ACLS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dalton, R. R.
Right arrow Articles by Martin, S. L. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dalton, R. R.
Right arrow Articles by Martin, S. L. A.
Annals of Clinical & Laboratory Science 33:435-442 (2003)
© 2003 Association of Clinical Scientists

Plasma C-Reactive Protein Levels in Severe Diabetic Ketoacidosis

Rory R. Dalton1, William H. Hoffman2, Gregory G. Passmore3 and S. Lee Anne Martin1
Departments of 1 Pathology, 2 Pediatrics, and 3 Radiologic Sciences, Medical College of Georgia, Augusta, Georgia

Address correspondence to William H. Hoffman, M.D., Section of Pediatric Endocrinology, BG-1012, Medical College of Georgia, Augusta, GA 30912, USA; tel 706 721 4158; fax 706 721 1484; e-mail: whoffman{at}mail.mcg.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Elevated plasma levels of C-reactive protein (CRP) and IL-6 have been reported to be sensitive indicators of infection in adults with diabetic ketoacidosis (DKA). However, both CRP and the pro-inflammatory cytokines, which regulate CRP, can be elevated without infection. Our hypothesis was that CRP is increased in young patients with severe DKA, even in the absence of an infection, and may serve as a marker for systemic inflammatory response syndrome (SIRS). In 7 patients with severe DKA without infection, we measured plasma CRP, IL-6, IL-1ß and TNF-{alpha} levels prior to, during, and following correction of DKA. CRP was significantly but transiently elevated in 4 of the patients prior to or during treatment of DKA, compared to their baseline values (96 hr after correction of DKA). There were significant positive relationships between CRP and both IL-6 and IL-1ß prior to treatment (p <0.05); between CRP and IL-6, IL-1ß, and TNF-{alpha} at 6 hr (p <0.05); and between CRP and IL-1ß at 24 hr (p <0.05). The results support the hypothesis that CRP is increased in some patients by severe DKA and its treatment, and that DKA can be associated with a non-infectious form of SIRS.

(received 13 November 2002; accepted 9 June 2003)

Keywords: C-reactive protein, diabetic ketoacidosis, cytokines, systemic inflammatory response syndrome


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
C-reactive protein (CRP) is a type I acute phase response protein whose synthesis in the liver is regulated by the pro-inflammatory cytokines IL-6, IL-1ß, and TNF-{alpha} [1,2]. CRP has been established as a marker for adverse outcome in acute coronary syndromes, atherosclerosis [3], and ischemic cerebro-vascular accidents [4]. Elevated plasma levels of CRP have been reported to be markers for endothelial cell dysfunction in uncomplicated, well-controlled, type 1 diabetes mellitus (TIDM) [5] and in children with TIDM within the first year after diagnosis [6]. A positive association between CRP and HbA1c has recently been found in adults with diabetes mellitus [7]. CRP and IL-6 have also been reported to be early markers of infection in adults with diabetic ketoacidosis (DKA) and with diabetic hyperosmolar nonketotic coma (DHNK)[8].

Brain and pulmonary edema are acute life-threatening complications that can occur in children with DKA [9]. The traditional explanations for these uncommon complications do not fully explain their apparently unpredictable occurrence. We have suggested that the subclinical forms of edema that develop prior to the treatment of DKA [10–12] are the consequence of metabolic stress on the micro-vasculature of the brain. Subsequent progression of subclinical edema [10–12] and the occasional decompensation to clinical brain edema [13,14] may be the result of various forms of endothelial perturbation induced by the treatment of DKA. This hypothesis is supported by in vitro studies of the effects of beta-hydroxybutyrate and acetoacetate on endothelial cells [15,16] and by measurements of in vivo cellular activation in DKA [17–19].

Although elevated plasma CRP levels have been viewed as an epi-phenomenon [20], experimental evidence indicates that CRP induces adhesion molecule expression in endothelial cells [21] and stimulates macrophage production of cytokines at sites of inflammation [22]. Support for a direct role of CRP on endothelial function has recently been demonstrated by Verma et al [23], who reported a quenching effect of CRP on nitric oxide production. The pleiotropic pro-inflammatory cytokines that regulate CRP synthesis can directly affect endothelial cell function by increasing capillary permeability [24]. Counter-regulatory hormones, which are elevated in DKA, have been reported to potentiate IL-6 in the in vitro production of CRP [25].

The purposes of this investigation were (a) to determine if increased plasma CRP levels occur in young patients with severe DKA who do not have clinical evidence of infection, and (b) to relate observed changes in CRP level to the pro-inflammatory cytokine levels and the time-course of subclinical brain edema [10,11].


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Human subjects.  Patients between the ages of 8 and 17 yr who came to the Medical College of Georgia Emergency Department with severe diabetic DKA (pH <7.2) and normal temperatures, with no clinical evidence of an acute infection, nor pancreatitis, nor a history of chronic infection, were eligible. They were enrolled after obtaining informed consent or assent in accordance with the policies and procedures of the Institutional Human Assurance Committee.

Acute infection was ruled out based upon the separate medical histories and physical examinations performed by the pediatric emergency physician and the pediatric endocrinologist, as well as the sequential evaluations by the pediatric intensivist, during the patient’s stay in the Pediatric Intensive Care Unit (PICU). Patients were treated in the PICU using a previously described protocol [11]. Two of the patients (#1 and 2) were included in a previously published report [19].

Blood collection and analysis.  Blood samples were obtained prior to the onset of insulin therapy (designated 0 hr) and at 6–8, 24, and 120 hr after the initiation of treatment. Samples for CRP and cytokine analyses were withdrawn into chilled EDTA tubes and immediately centrifuged at 4°C at 2500 rpm for 20 min. The plasma was separated and kept at -80°C until assayed.

Plasma IL-1ß, IL-6, and TNF-{alpha} were measured with commerical ELISA kits (Pierce-Endogen, Rockford, IL) according to the manufacturer’s instructions. These cytokine assays were performed in triplicate in the laboratory of Dr. R. Powell, University of Maryland.

Plasma CRP was measured in the laboratory of Dr. R. P. Tracy, University of Vermont, by a high-sensitivity ELISA assay [26]. Other laboratory tests were performed using standard clinical chemistry and hematological procedures in our hospital’s clinical laboratories.

Statistics.  Repeated measures ANOVA were planned to answer the research question about evidence of increases in plasma CRP and cytokine levels associated with sampling time during a DKA event, using each patient as his/her own control. If significant differences in CRP and cytokine levels over time were established, then pairwise comparisons were planned to determine when the significant differences existed with respect to time. Effect sizes for significant differences in CRP or cytokine groups over time were calculated. Further, tests of correlation and regression were planned to answer the research question about patterns of relationships in CRP and cytokine levels associated with sampling time during the DKA event.

Values for CRP and cytokines were grouped by time and compared using Friedman’s repeated measures ANOVA. Differences in CRP or cytokine groups were analyzed using Wilcoxon’s signed rank test. Relationships between cytokines at individual time-points were compared using Spearman’s Rho correlation coefficient. Patterns of CRP and cytokine expression in relation to time were tested by linear regression. The value at 120 hr was considered the "baseline" value for all analyses. Summary values for each time point are reported as mean ± SD, median, and range. Effect sizes for significant differences in CRP groups over time were calculated. The null hypothesis was rejected at p <0.05 [27].


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
Seven patients with TIDM were studied (5 male, 2 female; age range = 10.5 to 16 yr). The metabolic and hematologic profiles at admission for each patient are listed in Tables 1Go and 2Go. Acidosis was corrected in all patients within 24–36 hr, and no patient had blood glucose values less than 11.1 mmol/L (200 mg/dl) during treatment. All patients had uneventful hospital courses.


View this table:
[in this window]
[in a new window]
  		Table 1. Profiles of serum analytes in the 7 patients with severe diabetic ketoacidosis (DKA) on admission to the hospital.
 

View this table:
[in this window]
[in a new window]
  		Table 2. Hematological profiles in the 7 patients with severe diabetic ketoacidosis (DKA) on admission to the hospital.
 
The time course for plasma CRP levels is illustrated in Fig. 1Go. CRP was elevated (>3 ug/ml) [3] in 3 of 7 patients prior to treatment. The median pre-treatment CRP value was 1.91 µg/dl (range 0.45–5.42); at 6–8 hr, 3.41 µg/dl (range 0.5–6.8); at 24 hr, 2.09 µg/dl (range 0.78–13.11); and at 120 hr, 0.63 µg/dl (range 0.46–1.63). ANOVA comparisons indicated CRP levels had differences associated with sample time ({chi}2 = 9.386, p <0.05). Wilcoxon signed rank analyses showed that the pre-treatment, 6–8 hr, and 24-hr samples were each significantly elevated from the 120-hr (baseline) sample (p <0.05). The effect size for each CRP time comparison to baseline was large (0.78 to 1.05), meaning that the phenomenon observed in the sample is present in the population [28]. There were no significant differences in CRP levels between pre-treatment, 6–8 hr, and 24 hr, indicating significant elevations during the entire DKA event.



View larger version (18K):
[in this window]
[in a new window]
  		Fig. 1. Plasma concentrations of C-reactive protein (CRP) before, during, and after the correction of DKA. The dotted line represents the upper limit of normal.

 
The time courses for IL-6, IL-1ß and TNF-{alpha} are shown in Figs. 2Go–4Go. All patients had elevated levels of IL-6 (>5 pg/ml) prior to treatment; 3 increased after initiation of treatment; and 2 remained elevated at 120 hr. Three patients had elevated levels of IL-1ß (>5 pg/ml) prior to treatment; each had increases after initiation of treatment and each remained elevated at 120 hr. Five patients had elevated TNF-{alpha} levels (>5 pg/ml) prior to treatment; 3 of these had increases after initiation of treatment; all 5 remained elevated at 120 hr. The patient (#5) with the greatest elevation of IL-6 pretreatment also had the greatest elevation of CRP. This patient had no increase of IL-1ß or TNF-{alpha}. Three patients had elevations of cytokines and no increase in CRP.



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 2. Plasma concentrations of interleukin-6 (IL-6), before, during, and after the correction of DKA. The dotted line represents the upper limit of normal.

 


View larger version (17K):
[in this window]
[in a new window]
  		Fig. 4. Plasma concentrations of tumor necrosis factor-alpha (TNF-{alpha}) before, during, and after the correction of DKA. The dotted line presents the upper limit of normal.

 
Spearman Rho correlation analyses indicated statistically significant correlations for CRP and IL-6 at pre-treatment (r = 0.9, p <0.05) and at 6 hr (r = 1.0, p <0.05); for CRP and IL-1ß at pre-treatment (r = 1.0, p <0.05), at 6 hr (r = 1.0, p <0.05), and at 24 hr (r = 1.0, p <0.05); and for CRP and TNF-{alpha} at 6 hr (r = 1.0, p <0.05). None of the pretreatment clinical chemistry test results had statistically significant relationships to CRP, IL-6, IL-1ß, or TNF-{alpha}.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
We found that in the absence of infection, plasma CRP levels are elevated in some children and adolescents prior to and/or during the treatment of DKA, and that there is a positive association between CRP secretion and the regulatory pro-inflammatory cytokines. Positive correlations existed for CRP and each of the pro-inflammatory cytokines, either prior to or during treatment of DKA. All patients with an increase in CRP also had an increase in IL-6.

Our results support the hypothesis that CRP is secreted in DKA as the result of a stimulus distinct from infection [8]; however, the study does not allow us to identify definitely the initiating event for the increase in CRP. O’Riordain et al [25] suggest that both the cytokine and counter-regulatory hormone networks influence CRP and other acute phase proteins at the time of critical care illness, through complex interactions. Although it has been suggested that insulin is an anti-inflammatory hormone [29,30], our results do not support such a role in this setting.

Jonkers et al [31] reported that hypertriglyceridemia, which is known to occur in DKA, may be a contributing factor to the increased levels of CRP, IL-6, IL-1ß and TNF-{alpha}. Ohta et al [32] reported a role for triglycerides and apolipoproteins in the increased expression of the adhesion molecules VCAM-1 and ICAM-1. It is important to note that the antioxidants, vitamin E, which is reported to decrease CRP and IL-6 [33], and vitamin C [34], which has been reported to correlate with severity of atherosclerosis, were both recently reported to be decreased during the treatment of DKA [35].

Six of our patients had leukocyte counts >15,000/mm3, which returned to normal at 24 hr. Others have reported that leukocytosis is commonly present in DKA, even without an infection [36]. On admission to the Emergency Department, 6 of our patients, as would most patients with severe DKA, met the clinical criteria for the systemic inflammatory response syndrome (SIRS)[37]. In addition to the leukocytosis, all of the patients, except patient #6, had pre-treatment levels of IL-6 and/or CRP that gave them a SIRS score comparable to those reported for patients with SIRS without infection [8,38]. Pretreatment IL-1ß and TNF-{alpha} levels, additional markers of SIRS, were also in the ranges that supports the presence of SIRS [39]. Unlike CRP, which was lowest in all patients at 120 hr, each of the 3 cytokines remained elevated in 2 patients at 120 hr. In regard to the prolonged elevation of both IL-6 and TNF-{alpha} levels, it is interesting that Erbagci et al [40] studied children with TIDM and reported significant elevations of these cytokines when diabetes was present for <1 yr, compared to children who had diabetes for >1 yr.

Although clinical brain edema is an uncommon event [13], if present it usually becomes manifest within 13 hr after the initiation of treatment [14]. In this regard, patients who had increased plasma levels of CRP had their maximum level 6–24 hr following the initiation of treatment. This time course is consistent with other potential mediators of capillary perturbation [19,41]. In regard to the patients who did not have an increase in CRP, it has been reported that the anti-inflammatory hormone IL-10 correlates inversely with IL-6 and CRP in acute coronary syndromes [42,43].

In a comparable group of patients, we have recently reported that some patients had elevated plasma IL-10 levels prior to treatment [19]. While IL-10 was not measured in the present study, it is reasonable to speculate that patients who did not have increased levels of CRP may have had elevated levels of IL-10 prior to treatment. The variable response of CRP, despite comparable degrees of metabolic decompensation, is in keeping with the variable course of subclinical brain edema [10] and the unpredictable occurrence of clinical brain edema.

Elevated levels of CRP have also been associated with adverse outcomes in ischemic stroke [4]. Kossmann et al [44] reported a correlation between the elevations of CRP and IL-6 in the serum and cerebrospinal fluid of patients with traumatic brain injuries. CRP may not have an adverse effect on all organ systems. Several lines of evidence suggest that CRP may protect against the development of the acute respiratory distress syndrome (ARDS) [45,46].

Whether CRP or any of the other acute phase proteins are involved in the progression of subclinical edema and/or the development of clinical brain edema remains to be determined. However, it seems likely that the transient increase of CRP during DKA and its treatment, as well as increases in lipid peroxidation [35] and 3-deoxyglucosone [41], may augment the progression of atherosclerosis [47].

In summary, plasma levels of CRP and the inflammatory cytokines are increased in some children with DKA in the absence of infection. This observation supports a biologic role for the increased pro-inflammatory cytokines that are observed during the treatment of DKA [19]. It also supports the view that, in some patients, the metabolic insult of DKA and its treatment can result in SIRS [8]. The roles of acute phase proteins and the components of SIRS in the acute complications of DKA warrant further investigation.



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 3. Plasma concentrations of interleukin-1beta (IL-1ß) before, during, and after the correction of DKA. The dotted line represents the upper limit of normal.

 

   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
The authors acknowledge the dedicated care provided by the staff of the Emergency Department and Pediatric Critical Care Unit. The authors are grateful for the assistance of Dr. R. P. Tracy in performing CRP assays, Dr. R. Powell in performing cytokine assays, Dr. John Steele and Dr. Natalie Lane for reviewing the manuscript, and Ms. C Masters for expert secretarial support.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Moshage H. Cytokines and the hepatic acute phase response. J Pathol 1997;181:257–266.[Medline]
  2. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340:448–554.[Free Full Text]
  3. Burke AP, Tracy RP, Kolodgie F, et al. Elevated C-reactive protein values and atherosclerosis in sudden coronary death. Circulation 2002;105:2019–2023.[Abstract/Free Full Text]
  4. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001;32:917–924.[Abstract/Free Full Text]
  5. Ciarla MV, Bocciarelli A, Di Gregorio S, et al. Autoantibodies and endothelial dysfunction in well-controlled, uncomplicated insulin-dependent diabetes mellitus patients. Atherosclerosis 2001;158:241–246.[Medline]
  6. Romano M, Pomilio M, Vigneri S, et al. Endothelial perturbation in children and adolescents with type 1 diabetes: association with markers of the inflammatory reaction. Diabetes Care 2001;24:1674–1678.[Abstract/Free Full Text]
  7. King DE, Mainous AG, Buchanan A, et al. C-reactive protein and glycemic control in adults with diabetes. Diabetes Care 2003;26:1535–1539, 2003.[Abstract/Free Full Text]
  8. Gogos CA, Giali S, Paliogianni F, et al. Interleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis. Diabetologia 2001;44:1011–1014.[Medline]
  9. Scibilia,J, Finegold D, Dorman J, et al. Why do children with diabetes die? Acta Endocrinol (Suppl) 1986;279:326–333.
  10. Hoffman WH, Steinhart CM, el Gammal T, et al. Cranial CT in children and adolescents with diabetic ketoacidosis. Am J Neuroradiol 1988;9:733–739.[Abstract]
  11. Durr JA, Hoffman WH, Sklar AH, et al. Correlates of brain edema in uncontrolled IDDM. Diabetes 1992;41: 627–632.[Abstract]
  12. Hoffman WH, Locksmith EM, Burton, et al. Interstitial pulmonary edema in children and adolescents with diabetic ketoacidosis. J Diabetes Complic 1998;12:314–320.[Medline]
  13. Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin-dependent diabetes 1990–1996. Arch Dis Child 1999; 81:318–323.[Abstract/Free Full Text]
  14. Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med 2001; 344:264–269.[Abstract/Free Full Text]
  15. Isales CM., Min L, Hoffman WH. Acetoacetate and beta-hydroxybutyrate differentially regulate endothelin-1 and vascular endothelial growth factor in mouse brain micro-vascular endothelial cells. J Diabetes Complic 1999;13:91–97.[Medline]
  16. Hoffman WH, Cheng C, Passmore GG, et al. Aceto-acetate increases expression of ICAM-1 in human brain microvascular endothelial cells. Neurosci Lett 2002;334: 71–74.[Medline]
  17. Hoffman WH, Helman SW, Passmore G. Acute activation of peripheral lymphocytes during treatment of diabetic ketoacidosis. J Diabetes Complic 2001;15:144–149.[Medline]
  18. Carl GF, Hoffman WH, Passmore GG, et al. Diabetic ketoacidosis promotes a prothombotic state. Endocrine Res 2003;29:73–82.[Medline]
  19. Hoffman WH, Burek CL, Waller JL, et al. Cytokine response to diabetic ketoacidosis and its treatment. Clin Immunol (In press).
  20. Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation 1999;100:96–102.[Abstract/Free Full Text]
  21. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102:2165–2168.[Abstract/Free Full Text]
  22. Galve-de Rochemonteix B, Wiktorowicz K, Kushner I, et al. C-reactive protein increases production of IL-1 alpha, IL-1 beta, and TNF-alpha, and expression of mRNA by human alveolar macrophages. J Leukoc Biol 1993;53:439–445.[Abstract]
  23. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 2002; 106:913–919.[Abstract/Free Full Text]
  24. Nooteboom A, Van Der Linden CJ, Hendricks T. Tumor necrosis factor-alpha and interleukin-1 beta mediate endothelial permeability induced by lipopolysaccharide-stimulated whole blood. Crit Care Med 2002;30:2063–2068.[Medline]
  25. O’Riordain MG, Ross JA, Fearon KC, et al. Insulin and counterregulatory hormones influence acute-phase protein production in human hepatocytes. Am J Physiol 1995;269:E323–330.
  26. Macy E, Hayes T, Tracy R. Variability in the measurement of C-reactive protein in healthy subjects: implication for reference interval and epidemiological applications. Clin Chem 1997;43:52–58.[Abstract/Free Full Text]
  27. Zar, JH. Biostatistical Analyses. Prentice-Hall, Englewood Cliffs, NJ, 1974, pp 198–215.
  28. Cohen J, Statistical Power Analyses for the Behavioral Sciences (2nd ed), Lawrence Erlbaum Assoc Pub, Hillsdale, NJ, 1988, pp 20–27.
  29. Das UN. Is insulin an anti-inflammatory molecule? Nutrition 2001;17:409–413.[Medline]
  30. Sleightholm MA, Gallimore R, Tennent GA, et al. Continuous subcutaneous insulin infusion does not provoke significant acute-phase response. Diabetes Care 1986;9:50–52.[Abstract]
  31. Jonkers IJ, Mohrschladt MF, Westendorp RG, et al. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 2002; 112:275–280.[Medline]
  32. Ohta T, Saku K, Takata K, et al. Soluble vascular cell-adhesion molecule-1 and soluble intercellular adhesion molecule-1 correlate with lipid and apolipoprotein risk factors for coronary artery disease in children. Eur J Pediatr 1999;158:592–598.[Medline]
  33. Devaraj S, Jialal I. Alpha tocopheral supplementation decreases C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Radical Biol Med 2000;29:790–792.[Medline]
  34. Langlois M, Duprey D, Delanghe J, et al. Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis. Circulation 2001;103:1863–1886.[Abstract/Free Full Text]
  35. Lee DM, Hoffman WH, Carl GF, et al. Lipid peroxidation and antioxidant vitamins prior to, during, and after correction of diabetic ketoacidosis. J Diab Complic 2002; 16:294–300.
  36. Flood RG, Chiang VW. Rate and prediction of infection in children with diabetic ketoacidosis. Am J Emerg Med 2001;19:270–273.[Medline]
  37. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644–1655.[Abstract/Free Full Text]
  38. Takala A, Jousela I, Olkkola KT, et al. Systemic inflammatory response syndrome without systemic inflammation in acutely ill patients admitted to hospital in a medical emergency. Clin Sci 1999;96:287–295.[Medline]
  39. Rodriguez-Gaspar M, Santolaria F, Jarque-Lipez A. Prognostic value of cytokines in SIRS general medical patients. Cytokine 2001;15:232–236.[Medline]
  40. Erbagci AB, Tarakcioglu M, Coskun Y, et al. Mediators of inflammation with type 1 diabetes mellitus: cytokines in type 1 diabetic children. Clin Biochem 2001;34:645–650.[Medline]
  41. Hoffman WH, Kappler F, Passmore GG, et al. Diabetic ketoacidosis and its treatment increase 3-deoxyglucosone. Clin Biochem 2003;36:269–273.[Medline]
  42. Heeschen C, Dimmeler S, Hamm CW, et al. Serum level of the anti-inflammatory cytokine interleukin-10 is an important prognostic determinant in patients with acute coronary syndromes. Circulation 2003;107:2109–2114.[Abstract/Free Full Text]
  43. Yamashita H, Shimada K, Seki E, et al. Concentrations of interleukins, interferon, and C-reactive protein in stable and unstable angina pectoris. Am J Cardiol 2003;91:133–136.[Medline]
  44. Kossmann T, Hans VH, Imhof HG, et al. Intrathecal and serum interleukin-6 and the acute phase response in patients with severe traumatic brain injuries. Shock 1995; 4:311–317.[Medline]
  45. Abernathy VJ, Webster RO, Dahms TE. C-reactive protein inhibits increased pulmonary vascular permeability induced by fMLP in isolated rabbit lungs. Am J Physiol 1996;271:H507–513.
  46. Heuertz RM, Webster RO. Role of C-reactive protein in acute lung injury. Mol Med Today 1997;3:539–545.[Medline]
  47. Schalkwijk CG, Poland DCW, van Diyk W, et al. Plasma concentration of C-reactive protein is increased in type 1 diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation. Diabetologia 1993;42: 351–357.



This article has been cited by other articles:


Home page
 PediatricsHome page
F. H. Mahmud, D. A. Ramsay, S. D. Levin, R. N. Singh, T. Kotylak, and D. D. Fraser
Coma With Diffuse White Matter Hemorrhages in Juvenile Diabetic Ketoacidosis
Pediatrics, December 1, 2007; 120(6): e1540 - e1546.
[Abstract] [Full Text] [PDF]

Home page
 Postgrad. Med. J.Home page
A patient with urgency, frequency, and low serum C reactive protein concentration
Postgrad. Med. J., February 1, 2005; 81(952): 140 - 140.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dalton, R. R.
Right arrow Articles by Martin, S. L. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dalton, R. R.
Right arrow Articles by Martin, S. L. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS