The role of endothelial shear stress on haemodynamics, inflammation, coagulation and glycocalyx during sepsis.

Sepsis is a multifactorial syndrome primarily determined by the host response to an invading pathogen. It is common, with over 48 million cases worldwide in 2017, and often lethal. The sequence of events in sepsis begins with the damage of endothelium within the microvasculature, as a consequence of the inflammatory and coagulopathic responses to the pathogen that can progress to multiple organ failure and death. Most therapeutic interventions target the inflammation and coagulation pathways that act as an auto-amplified vicious cycle, which, if unchecked can be fatal. Normal blood flow and shear stress acting on a healthy endothelium and intact glycocalyx have anti-inflammatory, anticoagulant and self-repairing effects. During early stages of sepsis, the vascular endothelium and its glycocalyx become dysfunctional, yet they are essential components of resuscitation and recovery from sepsis. The effects of shear forces on sepsis-induced endothelial dysfunction, including inflammation, coagulation, complement activation and microcirculatory breakdown are reviewed. It is suggested that early therapeutic strategies should prioritize on the restoration of shear forces and endothelial function and on the preservation of the endothelial-glycocalyx barrier.

Fluid management in Acute Respiratory Distress Syndrome: A narrative review.

Acute Respiratory Distress Syndrome remains a major source of morbidity and mortality in the modern intensive care unit (ICU). Major advances in the understanding and management of this condition were made in the last two decades. The use of low tidal ventilation is a well-established therapy. Conservative fluid management is now another cornerstone of management. However, much remains to be understood in this arena. Assessing volume status in these patients may be challenging and the tools available to do so are far from perfect. Several dynamic measures including pulse pressures variation are used. Ultrasound of the lungs and the vascular system may also have a role. In addition, the type of fluid to administer when needed is still open to debate. Finally, supportive measures in these patients, early during their ICU stay and later after discharge continue to be crucial for survival and adequate recovery.

Complement inhibition decreases early fibrogenic events in the lung of septic baboons.

Acute respiratory distress syndrome (ARDS) induced by severe sepsis can trigger persistent inflammation and fibrosis. We have shown that experimental sepsis in baboons recapitulates ARDS progression in humans, including chronic inflammation and long-lasting fibrosis in the lung. Complement activation products may contribute to the fibroproliferative response, suggesting that complement inhibitors are potential therapeutic agents. We have been suggested that treatment of septic baboons with compstatin, a C3 convertase inhibitor protects against ARDS-induced fibroproliferation. Baboons challenged with 10(9) cfu/kg (LD50) live E. coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5 hrs thereafter. Changes in the fibroproliferative response at 24 hrs post-challenge were analysed at both transcript and protein levels. Gene expression analysis showed that sepsis induced fibrotic responses in the lung as early as 24 hrs post-bacterial challenge. Immunochemical and biochemical analysis revealed enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Specific inhibition of complement with compstatin down-regulated sepsis-induced fibrosis genes, including transforming growth factor-beta (TGF-ß), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1), various collagens and chemokines responsible for fibrocyte recruitment (e.g. chemokine (C-C motif) ligand 2 (CCL2) and 12 (CCL12)). Compstatin decreased the accumulation of myofibroblasts and proliferating cells, reduced the production of fibrosis mediators (TGF-ß, phospho-Smad-2 and CTGF) and inhibited collagen deposition. Our data demonstrate that complement inhibition effectively attenuates collagen deposition and fibrotic responses in the lung after severe sepsis. Inhibiting complement could prove an attractive strategy for preventing sepsis-induced fibrosis of the lung.

Acute lung injury and fibrosis in a baboon model of Escherichia coli sepsis.

Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6-27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-ß and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies.

Pathophysiology, staging and therapy of severe sepsis in baboon models.

We review our baboon models of Escherichia coli sepsis that mimic, respectively, the shock/disseminated intravascular coagulation (DIC) and organ failure variants of severe sepsis, and analyse the pathophysiologic processes that are unique to each. The multi-stage, multi-factorial characteristics of severe sepsis develop as a result of the initial insult, which - depending on its intensity - activates components of the intravascular compartment leading to overwhelming shock/DIC; or initiates a sequence of events involving both the intra- and extravascular (tissues) compartments that lead to organ failure. In the latter case, the disorder passes through two stages: an initial inflammatory/coagulopathic intravascular first stage triggered by E. coli, followed by an extravascular second stage, involving components unique to each organ and triggered by ischemia/reperfusion (oxidative stress and histone release). Although a myriad of overlapping cellular and molecular components are involved, it is the context in which these components are brought into play that determine whether shock/DIC or organ failure predominate. For example, inflammatory and thrombotic responses amplified by thrombin in the first case whereas similar responses are amplified by complement activation products in the second. Rather than blocking specific mediators, we found that attenuation of the thrombin and complement amplification pathways can effectively reverse the shock/DIC and organ failure exhibited by the LD(100) and LD(50) E. coli models of severe sepsis, respectively. Translation of these concepts to successful intervention in the respective baboon models of E. coli sepsis and the application to their clinical counterparts is described.

Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis.

Severe sepsis leads to massive activation of coagulation and complement cascades that could contribute to multiple organ failure and death. To investigate the role of the complement and its crosstalk with the hemostatic system in the pathophysiology and therapeutics of sepsis, we have used a potent inhibitor (compstatin) administered early or late after Escherichia coli challenge in a baboon model of sepsis-induced multiple organ failure. Compstatin infusion inhibited sepsis-induced blood and tissue biomarkers of complement activation, reduced leucopenia and thrombocytopenia, and lowered the accumulation of macrophages and platelets in organs. Compstatin decreased the coagulopathic response by down-regulating tissue factor and PAI-1, diminished global blood coagulation markers (fibrinogen, fibrin-degradation products, APTT), and preserved the endothelial anticoagulant properties. Compstatin treatment also improved cardiac function and the biochemical markers of kidney and liver damage. Histologic analysis of vital organs collected from animals euthanized after 24 hours showed decreased microvascular thrombosis, improved vascular barrier function, and less leukocyte infiltration and cell death, all consistent with attenuated organ injury. We conclude that complement-coagulation interplay contributes to the progression of severe sepsis and blocking the harmful effects of complement activation products, especially during the organ failure stage of severe sepsis is a potentially important therapeutic strategy.

Iloprost improves gas exchange and exercise tolerance in patients with pulmonary hypertension and chronic obstructive pulmonary disease.

BACKGROUND: Nonselective systemic vasodilators worsen ventilation perfusion (V/Q) matching and gas exchange in patients with chronic obstructive pulmonary disease (COPD). Inhaled iloprost has the potential to act preferentially in ventilated regions of the lung, thereby reducing pulmonary hypertension (PH) while alveolar ventilation is still maintained. OBJECTIVES: To investigate the acute effects of inhaled iloprost on V/Q matching in patients with COPD and PH. METHODS: Ten males with COPD and PH on echocardiography were evaluated before and after inhaling 2 doses of iloprost (2.5 microg). Measurements included lung function, arterial blood gas, 6-min walk test (6MWT) as well as ventilatory equivalents for oxygen (V(E)/VO(2)) and carbon dioxide (V(E)/VCO(2)) taken at baseline, 30 min following each dose of iloprost, and 2 h after the second dose. RESULTS: Mean differences in V(E)/VCO(2) and V(E)/VO(2) were -13.3 (95% CI -36.5 to -2.7; p = 0.002) and -15.0 (95% CI -36.7 to -0.4; p = 0.02), respectively, and the mean change in (A-a) gradient was -3.7 mm Hg (95% CI -6.1 to -1.0; p = 0.01) after a single dose of iloprost, whereas mean improvement in 6MWT was 49.8 m (95% CI 14.8 to 84.7; p = 0.02). Arterial blood gas, venous admixture, dead space fraction and lung functions were maintained after iloprost. The effects of iloprost were reproducible after the second dose. All measurements returned to baseline 2 h after the last dose. No adverse effects on systemic blood pressure or oxygen saturation were seen. CONCLUSIONS: Iloprost inhalation was safe in patients with COPD and PH, and was associated with improved V/Q matching and exercise tolerance.

Early anion gap metabolic acidosis in acetaminophen overdose.

PURPOSE: The study aimed to determine the incidence and clinical significance of early high (>15 mEq/L) anion gap metabolic acidosis in acetaminophen (APAP) overdose. METHODS: A retrospective review of a cohort of 74 patients presenting within 24 hours of APAP overdose was conducted. RESULTS: Early high anion gap metabolic acidosis was present in 41% of patients on admission and persisted for 1.5 ± 0.1 days. The anion gap was associated with an elevated lactate level (4.5 ± 1 mmol/L) (r(2) = 0.66, P < .05), which persisted for 1 day. The lactate level increased in proportion to the APAP concentration (r(2) = 0.75, P < .05). Patients with increased anion gap had a higher incidence of confusion (48% vs 3%; P < .001) and lethargy (39% vs 6%; P = .003). Early high anion gap metabolic acidosis was found in the absence of shock or liver failure. All patients were treated with N-acetylcysteine and, despite the early high anion gap metabolic acidosis, none developed hepatic failure or hypoglycemia. CONCLUSION: Early high anion gap metabolic acidosis in patients with APAP overdose is self-limited and does not predict clinical or laboratory outcomes. Persistent or late metabolic acidosis in the absence of liver failure is not likely due to APAP and should prompt a search for other causes of metabolic acidosis. Finally, APAP overdose should be considered in patients presenting to the emergency department with altered mental status, as this is a treatable condition when detected early.

Multicenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock.

OBJECTIVE: To assess the safety and efficacy of the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene (PHP), in patients with distributive shock. DESIGN: Phase II multicenter, randomized (1:1), placebo-controlled study. SETTING: Fifteen intensive care units in North America. PATIENTS: Sixty-two patients with distributive shock, > or = 2 systemic inflammatory response syndrome criteria, and persistent catecholamine dependence despite adequate fluid resuscitation (pulmonary capillary wedge pressure > or = 12). INTERVENTIONS: Patients were randomized to PHP at 0.25 mL/kg/hr (20 mg/kg/hr), or an equal volume of placebo, infused for up to 100 hrs, in addition to conventional vasopressor therapy. Because treatment could not be blinded, vasopressors and ventilatory support were weaned by protocol. MEASUREMENTS AND MAIN RESULTS: Sixty-two patients were randomized to PHP (n = 33) or placebo (n = 29). Age, sex, etiology of shock (sepsis in 94%), and Acute Physiology and Chronic Health Evaluation II scores (33.1 +/- 8.3 vs. 30 +/- 7) were similar in PHP and placebo patients, respectively. Baseline plasma nitrite and nitrate levels were markedly elevated in both groups. PHP infusion increased systemic blood pressure within minutes. Overall 28-day mortality was similar (58% PHP vs. 59% placebo), but PHP survivors were weaned off vasopressors faster (13.7 +/- 8.2 vs. 26.3 +/- 21.4 hrs; p = .07) and spent less time on mechanical ventilation (10.4 +/- 10.2 vs. 17.4 +/- 9.9 days; p = .21). The risk ratio (PHP/placebo) for mortality was .79 (95% confidence interval, .39-1.59) when adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II score, and etiology of sepsis. No excess medical interventions were noted with PHP use. PHP survivors left the intensive care unit earlier (13.6 +/- 8.6 vs. 17.9 +/- 8.2 days; p = .21) and more were discharged by day 28 (57.1 vs. 41.7%). CONCLUSIONS: PHP is a hemodynamically active nitric oxide scavenger. The role of PHP in distributive shock remains to be determined.

Early administration of high-dose antithrombin in severe sepsis: single center results from the KyberSept-trial.

BACKGROUND: The overall finding in the KyberSept trial of no treatment effect of high-dose antithrombin (AT) in severe sepsis was inconsistent for the primary outcome, 28-day mortality, possibly because of patient heterogeneity. No data have been reported on the effects of AT therapy administered early in severe sepsis when microcirculation is disturbed but irreversible organ damage has not yet developed. OBJECTIVE: We report the post hoc results of the KyberSept trial in patients with severe sepsis treated at a single center early after new onset organ failure. METHODS: All study participants from a United States tertiary care intensive care unit were analyzed. Patients had been randomized 1:1 (placebo: n = 41; AT: n = 40) to receive AT (30,000 IU IV over a period of four days) or placebo within 48 h. RESULTS: Baseline variables were well balanced between groups. Eighty percent of patients (n = 65) received study drug within 24 h after onset of severe sepsis; 94% (n = 76) received study drug within 48 h. Nine of 40 participants in the AT group (22.5%) had new organ dysfunction during the first 7 days which was not present at baseline compared with 17 of 39 subjects (43.6%) in the placebo group (P = 0.058; two participants had dysfunction of all organs at baseline and were therefore excluded). At 28 days, 16 of 40 patients (40%) treated with AT died versus 22 of 41 (54%) with placebo [absolute reduction, 14%; odds ratio (95% confidence interval), 0.58 (0.24-1.39)]. In patients receiving AT, a significantly increased bleeding incidence was observed (any bleeding, 8 of 40 (20.0%) for AT group vs 1/41 (2.4%) for placebo group; P < 0.015). CONCLUSIONS: Data from this post hoc analysis confirm an increased bleeding risk seen with AT treatment in these patients. When given early in severe sepsis, though statistically not significant, absolute risk reductions with AT of 21% and 14% for organ failure and mortality, respectively, indicate a potential for treatment benefit in selected sepsis patients. This observation may have implications for continuing sepsis trials with AT that focus on reduced patient heterogeneity.

The significance and outcome of continuous positive airway pressure-related central sleep apnea during split-night sleep studies.

OBJECTIVE: To determine whether central sleep apnea (CSA) occurring during continuous positive airway pressure (CPAP) titration in patients with obstructive sleep apnea (OSA) reflects subclinical congestive heart failure (CHF), and whether these events will improve with CPAP therapy. DESIGN: Cross-sectional analysis of patients with suspected sleep-related breathing disorders referred for split-night polysomnography PATIENTS AND METHODS: Forty-two OSA patients with and without CPAP-related CSA were analyzed. All CSA patients (n = 21) and control subjects (n = 21) underwent echocardiography, pulmonary function testing, and arterial blood gas (ABG) analysis. Repeat polysomnography with CPAP was performed 2 to 3 months after adequate CPAP therapy in CSA group patients. RESULTS: Demographic, Epworth sleepiness scale, pulmonary function test, ABG, and baseline diagnostic polysomnography findings were similar in both groups. There was no difference in the prevalence of subclinical left ventricular systolic dysfunction in the CSA group vs the control group. CSA patients had decreased sleep efficiency (SE), increased sleep stage 1 percentage, sleep stages shift, wake time after sleep onset (WASO), and total arousals compared to control subjects. Twelve of 14 patients (92%) in the CSA group demonstrated complete or near-complete resolution of CSA events on follow-up polysomnography and showed improvement in SE, WASO, and total arousals compared to their baseline study. CONCLUSIONS: CSA events occurring during CPAP titration are transient and self-limited. They may be precipitated by the sleep fragmentation associated with initial CPAP titration and are not associated with an increased prevalence of occult CHF compared to OSA patients without CPAP-related CSA.

The use of statins and lung function in current and former smokers.

BACKGROUND: Smokers are affected by a variety of inflammatory diseases, including COPD. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase inhibitors, are used for their lipid-lowering characteristics but also appear to have antiinflammatory and immunomodulatory activities. We assessed their ability to preserve lung function in current and former smokers. METHODS: All smokers and ex-smokers seen at the Oklahoma City VA hospital in 2005 with abnormal baseline spirometry findings and two or more pulmonary function tests done 6 months apart were classified into obstructive and restrictive groups based on the initial PFT result. Statin use, annual decline in FEV(1) and FVC, and need for respiratory-related urgent care (emergency department or inpatient) were compared. RESULTS: Approximately one half, 215 of 418 patients, were receiving a statin. Compared to the control group, statin users had a lower decline in FEV(1) (- 0.005 +/- 0.20 L/yr vs 0.085 +/- 0.17 L/yr, p < 0.0001) and FVC (- 0.046 +/- 0.45 L/yr vs 0.135 +/- 0.32 L/yr, p < 0.0001) [mean +/- SD]. This difference remained significant irrespective of whether the patient had obstructive (n = 319), or restrictive (n = 99) disease, and regardless of whether the patient continued or stopped smoking. In patients with an obstructive spirometry finding, we found a lower incidence of respiratory-related urgent care in favor of the statin group (0.12 +/- 0.29 patient-years vs 0.19 +/- 0.32/patient-years; p = 0.02). CONCLUSION: In smokers and former smokers, statins are associated with a slower decline in pulmonary function, independent of the underlying lung disease. CLINICAL IMPLICATION: Prospective, randomized trials are needed to study the effect of statins on lung function.

Activated protein C improves survival in severe sepsis patients with elevated troponin.

OBJECTIVE: Multiple studies in sepsis have demonstrated that elevated troponin is associated with poor outcome. The elevated troponin in this situation is thought to be secondary to microthrombi. We hypothesized that recombinant human activated protein C (APC) treatment would improve outcomes in severe sepsis patients who have elevated troponin. METHODS: Patients with severe sepsis by consensus criteria in a university ICU were divided into a troponin elevated group (cTnI+) and a normal troponin (cTnI(-)) group. Outcome was compared using Fisher's exact test. APACHE[Symbol: see text]II and MODS were calculated by standard methods. PATIENTS: We identified 105 patients with severe sepsis and troponin measured, of which 48 (46%) were in the cTnI+ group. The two groups were similar in terms of age and other comorbid conditions. RESULTS: APACHE II (28+/-8 vs. 25+/-8) was slightly higher and MODS (11+/-4 vs. 9+/-3) was significantly higher in the cTnI+ group. Mortality was 52% (25/48) in cTnI+ group and 30% (17/57) in cTnI(-) group. Mortality was 30% in cTnI+ patients treated with APC and 72% in untreated cTnI+ patients. CONCLUSIONS: Patients with severe sepsis who have elevated troponin have increased mortality. In patients with severe sepsis who have elevated troponin, treatment with APC improves outcome. Further study is needed to determine whether troponin can serve as a simple, readily available marker to identify which patients with severe sepsis will benefit from APC.

The effect of 1 week of continuous positive airway pressure treatment in obstructive sleep apnea patients with concomitant gastroesophageal reflux.

STUDY OBJECTIVES: Patients with obstructive sleep apnea (OSA) have a very high incidence of gastroesophageal reflux (GER). Previous studies have shown that the use of continuous positive airway pressure (CPAP) reduces the frequency of reflux events, but these studies only assessed the effect of a single night of treatment. The aim of this study was to assess the effect of 1 week of CPAP treatment on reflux in patients with OSA and GER. DESIGN: Sixteen patients with OSA and GER were recruited. Polysomnography followed by 24-h, continuous esophageal pH monitoring were performed at baseline. Patients with an apnea-hypopnea index (AHI) > 20/h and 24-h acid contact time (ACT) of at least 6% were included. As part of the polysomnography-qualifying evaluation, all patients underwent CPAP titration to reduce the AHI to < 10/h. Patients were then sent home receiving nasal CPAP for 1 week; after 1 week, esophageal pH monitoring was repeated while receiving CPAP. MEASUREMENTS AND RESULTS: The AHI fell from 63.3 +/- 38.5 to 3.2 +/- 2.2/h (mean +/- SD) [p < 0.001]. Total ACT fell from 13.9 +/- 11.6 to 5.6 +/- 2.7% (p < 0.001). The upright ACT was reduced from 12.4 +/- 6.8 to 6.8 +/- 3.8% (p = 0.01), and the supine (during the sleeping interval) ACT was reduced from 16.3 +/- 18.8 to 3.8 +/- 7.6% (p < 0.01). Eighty-one percent of the patients had a reduction in supine ACT to within the normal range (< 4%). CONCLUSIONS: In OSA patients with significant heartburn complaints, CPAP would appear to be an efficacious approach to the treatment of both disorders.

Rounded atelectasis with atypical computed tomography findings.

Rounded atelectasis is atelectasis of the peripheral part of the lung, typically in contact with thickened pleura, featuring characteristic computed tomography findings. In this case, a 61-year-old man with history of asbestos exposure presented with a right-middle-lobe nodule on chest radiograph, with computed tomography findings suspicious for neoplasm. The patient underwent surgical resection, which revealed rounded atelectasis. Our case raises a question about the sensitivity of radiographic criteria used in identifying rounded atelectasis, and it emphasizes the need to keep rounded atelectasis in the differential diagnosis of a single pulmonary nodule in a patient with a history of asbestos exposure.

Supportive management strategies for disseminated intravascular coagulation. An international consensus.

The cornerstone of the management of disseminated intravascular coagulation (DIC) is the treatment of the underlying condition triggering the coagulopathy. However, a number of uncertainties remain over the optimal supportive treatment. The aim of this study was to provide evidence and expert-based recommendations on the optimal supportive haemostatic and antithrombotic treatment strategies for patients with DIC. A working group defined five relevant clinical scenarios. Published studies were systematically searched in the MEDLINE and EMBASE databases (up to May 2014). Seven internationally recognised experts were asked to independently provide clinical advice. A two-phase blinded data collection technique was used to reach consensus. Only three randomised controlled trials (RCTs) on the supportive management of DIC were identified. The RCTs (overall less than 100 patients) investigated the use of fresh frozen plasma and platelet transfusion and found no differences in survival between the intervention and control groups. The experts' approach was heterogeneous, although there was consensus that supportive management should vary according to the underlying cause, clinical manifestations and severity of blood test abnormalities. Platelet transfusion should be given to maintain platelet count > 50×109/l in case of bleeding while a lower threshold of 20 to 30×109/l may be used in DIC without bleeding. Thromboprophylaxis with low-molecular-weight heparin is advised until bleeding ensues or platelet count drops below 30×109/l. In conclusion, in the absence of solid evidence from RCTs, an individualised supportive management of DIC is advisable based on the type of underlying disease, presence of bleeding or thrombotic complications and laboratory tests results.

Cough and spontaneous rupture of a normal spleen.

Rupture of the spleen is a relatively common complication of trauma and many systemic disorders affecting the reticuloendothelial system, including infections and neoplasias. A rare subtype of rupture occurring spontaneously and arising from a normal spleen was recognized as a distinct clinicopathologic entity. The pathogenesis is debated in the absence of external trauma or predisposing disease. It has been reported in association with apparently trivial insults such as vomiting. We report a case of a patient with spontaneous rupture of a normal spleen. Interestingly, it was observed after severe coughing.

Anticoagulant modulation of inflammation in severe sepsis.

Inflammation and coagulation are so tightly linked that the cytokine storm which accompanies the development of sepsis initiates thrombin activation and the development of an intravascular coagulopathy. This review examines the interaction between the inflammatory and coagulation cascades, as well as the role of endogenous anticoagulants in regulating this interaction and dampening the activity of both pathways. Clinical trials attempting to improve outcomes in patients with severe sepsis by inhibiting thrombin generation with heparin and or endogenous anticoagulants are reviewed. In general, these trials have failed to demonstrate that anticoagulant therapy is associated with improvement in mortality or morbidity. While it is possible that selective patients who are severely ill with a high expected mortality may be shown to benefit from such therapy, at the present time none of these anticoagulants are neither approved nor can they be recommended for the treatment of sepsis.

Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated).

Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0.80 (95% confidence interval [CI], 0.69-0.94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0.56; 95% CI, 0.35-0.88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.