Introduction

2008 was a significant year in Critical Care, with a number of landmark papers being published in sepsis research in this journal and in other publications. These studies cross the spectrum from some highly promising results to some very disappointing clinical and laboratory findings reported in the literature over the past year. The year started off on a positive note with the publication of the much anticipated and frequently quoted 2008 sepsis management guidelines from the Surviving Sepsis Campaign [1]. Encouraging evidence that the adoption of the Surviving Sepsis Campaign Guidelines can achieve measurable improvements in patient outcome has already appeared [2, 3]. Despite the intrinsic heterogeneity that typifies sepsis [4], standardized treatment regimens can improve outcome. Improvements in the process of care (for example, immediate resuscitation with intravenous fluids with preset physiologic goals, urgent administration of antimicrobial therapy, rapid identification and source control), and a variety of other evidence-based supportive measures, can improve survival in critically ill septic patients [1].

Two highly disappointing results were reported from large, randomized, clinical trials in 2008. The first major disappointment was the Corticus trial [5], which was expected to be a confirmatory trial from the Annane low-dose steroid study [6]. Treatment with relatively low doses of hydrocortisone (50 mg intravenously every 6 hours) followed by a tapering dose was compared with a placebo group in a multicenter randomized trial. The Corticus trial showed no overall survival benefit from the use of this seemingly logical, inexpensive treatment strategy for the relative adrenal insufficiency often accompanying septic shock. The study did find a significantly more rapid reversal in the duration of septic shock in the low-dose steroid group. This potential benefit of steroid-related shock reversal was accompanied by an increased incidence of secondary infections and secondary septic shock compared with the placebo group. The adrenocorticotrophic hormone stimulation test was used to differentiate responders from nonresponders with relative adrenal insufficiency. This finding did not distinguish patients more likely to respond to corticosteroids [5].

The German Sepsis Society clinical research group published two simultaneous clinical trials in which tight glycemic control was compared with standard glucose control, and pentastarch colloid solution was compared with crystalloid therapy for fluid resuscitation in severely septic patients (the VISEP trial) [7]. Again, the results were highly disappointing with no improvement in overall outcome of tight glycemic control with excess incidence of hypoglycemic events. These negative results were recently confirmed by a large prospective clinical trial of tight glycemic control versus conventional glycemic control from Australia, New Zealand and Canada (the NICE-SUGAR Study) [8]. This study, which included over 6,000 patients, actually revealed a significantly worse outcome for those patients randomized to tight glycemic control over conventional glucose management. Tight glycemic control carries a real risk of hypoglycemic episodes and is of uncertain efficacy in a general intensive care unit (ICU) population. Likewise, the colloid treatment strategy with pentastarch in the VISEP trial demonstrated a dose-dependent worsening in renal function compared with standard crystalloid resuscitation fluids, and its use should be discouraged in the future. Whether these findings can be extended to other colloids such as gelatin and albumin remains to be demonstrated. The results are not likely to end the continuing controversy regarding colloids versus crystalloids in sepsis therapy.

The year ended with an important publication addressing a decade-long argument about the value of selective decontamination of the digestive tract versus standard care in a general ICU population. deSmet and colleagues reported a modest survival advantage in the selective decontamination of the digestive tract population (including a systemic chemoprophylaxis group and an oral chemoprophylaxis only group) versus conventional therapy in a 5,939-patient trial [9]. The 28-day mortality rate was 27.5% for the control group, 26.9% for the oral selective decontamination of the digestive tract group, and 26.6% for the systemic selective decontamination of the digestive tract group (P < 0.05). The oral therapy might be easier to bring into standard ICU care as this strategy could limit the concerns about selecting for multidrug-resistant bacteria and even Clostridium difficile infection with widespread adoption of systemic chemoprophylaxis as a general strategy in ICU patients.

Major research findings in sepsis and systemic inflammatory states reported in Critical Care during 2008

Many important sepsis research papers appeared in Critical Care during the past year. Many of these studies are association studies where various novel biomarkers, enzymes and mediators were compared with the development of severe sepsis, organ dysfunction and adverse clinical outcomes [10–19]. These new research findings are summarized in Table 1. Some of the more notable findings from basic science to clinical research studies are highlighted in the following paragraphs.

Table 1 Selected biomarker studies and disease association studies in Critical Care (2008)
Full size table

Biomarkers for the diagnosis and risk stratification of multiorgan failure and sepsis

Soluble triggering receptor on myeloid cells 1

Soluble triggering receptor on myeloid cells 1 (sTREM-1) is a member of the immunoglobulin superfamily that is up-regulated on the surface of neutrophils, monocytes and macrophages in the presence of extracellular bacteria and fungi. Early studies by Gibot and colleagues demonstrated a diagnostic sensitivity of 98% and a specificity of 90% for detecting pneumonia by the measurement of sTREM-1 from mini-bronchoalveolar lavage (mini-BAL) fluids [20].

Huh and colleagues examined the diagnostic role of sTREM-1 in BAL fluid in 80 patients with bilateral lung infiltrates [10]. The authors compared BAL sTREM-1 with the clinical pneumonia infection severity score and the BAL neutrophil percentage in three patient groups: extracellular bacterial and fungal infection; pneumonia due to atypical intracellular bacteria, mycobacteria or viruses; and noninfectious illnesses. The levels of sTREM-1 were statistically significantly greater in the extracellular bacteria and fungal group (521.2 ± 94.7 pg/ml) compared with the viral/mycobacterial/atypical pathogen group (92.9 ± 20 pg/ml) and the non-infected group (92.8 ± 10.7 pg/ml). At a cutoff level of 184 pg/ml, sTREM-1 had a sensitivity of 86% and 90% specificity. While a clinical pneumonia infection severity score of 6 or greater and a BAL neutrophil percentage of 60% were statistically greater in the infected groups versus the non-infected group, sTREM-1 had the highest area under the receiver operating characteristic curve at 0.91 and was the only remaining variable statistically significant on multiple logistic regression analysis [10].

The findings in Huh and colleagues' study are in agreement with those of Richeldi and colleagues, where sTREM-1 differentiated community-acquired pneumonia from tuberculosis and interstitial lung disease [21]. Individual studies by Horonenko and colleagues and by Anand and colleagues did not show the same diagnostic accuracy with sTREM-1 as the Huh and colleagues study [22, 23] - both of these studies demonstrated false positive s-TREM levels in the setting of pulmonary hemorrhage. The allowance of patients with prior antibiotic administration in Anand and colleagues' study may have contributed to the discordant results. Future studies of sTREM-1 will need to be performed with a standardized assay and procedure for the BAL collection, and must examine the effect of antibiotic therapy on sTREM-1 levels.

Eosinopenia

A surprising simple measure to differentiate infection from noninfectious inflammation by eosinophil counts has resurfaced recently [11]. This is not a new idea but is appealing in its simplicity and availability [24]. The mechanism underlying eosinopenia is thought to be chemotactic factors, which draw the eosinophils to the site of infection [25].

Abidi and colleagues examined the value of eosinopenia in differentiating sepsis from noninfectious systemic inflammatory response syndrome in 198 medical ICU patients [11]. Patients without infection had a median eosinophil count of 109 cells/mm3 (interquartile range = 102 to 121), compared with 13 cells/mm3 (interquartile range = 8 to 28) in those with infection (P < 0.001). An eosinophil cutoff value < 50 cells/mm3 provided a sensitivity of 80%, a specificity of 91%, a likelihood ratio of 9.12, and an area under the receiver operating characteristic curve of 0.89. This was superior to C-reactive protein at a cutoff value of 70. By way of comparison, a meta-analysis by Tang and colleagues of the ability of procalcitonin to diagnose sepsis in critically ill patients with systemic inflammatory response syndrome revealed an area under the receiver operating characteristic curve of 0.78 [26]. Procalcitonin is the currently favored assay for distinguishing severe infection from systemic inflammation without infection, but it has its limitations [27]. The total eosinophil count as a biomarker in the diagnosis of sepsis needs to be studied in a large, multicenter study.

Gelsolin

Gelsolin is a cytoplasmic and plasma protein that works as an actin scavenger. Actin is released during tissue injury and has been noted to be toxic [28]. Additionally, gelsolin has been shown to inhibit inflammatory mediators released during sepsis including endotoxin, lysophosphatidic acid, and platelet activating factor [29]. Plasma gelsolin deficiencies have been described in patients with a variety of severe inflammatory states [30], and animal models of sepsis reveal a survival advantage with gelsolin replacement therapy [31].

Wang and colleagues investigated the time course of plasma gelsolin concentrations in 91 critically ill surgical patients [42]. It remains to be seen whether danaparoid will be taken forward in clinical trials of sepsis given the recent negative results of heparin in a severe sepsis trial [43].

Immunoparalysis

While a majority of papers in the sepsis literature focus on an exuberant proinflammatory and procoagulant response to critical illness, it is clear that a state of immune suppression or immunoparalysis also occurs in this setting. Lymphocyte death by programmed cell death or apoptosis occurs in critical illness patients via two pathways. The extrinsic pathway is triggered by TNFα and Fas ligand - which bind to death domains and ultimately activate caspase 8 and caspase 3, leading to DNA fragmentation and cell death. The intrinsic mitochondrial pathway is triggered by loss of growth factors IL-2, IL-4 or granulocyte-macrophage colony-simulating factor or by the addition of IL-6, IL-1, reactive oxygen intermediates or nitric oxide. These signals can either activate the proapoptotic BCL-2 family members Bax and t-Bid or the anti-apoptotic BCL-2 and MCI-1 proteins [44].

Hostmann and colleagues performed an in-depth assessment of the apoptotic kinetics in an animal model of hemorrhagic shock. Mice who underwent bleeding to a mean arterial pressure of 35 mmHg for 1 hour from the femoral artery followed by fluid resuscitation were compared with sham operated mice and control mice at 0 hours, 24 hours and 72 hours for lymphocyte counts, splenic lymphocyte apop-tosis, caspase activity, and proapoptotic and antiapoptotic protein levels. The authors found that lymphopenia occurs very early in the mice undergoing hemorrhagic shock and that it persists throughout the 72-hour observation period. Furthermore, splenic apoptosis in hemorrhagic shock occurs at 0 hours and 72 hours, and is associated with increased activity of caspase 3/7, caspase 8 and caspase 9, and with increased mitochondrial proapoptotic BAX levels and low antiapoptotic Bcl-2 proteins. Interestingly, the antiapoptotic protein MCI-1 is elevated at the 24 hours time point. These data suggest a biphasic response to traumatic hemorrhage where there is an attempt to counter-regulate proapoptotic forces by antiapoptotic proteins that ultimately fails [45]. These findings support the notion that attempts to intervene in trauma and sepsis by regulating the proapoptotic/antiapoptotic balance might be a useful therapeutic strategy.

High mobility group box-1 polymorphisms and sepsis

HMGB-1 is a fascinating and markedly complex nuclear and cytoplasmic protein that is readily measurable in the systemic circulation in response to severe injury. The protein has the propensity to bind to a variety of inflammatory mediators such as lipopolysaccharide and proinflammatory cytokines, including IL-1 [46]. HMGB-1 functions as an alarmin or damage-associated molecular pattern molecule, and acts as an endogenous ligand for pattern recognition receptors of the innate immune system.

In an important study on the outcome effects of polymorphisms of the HMGB-1 gene locus on human chromosome 13, Kornblit and colleagues reported the first evidence of the HMGB-1 genotype's impact on the risk of systemic inflammatory response and sepsis [47]. These investigators performed a long-term, 4-year study comparing HMGB-1 sequencing data in 239 ICU patients with HMGB-1 blood levels and clinical outcomes. The authors report significant disease associations with two of the eight major polymorphisms they discovered in the HMGB-1 gene complex. A promoter variant (-1377delA) was associated with a markedly reduced long-term survival rate after ICU admission in systemic inflammatory response syndrome patients (15% vs. 44% without this promoter variant; P < 0.01). Kornblit and colleagues also observed a significant interaction with a polymorphism within the coding region of the HMGB-1 gene at position 982 (C>T) in exon 4. Carriers of the polymorphism had an increased frequency of early death from infection along with higher Simplified Acute Physiology Score II compared with wild-type genotypes. Interestingly, this 982C>T variant was accompanied by significantly lower HMGB-1 blood levels (P < 0.01).

Gene association studies need to be interpreted with caution, and causality will remain elusive until larger datasets are available in diverse patient populations of differing genetic backgrounds. Linkage disequilibrium with other relevant gene loci and attention to the Hardy-Weinberg equilibrium needs to be carefully considered in small gene association studies. Gene association reports in the ICU literature are improving with respect to statistical methods and analytic detail but have further room for improvement [48].

Conclusions

The pace of discovery in critical care research and allied fields of inflammation research and infectious disease is truly remarkable. Critical Care is hel** the clinical investigator, basic scientist, and clinician alike by reporting an array of scientific papers in sepsis research. This trend is continuing in 2009 and we are confident that exciting discoveries will continue in this fast-paced area of critical care research.