Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy wasdeveloped at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroupsand among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.(AU)

Recombinant factor VIIa: unregulated continuous use in patients with bleeding and coagulopathy does not alter mortality and outcome.

Recombinant factor VIIa (rFVIIa) is used in patients with hemophilia who had developed inhibitors. A hemostatic effect has been demonstrated following the administration of rFVIIa in patients after trauma and bleeding. Currently, there is no widely accepted guideline for off-label rFVIIa usage in bleeding patients. We planned to review the rFVIIa utilization practice in our institution and develop policies and guidelines for future rFVIIa use. We acquired the medical records of 55 patients who received rFVIIa at our institution during 2003-2004. Patient charts were reviewed regarding their rFVIIa administration and indications, dose and frequency, cost, pre-rFVIIa blood component usage, utilization of hematology services and outcome were analyzed. Underlying liver disease with coagulopathy was the commonest (47%) indication for rFVIIa use. Recombinant FVIIa was successful (69%) in correcting laboratory parameters of coagulopathy, but did not alter outcome. Twenty-six of the 55 patients (47%) died during the same admission from their underlying diseases. Apart from two trauma patients, no one died from bleeding. We conclude that unregulated continuous administration of rFVIIa in bleeding/coagulopathic patients did not alter outcome. Closer monitoring of rFVIIa usage, including hematology consultation and enforcement of pre-rFVIIa blood component usage would optimize cost-effectiveness.

Epidermal growth factor and transforming growth factor-alpha in middle ear effusion.

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) promote the differentiation and proliferation of epithelia as well as the proliferation and chemotaxis of fibroblasts. Additionally, EGF promotes wound healing in tissues composed largely of epithelial cells and fibroblasts. We hypothesized that EGF and TGF-alpha regulate the differentiation and proliferation of the epithelial lining and the migration and proliferation of fibroblasts in the subepithelial space of the middle ear mucosa in children with otitis media. As an initial test of this hypothesis, EGF and TGF-alpha concentrations were measured in 82 middle ear effusions of children undergoing tympanostomy tube placement. EGF was present in 45% of these effusions, and TGF-alpha was present in 6%. The mean concentration +/- SEM values for EGF and TGF-alpha were 19+/-7.6 and 3.7+/-7.9 pg/mL, respectively. In addition, neutrophils, macrophages, and lymphocytes in middle ear effusions stained for EGF by immunocytochemistry. We conclude that growth factors are frequently present in middle ear effusions of children with otitis media.

Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation.

OBJECTIVE: To describe our experience with the use of extracorporeal membrane oxygenation (ECMO) as a rescue therapy in adult patients with severe cardiopulmonary failure from Hantavirus pulmonary syndrome. DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: Patients with confirmed Hantavirus infection, who developed severe cardiopulmonary failure in which conventional therapy was assessed as being unsuccessful. INTERVENTIONS: Records of previous patients treated for Hantavirus pulmonary syndrome were reviewed and findings consistent with 100% mortality were found. MEASUREMENTS AND MAIN RESULTS: Findings associated with a 100% mortality rate were a) cardiac index of <2.5 L/min/m2; b) serum lactate concentration of >4.0 mmol/L (normal range 0.0 to 2.2); c) pulseless electrical activity or ventricular fibrillation or ventricular tachycardia; and d) refractory shock despite fluid resuscitation, and vasoactive medications. From 1994 to 1996, seven patients were admitted with confirmed Hantavirus pulmonary syndrome and severe cardiopulmonary failure. Three of the seven patients had at least two of the four criteria for a 100% mortality rate listed above, and appeared to be failing optimal conventional therapy. These three patients received support with venoarterial ECMO. The first patient was placed on ECMO during cardiac arrest and died. The next two patients who received ECMO for Hantavirus pulmonary syndrome survived after relatively short, uncomplicated ECMO runs, and were discharged without complications. CONCLUSIONS: ECMO successfully provided cardiopulmonary support in two patients with severe Hantavirus pulmonary syndrome who survived with a good outcome. Our experience suggests that ECMO is a beneficial therapy for patients critically ill with Hantavirus pulmonary syndrome.

Pleural fluid characteristics in hantavirus pulmonary syndrome.

Hantavirus pulmonary syndrome (HPS), is a rodent-borne, acute, often fulminant cardiorespiratory illness. Noncardiogenic pulmonary edema is prominent in HPS as is cardiac dysfunction. Pleural effusions are commonly noted in patients with HPS and have been thought to be exudative. This report describes the prevalence and characteristics of pleural effusions by an assessment of chest radiographs for the presence of pleural fluid and reviews all pleural fluid specimens obtained from patients with HPS. Of 23 patients treated at the University of New Mexico Hospital for HPS, 22 had evidence of pleural fluid while 4 had sampling of their pleural fluid. Two samples met criteria for an exudate by pleural fluid protein to serum protein ratio of more than 0.5; one was clearly a transudate and the other had inconsistent characteristics. The two exudative samples were obtained 7 days after admission, while the other 2 were obtained within 1 day of admission. Pleural fluid cultures were sterile, and the total of nucleated cells was less than 170/mm3, and predominately mononuclear. A hypothesis may be formulated that the pleural fluid in HPS is initially transudative, consistent with the observed cardiopulmonary dysfunction. However, following aggressive resuscitative efforts and as the acute illness resolves, fluid shifts occur as cardiac function normalizes; the pleural fluid may take on characteristics of an exudate.

Interleukin-8 concentration predicts the neutrophil count in middle ear effusion.

Interleukin-8 (IL-8), a potent neutrophilic chemoattractant and inflammatory cytokine, is present in middle ear effusions (MEEs) of children with otitis media and is thought to be responsible for the accumulation of neutrophils in MEEs. We hypothesized that IL-8 concentration predicts the total number and proportion of neutrophils in MEEs. IL-8 concentration and total and differential cell counts were measured in MEEs of children undergoing tympanostomy tube placement for otitis media. IL-8 was present in 80 (98%) of 82 effusions. The mean +/- SEM value for IL-8 was 7342 +/- 847 pg/mL. The mean +/- SEM count and percentage of neutrophils were 1.34 x 10(6) +/- 3.44 x 10(5) and 70.6 +/- 3.1%, respectively. IL-8 concentrations correlated positively with the total number (r = +0.30; P = 0.02) and percentage of neutrophils (r = +0.32; P = 0.01) in the effusion. Additionally, purulent effusions had greater IL-8 concentrations (P = 0.003) and greater neutrophil count (P = 0.03) than mucoid or serous effusions. We conclude that IL-8 is consistently present in MEEs of children and IL-8 concentration predicts the total number and proportion of neutrophils. Furthermore, IL-8 concentration and the total number of neutrophils correlate positively with the type of effusion. These results support the hypothesis that IL-8 recruits neutrophils to the middle ear in MEEs.

Cardiopulmonary manifestations of hantavirus pulmonary syndrome.

OBJECTIVE: To describe the clinical characteristics of a group of patients infected with the newly recognized hantavirus in the Southwestern United States. DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: All patients with confirmed hantavirus infection admitted to the University of New Mexico Hospital between May 1, 1993 and January 1, 1994. INTERVENTIONS: Records of patients with hantavirus infection were reviewed to collect all pertinent clinical data. MEASUREMENTS AND MAIN RESULTS: Pulmonary disease in these patients was characterized by hypoxemia covering a wide range of severity. The cause of hypoxemia was an increased permeability (noncardiac) pulmonary edema which could be differentiated from hydrostatic (cardiac) pulmonary edema by its association with low pulmonary artery occlusion pressures and increased protein content of edema fluid. Hemodynamic measurements in severe cases showed a shock state characterized by a low cardiac index (range 1.6 to 3.0 L/min/min2), a low stroke volume index (range 10.5 to 29 mL/m2), and high systemic vascular resistance index (range 1,653 to 2,997 dyne.sec/cm5.m2). Progression to death was associated with worsening cardiac dysfunction unresponsive to treatment and causing oxygen debt and lactic acidosis. CONCLUSIONS: The two major life-threatening pathophysiologic changes in Hantavirus Pulmonary Syndrome are increased permeability pulmonary edema, and an atypical form of septic shock caused by myocardial depression and hypovolemia.

Hantavirus pulmonary syndrome: recognition and emergency department management.

Hantavirus infection with respiratory involvement is a new clinical entity. The respiratory and cardiovascular abnormalities associated with hantavirus infection define the hantavirus pulmonary syndrome (HPS). We present two cases of HPS and discuss the presentation, epidemiology, emergency department management, and differential diagnosis. Treatment of HPS involves intensive care monitoring, airway management, and cardiovascular support. Because human hantavirus infection with respiratory involvement has been recognized recently in all geographic regions of the United States, it is important for emergency physicians to recognize this syndrome's characteristic symptoms and laboratory abnormalities. The fulminant clinical course of HPS and its 65% mortality rate underscore the importance of early recognition if potentially life-saving interventions are to be initiated.

Unplanned extubation. Predictors of successful termination of mechanical ventilatory support.

BACKGROUND: Unplanned extubation (self-extubation or accidental extubation) occurs commonly in mechanically ventilated patients, and many patients do not receive mechanical ventilation indefinitely. Unfortunately, weaning parameters are often unavailable in the setting of unplanned extubation, and it would be useful to define pre-extubation respiratory and ventilatory parameters that predict which patients require reintubation. METHODS: The medical records of all patients who experienced unplanned extubation for the 2-year period of July 1989 to July 1991 were reviewed. Pre-extubation values of respiratory rate, tidal volume (VT), fraction of inspired oxygen (FIo2), PEEP, ventilatory mode, and ventilator-delivered minute volume (VVE, ventilator rate multiplied by set VT) were recorded. In addition, the following data were obtained: age, gender, respiratory failure diagnosis, duration of intubation, amount, and type of sedative agents in the 24 h before extubation. Comparisons of these values among patients who ultimately required reintubation and those who were not reintubated were made using the Mann-Whitney U two-sample test. RESULTS: During this period, there were 23 unplanned extubations involving 22 patients. Reintubation was required for 18 episodes of unplanned extubation, but was not required for 5 episodes. There were no significant differences between the two groups for any of the parameters except VVE and FIo2. The mean pre-extubation FIo2 of the reintubated group (0.49) was significantly higher than that of the patients who were not reintubated (0.35) (p = 0.021); all of the patients who remained extubated were receiving an FIo2 < or = 0.40. The VVE was also higher in the reintubated group (9.73 L/min) than in the patients who were not reintubated (1.40 L/min); all patients who remained extubated were receiving < or = 7.0 L/min of ventilator-delivered minute ventilation. CONCLUSIONS: Reintubation after unplanned extubation should not be considered mandatory. Patients who require reintubation have significantly higher preextubation FIo2 and ventilatory requirements than patients who remain extubated.

Heat-killed pneumococci and pneumococcal capsular polysaccharides stimulate tumor necrosis factor-alpha production by murine macrophages.

Tumor necrosis factor-alpha (TNF) is an important humoral mediator of sepsis and endotoxin-induced shock. However, Streptococcus pneumoniae, a gram-positive organism, is the most common causative agent of community-acquired pneumonia and sepsis. We hypothesized that the pathogenesis of pneumococcal pneumonia and sepsis involves pneumococcus-stimulated TNF synthesis, and we tested that hypothesis in vitro by comparing heat-killed type III and type V pneumococcus and 23-valent purified pneumococcal capsular polysaccharides with Escherichia coli and purified lipopolysaccharide (LPS) as stimuli for TNF production by the murine macrophage cell line RAW 264.7. We evaluated TNF production in response to various doses and times of exposure to these agents, as well as the effects of indomethacin on TNF production in response to these agents. Stimulation with both types of heat-killed pneumococcus resulted in TNF production in a dose-response fashion, as did stimulation with E. coli. Fewer type III pneumococci (10 bacteria/ml) were required to stimulate significant TNF secretion than either type V pneumococcus or E. coli, but the overall dose-response curves of the three bacteria were similar. The dose-response curves for pneumococcal capsular polysaccharides and LPS were very similar, although at the highest concentration pneumococcal capsular polysaccharides stimulated more TNF secretion than did LPS (469 versus 213 U/ml). The kinetics of pneumococcus-stimulated TNF secretion were identical to the kinetics of LPS-stimulated TNF secretion. In the presence of indomethacin, pneumococcus-stimulated TNF production decreased by 87.5%, as compared with pneumococcus alone. In contrast, LPS with indomethacin stimulated 19.5% more TNF than LPS alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced alveolar macrophage production of tumor necrosis factor during sepsis in mice and men.

BACKGROUND AND METHODS: Tumor necrosis factor (TNF) has been implicated as a major humoral mediator of sepsis and endotoxin shock. TNF is secreted by cells of the reticuloendothelial system, including alveolar macrophages. Alveolar macrophage TNF production has been postulated to play a pathogenetic role in the development of adult respiratory distress syndrome (ARDS) in sepsis. To evaluate alveolar macrophage production of TNF during sepsis and endotoxin shock, we studied the effects of sepsis and/or in vivo lipopolysaccharide on the in vitro production of TNF by pulmonary alveolar macrophages. Human pulmonary alveolar macrophages were obtained by bronchoalveolar lavage from six septic and five nonseptic patients, cultured in the presence or absence of lipopolysaccharide (1 ng/mL), and assayed for TNF activity in a bioassay using fibroblast lysis. A murine model of sepsis was also utilized to study pulmonary alveolar macrophage TNF production under more controlled conditions. Normal mice were given ip injections of either lipopolysaccharide or saline. After 2 hrs, pulmonary alveolar macrophages were obtained and cultured in saline or various concentrations of lipopolysaccharide (0.001 to 10 micrograms/mL). RESULTS: There was no difference in baseline TNF activity, expressed as per cent lysis at 1:10 dilution, between pulmonary alveolar macrophages from control and septic patients (35.7 +/- 5.5% vs. 24.4 +/- 9.3%, respectively) (p greater than .05). However, when stimulated with lipopolysaccharide in vitro, the pulmonary alveolar macrophages from nonseptic patients produced significantly (p less than .01) more TNF (82.8 +/- 3.6%) than did pulmonary alveolar macrophages from patients with the septic syndrome (35.2 +/- 3.8%). Similar findings were obtained using the murine sepsis model. The baseline TNF activity in pulmonary alveolar macrophages from control mice was 22.9 +/- 7.0% (mean +/- SEM) and from lipopolysaccharide-injected mice was 26.8 +/- 3.3% (p greater than .05). Stimulation with 1 ng/mL lipopolysaccharide in vitro produced an increase in TNF activity in both groups, but the increase was greater in the control mice (68.1 +/- 5.7%) than in the lipopolysaccharide-injected mice (47.5 +/- 5.3%) (p less than .01). When the murine pulmonary alveolar macrophages were stimulated with higher concentrations of lipopolysaccharide (0.1 to 10 micrograms/mL), pulmonary alveolar macrophages from lipopolysaccharide-injected mice produced less than 25.5% of the TNF produced by pulmonary alveolar macrophages from control mice. CONCLUSIONS: These studies indicate that sepsis and endotoxin injection result in a rapid decrease in the ability of pulmonary alveolar macrophages from both humans and mice to produce and secrete TNF in response to lipopolysaccharide. We speculate that a downregulation of TNF production or of macrophage responsiveness to lipopolysaccharide has occurred. These results suggest that sustained TNF production by macrophages is not required for lung injury in sepsis.

Role of tumor necrosis factor in sepsis and acute lung injury.

TNF is a small protein secreted by activated monocytes and macrophages that mediates the in vivo effects of endotoxin. When injected into experimental animals, TNF reproduces the picture of septic or endotoxin shock. In addition, antibodies to TNF protect animals against the deleterious effects of IV injections of either LPS or live bacteria. Specifically, the available evidence suggests that TNF may be necessary for the organ injury and failure seen in sepsis. However, TNF probably is not the final common pathway to shock and tissue injury. Inhibition of cyclooxygenase is protective from the lethal effects of both LPS and TNF infusion, suggesting that prostanoids play an important, and perhaps more proximal role in the generation of tissue injury. In addition, TNF is produced and cleared from the blood-stream within a short period of time after an LPS stimulus, suggesting that TNF sets into motion a chain of events that may be self-perpetuating even in the absence of further TNF stimulus. In the near future, the treatment of sepsis may involve the administration of antibodies both to TNF and to LPS. Cyclooxygenase inhibitors should also begin to play a role in the therapy of sepsis. In the more distant future it is likely that we will be able to manipulate the state of activation of genes that code for TNF to exert some control over its production and secretion. It is perhaps within our grasp to finally reduce the morbidity and mortality of this lethal condition.