Intensive Care Med (1990) 16 [Suppl 3]:S187-S191
IntensiveCare Medicine 9 Springer-Verlag1990
A model for the interplay of inflammatory mediators in sepsis a study in 48 patients C.E. H a c k 1, J.H. Nuijens t, R . J . M . Strack van Schijndel 2, J.J. Abbink 1, A . J . M . Eerenberg t and L . G . Thijs 2 1Central Laboratoryof the Netherlands Red Cross Blood TransfusionService and Laboratory for Clinical and ExperimentalImmunology, University of Amsterdam and 2Medical IntensiveCare Unit, Free UniversityHospital, Amsterdam, The Netherlands
Abstract. Previously we studied levels of the cytokine IL-6 and activation of the complement and contact system and of neutrophils in a group of 48 patients with sepsis. Some of these inflammatory parameters appeared to be associated with a poor prognosis. Here we report on the relationships of C4a and C3a (complement activation products), of factor XII and prekallikrein (contact system proteins), of elastase (a protease released by activated neutrophils) and of the cytokine IL-6 to hemodynamic and biochemical parameters measured in those 48 patients at the time of admission to the Intensive Care Unit. No significant correlations between any inflammatory parameter and either systemic vascular resistance or cardiac index were found. Mean arterial pressure significantly correlated with both factor XII and prekallikrein levels. Lactate correlated with C3a and C4a, with elastase, and in particular, with IL-6, whereas it did not correlate with either factor XII or prekallikrein. Platelet numbers inversely correlated with both C3a and C4a, as well as with elastase and IL-6, whereas they positively correlated with factor XII and prekallikrein. Based on these findings we propose a model for the interplay of these inflammatory mediators in the pathogenesis of sepsis. This model takes into consideration the occurrence of capillary leakage, shock, disseminated intravascular coagulation, thrombocytopenia and of acute phase reactions in sepsis. Key words: Complement - Contact system - Neutrophils - IL-6 - Sepsis
Sepsis is a serious syndrome, mostly induced by bacterial infections, which may be complicated by shock, multiple organ failure, and which carries a high mortality [1, 2]. Although the pathogenesis is still not completely understood, sepsis is generally believed to be caused by the release and activation of endogenous mediators in the body in response to bacterial products, in particular endotoxins [3]. Several mediators have been proposed to play a role in the pathogenesis of sepsis including
cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) [4-8], nentrophilic proteases [9], activation products of complement [10, 11], and the contact system [12-14], and of the coagulation and fibrinolytic systems [14, 15]. In 48 patients with sepsis, we recently found that levels of C4a and C3a, peptides both generated during activation of the complement system, correlated with a fatal outcome [16], which suggests that complement activation is involved in the development of lethal complications in sepsis. In the same patients we did not find definite evidence for activation of the contact system, though levels of the contact proteins factor XII and prekallikrein were markedly decreased, being the lowest in patients with shock [17]. In addition, levels of the cytokine IL-6 appeared to be strongly increased in these patients and related to clinical outcome [18]. Finally, in these patients we recently measured elevated levels of elastase and lactoferrin, which both are released by activated neutrophils, and also these inflammatory parameters to some extent were related to clinical outcome (J. H. Nuijens et al., unpublished observations). Together these findings support the hypothesis that several endogenous mediator systems are involved in the pathogenesis of sepsis, but raise questions on how these mediator systems become activated in sepsis, on their mutual relationships, and how they are related to the clinical, biochemical and hemodynamic manifestations of sepsis. The aim of the present study was to analyze the relationships of several inflammatory parameters to some important hemodynamic and biochemical variables in the 48 patients that we previously studied [16-19]. Based on our analysis we propose a model that describes the interplay of inflammatory parameters in the pathogenesis of sepsis. Patients, materials and methods Patients
All patients studied were admitted to the Intensive Care Unit and fulfilled at least four of the following criteria
$188
for clinical sepsis: a suspected infectious focus; rigors, fever (>38.5~ or hypothermia (20 breaths/min); tachycardia (> 100beats/min); leukocytosis (> 15000 cells/mm3); and thrombocytopenia (< 100 000 platelets/mm3). Septic shock was diagnosed when patients fulfilled criteria for clinical sepsis as well as those for shock, i.e., a fall in systolic blood pressure of 50mmHg or more, or a systolic blood pressure of 90 mmHg or less, in combination with a least one of the following symptoms: oliguria (< 20 ml/h); arterial lactate level exceeding 1.6 mmol/1; or altered mentation. Forty-eight consecutive patients who fulfilled the criteria for clinical sepsis were studied. The clinical diagnosis was made before knowledge of the results of bacteriologic studies. In 37 of the 48 patients, local and or blood cultures yielded pathogenic bacteria: in 11 patients gram-positive, in 23 gram-negative, and in 3 both gram-positive and gram-negative bacteria. These patients were classified as having definite sepsis. In 11 patients, designated as critically ill, cultures did not yield pathogenic microorganisms. Hemodynamic studies were performed in all patients as described [20, 21], and included measurements of cardiac index, mean arterial and pulmonary arterial pressures, and of systemic and pulmonary vascular resistance indices. In addition, biochemical and hematological parameters were assessed including arterial lactate levels and numbers of circulating platelets and leukocytes. Measurements obtained at the time of admission were used for the present study. All patients were treated with appropriate antibiotics, fluid therapy, and vasopressor and inotropic medication when indicated. The overall mortality of the patients was 56~ being the highest (70%) in 23 patients, who had septic shock (these patients had definite sepsis and fulfilled criteria for shock). More detailed information on clinical signs of the patients as well as extensive studies on their complement and contact system and on IL-6 levels are described elsewhere [16-19].
Blood sampling Blood from each patient was drawn via arterial catheters that had been inserted for hemodynamic monitoring. Samples were collected in siliconized tubes that contained EDTA and Polybrene to prevent in vitro activation of the complement and of the contact system, and plasma was stored at - 7 0 ~ until tests were performed. Details on the collection procedure have been described previously [17, 19, 22].
Assessment of mediator systems C3a and C4a (both presumably in the desarg-form) were measured with competitive radioimmunoassays as described [16, 23] and expressed as nmol/1. Factor XII and prekaltikrein were measured with sandwich-type radioimmunoassays performed with monoclonal and polyclonal antibodies as described [17], results were expressed as a percentage of the normal value. Elastase, in complex with its inhibitor alpha-l-antitrypsin, was measured with a specific radioimmunoassay
C.E. Hack et al.: Mediators in sepsis
that will be described elsewhere (J. H. Nuijens et al., unpublished observations). Briefly, plasma was incubated with anti-elastase polyclonal antibodies coupled to a solid-phase. Subsequently, bound elastase-alpha-l-antitrypsin complexes were quantitated by incubation with radiolabeled monoclonal antibody against complexed alpha-l-antitrypsin. Results were related to a standard that was prepared by adding purified elastase to fresh normal plasma, and expressed as ng of elastase per ml. Plasma levels of IL-6 were measured with the B9 bioassay as described previously [18, 24], results were expressed as U/ml.
Analysis of data All calculations were done on an IBM-compatible personal computer using a standard statistical package (SPSS/PC). Distribution of parameters was evaluated by the Kolmogorov-Smirnov test. Most parameters were not distributed normally. Regression analysis of these parameters was done after log-transformation. A two-tailed pvalue < 0.05 was considered to represent a significant difference. Results
Plasma levels of several parameters of mediator systems We decided to analyze only measurements that were performed in the patients at the time of admission to the Intensive Care Unit as we expected that hemodynamic measurements later on in the course of the disease would be influenced by the therapy instituted. As we already described in detail in several other papers [16-18], plasma levels of several parameters of mediator systems were highly abnormal in the patients. Levels of C3a and of C4a were elevated in 96% and in 89% of the patients, respectively, compared with those in normal donors. Levels of factor XII and prekaUikrein were reduced below 50% of the normal value in more than 70~ of the patients. Elastase and IL-6 were increased in 96~ and in 81% of the patients, respectively. The levels of these parameters did not significantly differ between patients with definite sepsis and the critically ill patients, nor between patients with gram-positive and gram-negative infections. We therefore decided to analyze the data from all patients together.
Relation of mediators to hemodynamic parameters Most prominent hemodynamic alterations in sepsis are an increase in cardiac index (CI), and decreases in mean arterial pressure (MAP) and in systemic vascular resistance index (SVRI) [20, 21]. CI did not correlate with any parameter of the mediator systems (data not shown). MAP significantly correlated with factor XII (Fig, 1) and prekallikrein levels, and inversely with IL-6 levels (Table 1). SVRI tended to correlate inversely with C3a, C4a as well as with IL-6, and positively with factor XII, prekallikrein and elastase. However, none of these correlations was significant.
C.E. Hack et al.: Mediators in sepsis 120
S189
Table 2. Relation of lactate a to inflammatory mediators in 48 sepsis patients
MAP (mmHg)
D
100
[]
Correlation coefficient
p-Value (two-sided)
0.2776 0.3374 - 0.0055 0.0178 0.3599 0.6053
0.059 0.027 0.972 0.911 0.013 < 0.001
s
[]D C3a a C4a a Factor XII Prekallikrein Elastase a IL-6 a
80 [] []
60
8%0% o~o 0
cfl
o D
40
0
[]
I
i
20
40
20
a~
I
r
60 80 factor XII (%)
i
100
120
Fig. 1. Relation of MAP to factor X I I levels in sepsis
a log-transformed
The pathogenesis of sepsis is complicated and involves the activation of several mediator systems, including complement, contact, coagulation and fibrinolytic systems as well as of neutrophils, and the release of cytokines [3-18]. In this study we analyzed the relation of activation of these mediator systems to hemodynamic and biochemical parameters that are important for the management of sepsis patients. Our results indicate that the complement and contact systems as well as neutrophils and the cytokine IL-6 very likely are involved in the development of some of the hemodynamic and
biochemical alterations of sepsis. In Fig. 2 we propose a tempting scheme that considers the interrelationships between these mediator systems and their role in the pathogenesis of sepsis. MAP appeared to be correlated most closely with parameters of the contact system, i.e., levels of factor XII and of prekallikrein (Table 1). This suggests that the activation of the contact system in sepsis plays a predominant role in regulating blood pressure. In a previous study [17], we found no conclusive evidence for a role of the contact system in sepsis: plasma levels of both factor XIIa- and kallikrein-Cl-inhibitor complexes, measured with an assay that is able to detect as less as 0.05~ activation of factor XII and of kallikrein in vitro, were slightly increased at the time of admission in only 21% of the 48 patients that were also studied here. However, both factor XII and prekallikrein were (markedly) decreased in more than 70~ of the patients [17]. We assume that plasma levels of factor XII and of prekallikrein rather than levels of the respective Cl-inhibitor complexes, more properly reflect activation of the contact system, either because of a rapid clearance of complexes in vivo, or because of the presence of increased levels of other inhibitors, e.g., plasminogen activator inhibitor-I (PAI-1), of factor XII a and of kallikrein. PAI-I, of which levels are increased in sepsis [26], has been shown to be an inhibitor of both factor XIIa as well as of kallikrein [27]. Further studies are needed to establish definitely whether or not the contact system is activated in sepsis. The inverse correlation of IL-6 with MAP (Table 1) probably indicates that endothelium injury (see below) to a certain extent may influence MAP. Activation of the contact system presumably induces hypotension via the vasodilating effects of bradykinin
Table 1. Relation of MAP to inflammatory mediators in 48 sepsis p a tients
Table 3. Relation of thrombocytes to inflammatory mediators in 48 sepsis patients
Arterial lactate levels in sepsis are generally believed to reflect the degree of tissue ischaemia. C4a, elastase, and IL-6, but not C3a, factor XII and prekallikrein, correlated with lactate levels (Table 2).
Relation of mediators to hematological parameters We also assessed relationships of parameters of the mediator systems with hematological variables. Platelet numbers showed a strong negative correlation with both C3a and C4a (Table 3). In addition, negative correlations with elastase and, in particular, II~6 were found. In contrast, factor XII positively correlated with platelet numbers (Table 3). Leukocyte numbers appeared to be inversely correlated with C3a, whereas they correlated positively with factor XII (Table 4). Correlations with the other inflammatory parameters were not significant. Discussion
C3a a C4a a Factor XII Prekallikrein Elastase a IL-6 a a log-transformed
Correlation coefficient
p-Value (two-sided)
- 0.1196 - 0.0673 0.4965 0.4416 0.2545 -0.2979
0.432 0.668 0.001 0.003 0.084 0.042
C3a a C4a a Factor XlI Prekallikrein Elastase a IL-6 a a log-transformed
Correlation coefficient
p-Value (two-sided)
-0.4863 - 0.3628 0.4203 0.2684 - 0.3198 - 0.5843
IntensiveCare Medicine 9 Springer-Verlag1990
A model for the interplay of inflammatory mediators in sepsis a study in 48 patients C.E. H a c k 1, J.H. Nuijens t, R . J . M . Strack van Schijndel 2, J.J. Abbink 1, A . J . M . Eerenberg t and L . G . Thijs 2 1Central Laboratoryof the Netherlands Red Cross Blood TransfusionService and Laboratory for Clinical and ExperimentalImmunology, University of Amsterdam and 2Medical IntensiveCare Unit, Free UniversityHospital, Amsterdam, The Netherlands
Abstract. Previously we studied levels of the cytokine IL-6 and activation of the complement and contact system and of neutrophils in a group of 48 patients with sepsis. Some of these inflammatory parameters appeared to be associated with a poor prognosis. Here we report on the relationships of C4a and C3a (complement activation products), of factor XII and prekallikrein (contact system proteins), of elastase (a protease released by activated neutrophils) and of the cytokine IL-6 to hemodynamic and biochemical parameters measured in those 48 patients at the time of admission to the Intensive Care Unit. No significant correlations between any inflammatory parameter and either systemic vascular resistance or cardiac index were found. Mean arterial pressure significantly correlated with both factor XII and prekallikrein levels. Lactate correlated with C3a and C4a, with elastase, and in particular, with IL-6, whereas it did not correlate with either factor XII or prekallikrein. Platelet numbers inversely correlated with both C3a and C4a, as well as with elastase and IL-6, whereas they positively correlated with factor XII and prekallikrein. Based on these findings we propose a model for the interplay of these inflammatory mediators in the pathogenesis of sepsis. This model takes into consideration the occurrence of capillary leakage, shock, disseminated intravascular coagulation, thrombocytopenia and of acute phase reactions in sepsis. Key words: Complement - Contact system - Neutrophils - IL-6 - Sepsis
Sepsis is a serious syndrome, mostly induced by bacterial infections, which may be complicated by shock, multiple organ failure, and which carries a high mortality [1, 2]. Although the pathogenesis is still not completely understood, sepsis is generally believed to be caused by the release and activation of endogenous mediators in the body in response to bacterial products, in particular endotoxins [3]. Several mediators have been proposed to play a role in the pathogenesis of sepsis including
cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) [4-8], nentrophilic proteases [9], activation products of complement [10, 11], and the contact system [12-14], and of the coagulation and fibrinolytic systems [14, 15]. In 48 patients with sepsis, we recently found that levels of C4a and C3a, peptides both generated during activation of the complement system, correlated with a fatal outcome [16], which suggests that complement activation is involved in the development of lethal complications in sepsis. In the same patients we did not find definite evidence for activation of the contact system, though levels of the contact proteins factor XII and prekallikrein were markedly decreased, being the lowest in patients with shock [17]. In addition, levels of the cytokine IL-6 appeared to be strongly increased in these patients and related to clinical outcome [18]. Finally, in these patients we recently measured elevated levels of elastase and lactoferrin, which both are released by activated neutrophils, and also these inflammatory parameters to some extent were related to clinical outcome (J. H. Nuijens et al., unpublished observations). Together these findings support the hypothesis that several endogenous mediator systems are involved in the pathogenesis of sepsis, but raise questions on how these mediator systems become activated in sepsis, on their mutual relationships, and how they are related to the clinical, biochemical and hemodynamic manifestations of sepsis. The aim of the present study was to analyze the relationships of several inflammatory parameters to some important hemodynamic and biochemical variables in the 48 patients that we previously studied [16-19]. Based on our analysis we propose a model that describes the interplay of inflammatory parameters in the pathogenesis of sepsis. Patients, materials and methods Patients
All patients studied were admitted to the Intensive Care Unit and fulfilled at least four of the following criteria
$188
for clinical sepsis: a suspected infectious focus; rigors, fever (>38.5~ or hypothermia (20 breaths/min); tachycardia (> 100beats/min); leukocytosis (> 15000 cells/mm3); and thrombocytopenia (< 100 000 platelets/mm3). Septic shock was diagnosed when patients fulfilled criteria for clinical sepsis as well as those for shock, i.e., a fall in systolic blood pressure of 50mmHg or more, or a systolic blood pressure of 90 mmHg or less, in combination with a least one of the following symptoms: oliguria (< 20 ml/h); arterial lactate level exceeding 1.6 mmol/1; or altered mentation. Forty-eight consecutive patients who fulfilled the criteria for clinical sepsis were studied. The clinical diagnosis was made before knowledge of the results of bacteriologic studies. In 37 of the 48 patients, local and or blood cultures yielded pathogenic bacteria: in 11 patients gram-positive, in 23 gram-negative, and in 3 both gram-positive and gram-negative bacteria. These patients were classified as having definite sepsis. In 11 patients, designated as critically ill, cultures did not yield pathogenic microorganisms. Hemodynamic studies were performed in all patients as described [20, 21], and included measurements of cardiac index, mean arterial and pulmonary arterial pressures, and of systemic and pulmonary vascular resistance indices. In addition, biochemical and hematological parameters were assessed including arterial lactate levels and numbers of circulating platelets and leukocytes. Measurements obtained at the time of admission were used for the present study. All patients were treated with appropriate antibiotics, fluid therapy, and vasopressor and inotropic medication when indicated. The overall mortality of the patients was 56~ being the highest (70%) in 23 patients, who had septic shock (these patients had definite sepsis and fulfilled criteria for shock). More detailed information on clinical signs of the patients as well as extensive studies on their complement and contact system and on IL-6 levels are described elsewhere [16-19].
Blood sampling Blood from each patient was drawn via arterial catheters that had been inserted for hemodynamic monitoring. Samples were collected in siliconized tubes that contained EDTA and Polybrene to prevent in vitro activation of the complement and of the contact system, and plasma was stored at - 7 0 ~ until tests were performed. Details on the collection procedure have been described previously [17, 19, 22].
Assessment of mediator systems C3a and C4a (both presumably in the desarg-form) were measured with competitive radioimmunoassays as described [16, 23] and expressed as nmol/1. Factor XII and prekaltikrein were measured with sandwich-type radioimmunoassays performed with monoclonal and polyclonal antibodies as described [17], results were expressed as a percentage of the normal value. Elastase, in complex with its inhibitor alpha-l-antitrypsin, was measured with a specific radioimmunoassay
C.E. Hack et al.: Mediators in sepsis
that will be described elsewhere (J. H. Nuijens et al., unpublished observations). Briefly, plasma was incubated with anti-elastase polyclonal antibodies coupled to a solid-phase. Subsequently, bound elastase-alpha-l-antitrypsin complexes were quantitated by incubation with radiolabeled monoclonal antibody against complexed alpha-l-antitrypsin. Results were related to a standard that was prepared by adding purified elastase to fresh normal plasma, and expressed as ng of elastase per ml. Plasma levels of IL-6 were measured with the B9 bioassay as described previously [18, 24], results were expressed as U/ml.
Analysis of data All calculations were done on an IBM-compatible personal computer using a standard statistical package (SPSS/PC). Distribution of parameters was evaluated by the Kolmogorov-Smirnov test. Most parameters were not distributed normally. Regression analysis of these parameters was done after log-transformation. A two-tailed pvalue < 0.05 was considered to represent a significant difference. Results
Plasma levels of several parameters of mediator systems We decided to analyze only measurements that were performed in the patients at the time of admission to the Intensive Care Unit as we expected that hemodynamic measurements later on in the course of the disease would be influenced by the therapy instituted. As we already described in detail in several other papers [16-18], plasma levels of several parameters of mediator systems were highly abnormal in the patients. Levels of C3a and of C4a were elevated in 96% and in 89% of the patients, respectively, compared with those in normal donors. Levels of factor XII and prekaUikrein were reduced below 50% of the normal value in more than 70~ of the patients. Elastase and IL-6 were increased in 96~ and in 81% of the patients, respectively. The levels of these parameters did not significantly differ between patients with definite sepsis and the critically ill patients, nor between patients with gram-positive and gram-negative infections. We therefore decided to analyze the data from all patients together.
Relation of mediators to hemodynamic parameters Most prominent hemodynamic alterations in sepsis are an increase in cardiac index (CI), and decreases in mean arterial pressure (MAP) and in systemic vascular resistance index (SVRI) [20, 21]. CI did not correlate with any parameter of the mediator systems (data not shown). MAP significantly correlated with factor XII (Fig, 1) and prekallikrein levels, and inversely with IL-6 levels (Table 1). SVRI tended to correlate inversely with C3a, C4a as well as with IL-6, and positively with factor XII, prekallikrein and elastase. However, none of these correlations was significant.
C.E. Hack et al.: Mediators in sepsis 120
S189
Table 2. Relation of lactate a to inflammatory mediators in 48 sepsis patients
MAP (mmHg)
D
100
[]
Correlation coefficient
p-Value (two-sided)
0.2776 0.3374 - 0.0055 0.0178 0.3599 0.6053
0.059 0.027 0.972 0.911 0.013 < 0.001
s
[]D C3a a C4a a Factor XII Prekallikrein Elastase a IL-6 a
80 [] []
60
8%0% o~o 0
cfl
o D
40
0
[]
I
i
20
40
20
a~
I
r
60 80 factor XII (%)
i
100
120
Fig. 1. Relation of MAP to factor X I I levels in sepsis
a log-transformed
The pathogenesis of sepsis is complicated and involves the activation of several mediator systems, including complement, contact, coagulation and fibrinolytic systems as well as of neutrophils, and the release of cytokines [3-18]. In this study we analyzed the relation of activation of these mediator systems to hemodynamic and biochemical parameters that are important for the management of sepsis patients. Our results indicate that the complement and contact systems as well as neutrophils and the cytokine IL-6 very likely are involved in the development of some of the hemodynamic and
biochemical alterations of sepsis. In Fig. 2 we propose a tempting scheme that considers the interrelationships between these mediator systems and their role in the pathogenesis of sepsis. MAP appeared to be correlated most closely with parameters of the contact system, i.e., levels of factor XII and of prekallikrein (Table 1). This suggests that the activation of the contact system in sepsis plays a predominant role in regulating blood pressure. In a previous study [17], we found no conclusive evidence for a role of the contact system in sepsis: plasma levels of both factor XIIa- and kallikrein-Cl-inhibitor complexes, measured with an assay that is able to detect as less as 0.05~ activation of factor XII and of kallikrein in vitro, were slightly increased at the time of admission in only 21% of the 48 patients that were also studied here. However, both factor XII and prekallikrein were (markedly) decreased in more than 70~ of the patients [17]. We assume that plasma levels of factor XII and of prekallikrein rather than levels of the respective Cl-inhibitor complexes, more properly reflect activation of the contact system, either because of a rapid clearance of complexes in vivo, or because of the presence of increased levels of other inhibitors, e.g., plasminogen activator inhibitor-I (PAI-1), of factor XII a and of kallikrein. PAI-I, of which levels are increased in sepsis [26], has been shown to be an inhibitor of both factor XIIa as well as of kallikrein [27]. Further studies are needed to establish definitely whether or not the contact system is activated in sepsis. The inverse correlation of IL-6 with MAP (Table 1) probably indicates that endothelium injury (see below) to a certain extent may influence MAP. Activation of the contact system presumably induces hypotension via the vasodilating effects of bradykinin
Table 1. Relation of MAP to inflammatory mediators in 48 sepsis p a tients
Table 3. Relation of thrombocytes to inflammatory mediators in 48 sepsis patients
Arterial lactate levels in sepsis are generally believed to reflect the degree of tissue ischaemia. C4a, elastase, and IL-6, but not C3a, factor XII and prekallikrein, correlated with lactate levels (Table 2).
Relation of mediators to hematological parameters We also assessed relationships of parameters of the mediator systems with hematological variables. Platelet numbers showed a strong negative correlation with both C3a and C4a (Table 3). In addition, negative correlations with elastase and, in particular, II~6 were found. In contrast, factor XII positively correlated with platelet numbers (Table 3). Leukocyte numbers appeared to be inversely correlated with C3a, whereas they correlated positively with factor XII (Table 4). Correlations with the other inflammatory parameters were not significant. Discussion
C3a a C4a a Factor XII Prekallikrein Elastase a IL-6 a a log-transformed
Correlation coefficient
p-Value (two-sided)
- 0.1196 - 0.0673 0.4965 0.4416 0.2545 -0.2979
0.432 0.668 0.001 0.003 0.084 0.042
C3a a C4a a Factor XlI Prekallikrein Elastase a IL-6 a a log-transformed
Correlation coefficient
p-Value (two-sided)
-0.4863 - 0.3628 0.4203 0.2684 - 0.3198 - 0.5843
