Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017

OBJECTIVE: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. PARTICIPANTS: A multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine. DESIGN/METHODS: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members. RESULTS: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2 < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence). CONCLUSIONS: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

Breath sound changes associated with malpositioned endotracheal tubes.

Endotracheal tubes (ETTs) are used to establish airway access in patients with ventilatory failure and during general anaesthesia. Tube malpositioning can compromise respiratory function and can be associated with increased morbidity and mortality. Clinical assessment of ETT position normally involves chest auscultation, which is highly skill-dependent and can be misleading. The objective of this pilot study was to investigate breath sound changes associated with ETT malpositioning. Breath sounds were acquired in six human subjects over each hemithorax and over the epigastrium for tracheal, bronchial and oesophageal intubations. When the ETT was in the oesophagus, the acoustic energy ratio between epigastrium and chest surface increased in all subjects (p < 0.04). In addition, ETT placement in the right mainstem bronchus decreased the acoustic energy ratio between the left and right hemithoraxes in all subjects (p < 0.04). A baseline measurement of this energy ratio was needed for bronchial intubation identification. However, using this ratio after bandpass filtering (200-500 Hz) did not require a baseline value, which would increase the utility of this method for initial ETT placement. These results suggest that computerised analysis of breath sounds may be useful for assessment of ETT positioning. More studies are needed to test the feasibility of this approach further.

Pneumothorax detection using pulmonary acoustic transmission measurements.

Pneumothorax is a common clinical condition that can be life threatening. The current standard of diagnosis includes radiographic procedures that can be costly and may not always be readily available or reliable. The objective of this study was to investigate the hypothesis that pneumothorax causes detectable pathognomonic changes in pulmonary acoustic transmission. An animal model was developed whereby 15 mongrel dogs were anaesthetised, intubated and mechanically ventilated. A thoracoscopic trocar was placed into the pleural space for the introduction of air and confirmation of a approximately 30% pneumothorax by direct visualisation. Broadband acoustic signals were introduced into the endotracheal tube, while transmitted waves were measured at the chest surface. Pneumothorax was found consistently to lower the pulmonary acoustic transmission in the 200-1200 Hz frequency band, whereas smaller transmission changes occurred at lower frequencies (p< 0.0001, sign test). The ratio of acoustic energy between low-(< 220 Hz) and high-(550-770 Hz) frequency bands was significantly different in the control and pneumothorax states (p < 0.0001, sign test). This implies that pneumothoraces can be reliably detected using pulmonary acoustic transmission measurements in the current animal model. Further studies are needed to investigate the feasibility of using this technique in humans.

Pneumothorax detection using computerised analysis of breath sounds.

The primary objective of the study was to investigate the effects of pneumothorax (PTX) on breath sounds and to evaluate their use for PTX diagnosis. The underlying hypothesis is that there are diagnostic breath sound changes with PTX. An animal model was created in which breath sounds of eight mongrel dogs were acquired and analysed for both normal and PTX states. The results suggested that pneumothorax was associated with a reduction in sound amplitude, a preferential decrease in high-frequency acoustic components and a reduction in sound amplitude variation during the respiration cycle (p<0.01 for each, using the Wilcoxson signed-rank test). Although the use of diminished sound amplitude for PTX diagnosis assumes availability of baseline measurements, this appears unnecessary for high-frequency reduction or sound amplitude changes over the respiratory cycle. Further studies are warranted to test the clinical feasibility of the method in humans.

Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations.

Severe sepsis and septic shock are frequently encountered conditions in today's hospital environment. The incidence appears to be increasing despite our growing armamentarium of antibiotics and our enhanced knowledge of the pathophysiologic processes at play. The clinical presentation may take a variety of forms, especially in patients at the extremes of age and in the immunocompromised population. A high index of suspicion and prompt institution of appropriate antimicrobial treatment is mandatory for a successful outcome. It is hoped that adoption of uniform definitions will aid in research and in effective communication concerning sepsis and its adverse sequelae.

Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock.

Organ system dysfunction is a common adverse sequelae of severe sepsis and septic shock and has been reported to be the most common cause of death in the noncoronary intensive care unit. The pathophysiology of the development of multiple organ system dysfunction is likely multifactoral and may take several different pathways. The frequency of specific organ system involvement is dependent on the definition used to describe the organ dysfunction. The presence of organ dysfunction has great clinical impact on the underlying disease process, can prolong the hospital stay, increase the cost of care, and has been associated with an increase in mortality rate. At present, there is no recognized specific treatment for established organ failure, this primary attention has been directed toward prevention.

E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators.

CONTEXT: Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not. OBJECTIVE: To assess the efficacy and safety of E5 in the treatment of patients with severe gram-negative sepsis. DESIGN: A multicenter, double-blind, randomized, placebo-controlled trial conducted at 136 US medical centers from April 1993 to April 1997, designed with 90% power to detect a 25% relative risk reduction, incorporating 2 planned interim analyses. SETTING: Intensive care units at university medical centers, Veterans Affairs medical centers, and community hospitals. PATIENTS: Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection. INTERVENTION: Patients were assigned to receive 2 doses of either E5, a murine monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552). MAIN OUTCOME MEASURES: The primary end point was mortality at day 14; secondary end points were mortality at day 28, adverse event rates, and 14-day and 28-day mortality in the subgroup without shock at presentation. RESULTS: The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infection confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56). Patients presenting without shock had a slightly lower mortality when treated with E5 but the difference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse event rates between E5 and placebo. CONCLUSIONS: Despite adequate sample size and high enrollment of patients with confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before further large-scale studies of patients with sepsis are conducted.

Nitric oxide in the pathogenesis of sepsis.

In sepsis and septic shock, inflammatory mediators result in the production of increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the amino acid L-arginine. The increased amounts of NO are responsible for changes in vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial function, characteristic of septic insult. Therapeutic strategies designed to reduce the concentration of NO by inhibiting the action of the nitric oxide synthase enzyme, or by scavenging the excess NO, offer the potential to treat directly the vasomotor abnormalities and myocardial depression seen in sepsis and other inflammatory states. This article reviews the biology of NO in sepsis and discusses strategies for neutralization of the increased NO production, in the setting of severe sepsis and septic shock.

The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome.

BACKGROUND: In patients with the acute respiratory distress syndrome, pneumothorax and other air leaks - any extrusion of air outside the tracheobronchial tree - have been attributed to high ventilatory pressures or volumes and linked to increased mortality. METHODS: We analyzed data from a prospective trial of aerosolized synthetic surfactant in 725 patients with the acute respiratory distress syndrome induced by sepsis. We compared the ventilatory pressures and volumes in the patients without any air leaks (the highest values during the five-day study) with the pressures and volumes in those with pneumothorax or with any air leaks (the highest values during the 16- and 24-hour periods before the complication developed). RESULTS: Fifty patients (6.9 percent) had pneumothorax and 77 (10.6 percent) had pneumothorax or other air leaks. There were no significant differences between patients with air leaks and those without air leaks in any pressure or volume examined. Overall mortality at 30 days was 40.0 percent (95 percent confidence interval, 36.4 to 43.6); among the patients with pneumothorax, it was 46.0 percent (95 percent confidence interval, 32.2 to 59.8), and among those without pneumothorax, it was 39.3 percent (95 percent confidence interval, 35.6 to 43.0; P=0.35). The mortality rate was 45.5 percent (95 percent confidence interval, 34.4 to 56.6) in the group with any air leaks and 39.0 percent (95 percent confidence interval, 35.3 to 42.8) in the group without air leaks (P=0.28). CONCLUSIONS: In patients with sepsis-induced acute respiratory distress syndrome who were receiving mechanical ventilation with conventional pressures and volumes, there were no significant correlations between high ventilatory pressures or volumes and the development of pneumothorax or other air leaks. Pneumothorax or other air leaks were not associated with a significantly increased mortality rate.

Radiographic patterns of pulmonary disease.

Pulmonary radiographs are essential adjuncts to the evaluation and diagnosis of suspected pulmonary disease. In the intensive care unit, radiographs are useful to confirm correct positioning of diagnostic and therapeutic devices. Patterns seen on the radiograph may be within broadly normal limits or may be interpreted as abnormal, especially when placed in the clinical context of a specific patient's problem. The description abnormal can be related to both nonspecific and specific radiographic patterns of disease. Nonspecific radiographic patterns of disease include location of disease, temporal course of disease, pleural abnormalities, hyperinflation, extra-alveolar air, atelectasis, bronchiectasis, and vascular disease. Specific radiographic patterns of disease are discrete anatomic structures seen on a radiograph, for example, cavitary and cystic disease. The interpretation of nonspecific and specific radiographic patterns is useful in diagnosis, selection of treatment, and monitoring of the course of disease and the patient's response to treatment.

Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.

OBJECTIVE: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis. SETTING: Ninety-one academic medical center intensive care units in North America and Europe. PATIENTS: Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. INTERVENTIONS: Patients were randomized to receive either rhIL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg/hr) or placebo. MEASUREMENTS AND MAIN RESULTS: The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study. CONCLUSIONS: A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

Indwelling small pleural catheter needle thoracentesis in the management of large pleural effusions.

STUDY OBJECTIVES: To evaluate the clinical safety, efficacy, and cost of a small indwelling pleural catheter (7F, Turkel Safety Thoracentesis System [Sherwood, Davis, and Geck; St. Louis]) vs repeated needle thoracentesis or closed tube thoracostomy as a means to drain a large-volume pleural effusion. SETTING: Inpatients in a tertiary care university teaching hospital in urban Chicago. DESIGN: Prospective, consecutive patient comparative study using historical controls. PATIENTS: Fifty-seven therapeutic aspirations in 23 patients with large pleural effusions as defined by opacification of at least one third of the hemithorax on chest radiography. Patients were excluded if they had a history of thoracic surgery, documented loculations, structural chest abnormalities, severe coagulopathy, or refused to give informed consent. MEASUREMENTS: Volume of each pleural aspiration, total fluid removed, pleural fluid lactate dehydrogenase, protein, glucose, cytologic analysis, microbiologic stains, and cultures based on clinical indications. RESULTS: We found that initial thoracentesis and repeated pleural drainage using the indwelling catheter system is a safe, efficacious, and cost-effective procedure that may aid the evacuation and management of a large-volume pleural effusion. There were fewer adverse effects and complications such as pneumothorax, splenic laceration, hemopneumothorax, local pain, dry tap, and hematomas, as compared with previous reports. The overall complication rate was 12% (7/57). There were two pneumothoraces detected (3.5%), one of which required closed tube thoracostomy for treatment (1.75%). A further benefit comes in the form of a significant cost savings at our institution ($80 vs $240) when this needle-catheter system is used in place of closed tube thoracostomy in the drainage of a large-volume pleural effusion. CONCLUSION: An indwelling pleural catheter with the Turkel safety needle-catheter (as described in the study) can be used to successfully drain the pleural space with reduced morbidity and a significant cost saving in comparison to repeated needle thoracenteses or closed tube thoracostomy.

Radiographic patterns of pulmonary disease.

Pulmonary radiographs are essential adjuncts to the evaluation and diagnosis of suspected pulmonary disease. In the intensive care unit, radiographs are useful to confirm correct positioning of diagnostic and therapeutic devices. Patterns seen on the radiograph may be within broadly normal limits or may be interpreted as abnormal, especially when placed in the clinical context of a specific patient's problem. The description abnormal can be related to both nonspecific and specific radiographic patterns of disease. Nonspecific radiographic patterns of disease include location of disease, temporal course of disease, pleural abnormalities, hyperinflation, extra-alveolar air, atelectasis, bronchiectasis, and vascular disease. Specific radiographic patterns of disease are discrete anatomic structures seen on a radiograph, for example, cavitary and cystic disease. The interpretation of nonspecific and specific radiographic patterns is useful in diagnosis, selection of treatment, and monitoring of the course of disease and the patient's response to treatment.

Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group.

BACKGROUND: A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human tumor necrosis factor (TNF) receptor and the Fc portion of IgG1 (TNFR:Fc) binds and neutralizes TNF-alpha and prevents death in animal models of bacteremia and endotoxemia. METHODS: To evaluate the safety and efficacy of TNFR:Fc in the treatment of septic shock, we conducted a randomized, double-blind, placebo-controlled, multicenter trial. A total of 141 patients were randomly assigned to receive either placebo or a single intravenous infusion of one of three doses of TNFR:Fc (0.15, 0.45, or 1.5 mg per kilogram of body weight). The primary end point was mortality from all causes at 28 days. RESULTS: There were 10 deaths among the 33 patients in the placebo group (30 percent mortality), 9 deaths among the 30 patients receiving the low dose of TNFR:Fc (30 percent mortality), 14 deaths among the 29 receiving the middle dose (48 percent mortality), and 26 deaths among the 49 receiving the high dose (53 percent mortality) (P = 0.02 for the dose-response relation). Baseline differences in the severity of illness did not account for the increased mortality in the groups receiving the higher doses of TNFR:Fc. CONCLUSIONS: In patients with septic shock, treatment with the TNFR:Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality.

The relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that preexisting lung disease is a risk factor for the development of methotrexate (MTX) pneumonitis in patients with rheumatoid arthritis (RA) treated with low dose MTX. METHODS: We measured the proportion of patients with and without preexisting lung disease who developed MTX pneumonitis in a historical cohort from a university affiliated rheumatology private practice in Chicago. Patients comprised 93 women and 32 men with RA treated with MTX for any period of time between January, 1980 and July, 1989. RESULTS: MTX pneumonitis occurred in 4 of 77 patients without preexisting lung disease (5.2%) and 5 of 29 (17.2%) patients with preexisting lung disease (p = 0.0610, Fisher's exact test). Five of 24 (20.1%) patients with preexisting lung disease characterized by the report of an abnormal chest radiograph developed MTX pneumonitis (p = 0.2328, Fisher's exact test) and 4 of 16 (25%) patients with interstitial infiltrates reported on their chest radiograph developed MTX pneumonitis (p = 0.0276, Fisher's exact test). CONCLUSION: The presence of preexisting lung disease characterized by radiographic interstitial infiltrates predisposes patients with RA to develop MTX pneumonitis.

A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group.

OBJECTIVE: To evaluate the safety and efficacy of E5, a murine, monoclonal antibody directed against endotoxin, in the treatment of patients with Gram-negative sepsis. DESIGN: A multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Fifty-three hospitals across the United States, including university medical centers, Veterans Affairs Medical Centers, and community hospitals. PATIENTS: 847 patients were randomized into this study. Enrolled patients met criteria for three conditions: a) known or suspected Gram-negative infection; b) clinical evidence of sepsis; and c) signs of end-organ dysfunction. Patients with refractory shock were excluded from the study. INTERVENTIONS: Two doses of E5 (2 mg/kg/day by intravenous infusion 24 hrs apart), or placebo that was identical in appearance were administered. In addition, all patients received standard supportive therapy and broad-spectrum antibiotics. MEASUREMENTS AND MAIN RESULTS: The primary end point was mortality over 30 days. Secondary outcome measures included the resolution and prevention of organ failure in the same two populations. Additionally, the safety of E5 was evaluated. There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo (n = 530; p = .21). In addition, E5 did not improve survival for patients with Gram-negative sepsis and organ failure (n = 139; p = .3). However, a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received E5, compared with those patients who received placebo (n = 139; 48% E5 vs. 25% placebo; p = .005). This result extended to all patients who entered the study with one or more major organ failures, regardless of the etiology of the infection (n = 225; 41% E5 vs. 27% placebo; p = .024). E5 also provided protection against the development of some organ failures, but significant prevention was only observed for adult respiratory distress syndrome (p = .007) and central nervous system dysfunction (p = .050). Hypersensitivity reactions attributable to E5 occurred in 2.6% of patients. An asymptomatic antibody response occurred in 44% of the E5-treated patients and in 12% of the patients who received placebo. CONCLUSIONS: In this study, E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure. However, E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis. This benefit extended to those patients with suspected Gram-negative etiology. This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results. In addition, E5 resulted in the prevention of adult respiratory distress syndrome and central nervous system organ failure. However, more studies are needed to determine if this result can be extended to organ failure in general. E5 is safe as a treatment for patients with Gram-negative sepsis.

Medical effectiveness of esophageal balloon pressure manometry in weaning patients from mechanical ventilation.

OBJECTIVE: To determine the efficacy of a new respiratory monitor, which uses esophageal balloons, in aiding clinicians attempting to wean patients from mechanical ventilation. DESIGN: Prospective study of patients who were deemed ready to be weaned after having required mechanical ventilation for a minimum of 3 days. Each of the patients served as his or her own control. SETTING: University medical intensive care unit. PATIENTS: The series consisted of 23 consecutive patients who were ready to wean from mechanical ventilation. INTERVENTIONS: Before the onset of the study, two weaning strategies were developed. One strategy involved using clinically available weaning parameters. The other strategy involved using esophageal balloon data that was recorded via a new respiratory monitor. Each of the weaning strategies resulted in the development of a scoring system that could be rigidly adhered to and which determined, without bias, to what extent the patient could be weaned each day. Rigid criteria were also developed to determine whether the weaning trial was successful or not. The two strategies were then compared to determine the ability of the strategy to shorten ventilatory time. MEASUREMENTS AND MAIN RESULTS: Each patient was evaluated daily by the two weaning protocols. At each weaning step, the two protocols were compared with respect to degree of aggressiveness and tolerance of the weaning maneuver by the patient. A protocol was judged superior if it resulted in more aggressive weaning without increased patient intolerance. The clinicians evaluating the patient with the clinical protocol could accelerate or retard the number of weaning steps by one step, based on the patient's clinical state and the clinician's experience. There was no such freedom in the esophageal protocol. The major finding was that in 40.5% of the instances, the protocol involving the esophageal balloon resulted in more aggressive weaning without patient intolerance. In 11.6% of the cases, the clinical protocol was more aggressive. Both protocols predicted the same number of weaning steps 39.8% of the time. In all these instances, the patient tolerated the weaning suggested. The use of data from the esophageal protocol resulted in weaning the patients 1.68 days faster than the use of data from the clinical protocol. CONCLUSIONS: The respiratory monitor, using esophageal balloon technology, is effective in that it can provide the clinician with data that can result in more aggressive weaning from mechanical ventilation without an increase in patient intolerance. The duration of mechanical ventilation can be shortened when these data are applied via a rigidly controlled weaning strategy.