Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.     

Exogenous platelet-activating factor acetylhydrolase reduces mortality in mice with systemic inflammatory response syndrome and sepsis

Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis and in those with systemic inflammatory response syndrome. Strategies to block inflammatory mediators, often with complicated outcomes, are currently being investigated as new adjuvant therapies for sepsis. Here, we determined if administration of recombinant platelet-activating factor (rPAF)-acetylhydrolase (rPAF-AH), an enzyme that inactivates PAF and PAF-like lipids, protects mice from inflammatory injury and death after administration of lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). Administration of rPAF-AH increased plasma PAF-AH activity and reduced mortality in both models. Treatment with rPAF-AH increased peritoneal fluid levels of monocyte chemoattractant protein 1/CCL-2 and decreased interleukin 6 and migration inhibitory factor levels after LPS administration or CLP. Administration of a broad-spectrum antibiotic together with rPAF-AH was more protective than single treatment with either of these agents. The combined treatment was associated with reduced interleukin 6 levels in mice subjected to CLP. We observed acute decreases in plasma PAF-AH activity in mice subjected to CLP or challenged with LPS and in human patients with sepsis. We conclude that alterations in the endogenous PAF-AH contribute to the pathophysiology of sepsis and that administration of exogenous rPAF-AH reduces inflammatory injury and mortality in models relevant to the clinical syndrome. Variations in endogenous PAF-AH activity may potentially account for variable responses to exogenous rPAF-AH in previous clinical trials. Serial measurements of plasma PAF-AH activity in murine models demonstrate dynamic regulation of the endogenous enzyme, potentially explaining the variations in human subjects.     

Inter-individual variability of plasma PAF-acetylhydrolase activity in ARDS patients and PAFAH genotype

Background:  Platelet activating factor (PAF), a pro-inflammatory phospholipid, stimulates cytokine secretion from polymorphonuclear leukocytes expressing the transmembrane G-protein coupled PAF receptor. Elevated PAF levels are associated with acute respiratory distress syndrome (ARDS) and sepsis severity. The pro-inflammatory effects of PAF are terminated by PAF acetylhydrolase (PAF-AH).
Objective:  We sought to determine whether allelic variants in the human PAFAH gene (Arg92His, Ile198Thr, and Ala379Val) contribute to variability in PAF-AH activity in patient plasma obtained within 72 h of ARDS diagnosis.
Results:  Plasma PAF-AH activity (mean ± SD) was higher in patients homozygous for the Arg92 allele compared to His92 allele carriers (2·21 ± 0·77 vs. 1·64 ± 0·68 U/min; P  < 0·01; n  = 31 and 21 respectively). Baseline plasma PAF-AH activity was higher among day 7 survivors vs. day 7 non-survivors (2·05 ± 0·75 vs. 1·27 ± 0·63, P  = 0·05).
Conclusion:  These data demonstrate an association between PAF-AH allelic variation, plasma activity, and outcome in ARDS.     

Platelet-activating factor acetylhydrolase is increased in lung lavage fluid from patients with acute respiratory distress syndrome

OBJECTIVE: Platelet-activating factor (PAF) is a proinflammatory phospholipid that may contribute to inflammation in the acute respiratory distress syndrome (ARDS). PAF acetylhydrolase (PAF-AH) degrades PAF and regulates its biological activity. We characterized PAF-AH in bronchoalveolar lavage fluid from ARDS patients (n = 33, 22 survivors), patients at risk for ARDS (n = 6), and healthy controls (n = 6). DESIGN: Bronchoalveolar lavage was performed during acute (<96 hrs from onset), plateau (6 to 12 days), and late (> or = 14 days) phases of ARDS. PATIENTS: Intubated patients with ARDS or a risk factor for ARDS. MEASUREMENTS AND MAIN RESULTS: In ARDS, total bronchoalveolar lavage PAF-AH activity was markedly increased in the acute phase (87 +/- 89 mU/mL, n = 33) and then decreased in the plateau (23 +/- 14 mU/mL, n = 10) and late phases (19 +/- 14 mU/mL, n = 7) (p = .003). Total bronchoalveolar lavage PAF-AH activity during the acute phase of ARDS was also increased as compared with patients at risk for ARDS (16 +/- 13 mU/mL, n = 6) and healthy controls (3 +/- 3 mU/mL, n = 6) (p < .001). In contrast, plasma PAF-AH activities were the same in controls (3215 +/- 858 mU/mL, n = 6), in patients at risk for ARDS (3606 +/- 1607 mU/mL, n = 6), and during the acute phase of ARDS (3098 +/- 2395 mU/mL, n = 33) (p = .18). PAF-AH mRNA was present in alveolar macrophages in the acute phase of ARDS (five of six) and in at-risk patients (two of three) but not in healthy controls. CONCLUSIONS: PAF-AH activity is increased in bronchoalveolar lavage fluid from patients with ARDS. Likely sources include leakage of plasma PAF-AH into alveoli or release of PAF-AH from injured cells; however, the presence of PAF-AH mRNA in alveolar macrophages suggests that PAF-AH may be actively synthesized in the lungs of patients with ARDS. PAF-AH activity in the lungs of ARDS patients may regulate inflammation caused by PAF and related oxidized phospholipids generated in the inflammatory response.     

The use of corticosteroids in severe sepsis and acute respiratory distress syndrome

During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Relative adrenal insufficiency and peripheral glucocorticoid resistance syndrome are the two main features of the inappropriate hormonal response and provide the grounds for cortisol replacement in these diseases. In practice, a high dose of corticosteroids (i.e. one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomised controlled trials reporting the benefits and risks of low dose corticosteroids (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.     

The use of corticosteroids in severe sepsis and acute respiratory distress syndrome

During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Relative adrenal insufficiency and peripheral glucocorticoid resistance syndrome are the two main features of the inappropriate hormonal response and provide the grounds for cortisol replacement in these diseases. In practice, a high dose of corticosteroids (i.e. one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomised controlled trials reporting the benefits and risks of low dose corticosteroids (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.     

Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

OBJECTIVE: To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis. DESIGN: Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. SETTING: Thirty-eight intensive care units in the United States and Europe. PATIENTS: Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). MEASUREMENTS AND MAIN RESULTS: There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p =.037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p =.026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%; p =.39). CONCLUSIONS: Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.     

Plasma platelet-activating factor acetylhydrolase activity in critically ill patients

OBJECTIVE: Platelet-activating factor (PAF) is a potent proinflammatory mediator in systemic inflammation and sepsis and is inactivated by the enzyme PAF-acetylhydrolase (PAF-AH). Recently, a large phase III clinical trial using recombinant PAF-AH to treat patients with severe sepsis was performed but failed to reduce 28-day mortality rate. To get more information on the activity of PAF-AH in sepsis, we repeatedly measured its activity in plasma in critically ill patients compared with healthy controls. DESIGN: Retrospective cohort study. SETTING: Intensive care unit. PATIENTS: Two hundred thirty-one patients who were admitted to an operative intensive care unit within 1 yr were enrolled and evaluated daily for American College of Chest Physicians/Society of Critical Care Medicine criteria. PAF-AH activity was measured as the release of [H]-acetate from [H]-acetyl-PAF. INTERVENTIONS: Analysis of plasma samples. MEASUREMENTS AND MAIN RESULTS: At the day of admission, PAF-AH activity of patients was below controls but markedly increased over time. Higher activities were seen in patients with severe sepsis or septic shock compared with those without organ failure. With respect to the clinical outcome, lower values were found in nonsurvivors only as long as they had not developed organ failure. In severe sepsis/septic shock, values of nonsurvivors exceeded those of survivors. PAF-AH activity was positively correlated with plasma levels of inflammatory mediators such as neopterine and tumor necrosis factor-alpha but not with acute phase reactants such as C-reactive protein, interleukin-6, or PCT. In addition, parenteral nutrition with lipid emulsions was seemingly associated with low PAF-AH activity compared with enteral nutrition. CONCLUSION: The data indicate severity- and time-dependent changes in PAF-AH activity and may help to explain the failure of recombinant PAF-AH treatment strategies that were not based on activity measurements.     

Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome

OBJECTIVE: To evaluate the effects of a 48-hr neuromuscular blocking agents (NMBA) infusion on gas exchange over a 120-hr time period in patients with acute respiratory distress syndrome. DESIGN: Multiple center, prospective, controlled, and randomized trial. SETTING: Four adult medical or mixed medical-surgical intensive care units. PATIENTS: A total of 56 patients with acute respiratory distress syndrome with a PaO2/FiO2 ratio of <150 at a positive end-expiratory pressure of > or =5 cm H2O. INTERVENTIONS: After randomization, patients received either conventional therapy without NMBA (control group) or conventional therapy plus NMBA for the next 48 hrs. The initial ventilator mode was volume-assist/control. The ventilator remained on assist-control mode throughout the initial 48-hr period in both groups. Tidal volume was 6-8 mL/kg ideal body weight. MEASUREMENTS AND MAIN RESULTS: When analyzed for the entire 120 hrs, there was a significant effect of the NMBA on the course of PaO2/FiO2 ratio (p =.021). Separate comparisons at each time point indicated that patients randomized to the NMBA group had a higher PaO2/FiO2 at 48, 96, and 120 hrs after randomization. Moreover, a decrease of positive end-expiratory pressure (p =.036) was only found in the NMBA group. Two-way repeated-measures analysis of variance exhibited a decrease in positive end-expiratory pressure over time (p =.036). Concerning short-term effects, there was no modification of PaO2/FiO2 ratio 1 hr after randomization in either group. Only one patient (from the control group) developed pneumothorax. CONCLUSIONS: Use of NMBA during a 48-hr period in patients with acute respiratory distress syndrome is associated with a sustained improvement in oxygenation.     

Incidence,clinical course,and outcome in 217 patients with acute respiratory distress syndrome

OBJECTIVE: To assess prospectively acute respiratory distress syndrome incidence, etiologies, physiologic and clinical features, and mortality and its predictors in four intensive care units in Argentina. DESIGN: Prospective inception cohort. SETTING: Four general intensive care units in teaching hospitals. PATIENTS: All consecutive adult patients admitted between January 3, 1999, and January 6, 2000, that met the criteria of the American-European Consensus Conference for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 235 patients developed acute respiratory distress syndrome, and 217 survived for >24 hrs; these were further analyzed. Main risk factors were: sepsis (44%, including 65 pneumonia cases), shock (15%), trauma (11%), gastric aspiration (10%), and other (34%). At admission, nonsurvivors had significantly higher Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment and McCabe scores, and lower oxygenation and pH. During the first week, Pao2/Fio2, Sequential Organ Failure Assessment, pH, base excess, and driving pressure consistently discriminated between survivors and nonsurvivors. Hospital mortality was 58%. One third of patients died early. Main causes of death were multiple organ dysfunction syndrome, sepsis, and septic shock; refractory hypoxemia was uncommon. Factors independently associated with mortality were organ dysfunctions on day 3, Pao2/Fio2 on day 3, and McCabe score. CONCLUSIONS: Acute respiratory distress syndrome was a frequent syndrome in this cohort. Sepsis was its leading cause, and pneumonia was the most common single diagnosis. Mortality was high but similar to most recent series that included serious comorbidities. Independent predictors of death 72 hrs after admission emphasize the importance of both extrapulmonary and pulmonary factors together with preexisting severe illnesses.     

Chemically modified tetracycline 3 prevents acute respiratory distress syndrome in a porcine model of sepsis + ischemia/reperfusion-induced lung injury

Experimental pharmacotherapies for the acute respiratory distress syndrome (ARDS) have not met with success in the clinical realm. We hypothesized that chemically modified tetracycline 3 (CMT-3), an anti-inflammatory agent that blocks multiple proteases and cytokines, would prevent ARDS and injury in other organs in a clinically applicable, porcine model of inflammation-induced lung injury. Pigs (n = 15) were anesthetized and instrumented for monitoring. A "2-hit" injury was induced: (a) peritoneal sepsis-by placement of a fecal clot in the peritoneum, and (b) ischemia/reperfusion-by clamping the superior mesenteric artery for 30 min. Animals were randomized into two groups: CMT-3 group (n = 7) received CMT-3 (200 mg/kg); placebo group (n = 9) received the same dose of a CMT-3 vehicle (carboxymethylcellulose). Experiment duration was 48 h or until early mortality. Animals in both groups developed polymicrobial bacteremia. Chemically modified tetracycline 3 treatment prevented ARDS as indicated by PaO(2)/FIO(2) ratio, static compliance, and plateau airway pressure (P < 0.05 vs. placebo). It improved all histological lesions of ARDS (P < 0.05 vs. placebo). The placebo group developed severe ARDS, coagulopathy, and histological injury to the bowel. Chemically modified tetracycline 3 treatment prevented coagulopathy and protected against bowel injury. It significantly lowered plasma concentrations of interleukin 1β (IL-1β), tumor necrosis factor α, IL-6, IL-8, and IL-10. This study presents a clinically relevant model of lung injury in which CMT-3 treatment prevented the development of ARDS due in part to reduction of multiple plasma cytokines. Treatment of sepsis patients with CMT-3 could significantly reduce progression from sepsis into ARDS.     

A CXCL2 polymorphism is associated with better outcomes in patients with severe sepsis

OBJECTIVE: Several studies have implicated the CXCL2 chemokine as a mediator in the development of sepsis. We hypothesized that a tandem repeat polymorphism (AC)n in the CXCL2 gene, previously associated with susceptibility to severe sepsis, contributes to morbidity and mortality in severe sepsis. DESIGN: Prospective, observational, genetic study of septic patients. SETTING: A network of Spanish postsurgical and critical care units. PATIENTS: A total of 183 critically ill patients fulfilling the International Sepsis Criteria for severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were classified into three groups according to the presence of compound 24 +/- 1 (AC) repeat genotypes: homozygote 24 +/- 1 carriers (HC group), heterozygote 24 +/- 1 carriers (HTC), and non 24 +/- 1 carriers (NC group). Mortality, development of acute respiratory distress syndrome, and number of failing organs were determined for each group. Overall mortality was 46.4%. HC patients had a lower mortality (39.9%) than HTC (52.2%) and NC (72.7%) patients (trend test p = .018). This difference remained significant when using a multiple logistic regression analysis (p = .035). The presence of population stratification was ruled out, since 20 independent genomic control markers demonstrated homogeneity among groups. An exploratory analysis of the effect of acute respiratory distress syndrome on mortality showed a relative risk of 2.60 in the HC group (p = .0004), while in the nonhomozygote carriers (NHC) group the relative risk was 3.34 (p = .0001). CONCLUSIONS: Our data suggest that a tandem repeat polymorphism (AC)n at position -665 in the CXCL2 gene may be an independent predictor of mortality for severe sepsis. Additional studies are needed to confirm these results.     

重症急性胰腺炎早期合并呼吸窘迫综合征的危险因素

目的探讨重症急性胰腺炎早期合并呼吸窘迫综合征的高危因素,并讨论其防护策略。方法选郑州大学第一附属医院消化内科2018年5月—2020年10月住院治疗的100例重症急性胰腺炎患者为研究对象,记录患者临床资料,其中,54例早期合并呼吸窘迫综合征,作为病例组;其余早期未合并呼吸窘迫综合征的46例,作为对照组,比较两组患者各项指标的差异。结果经单因素及多因素分析,结果显示,年龄、CT评分、急性生理学与慢性健康状况评分系统(APACHEⅡ评分)、Ranson评分是影响重症急性胰腺炎早期合并呼吸窘迫综合征的危险因素。结论对于合并上述独立危险因素的重症急性胰腺炎患者,应加强防护,以减少重症急性胰腺炎患者早期合并呼吸窘迫综合征的发生概率。     

Anti-interleukin-8 autoantibodies in patients at risk for acute respiratory distress syndrome

OBJECTIVE: To test the hypothesis that elevated concentrations of interleukin-8 associated with anti-interleukin-8 autoantibodies (anti-interleukin-8:interleukin-8 complexes) are found in patients at risk for acute respiratory distress syndrome who developed the disease. DESIGN: Measurement of anti-interleukin-8:interleukin-8 complex concentrations in previously collected bronchoalveolar lavage fluids. These fluids were obtained from patients at risk for acute respiratory distress syndrome who subsequently either recovered or developed acute respiratory distress syndrome. PATIENTS: A unique population of patients at risk for acute respiratory distress syndrome was studied. There were 26 patients at risk for acute respiratory distress syndrome who were divided into three groups. Group I patients had high interleukin-8 concentrations and developed acute respiratory distress syndrome, group II had high interleukin-8 concentrations and did not develop acute respiratory distress syndrome, and group III had low interleukin-8 concentrations and did not develop acute respiratory distress syndrome. These patients were selected to test the hypothesis that presence of elevated concentrations of anti-interleukin-8:interleukin-8 complexes differentiates patients at risk for acute respiratory distress syndrome who developed acute respiratory distress syndrome from patients who did not. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid concentrations of interleukin-8 associated with the anti-interleukin-8 autoantibodies were significantly different between groups (p <.03). The amount of interleukin-8 bound to the anti-interleukin-8 autoantibody was higher in group I than in group II and group III. CONCLUSIONS: Bronchoalveolar lavage fluid concentration of anti-interleukin-8:interleukin-8 complexes may serve as a marker of disease progression in patients at risk for acute respiratory distress syndrome.     

Sepsis-associated pulmonary complications in emergency department patients monitored with serial lactate: An observational cohort study

PurposePatients with severe sepsis and septic shock are at high risk for development of pulmonary complications, including acute respiratory distress syndrome (ARDS). Serial lactate monitoring is a useful tool to gauge global tissue hypoxia in emergency department (ED) patients with sepsis. We hypothesized that patients undergoing serial lactate monitoring (SL) would demonstrate a decreased incidence of pulmonary complications.MethodsThis is a retrospective observational cohort study of adult severe sepsis and septic shock patients with elevated lactate presenting to a large academic ED. A total of 243 patients were assigned to SL (n = 132) or no serial lactate monitoring (NL; n = 111). The primary outcome was a composite of pulmonary complications: (1) ARDS development and (2) respiratory failure.ResultsTwenty-eight patients (21%) in the SL group and 37 patients (33%) in the NL group developed the primary outcome (P = .03). Multivariate analysis demonstrated an association between the NL group and development of pulmonary complications (adjusted odds ratio [aOR], 2.1; confidence interval [CI], 1.15-3.78). Emergency department mechanical ventilation was independently associated with development of ARDS (aOR, 3.5; 1.8-7.0). In the a priori subgroup of patients mechanically ventilated in the ED (n = 97), those who developed ARDS received higher tidal volumes compared to patients who did not develop ARDS (8.7 mL/kg predicted body weight [interquartile range, 7.6-9.5] vs 7.6 [interquartile range, 6.8-9.0]; P < .01).ConclusionsSerial lactate monitoring is associated with a decrease in major pulmonary complications in severe sepsis and septic shock. Acute respiratory distress syndrome incidence is also influenced by ED-based mechanical ventilation. These results provide 2 potentially modifiable variables to be targeted in future studies to prevent pulmonary complications in this patient subset.     

Dazoxiben in human sepsis and adult respiratory distress syndrome

Levels of thromboxane B2 (TxB2), the stable metabolite of thromboxane A2, are elevated in human and experimental septic shock. The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia. A randomized prospective study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome (hypoxemia, radiologic evidence of the syndrome, and intrapulmonary shunt greater than 20%) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis. Five subjects received dazoxiben and five received placebo. Dazoxiben, 100 mg, or placebo was injected intravenously every 4 hours for a maximum of 72 hours. Plasma immunoreactive TxB2 (iTxB2) levels were determined by radioimmunoassay. Before dazoxiben, the plasma iTxB2 level was 752 +/- 261 pg/ml (n = 5) and was reduced within 1 hour to 333 +/- 137 pg/ml. The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 +/- 67 pg/ml (n = 4) 60 hours after dosing. In contrast, placebo had no significant effect on plasma iTxB2 levels (n = 5) throughout the entire period of observation. Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance, intrapulmonary shunting, clotting studies, or extravascular lung water. One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died. We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom, but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis.     

Clinical implementation of the ARDS network protocol is associated with reduced hospital mortality compared with historical controls

OBJECTIVE: To assess the impact of implementing a low tidal volume ventilation strategy on hospital mortality for patients with acute lung injury or acute respiratory distress syndrome. DESIGN: Retrospective, uncontrolled study. SETTING: Adult medical-surgical and trauma intensive care units at a major inner city, university-affiliated hospital. PATIENTS: A total of 292 patients with acute lung injury or acute respiratory distress syndrome. INTERVENTIONS: Between the years 2000 and 2003, 200 prospectively identified patients with acute lung injury/acute respiratory distress syndrome were managed by the ARDS Network low tidal volume protocol. A historical control group of 92 acute respiratory distress syndrome patients managed by routine practice from 1998 to 1999 was used for comparison. MEASUREMENTS AND MAIN RESULTS: Patients managed with the ARDS Network protocol had a lower hospital mortality compared with historical controls (32% vs. 51%, respectively; p = .004). Multivariate logistic regression estimated an odds ratio of 0.32 (95% CI, 0.17-0.59; p = .0003) for mortality risk with use of the ARDS Network protocol. Protocol-managed patients had a lower tidal volume (6.2 +/- 1.1 vs. 9.8 +/- 1.5 mL/kg; p < .0001) and plateau pressure (27.5 +/- 6.4 vs. 33.8 +/- 8.9 cm H2O; p < .0001) than historical controls. CONCLUSION: Adoption of the ARDS Network protocol for routine ventilator management of acute lung injury/acute respiratory distress syndrome patients was associated with a lower mortality compared with recent historical controls.     

Prognostic factors,clinical course,and hospital outcome of patients with chronic obstructive pulmonary disease admitted to an intensive care unit for acute respiratory failure

OBJECTIVE: To describe prognostic factors, clinical course, and hospital outcome of patients with chronic obstructive pulmonary disease admitted to an intensive care unit for acute respiratory failure. DESIGN: Analysis of prospectively collected data. SETTING: A multidisciplinary intensive care unit of an inner-city university hospital. PATIENTS: Patients with chronic obstructive pulmonary disease admitted to an intensive care unit for acute respiratory failure from August 1995 through July 1998. MEASUREMENTS AND MAIN RESULTS: Data were obtained concerning demographics, arterial blood gas, Acute Physiology and Chronic Health Evaluation (APACHE) II score, sepsis, mechanical ventilation, organ failure, complications, and hospital mortality rate. Fifty-nine percent of patients were male, 63% white, and 36% African-American; the mean age was 63.1 +/- 8.9 yrs. Noninvasive mechanical ventilation was tried in 40% of patients and was successful in 54% of them. Invasive mechanical ventilation was required in 61% of the 250 admissions. Sepsis developed in 31% of patients, nonpulmonary organ failure in 20%, pneumothorax in 3%, and acute respiratory distress syndrome in 2%. Multiple organ failure developed in 31% of patients with sepsis compared with 3% without sepsis (p <.0001). Predicted and observed hospital mortality rates were 30% and 15%, respectively. Differences in age and arterial carbon dioxide and oxygen tensions between survivors and nonsurvivors were not significant. Arterial pH was lower in nonsurvivors than in survivors (7.21 vs. 7.25, p =.0408). The APACHE II-predicted mortality rate (p =.0001; odds ratio, 1.046; 95% confidence interval, 1.022-1.070) and number of organ failures (p <.0001; odds ratio, 5.524; 95% confidence interval, 3.041-10.031) were independent predictors of hospital outcome; invasive mechanical ventilation was not an independent predictor. CONCLUSIONS: Physiologic abnormalities at admission to an intensive care unit and development of nonrespiratory organ failure are important predictors of hospital outcome for critically ill patients with chronic obstructive pulmonary disease who have acute respiratory failure. Improved outcome would require prevention and appropriate treatment of sepsis and multiple organ failure.