursos de Internet Enlaces Bibliograficos [Context Link]
39. Vincent JL: Dear SIRS, I'm sorry to say that I don't like you... Crit Care Med 1997; 25:372-374 Texto Completo BV-SSPA Texto Completo OVID Recursos de Internet Enlaces Bibliograficos [Context Link]
40. Van Snick J: Interleukin-6. An overview. Annu Rev Immunol 1990; 8:253-278 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
41. Hoch RC, Rodriguez R, Manning T, et al: Effects of accidental trauma on cytokine and endotoxin production. Crit Care Med 1993; 21:839-845 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
42. Casey L, Balk RA, Bone RC: Plasma cytokine and endotoxin levels correlate with survival in patients with septic syndrome. Ann Intern Med 1993; 119:771-778 Texto Completo BV-SSPA Texto Completo OVID Recursos de Internet Enlaces Bibliograficos [Context Link]
43. de Groote MA, Martin MA, Densen P, et al: Plasma tumor necrosis factor levels in patients with presumed sepsis. JAMA 1989; 262:249-251 [Context Link]
44. Damas P, Canivet JL, De Groote D, et al: Sepsis and serum cytokine concentrations. Crit Care Med 1997; 25:405412 Texto Completo BV-SSPA Texto Completo OVID Recursos de Internet Enlaces Bibliograficos [Context Link]
45. Pinsky MR, Vincent JL, Deviere J, et al: Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest 1993; 103:65-75 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet [Context Link]
46. Calandra T, Gerain J, Heumann D, et al: High circulating levels of interleukin-6 in patients with septic shock: Evolution during sepsis, prognostic value, and interplay with other cytokines. Am J Med 1991; 91:23-29 [Context Link]
47. Meisner M, Tschaikowsky K, Schnabel S, et al: Procalcitonin-Influence of temperature, storage, anticoagulation and arterial or venous asservation of blood samples on procalcitonin concentrations. Eur J Clin Chem Clin Biochem 1997; 35:597-601 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
48. Canale DD, Donabedian RK: Hypercalcitonemia in acute pancreatitis. J Clin Endocrinol Metab 1975; 40:738-741 [Context Link]
49. Rau B, Steinbach G, Gansauge F, et al: The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis. Gut 1997; 41:832-840 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos Open Access [Context Link]
50. Nylen ES, Snider RH Jr, Thompson KA, et al: Pneumonitis-associated hyperprocalcitoninemia. Am J Med Sci 1996; 312:12-18 [Context Link]
51. O'Neill WJ, Jordan MH, Lewis MS, et al: Serum calcitonin may be a marker for inhalation injury in burns. J Burn Care Rehabil 1992; 13:605-616 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
52. Nylen ES, O'Neill W, Jordan MH, et al: Serum procalcitonin as an index of inhalation injury in burns. Horm Metab Res 1992; 24:439-442 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
53. Nylen ES, Arifi A, Becker KL, et al: Effect of classic heatstroke on serum procalcitonin. Crit Care Med 1997; 25:1362-1365 Texto Completo BV-SSPA Texto Completo OVID Recursos de Internet Enlaces Bibliograficos [Context Link]
Pgina 11 de 12
[Context Link]
20/01/13 23:51
54. Davis TME, Assicot M, Bohuon C, et al: Serum procalcitonin concentrations in acute malaria. Trans R Soc Trop Med Hyg 1994; 88:670-671 Texto Completo BV-SSPA Texto Completo Recursos de Internet Enlaces Bibliograficos [Context Link]
55. Grard Y, Hober D, Petitjean S, et al: High serum procalcitonin level in a 4-year-old liver transplant recipient with disseminated candidiasis. Infection 1995; 5:310-311 [Context Link]
56. Gendrel D, Raymond J, Assicot M, et al: Measurement of procalcitonin levels in children with bacterial or viral meningitis. Clin Infect Dis 1997; 24:1240-1242 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos Open Access [Context Link]
57. Swank GM, Deitch EA: Role of the gut in multiple organ failure: Bacterial translocation and permeability changes. World J Surg 1996; 20:411-417 Solicitud de Documentos Texto Completo BV-SSPA Recursos de Internet Enlaces Bibliograficos [Context Link]
58. Nylen ES, Whang KT, White JC: Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis. Crit Care Med 1998; 26:1001-1006 Texto Completo BV-SSPA Texto Completo OVID Recursos de Internet Enlaces Bibliograficos [Context Link]
Key Words: calcitonin; infection; sepsis; inflammation; critical illness; acute disease; protein precursors; diagnosis; differential diagnosis; biological markers; antibiotics
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2000 - Calcitonin Precursors Are Reliable Markers of Sepsis in A Medical Intensive Care Unit (CritCare)

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2000 - Calcitonin Precursors Are Reliable Markers of Sepsis in A Medical Intensive Care Unit (CritCare)

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Ovid: Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit.

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MATERIALS AND METHODS

Table 1. Clinical diagnoses of the patients

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