The blood-brain barrier in sepsis: are intravenous immunoglobulins preventive?

Crit Care Med 2012 Vol. 40, No. 4 In this issue of Critical Care Medicine, Esen and colleagues (1) examined in a rat sepsis model (cecal ligation and puncture, CLP) the effects of immunoglobulins on the bloodbrain barrier (BBB). They found that sepsis induced by CLP in animals causes an increase in the BBB permeability, predominantly through the transcellular vesicular pathway. Additionally, the data demonstrate that treatment with intravenous immunoglobulin G (IgG) and immunoglobulins enriched with IgA and IgM (IgGAM) 5 mins before CLP improves the integrity of the BBB, inhibits CLPinduced sickness behavior, and reduces the mortality rate of septic animals. Sepsis and its complications remain the leading causes of morbidity and mortality in intensive care units, accounting for 10%-50% of deaths (2, 3). Although the underlying pathophysiology of sepsis is very complex and remains far from fully understood (4, 5), cerebral endothelial activation and the alteration of the BBB has been documented in in vivo and in vitro models of the septic brain (6, 7). Under physiologic conditions, the BBB maintains the cerebral microenvironment by tightly regulating the transfer of molecules into and out of the brain to protect the brain from toxic substances and microorganisms. During sepsis, the BBB is exposed to harmful proinflammatory mediators from the brain as well as blood-borne proinflammatory mediators from the systemic circulation (8). The breakdown of the BBB, which facilitates the passage of cytokines and neurotoxic substances into the brain parenchyma, is considered to be the major pathophysiologic mechanism of brain involvement in sepsis (6). In the study of Esen et al (1), tight junctions were ultrastructurally intact, suggesting that the paracellular pathway of the BBB is not responsible for the BBB breakdown in sepsis. These morphologic changes are in accordance with other studies, which stated that sepsis did not result in changes in the mean cross-sectional areas of microvessel endothelial cells and tight junction morphology (9, 10). Intravenous immunoglobulins (IVIGs) are known to be beneficial in the treatment of sepsis (11, 12), and many of mechanisms, including inhibition of the complement cascade, influence on cytokine production, blockage of cellular receptors for immunoglobulins (Fc receptors), modulation of inhibitory Fc receptor expressions, and cell apoptosis, have been attributed to the antiinflammatory actions of IVIG (8, 13, 14). Esen et al (1) used two different types of immunoglobulin preparations, assuming that an IgM-enriched preparation would have a better effect on the BBB integrity than a standard IgG preparation in the CLP-induced sepsis model. Previous in vivo and in vitro studies have demonstrated superior activities of IgM in comparison to IgG (15, 16). The polyclonal IVIG in septic patients is still not universally accepted, albeit the results from meta-analyses show that the risk of death is lower in septic patients who received IgGAM-enriched IVIG than in controls (11, 17). Although Sablotzki et al (18) and Pilz et al (19) demonstrated the efficacy of IVIG when given as a prophylaxis in subjects at risk of sepsis, and Buda et al (20) and Rodriguez et al (21) as a treatment in patients with established severe sepsis and septic shock, less is known about the relationship existing between the timing of their administration and the outcome. However, the time as a factor appears to be relevant, since Jacobs et al (22) were able to demonstrate that the administration of IgGAM-enriched IVIG in a model of fecal peritonitis was most effective if started within 6 hrs from the insult but completely ineffective when given 12 hrs afterward. It remains to be determined if the findings of Esen et al (1) can be extrapolated to humans. Several reports have stressed the disconnection between rodent and human sepsis (23–25), making it difficult to draw definitive conclusions from an experimental study for the clinical setting. Furthermore, in the current study, the intravenous IgG and IgGAM were administered 5 mins before the CLP-induced sepsis. Follow-up studies need to address the effects of a later time point of intravenous IgG and IgGAM treatment, because diagnosis of the sepsis syndrome in patients might be delayed due to several comorbidities. Thus, it is worthwhile to address if intravenous IgG and IgGAM treatment also reverses BBB breakdown after onset of CLP-induced sepsis, which might greatly enhance the therapeutic impact of IVIG in humans and merits consideration for clinical trials in patients. Marco Sifringer, PhD Claudia D. Spies, MD, PhD Department of Anaesthesiology and Surgical Intensive Care Campus Virchow-Klinikum Campus Charité Mitte Charité-Universitätsmedizin Berlin Berlin, Germany