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Original Article

Therapeutic approaches to reduce systemic inflammation in septic-associated neurologic complications

Wratten, M. L.a

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European Journal of Anaesthesiology: February 2008 - Volume 25 - Issue - p 1-7
doi: 10.1017/S0265021507003444
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Abstract

Introduction

Sepsis remains a major challenge with high morbidity and mortality. While, overall, there have been significant improvements in case fatalities, both the number of patients diagnosed with severe sepsis and the number of simultaneous failing organs continue to increase [1,2].

The inappropriate systemic inflammatory response is one of the major manifestations of the septic response to infection [3-6]. At the clinical level, there is a complex interplay between dysfunctional organs, which is sometimes exasperated by therapeutic support. For example, barotrauma induced by mechanical ventilation has been implicated in contributing towards renal dysfunction [7]. Organs are intimately tied together by a systemic activation of inflammatory and stress responses. Activated immune cells, endothelial cells and several chemokines, and cytokines and mediators orchestrate the responses.

The ‘healthy' response to infection involves a well-coordinated effort to eradicate the micro-organism. Inflammation usually remains compartmentalized, and is associated with clear signals to turn on different cellular signalling pathways with production of cytokines, chemokines and free radicals to eradicate the micro-organisms. There is a concomitant or sequential production of anti-inflammatory mediators to limit the area of responsiveness and to diminish the inflammatory response after the infection has been eliminated. Finally, there is a coordinated system of mediators that are involved in the repair or remodelling of any damaged tissue that occurred as a result of the inflammatory response.

The septic patient presents a particular challenge as there is hyperresponsiveness of many signalling pathways that produce excess proinflammatory, anti-inflammatory and modulatory molecules. All of these lead to a systemic inflammatory response with complex interactions between different cell types. Probably upregulation of some of these molecules is beneficial, and can be viewed as a physiologic adaptive response to stress, while others are detrimental and represent a maladaptive pathophysiologic response [3,5,8]. Some patients respond with a predominant proinflammatory cytokine, while others may have only a minor production of proinflammatory cytokines and have greater problems with immune dysregulation or hyperactivity to further infectious challenges. Thus, the systemic inflammatory milieu is not limited to only hyperinflammatory single burst of cytokines, but rather to a dynamic response that varies according to the patient age, type of organism and genetic characteristics of the patient.

Neurologic complications associated with sepsis

Although neurological complications are frequently underestimated, they are quite common in sepsis and often precede other organ dysfunction [9-11]. Often brain dysfunction and alternations in mental status are not taken into great consideration as there are many confounding factors in septic patients, such as the simultaneous use of analgesia-sedation during mechanical ventilation or the presence of neuromuscular blocking agents. These often confound clinical evaluation and frequently neurologic complications are not taken into primary consideration. Studies specifically looking at neurologic complications have found sepsis-associated encephalopathy (SAE) or polyneuropathy in up to 70% of septic patients [12-15]. Many of these studies suggest that SAE increases mortality hospital stay and long-term complications [16,17]. It should also be emphasized that while central nervous system (CNS) dysfunction appears to result as a consequence of sepsis, it also may directly contribute to the physiologic derangements thus setting up a vicious cycle. Currently there is no specific treatment or specific support for SAE.

Diagnostic tools

Acute encephalopathy can encompass a state of agitation, confusion, irritability and convulsions (type A) or a low consciousness (type B), which is characterized by somnolence, stupor and coma. Although there are many variations on the exact definition of SAE, the diagnosis of septic encephalopathy generally requires evidence of extracranial infection and impaired mental state.

Evaluation of the mental state by clinical bedside assessment is often difficult. The Glasgow Coma Score (GCS) is frequently used to evaluate cerebral dysfunction upon ICU admission. Although it is quite easy to use, it has a severe limitation in that the GCS is considered to be unchanged or normal in patients under prolonged sedation. This limits the use of the GCS in evaluating dynamic changes in brain dysfunction or to detect structural damage in advanced cases. For this reason, use of more sensitive tests such as electroencephalography (EEG), somatosensory evoked potential and imaging tests (cerebral computed tomography, magnetic resonance imaging) are often more commonly used. EEG in particular has been used to evaluate the severity of encephalopathy and often correlates well with survival [9,18].

Serum levels of two marker proteins, S100β and neuron-specific enolase (NES), have also been proposed as tools to aid in diagnosis and evaluation of severity. These proteins are frequently increased and associated with brain injury in patients with severe sepsis and septic shock. Recently Nguyen and colleagues [19] studied serum levels of S100β and NES in 170 patients with severe sepsis or septic shock. Both markers were associated with organ dysfunction and both predicted early death (increased risk of dying within the first 4 days of sepsis), but not late mortality. S100β (but not NSE) levels were associated with the extent of brain damage and low-consciousness encephalopathy.

Blood-brain barrier permeability

The brain is an interesting organ with relation to other organs affected by the systemic response of sepsis [10]. First, it is immunologically isolated. Not only does the CNS lack lymphatic drainage it also has the blood-brain barrier (BBB) that isolates the circulation from the brain parenchyma. The barrier plays an important role in maintaining the brain microenvironment. The structure of the BBB consists of brain microvascular endothelial cells, astrocytes, pericytes and neurons. The cerebral endothelial cells have no fenestrations, possess intercellular tight junctions and contain few pinocytotic vesicles. They are wrapped by astrocytes, which also secrete factors to induce barrier properties in the endothelial cells. Thus, blood-borne immune cells, such as lymphocytes, monocytes and neutrophils, as well as large proteins, cytokines and pathogens are normally prevented from breaching the barrier. Any compromise to the BBB may jeopardize its selective permeability and permit migration of inflammatory cells and mediators into the brain microenvironment, leading to CNS dysfunction. Prior brain injury, or concurrent brain injury, such as traumatic brain injury or subarachnoid haemorrhage appears to increase the vulnerability and degree of SAE [20].

One of the key events in the development of SAE is increased BBB permeability. Septic encephalopathy patients often have high levels of circulating proteins in the cerebrospinal fluid (CSF) [18] and several animal studies have shown direct correlations between administration of cytokines, bacterial or endotoxin administration and increased BBB permeability [21-23].

By definition, sepsis implies the presence of infection and a systemic inflammatory response. Both the infectious and the inflammatory component probably play a role in the development of neurologic complications. Some bacteria appear to have sophisticated mechanisms that offer advantages in crossing the monolayer of tight junction expressing endothelial cells to invade the meninges. As an example, Neisseria meningitidis has type IV pili that appear to be essential for meningeal invasion [24]. In other cases, it appears that it is the triggering of the systemic inflammation, with subsequent production of cytokines and mediators, that is crucial in initial breach of the BBB.

Role of infection

The presence of neurologic complications among critically ill patients is often very similar and does not seem to be particularly associated with any specific type of bacteria. Sprung and colleagues [17] observed a nearly equal incidence of neurologic complications among patients with Gram-negative bacteremia (28%), Gram-positive bacteremia (25%) or patients with negative blood cultures. In addition, patients with non-infections systemic inflammation, such as pancreatitis, also commonly show encephalopathy, suggesting that systemic inflammation may be as important as infection per se [25].

In spite of this, it does appear that there are some unique aspects of encephalopathy associated with infection. A recent study by Sharshar and colleagues [26] examined neuropathologic complications in 23 septic shock patients, eight critically ill non-septic ICU patients and five controls who died suddenly from extracranial injury. In the septic shock group, they found a 100% incidence of ischaemia, 26% with haemorrhage, 9% with hypercoagulability syndrome, 9% with multifocal necrotizing leucoencephalopathy and 9% with microabscesses. Although they did not observe a significant difference in tumour necrosis factor-α (TNF-α) expression, they did observe a significant difference in vascular inducible nitric oxide synthase (iNOS), more pronounced neuronal apoptosis and ischaemia in the autonomic centres of the septic patients. Although this does not preclude that pathogenic bacteria stimulate different inflammatory responses leading to specific neurologic complications, it highlights that there may be important differences between patients with and without SAE.

Evaluation of histopathologic injury during SAE is often limited to small numbers of human autopsy samples and animal models that do not necessarily reflect the clinical situation. In addition, septic animal models are often limited to young healthy animals with no existing comorbidities. They often use well-defined exaggerated doses of endotoxin or bacterial infiltrates and usually do not mimic the various clinical conditions (such as the presence of hyperdynamic and hypodynamic shock, ventilatory support, use of antibiotics and other drugs). Despite these limitations, they are useful in understanding basic mechanisms that occur during infection.

Animal studies show clear pathologic changes that can be produced during various models of septic encephalopathy. A study by Papadopoulos and colleagues [23] observed perimicrovessel oedema and neuronal injury in the frontal cortex during faecal peritonitis in a septic pig model. They observed a bleak picture of dark apopototic neurons, grossly swollen astrocytes with feet that appeared detached from the vessel wall and showed signs of membrane disruption. This was later confirmed by a more recent study by Moss and colleagues [27] in a similar pig model. Several studies have also tried to evaluate whether there are changes in cerebral blood flow (CBF) during sepsis. A very recent study by Hinkelbein and colleagues [28] evaluated whether changes occurred in either local or whole-brain blood flow during sepsis in a rat model caecal ligation and puncture-induced sepsis. Although they observed several well-characterized responses to sepsis (such as tachycardia, leucocytopenia, hypocapnia and higher lactate), neither local CBF nor whole-brain blood showed any difference from sham-operated control rats, despite a mortality of 43% in the septic rats. However, another recent study observed decreased activation flow coupling in the brain of endotoxin-induced septic rats, suggesting early microcirculatory dysfunction [29].

Role of cytokines

Numerous studies have suggested that cytokines, chemokines and inflammatory mediators play a key role in the pathogenesis of sepsis. Although it is more difficult to study the role of cytokines in cerebral dysfunction, several clinical and animal studies have also started to elucidate the key role of specific cytokines with relation to cerebral dysfunction, increased BBB permeability and amplification of the inflammatory response. One of the great difficulties in studying cytokines and other molecules involved in the inflammatory cascade is that there is a complex and dynamic interplay between the various molecules and their observed isolated effects maybe completely different than when the particular molecule is in a local environment or in the presence of other cell types or mediators.

Many cytokines, chemokines and other inflammatory molecules have been implicated in various aspects of neurologic complications. Much of the initial focus has been on molecules that might be able to change the BBB permeability or increase the inflammatory response.

Septic patients with neurologic complications have increased levels of cytokines, such as TNF-α, interleukin (IL)1β and IL6 in both the serum and CSF [30]. The dual face of cytokines was recently highlighted in a study by Paul and colleagues [31] that showed that although IL6 increased BBB permeability, brain oedema and resulting intracranial pressure, it also acted as an anti-inflammatory cytokine by decreasing leucocyte infiltration and cytokine production. Their results suggested that perhaps leucocyte migration is a distinct process from increased vascular permeability during bacterial meningitis.

The complement system has also been suggested to play a role in the activation of the innate immune response. A study by Rupprecht and colleagues [32] observed a 12-20-fold higher bacterial titre in C1q- and C3-deficient mice than the wild-type counterpart in a mouse model of pneumococcal meningitis. Interestingly, they also observed a concomitant decrease in CSF leucocytes and reduced brain expression of cytokines and chemokines. Although there were less meningitis-induced intracranial complications in the C1q- or C3-deficient mice, they actually observed a worse short-term outcome with more than one-third of either the C1q- or C3-deficient mice dying within 24 h after intracisternal pneumococcal challenge. No deaths were observed for the challenged wild-type mice during the same period [32].

IL1β has also been implicated in behavioural and pathophysiologic changes observed during encephalopathy. Intracerebral injection of IL1β in rodents mimics many of the characteristics of low-conscious encephalopathy [33-35]. Furthermore, intraventricular injection of IL1 receptor antagonist (IL1ra) can attenuate the sickness behaviour induced by lipopolysaccharide (LPS) [36]. Serentas and colleagues [37] observed significantly higher levels of IL1β in SAE patients compared with septic patients without SAE. In the same study, they also observed the effects of IL1β on rat hippocampal neuron and Xenopus oocytes injected with rat brain mRNA to determine how cytokines affect γ-aminobutyric acid receptors (GABAARs), which mediate fast synaptic transmission. Based on their observations they proposed that IL1β may alter synaptic strength at central synapses and contribute towards cognitive dysfunction.

The proinflammatory cytokine TNF-α has also been suggested to play a role in septic encephalopathy through several different mechanisms. Moller and colleagues [38] observed distinct changes in global CBF after an intravenous bolus injection of endotoxin in young healthy volunteers. They observed a peak of TNF-α at 90 min that correlated with the CBF change. No differences in baseline were observed for the cerebral metabolic rate of oxygen [38].

Tsao and colleagues [39] performed an interesting series of experiments to determine how different models of bacterial sepsis could affect BBB permeability in a septic mouse model. In their study, the BBB permeability increased after peritoneal injection with either Escherichia coli or Streptococcus pneumoniae bacteria. In both cases, they observed TNF-α in the brain by immunohistochemical staining localized on the meninges and venules. One of the interesting aspects of the study was that animals injected with E. coli showed BBB permeability changes and TNF-α staining at 1-3 h, whereas this occurred much later (9-12 h) in S. pneumoniae-injected mice. They could reproduce the same permeability changes by direct injection of TNF-α but not with IL1β. They attributed the observed changes between the two different bacterial challenges to differences in the kinetics of TNF-α production, since the LPS of E. coli is a much stronger inducer of TNF-α than the peptidoglycan and lipoteichoic acid component of Gram-positive bacteria. The permeability changes in both bacterial groups could be blocked by the addition of anti TNF-α antibodies [39].

Therapeutic approaches to reduce systemic inflammation

The heterogeneity of the septic response, the large variability among different patients and the unpredictable time frame of the inflammatory cascade represent a challenge in developing treatment strategies. Several early treatments were aimed at single early cytokines or bacterial products. Although these often worked well in animal models, they were largely unsuccessful in demonstrating clinical benefit. Newer strategies are now tending to target signal pathways and attempting dampening of the systemic inflammatory response. Although there is still much controversy on the use of extracorporeal therapies for non-renal indications, such as sepsis [40], there is continued interest in attempts to modify the systemic inflammatory response by these same therapies.

The use of sorbents and various types of carbon for extracorporeal depuration is not a new concept. Nearly 60 yr back Muirhead and Rein [41] studied the use of an amberlite ion-exchange resin as an artificial kidney to remove urea. The studies were followed by many other attempts to remove different types of toxins and poisons, but early sorbent techniques were also associated with many problems related to haemolysis, electrolyte disturbances, pyrogenic reactions, heavy metal release and bioincompatibility reactions such as thrombocytopenia.

Over the last 20 yr there have been great improvements in resin technologies that have sparked new interest in using adsorption as an additional method of depurification [42-44]. Today, resins used in medical-device applications must undergo rigid toxicologic and biocompatibility tests and guarantee no release of resin particles or extractables that could potentially be returned to the patient. Extracorporeal adsorption therapies are now proposed for a wide range of different pathologic conditions ranging from specific antibody removal, low-density lipoprotein columns for hypercholesterolemia, arthritis, activated cell removal and removal of mediators in inflammatory conditions such as sepsis.

There are several advantages that adsorption can offer over traditional dialytic techniques such as haemodialysis, haemodiafiltration or haemofiltration. Most haemofilters have relatively small pores that are designed to allow passage of small toxins while retaining albumin. Haemofilters are very effective when used in haemodialysis for small water-soluble uremic toxin removal or in techniques such as haemodiafiltration in which increased convection is useful in removing larger uremic toxins such as β2 microglobulin. Removal of larger proteins such as IL1, IL6 or TNF-α is much more challenging as many of these molecules have very low sieving coefficients and are not easily cleared by the small pores of the haemofilter. Although clearance can be improved by greatly increasing the amount of convection, as in high-volume haemofiltration, this does not necessarily increase the amount of cytokine that can be found in the ultrafiltrate. In addition, there is an increased amount of many beneficial substances such as vitamins, hormones and amino acids that are lost during convection. Increasing the permeability of the membrane is another approach to improve cytokine clearance, however, this is often at the expense of increased albumin loss. Adsorption is the process of binding of molecules to a surface. By identifying sorbents that have particular chemical or physical characteristic, it is possible to use these in extracorporeal depurification techniques to selectively remove either single molecules or groups of molecules that share common properties.

Extracorporeal adsorption can be done by either haemoperfusion with direct passage of the blood through an adsorbent cartridge or by plasma perfusion, which passes separated plasma (by use of a plasma filter) through the adsorption cartridge. Although a higher amount of total blood per unit time can be treated with haemoperfusion, it also has drawbacks of biocompatibility issues (unless the sorbent has a biocompatible surface coating that can sometimes decrease efficacy), tendency for increased fouling and less contact time with the resin (which often decreases total adsorption efficacy).

Coupled plasma filtration adsorption (CPFA) is an example of an extracorporeal adsorption therapy that was developed with the goal of simultaneously removing several different cytokines and mediators inflammatory cascade during systemic inflammation [44]. The technique uses a plasma filter to first separate the plasma, which is then passed through a cartridge containing a synthetic divinylbenzene styrenic resin. The resin has a surface area of over 700 m2 g−1 of resin and a high affinity for several inflammatory mediators. The purified plasma is then returned to the patient where the blood undergoes haemofiltration in post-dilution. The haemofiltration step allows additional purification of molecules that are not removed by the adsorption step (see Fig. 1). The treatment is performed for a 10 h period, after which haemofiltration in the post-dilution mode can continue if needed for renal support.

Figure 1.
Figure 1.:
Scheme of coupled plasma filtration adsorption.

The first clinical experiments with CPFA were done to determine safety and efficacy, as well as to determine whether CPFA could actually play a role in modulating the inflammatory response. A study, several years ago, by Ronco and colleagues [45] compared haemodynamic parameters and the ability to restore leucocyte responsiveness in a cross-over trial of septic patients who underwent 10 h of CPFA followed by 10 h of continuous venovenous haemodiafiltration (or vice versa). Although several types of extracorporeal renal replacement therapies can improve mean arterial pressure, they observed a greater improvement in haemodynamic parameters for the CPFA group compared to the haemodiafiltration group. They also monitored leucocyte responsiveness to in vitro stimulation by endotoxin. At the beginning of the CPFA treatment the cells were not able to produce appropriate amounts of TNF-α, whereas production was restored at the end of treatment. Cell hyporesponsiveness to secondary bacterial challenges is part of an overall immunosuppressive effect seen in septic patients and is frequently associated with worse outcomes [3,6].

Another study by Mariano and colleagues [46] evaluated CPFA in burn patient and polytrauma patients with septic shock and acute renal failure. Patients were divided into either heparin or citrate anticoagulation based on whether they had a high bleeding risk. The citrate anticoagulation was well tolerated and gave comparable results to the group with heparin anticoagulation.

The previous CPFA studies included septic patients with acute renal failure that required renal support. Formica and colleagues [47] conducted one of the first trials of CPFA to include septic patients with and without renal insufficiency. In this study, they also observed a haemodynamic improvement with reduced vasopressor requirement, improved pulmonary function and a reduction in C-reactive protein [47].

Based on these previous studies, which were designed to evaluate short-term clinical effects, an independently sponsored study by an Italian group of intensivists (Gruppo Italiano per la Valutazione degli interventi in Terapia Intensiva, GiViTi) is currently conducting a large multicentre randomized study (COMbining Plasmafiltration and Adsorption Trial, COMPACT) to determine whether CPFA can improve hospital mortality in septic shock patients. This is an important goal since mortality is so high in this patient group.

Whether removal of excess inflammatory mediators can also effect long-term neurologic complication still remains to be determined. Several studies are currently ongoing to see whether removal of cytokines involved in sepsis-related encephalopathy, or modulation of the systemic inflammatory response by CPFA, can reduce long-term neurologic complications.

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Keywords:

SEPSIS; CYTOKINES; ENCEPHALOPATHY; FILTRATION, plasma

© 2008 European Society of Anaesthesiology