Amisha V. Barochia

Bundled care for septic shock: An analysis of clinical trials

Context: Sepsis bundles have been developed to improve patient outcomes by combining component therapies. Valid bundles require effective components with additive benefits. Proponents encourage evaluation of bundles, both as a whole and based on the performance of each component. Objective: Assess the association between outcome and the utilization of component therapies in studies of sepsis bundles. Data Source: Database searches (January 1980 to July 2008) of PubMed, Embase, and the Cochrane Library, using the terms sepsis, bundles, guidelines, and early goal directed therapy. Data Extraction: Inclusion required comparison of septic adults who received bundled care vs. nonprotocolized care. Survival and use rates for individual interventions were abstracted. Main Results: Eight unblinded trials, one randomized and seven with historical controls, were identified. Sepsis bundles were associated with a consistent (I2 = 0%, p = .87) and significant increase in survival (odds ratio, 1.91; 95% confidence interval, 1.49–2.45; p < .0001). For all studies reporting such data, there were consistent (I2 = 0%, p ≥ .64) decreases in time to antibiotics, and increases in the appropriateness of antibiotics (p ≤ .0002 for both). In contrast, significant heterogeneity was seen across trials for all other treatments (antibiotic use within a specified time period; administration of fluids, vasopressors, inotropes, and packed red blood cells titrated to hemodynamic goals; corticosteroids and human recombinant activated protein C use) (all I2 ≥ 67%, p < .002). Except for antibiotics, sepsis bundle components are still being investigated for efficacy in randomized controlled trials. Conclusion: Bundle use was associated with consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain. However, this analysis should be interpreted cautiously as these studies were unblinded, and only one was randomized.

Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies.

Introduction: Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4. Areas covered: This review focuses on the rationale for the use of eritoran tetrasodium in sepsis as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Preclinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms ‘eritoran’ and ‘E5564’ are discussed. Expert opinion: Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis are currently under investigation. Even if the ongoing Phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies would be necessary to define its clinical usage.

The evolving experience with therapeutic TNF inhibition in sepsis: considering the potential influence of risk of death

Introduction: Septic shock is highly lethal and its incidence is increasing. Although TNF-α plays a key role in sepsis pathogenesis, past efforts to therapeutically inhibit it had limited success. However, there is continued interest in such therapies and there are now ongoing Phase II sepsis trials testing the effects of AZD9773, a TNF-directed polyclonal antibody fragment preparation. Experience with anti-inflammatory agents suggested that their efficacy may relate to sepsis-associated risk of death. Areas covered: An overview of the biology of TNF and experimental data implicating TNF as a key mediator in sepsis pathogenesis; a review of the earlier clinical experience with anti-TNF therapies demonstrating that when examined across 12 trials, these agents had a highly consistent overall effect which although not reaching significance, was on the side of benefit; a review of data showing that sepsis-associated risk of death may influence the efficacy of anti-inflammatory agents like anti-TNF ones and a review of the rational and clinical experience to date with AZD9773 and its precursor, CytoFab. Expert opinion: Discusses variables that may need to be accounted for to maximize the success of clinical trials in sepsis testing agents that modulate host inflammation.

Serum Apolipoprotein A-I and Large High-Density Lipoprotein Particles Are Positively Correlated with FEV1 in Atopic Asthma

RATIONALE Although lipids, apolipoproteins, and lipoprotein particles are important modulators of inflammation, varying relationships exist between these parameters and asthma. OBJECTIVES To determine whether serum lipids and apolipoproteins correlate with the severity of airflow obstruction in subjects with atopy and asthma. METHODS Serum samples were obtained from 154 atopic and nonatopic subjects without asthma, and 159 subjects with atopy and asthma. Serum lipid and lipoprotein levels were quantified using standard diagnostic assays and nuclear magnetic resonance (NMR) spectroscopy. Airflow obstruction was assessed by FEV1% predicted. MEASUREMENTS AND MAIN RESULTS Serum lipid levels correlated with FEV1 only in the subjects with atopy and asthma. Serum levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) were positively correlated with FEV1 in subjects with atopy and asthma, whereas a negative correlation existed between FEV1 and serum levels of triglycerides, low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), and the apoB/apoA-I ratio. NMR spectroscopy identified a positive correlation between FEV1 and HDLNMR particle size, as well as the concentrations of large HDLNMR particles and total IDLNMR (intermediate-density lipoprotein) particles in subjects with atopy and asthma. In contrast, LDLNMR particle size and concentrations of LDLNMR and VLDLNMR (very-low-density lipoprotein) particles were negatively correlated with FEV1 in subjects with atopy and asthma. CONCLUSIONS In subjects with atopy and asthma, serum levels of apoA-I and large HDLNMR particles are positively correlated with FEV1, whereas serum triglycerides, LDL cholesterol, and apoB are associated with more severe airflow obstruction. These results may facilitate future studies to assess whether apoA-I and large HDLNMR particles can reduce airflow obstruction and disease severity in asthma.

The potential contributions of lethal and edema toxins to the pathogenesis of anthrax associated shock.

Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shock has developed. Anthrax bacilli produce several different components which likely contribute to this shock. Growing evidence indicates that both major anthrax toxins may produce substantial cardiovascular dysfunction. Lethal toxin (LT) can alter peripheral vascular function; it also has direct myocardial depressant effects. Edema toxin (ET) may have even more pronounced peripheral vascular effects than LT, including the ability to interfere with the actions of conventional vasopressors. Additionally, ET also appears capable of interfering with renal sodium and water retention. Importantly, the two toxins exert their actions via quite different mechanisms and therefore have the potential to worsen shock and outcome in an additive fashion. Finally, both toxins have the ability to inhibit host defense and microbial clearance, possibly contributing to the very high bacterial loads noted in patients dying with anthrax. This last point is clinically relevant since emerging data has begun to implicate other bacterial components such as anthrax cell wall in the shock and organ injury observed with infection. Taken together, accumulating evidence regarding the potential contribution of LT and ET to anthrax-associated shock supports efforts to develop adjunctive therapies that target both toxins in patients with progressive shock.

Can we predict the effects of NF-κB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate

Background: Based partially on encouraging findings from preclinical models, interest has grown in therapeutic inhibition of NF-κB to limit inflammatory injury during sepsis. However, NF-κB also regulates protective responses, and predicting the net survival effects of such inhibition may be difficult. Objectives: To highlight the caution necessary with this therapeutic approach, we review our investigations in a mouse sepsis model with parthenolide and ethyl pyruvate, two NF-κB inhibitors proposed for clinical study. Results: Consistent with published studies, parthenolide decreased NF-κB binding activity and inflammatory cytokine release from lipopolysaccharide (LPS) stimulated RAW 264.7 cells in vitro. In LPS-challenged mice (C57BL/6J), however, while both agents decreased lung and kidney NF-κB binding activity and plasma cytokines early (1 – 3 h), these measures were increased later (6 – 12 h) in patterns differing significantly over time. Furthermore, despite studying several doses of parthenolide (0.25 – 4.0 mg/kg) and ethyl pyruvate (0.1 – 100 mg/kg), each produced small but consistent decreases in survival which overall were significant (p ≤ 0.04 for each agent). Conclusion: While NF-κB inhibitors hold promise for inflammatory conditions such as sepsis, caution is necessary. Clear understanding of the net effects of NF-κB inhibitors on outcome will be necessary before such agents are used clinically.

Protective Antigen Antibody Augments Hemodynamic Support in Anthrax Lethal Toxin Shock in Canines

BACKGROUND Anthrax-associated shock is closely linked to lethal toxin (LT) release and is highly lethal despite conventional hemodynamic support. We investigated whether protective antigen-directed monoclonal antibody (PA-mAb) treatment further augments titrated hemodynamic support. METHODS AND RESULTS Forty sedated, mechanically ventilated, instrumented canines challenged with anthrax LT were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinephrine), PA-mAb alone (administered at start of LT infusion [0 hours] or 9 or 12 hours later), or both, and observed for 96 hours. Although all 8 controls died, 2 of 8 animals receiving hemodynamic support alone survived (median survival times 65 vs 85 hours, respectively; P = .03). PA-mAb alone at 0 hour improved survival (5 of 5 animals survived), but efficacy decreased progressively with delayed treatment (9 hours, 2 of 3 survived; 12 hours, 0 of 4 survived) (P = .004 comparing survival across treatment times). However, combined treatment increased survival irrespective of PA-mAb administration time (0 hours, 4 of 5 animals; 9 hours, 3 of 3 animals; and 12 hours, 4 of 5 animals survived) (P = .95 comparing treatment times). Compared to hemodynamic support alone, when combined over PA-mAb treatment times (0, 9, and 12 hours), combination therapy produced higher survival (P = .008), central venous pressures, and left ventricular ejection fractions, and lower heart rates, norepinephrine requirements and fluid retention (P ≤ .03). CONCLUSIONS PA-mAb may augment conventional hemodynamic support during anthrax LT-associated shock.

High-density Lipoproteins and Apolipoprotein A-I: Potential New Players in the Prevention and Treatment of Lung Disease

Apolipoprotein A-I (apoA-I) and high-density lipoproteins (HDL) mediate reverse cholesterol transport out of cells. Furthermore, HDL has additional protective functions, which include anti-oxidative, anti-inflammatory, anti-apoptotic, and vasoprotective effects. In contrast, HDL can become dysfunctional with a reduction in both cholesterol efflux and anti-inflammatory properties in the setting of disease or the acute phase response. These paradigms are increasingly being recognized to be active in the pulmonary system, where apoA-I and HDL have protective effects in normal lung health, as well as in a variety of disease states, including acute lung injury (ALI), asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary arterial hypertension, pulmonary fibrosis, and viral pneumonia. Similar to observations in cardiovascular disease, however, HDL may become dysfunctional and contribute to disease pathogenesis in respiratory disorders. Furthermore, synthetic apoA-I mimetic peptides have been shown to have protective effects in animal models of ALI, asthma, pulmonary hypertension, and influenza pneumonia. These findings provide evidence to support the concept that apoA-I mimetic peptides might be developed into a new treatment that can either prevent or attenuate the manifestations of lung diseases, such as asthma. Thus, the lung is positioned to take a page from the cardiovascular disease playbook and utilize the protective properties of HDL and apoA-I as a novel therapeutic approach.

Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease.

Emerging roles are being recognized increasingly for apolipoproteins in the pathogenesis and treatment of lung diseases on the basis of their ability to suppress inflammation, oxidative stress, and tissue remodeling, and to promote adaptive immunity and host defense. Apolipoproteins, such as apolipoprotein E (apoE) and apolipoprotein A-I (apoA-I), are important components of lipoprotein particles that facilitate the transport of cholesterol, triglycerides, and phospholipids between plasma and cells. ApoE-containing lipoprotein particles are internalized into cells by low-density lipoprotein receptors (LDLRs), whereas apoA-I can interact with the ATP-binding cassette subfamily A member 1 (ABCA1) transporter to efflux cholesterol and phospholipids out of cells. ApoE and apoA-I also mediate receptor-independent effects, such as binding to and neutralizing LPS. Both apoE and apoA-I are expressed by lung cells, which allows apoE/LDLR- and apoA-I/ABCA1-dependent pathways to modulate normal lung health and the pathogenesis of respiratory diseases, including asthma, acute lung injury, cancer, emphysema, pulmonary fibrosis, and pulmonary hypertension. Data from human studies and research using experimental murine model systems have shown that both apoE and apoA-I pathways play primarily protective roles in lung biology and respiratory disease. Furthermore, apolipoprotein mimetic peptides, corresponding to the LDLR-binding domain of apoE or the class A amphipathic α-helical structure of apoA-I, have antiinflammatory and antioxidant effects that attenuate the severity of lung disease in murine models. Thus, the development of inhaled apolipoprotein mimetic peptides as a novel treatment paradigm could represent a significant advance for patients with respiratory disease who do not respond to current therapies.

Risk of death and the efficacy of eritoran tetrasodium (E5564): design considerations for clinical trials of anti-inflammatory agents in sepsis.

In this issue of Critical Care Medicine, Tidswell et al (1) report the results of a randomized, multicenter phase II trial of eritoran tetrasodium (E5564), a synthetic competitive lipopolysaccharide inhibitor. Three hundred septic patients were first stratified based on Acute Physiology and Chronic Health Evaluation II (APACHE II) scores into groups with either low (20%–50%) or high (50%–80%) predicted mortality rates. Subjects were then randomized to receive either a low or high dose of E5564 or placebo for 6 days. Twenty-eight–day mortality rates in the low- (32.0%) and high- (26.6%) dose E5564 groups were lower than placebo (33.3%) independent of predicted mortality, but this difference was not statistically significant (p = .335). The investigators note increasing control mortality rates with increasing APACHE II scores (0%, 32%, 37%, and 56% for quartiles 1 to 4, respectively). Importantly, as risk of death (i.e., control mortality rate) increased across these quartiles, the odds ratio of survival with both low- and high-dose E5564 increased as well, in relationships that were significant (p ≤ .025 for both doses) (Fig. 1). As the investigators reported, despite the relatively small numbers of patients in each quartile, high-dose E5564 was associated with clearly trends toward harm in the lowest quartile but benefit in the highest (p = .08 and .11, respectively). Figure 1 The regression lines in this figure show the relationship between control odds and the odds ratio of survival with low- (45 mg) or high- (105 mg) dose E5564 alone (A and B, respectively) or overall (C) comparing patients with increasing predicted mortality ... Of note, trials of other anti-inflammatory agents, recombinant human activated protein C (rhAPC), and corticosteroids demonstrated a similar relationship between treatment effect and risk of death in sepsis. A metaregression analysis of published preclinical and clinical trials of six different mediator-specific anti-inflammatory agents, as well as prospective preclinical investigations of such agents, showed benefit when risk of death was high but decreasing efficacy and even harm as risk decreased (2, 3). Although published preclinical studies tested these agents against highly lethal septic challenges and showed significant benefit, overall treatment effects were substantially diminished in clinical trials with lower control mortality rates. After Food and Drug Administration analysis of the pivotal rhAPC trial showed the drug’s benefit was evident primarily in high-risk patients (APACHE II ≥25), the agency’s approval of rhAPC was restricted to this subgroup (4 – 6). Finally, recent meta-analyses of low-dose corticosteroid use in sepsis indicate that this therapy’s efficacy may also relate to risk of death (7, 8). Similar to this previous experience, while E5564 showed convincing benefit in highly lethal preclinical sepsis models (control mortality rates of 60%–90%), potential benefit in the present clinical study is only evident in high-risk subgroups (1, 9, 10). If E5564 proves beneficial in high-risk septic patients, but portends harm in low-risk patients, practitioners must clearly understand whether and in which low-risk patients the diminution of E5564’s efficacy may cross over to a potential harmful effect. A trend toward increased hepatobiliary and renal complications overall with E5564 in the trial by Tidswell et al may provide a basis for potentially worse outcomes with treatment in the low-risk patients. Data from this study also suggest that only patients with a predicted mortality rate of ≥50% might benefit from E5564 (Fig. 1). Clearly, an agent with a broad therapeutic window will be far more useful than one that is safe and beneficial only in the sickest septic patients. Furthermore, if an agent’s efficacy varies based on underlying risk of death, then precise criteria for defining the risk–benefit ratio and the appropriateness of administration in individual patients must be defined. Although treatment with rhAPC is frequently based on the APACHE II score in the United States and the number of injured organs in Europe, neither system was ever prospectively tested for such use. In the Administration of Drotrecogin Alfa (Activated in Early Stage Severe Sepsis) trial, patients with APACHE II scores ≥25, who should have had improved survival with rhAPC based on Food and Drug Administration recommendations, did not (11). Even in the Tidswell study, although the APACHE II score was expected to select patients with mortality rates ranging between 20% and 80%, the observed range was lower. Another stratification tool currently used—the presence of ongoing vasopressor-dependent shock—also remains unproven (7, 12). Finally, if risk of death influences E5564’s efficacy within the strict confines of a randomized, controlled trial, widespread clinical use would surely alter the relationship. Clinical surveys have shown that rhAPC is routinely administered to patients with APACHE II scores lower than FDA recommendations (5, 13, 14). Complicating matters, the predictive ability of the APACHE II scores is influenced by patient case mix, location and the time of measurement, each of which will vary to a greater degree during clinical use than in a randomized, controlled trial (15–19). Tidswell et al report a phase III trial of E5564 is currently underway that limits enrollment to patients with a significant risk of mortality (APACHE II scores ≥21). Although this design may demonstrate efficacy for E5564, it may not establish whether the agent poses harm, has no effect, or is beneficial for patients with a lower risk of death. Concurrent conduct of preclinical studies exploring this relationship could begin to address this question. Additionally, the ongoing phase III trial could be amended to include patients with APACHE II scores <21, with strict provisions for frequent and vigilant safety monitoring. If all risk groups were studied together, a smaller sample size could determine whether differing treatment trends based on predicted risk of death confirm concerns raised by the phase II trial. Analysis of such data would also more clearly delineate the scope of a relationship between risk of death and E5564’s effects, if present. Even with such measures, extensive phase IV testing may be essential to appropriately narrow the target population of E5564. The failure of anti-inflammatory agents to demonstrate convincing benefits in sepsis is thought to relate in part to patient heterogeneity. Sepsis-associated risk of death contributes to this heterogeneity, and evolving experience suggests it may play a pivotal role in calibrating this therapeutic approach. Inflammation represents an interconnected group of host responses to infection. When it is excessive, inflammation overshadows the effects of the underlying infection and in itself causes a higher mortality rate. Thus, in this scenario, inhibiting even a single inflammatory mediator may be sufficient to depress this interconnected response and improve outcome. Conversely, when inflammation is appropriate and protective for a majority of subjects, disrupting this necessary host response may be harmful. Recognizing and investigating the potential influence of risk of death during the preclinical and clinical evaluation of anti-inflammatory agents like E5564, although requiring careful oversight and additional resources, may greatly improve the ability of physicians to safely and effectively administer these treatments in septic patients.