Prospective Evaluation of Autonomic Dysfunction in Post-Acute Sequela of COVID-19.

BACKGROUND: Patients with post-acute sequela of COVID-19 (PASC) often report symptoms of orthostatic intolerance and autonomic dysfunction. Numerous case reports link postural orthostatic tachycardia syndrome (POTS) to PASC. No prospective analysis has been performed. OBJECTIVES: This study performed head-up tilt table (HUTT) testing in symptomatic patients with PASC to evaluate for orthostatic intolerance suggestive of autonomic dysfunction. METHODS: We performed a prospective, observational evaluation of patients with PASC complaining of poor exertional tolerance, tachycardia with minimal activity or positional change, and palpitations. Exclusion criteria included pregnancy, pre-PASC autonomic dysfunction or syncope, or another potential explanation of PASC symptoms. All subjects underwent HUTT. RESULTS: Twenty-four patients with the described PASC symptoms were included. HUTT was performed a mean of 5.8 ± 3.5 months after symptom onset. Twenty-three of the 24 had orthostatic intolerance on HUTT, with 4 demonstrating POTS, 15 provoked orthostatic intolerance (POI) after nitroglycerin, 3 neurocardiogenic syncope, and 1 orthostatic hypotension. Compared with those with POTS, patients with POI described significantly earlier improvement of symptoms. CONCLUSIONS: This prospective evaluation of HUTT in patients with PASC revealed orthostatic intolerance on HUTT suggestive of autonomic dysfunction in nearly all subjects. Those with POI may be further along the path of clinical recovery than those demonstrating POTS.

Hemodynamic Profiles of Shock in Patients With COVID-19.

Patients with serious COVID infections develop shock frequently. To characterize the hemodynamic profile of this cohort, 156 patients with COVID pneumonia and shock requiring vasopressors had interpretable echocardiography with measurement of ejection fraction (EF) by Simpson's rule and stroke volume (SV) by Doppler. RV systolic pressure (RVSP) was estimated from the tricuspid regurgitation peak velocity. Patients were divided into groups with low or preserved EF (EFL or EFP, cutoff ≤45%), and low or normal cardiac index (CIL or CIN, cutoff ≤2.2 L/min/m2). Mean age was 67 ± 12.0, EF 59.5 ± 12.9, and CI 2.40 ± 0.86. A minority of patients had depressed EF (EFLCIL, n = 15, EFLCIN, n = 8); of those with preserved EF, less than half had low CI (EFPCIL, n = 55, EFPCIN, n = 73). Overall hospital mortality was 73%. Mortality was highest in the EFLCIL group (87%), but the difference between groups was not significant (p = 0.68 by ANOVA). High PEEP correlated with low CI in the EFPCIL group (r = 0.44, p = 0.04). In conclusion, this study reports the prevalence of shock characterized by EF and CI in patients with COVID-19. COVID-induced shock had a cardiogenic profile (EFLCIL) in 9.6% of patients, reflecting the impact of COVID-19 on myocardial function. Low CI despite preservation of EF and the correlation with PEEP suggests underfilling of the LV in this subset; these patients might benefit from additional volume. Hemodynamic assessment of COVID patients with shock with definition of subgroups may allow therapy to be tailored to the underlying causes of the hemodynamic abnormalities.

Monocyte distribution width enhances early sepsis detection in the emergency department beyond SIRS and qSOFA.

BACKGROUND: The initial presentation of sepsis in the emergency department (ED) is difficult to distinguish from other acute illnesses based upon similar clinical presentations. A new blood parameter, a measurement of increased monocyte volume distribution width (MDW), may be used in combination with other clinical parameters to improve early sepsis detection. We sought to determine if MDW, when combined with other available clinical parameters at the time of ED presentation, improves the early detection of sepsis. METHODS: A retrospective analysis of prospectively collected clinical data available during the initial ED encounter of 2158 adult patients who were enrolled from emergency departments of three major academic centers, of which 385 fulfilled Sepsis-2 criteria, and 243 fulfilled Sepsis-3 criteria within 12 h of admission. Sepsis probabilities were determined based on MDW values, alone or in combination with components of systemic inflammatory response syndrome (SIRS) or quick sepsis-related organ failure assessment (qSOFA) score obtained during the initial patient presentation (i.e., within 2 h of ED admission). RESULTS: Abnormal MDW (> 20.0) consistently increased sepsis probability, and normal MDW consistently reduced sepsis probability when used in combination with SIRS criteria (tachycardia, tachypnea, abnormal white blood count, or body temperature) or qSOFA criteria (tachypnea, altered mental status, but not hypotension). Overall, and regardless of other SIRS or qSOFA variables, MDW > 20.0 (vs. MDW ≤ 20.0) at the time of the initial ED encounter was associated with an approximately 6-fold increase in the odds of Sepsis-2, and an approximately 4-fold increase in the odds of Sepsis-3. CONCLUSIONS: MDW improves the early detection of sepsis during the initial ED encounter and is complementary to SIRS and qSOFA parameters that are currently used for this purpose. This study supports the incorporation of MDW with other readily available clinical parameters during the initial ED encounter for the early detection of sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03145428. First posted May 9, 2017. The first subjects were enrolled June 19, 2017, and the study completion date was January 26, 2018.

Monocyte Distribution Width: A Novel Indicator of Sepsis-2 and Sepsis-3 in High-Risk Emergency Department Patients.

OBJECTIVES: Most septic patients are initially encountered in the emergency department where sepsis recognition is often delayed, in part due to the lack of effective biomarkers. This study evaluated the diagnostic accuracy of peripheral blood monocyte distribution width alone and in combination with WBC count for early sepsis detection in the emergency department. DESIGN: An Institutional Review Board approved, blinded, observational, prospective cohort study conducted between April 2017 and January 2018. SETTING: Subjects were enrolled from emergency departments at three U.S. academic centers. PATIENTS: Adult patients, 18-89 years, with complete blood count performed upon presentation to the emergency department, and who remained hospitalized for at least 12 hours. A total of 2,212 patients were screened, of whom 2,158 subjects were enrolled and categorized per Sepsis-2 criteria, such as controls (n = 1,088), systemic inflammatory response syndrome (n = 441), infection (n = 244), and sepsis (n = 385), and Sepsis-3 criteria, such as control (n = 1,529), infection (n = 386), and sepsis (n = 243). INTERVENTIONS: The primary outcome determined whether an monocyte distribution width of greater than 20.0 U, alone or in combination with WBC, improves early sepsis detection by Sepsis-2 criteria. Secondary endpoints determined monocyte distribution width performance for Sepsis-3 detection. MEASUREMENTS AND MAIN RESULTS: Monocyte distribution width greater than 20.0 U distinguished sepsis from all other conditions based on either Sepsis-2 criteria (area under the curve, 0.79; 95% CI, 0.76-0.82) or Sepsis-3 criteria (area under the curve, 0.73; 95% CI, 0.69-0.76). The negative predictive values for monocyte distribution width less than or equal to 20 U for Sepsis-2 and Sepsis-3 were 93% and 94%, respectively. Monocyte distribution width greater than 20.0 U combined with an abnormal WBC further improved Sepsis-2 detection (area under the curve, 0.85; 95% CI, 0.83-0.88) and as reflected by likelihood ratio and added value analyses. Normal WBC and monocyte distribution width inferred a six-fold lower sepsis probability. CONCLUSIONS: An monocyte distribution width value of greater than 20.0 U is effective for sepsis detection, based on either Sepsis-2 criteria or Sepsis-3 criteria, during the initial emergency department encounter. In tandem with WBC, monocyte distribution width is further predicted to enhance medical decision making during early sepsis management in the emergency department.

Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial.

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. Main Outcome and Measures: The primary end point was 28-day all-cause mortality. Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.

Culture-Negative Septic Shock Compared With Culture-Positive Septic Shock: A Retrospective Cohort Study.

OBJECTIVES: To determine the clinical characteristics and outcomes of culture-negative septic shock in comparison with culture-positive septic shock. DESIGN: Retrospective nested cohort study. SETTING: ICUs of 28 academic and community hospitals in three countries between 1997 and 2010. SUBJECTS: Patients with culture-negative septic shock and culture-positive septic shock derived from a trinational (n = 8,670) database of patients with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with culture-negative septic shock (n = 2,651; 30.6%) and culture-positive septic shock (n = 6,019; 69.4%) were identified. Culture-negative septic shock compared with culture-positive septic shock patients experienced similar ICU survival (58.3% vs 59.5%; p = 0.276) and overall hospital survival (47.3% vs 47.1%; p = 0.976). Severity of illness was similar between culture-negative septic shock and culture-positive septic shock groups ([mean and SD Acute Physiology and Chronic Health Evaluation II, 25.7 ± 8.3 vs 25.7 ± 8.1]; p = 0.723) as were serum lactate levels (3.0 [interquartile range, 1.7-6.1] vs 3.2 mmol/L [interquartile range, 1.8-5.9 mmol/L]; p = 0.366). As delays in the administration of appropriate antimicrobial therapy after the onset of hypotension increased, patients in both groups experienced congruent increases in overall hospital mortality: culture-negative septic shock (odds ratio, 1.56; 95% CI [1.47-1.66]; p < 0.0001) and culture-positive septic shock (odds ratio, 1.65; 95% CI [1.59-1.71]; p < 0.0001). CONCLUSIONS: Patients with culture-negative septic shock behave similarly to those with culture-positive septic shock in nearly all respects; early appropriate antimicrobial therapy appears to improve mortality. Early recognition and eradication of infection is the most obvious effective strategy to improve hospital survival.

Improved Early Detection of Sepsis in the ED With a Novel Monocyte Distribution Width Biomarker.

BACKGROUND: Sepsis most often presents to the ED, and delayed detection is harmful. WBC count is often used to detect sepsis, but changes in WBC count size also correspond to sepsis. We sought to determine if volume increases of circulating immune cells add value to the WBC count for early sepsis detection in the ED. METHODS: A blinded, prospective cohort study was conducted in two different ED populations within a large academic hospital. RESULTS: Neutrophil and monocyte volume parameters were measured in conjunction with routine CBC testing on a UniCel DxH 800 analyzer at the time of ED admission and were evaluated for the detection of sepsis. There were 1,320 subjects in the ED consecutively enrolled and categorized as control subjects (n = 879) and those with systemic inflammatory response syndrome (SIRS) (n = 203), infection (n = 140), or sepsis (n = 98). Compared with other parameters, monocyte distribution width (MDW) best discriminated sepsis from all other conditions (area under the curve [AUC], 0.79; 95% CI, 0.73-0.84; sensitivity, 0.77; specificity, 0.73; MDW threshold, 20.50), sepsis from SIRS (AUC, 0.74; 95% CI, 0.67-0.84), and severe sepsis from noninfected patients in the ED (AUC, 0.88; 95% CI, 0.75-0.99; negative predictive value, 99%). The added value of MDW to WBC count was statistically significant (AUC, 0.89 for MDW + WBC vs 0.81 for WBC alone; P < .01); a decision curve analysis also showed improved performance compared with WBC count alone. CONCLUSIONS: The incorporation of MDW with WBC count is shown in this prospective cohort study to improve detection of sepsis compared with WBC count alone at the time of admission in the ED. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02232750; URL: www.clinicaltrials.gov.

Randomized controlled trial of inhaled nitric oxide for the treatment of microcirculatory dysfunction in patients with sepsis*.

OBJECTIVES: Sepsis treatment guidelines recommend macrocirculatory hemodynamic optimization; however, microcirculatory dysfunction is integral to sepsis pathogenesis. We aimed to test the hypothesis that following macrocirculatory optimization, inhaled nitric oxide would improve microcirculation in patients with sepsis and that improved microcirculation would improve lactate clearance and multiple organ dysfunction. DESIGN: Randomized, sham-controlled clinical trial. SETTING: Single urban academic medical center. PATIENTS: Adult patients with severe sepsis and systolic blood pressure less than 90 mm Hg despite intravascular volume expansion and/or serum lactate greater than or equal to 4.0 mmol/L. INTERVENTIONS: After achievement of macrocirculatory resuscitation goals, we randomized patients to 6 hours of inhaled nitric oxide (40 ppm) or sham inhaled nitric oxide administration. We administered study drug via a specialized delivery device that concealed treatment allocation so that investigators and clinical staff remained blinded. MEASUREMENTS AND MAIN RESULTS: We performed sidestream dark-field videomicroscopy of the sublingual microcirculation prior to and 2 hours after study drug initiation. The primary outcome measure was the change in microcirculatory flow index. Secondary outcomes were lactate clearance and change in Sequential Organ Failure Assessment score. We enrolled 50 patients (28 of 50 [56%] requiring vasopressor agents; 15 of 50 [30%] died). Although inhaled nitric oxide significantly raised plasma nitrite levels, it did not improve microcirculatory flow, lactate clearance, or organ dysfunction. In contrast to previous studies conducted during the earliest phase of resuscitation, we found no association between changes in microcirculatory flow and lactate clearance or organ dysfunction. CONCLUSIONS: Following macrocirculatory optimization, inhaled nitric oxide at 40 ppm did not augment microcirculatory perfusion in patients with sepsis. Further, we found no association between microcirculatory perfusion and multiple organ dysfunction after initial resuscitation.

Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study.

OBJECTIVE: Fluids and vasoactive agents are both used to treat septic shock, but little is known about how they interact or the optimal way to administer them. We sought to determine how hospital mortality was influenced by combined use of these two treatments. DESIGN: Retrospective evaluation using multivariable logistic regression to evaluate the association between hospital mortality and categorical variables representing initiation of vasoactive agents and volumes of IV fluids given 0-1, 1-6, and 6-24 hours after onset, including interactions and adjusting for potential confounders. SETTING: ICUs of 24 hospitals in 3 countries. PATIENTS: Two thousand eight hundred forty-nine patients who survived more than 24 hours after after onset of septic shock, admitted between 1989 and 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fluids and vasoactive agents had strong, interacting associations with mortality (p < 0.0001). Mortality was lowest when vasoactive agents were begun 1-6 hours after onset, with more than 1 L of fluids in the initial hour after shock onset, more than 2.4 L from hours 1-6, and 1.6-3.5 L from 6 to 24 hours. The lowest mortality rates were associated with starting vasoactive agents 1-6 hours after onset. CONCLUSIONS: The focus during the first hour of resuscitation for septic shock should be aggressive fluid administration, only thereafter starting vasoactive agents, while continuing aggressive fluid administration. Starting vasoactive agents in the initial hour may be detrimental, and not all of that association is due to less fluids being given with such early initiation of vasoactive agents.

Timing of vasopressor initiation and mortality in septic shock: a cohort study.

INTRODUCTION: Despite recent advances in the management of septic shock, mortality remains unacceptably high. Earlier initiation of key therapies including appropriate antimicrobials and fluid resuscitation appears to reduce the mortality in this condition. This study examined whether early initiation of vasopressor therapy is associated with improved survival in fluid therapy-refractory septic shock. METHODS: Utilizing a well-established database, relevant information including duration of time to vasopressor administration following the initial documentation of recurrent/persistent hypotension associated with septic shock was assessed in 8,670 adult patients from 28 ICUs in Canada, the United States of America, and Saudi Arabia. The primary endpoint was survival to hospital discharge. Secondary endpoints were length of ICU and hospital stay as well as duration of ventilator support and vasopressor dependence. Analysis involved multivariate linear and logistic regression analysis. RESULTS: In total, 8,640 patients met the definition of septic shock with time of vasopressor/inotropic initiation documented. Of these, 6,514 were suitable for analysis. The overall unadjusted hospital mortality rate was 53%. Independent mortality correlates included liver failure (odds ratio (OR) 3.46, 95% confidence interval (CI), 2.67 to 4.48), metastatic cancer (OR 1.63, CI, 1.32 to 2.01), AIDS (OR 1.91, CI, 1.29 to 2.49), hematologic malignancy (OR 1.88, CI, 1.46 to 2.41), neutropenia (OR 1.78, CI, 1.27 to 2.49) and chronic hypertension (OR 0.62 CI, 0.52 to 0.73). Delay of initiation of appropriate antimicrobial therapy (OR 1.07/hr, CI, 1.06 to 1.08), age (OR 1.03/yr, CI, 1.02 to 1.03), and Acute Physiology and Chronic Health Evaluation (APACHE) II Score (OR 1.11/point, CI, 1.10 to 1.12) were also found to be significant independent correlates of mortality. After adjustment, only a weak correlation between vasopressor delay and hospital mortality was found (adjusted OR 1.02/hr, 95% CI 1.01 to 1.03, P <0.001). This weak effect was entirely driven by the group of patients with the longest delays (>14.1 hours). There was no significant relationship of vasopressor initiation delay to duration of vasopressor therapy (P = 0.313) and only a trend to longer duration of ventilator support (P = 0.055) among survivors. CONCLUSION: Marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock.

Biphasic intra-thoracic pressure regulation augments cardiac index during porcine peritonitis: a feasibility study.

Preservation of cardiac output (CO) and pulmonary artery pressure (PAP) is vital to maintaining tissue oxygenation in sepsis. This feasibility study tested the hypothesis that therapeutic intra-thoracic pressure regulation (tIPR), delivered with a novel device, was designed to non-invasively enhance venous return by creating sub-atmospheric intra-thoracic pressure during the expiratory phase of mechanical ventilation, improves CO without fluid resuscitation in a porcine E. coli peritonitis model of sepsis. Seven pigs were intubated, anaesthetized and instrumented with a Swan-Ganz and femoral artery catheter. After a 30 min basal period, a fibrin clot containing 4-5 × 10(9) cfu kg(-1) E. coli O111.B4 was implanted in the peritoneum. One hour after clot implantation, tIPR was utilized for 30 min and then removed from the ventilator circuit for 30 min. This tIPR cycle was repeated 4-times. Changes in haemodynamic parameters were calculated by comparing pre-tIPR values to peak values during tIPR administration. Following peritonitis, tIPR significantly increased the peak cardiac index (mean ± SEM) (14.8 ± 2.6 vs 7.9 ± 2.3 ml kg(-1)) and mean arterial pressure (10.2 ± 1.5 vs 4.9 ± 1.1 mmHg) and simultaneously decreased PAP (-7.7 ± 1.5 vs -2.7 ± 0.8 mmHg). These results support the feasibility of the concept that therapeutic application of negative expiratory pressure may provide a non-invasive and complementary approach to increase cardiac output and organ perfusion in the setting of septic shock.

Incidence and outcomes associated with early heart failure pharmacotherapy in patients with ongoing cardiogenic shock.

OBJECTIVES: Guidelines recommend ß-blockers and renin-angiotensin-aldosterone system blockers to improve long-term survival in hemodynamically stable myocardial infarction patients with a reduced left ventricular ejection fraction. The prevalence and outcomes associated with ß and renin-angiotensin-aldosterone system blocker therapy in patients with ongoing cardiogenic shock is unknown. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: In patients with cardiogenic shock lasting more than 24 hours enrolled in Tilarginine Acetate Injection in a Randomized International Study in Unstable Myocardial Infarction Patients With Cardiogenic Shock, we compared 30-day mortality in patients who received ß or renin-angiotensin-aldosterone system blockers (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or aldosterone antagonists) within 24 hours of randomization with those who did not. INTERVENTIONS: None. PATIENTS: The final study population included 240 patients. A total of 66 patients (27.5%) had either ß blocker or renin-angiotensin-aldosterone system blocker administered within the first 24 hours after the diagnosis of cardiogenic shock. ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists were prescribed in 18.8%, 10.6%, and 5.0% of patients, respectively. MEASUREMENTS AND MAIN RESULTS: The observed 30-day mortality among patients was higher in patients who received ß or renin-angiotensin-aldosterone system blockers prior to cardiogenic shock resolution (27.3% vs 16.9%; adjusted hazard ratio, 2.36; 95% CI, 1.06-5.23; p = 0.035). Compared with patients not given ß or renin-angiotensin-aldosterone system blockers, the 30-day mortality was higher among patients treated only with ß-blockers (33.3% vs 16.9%, p = 0.017) but not among those only treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (18.2% vs 16.9%, p = 1.000). CONCLUSIONS: The administration of ß or renin-angiotensin-aldosterone system blockers is common in North America and Europe in patients with myocardial infarction and cardiogenic shock prior to cardiogenic shock resolution. This therapeutic practice was independently associated with higher 30-day mortality, although a statistically significant difference was only observed in the subgroup of patients administered ß-blockers.

Organization and staffing practices in US cardiac intensive care units: a survey on behalf of the American Heart Association Writing Group on the Evolution of Critical Care Cardiology.

BACKGROUND: The cardiac intensive care unit (CICU) has evolved into a complex patient-care environment with escalating acuity and increasing utilization of advanced technologies. These changing demographics of care may require greater clinical expertise among physician providers. Despite these changes, little is known about present-day staffing practices in US CICUs. METHODS AND RESULTS: We conducted a survey of 178 medical directors of ICUs caring for cardiac patients to assess unit structure and physician staffing practices. Data were obtained from 123 CICUs (69% response rate) that were mostly from academic medical centres. A majority of hospitals utilized a dedicated CICU (68%) and approximately half of those hospitals employed a 'closed' unit model. In 46% of CICUs, an intensivist consult was available, but not routinely involved in care of critically ill cardiovascular patients, while 11% did not have a board-certified intensivist available for consultation. Most CICU directors (87%) surveyed agreed that a closed ICU structure provided better care than an open ICU and 81% of respondents identified an unmet need for cardiologists with critical care training. CONCLUSIONS: We report contemporary structural models and staffing practices in a sample of US ICUs caring for critically ill cardiovascular patients. Although most hospitals surveyed had dedicated CICUs, a minority of CICUs employed a 'closed' CICU model and few had routine intensivist staffing. Most CICU directors agree that there is a need for cardiologists with intensivist training and expertise. These survey data reveal potential areas for continued improvement in US CICU organizational structure and physician staffing.

A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

OBJECTIVES: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. DESIGN: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. SETTING: Two hundred and thirty-three ICUs in 17 countries. PATIENTS: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. INTERVENTIONS: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. MEASUREMENTS AND MAIN RESULTS: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline. CONCLUSIONS: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

Fulminant myocarditis.

Myocarditis is most often caused by a viral infection. Less common causes include other infectious agents and autoimmune diseases. Fulminant myocarditis is an unusual complication with a rapidly progressive course resulting in severe heart failure and cardiogenic shock. Fulminant myocarditis should be treated with full supportive care, using aggressive pharmacologic therapy and mechanical circulatory support, because significant improvement in left ventricular function will often occur. Cardiac transplantation is required in a small minority of patients. Cardiac magnetic resonance imaging is becoming a frequently used modality to aid in the diagnosis of myocarditis.

Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study.

INTRODUCTION: Data are sparse as to whether obesity influences the risk of death in critically ill patients with septic shock. We sought to examine the possible impact of obesity, as assessed by body mass index (BMI), on hospital mortality in septic shock patients. METHODS: We performed a nested cohort study within a retrospective database of patients with septic shock conducted in 28 medical centers in Canada, United States and Saudi Arabia between 1996 and 2008. Patients were classified according to the World Health Organization criteria for BMI. Multivariate logistic regression analysis was performed to evaluate the association between obesity and hospital mortality. RESULTS: Of the 8,670 patients with septic shock, 2,882 (33.2%) had height and weight data recorded at ICU admission and constituted the study group. Obese patients were more likely to have skin and soft tissue infections and less likely to have pneumonia with predominantly Gram-positive microorganisms. Crystalloid and colloid resuscitation fluids in the first six hours were given at significantly lower volumes per kg in the obese and very obese patients compared to underweight and normal weight patients (for crystalloids: 55.0 ± 40.1 ml/kg for underweight, 43.2 ± 33.4 for normal BMI, 37.1 ± 30.8 for obese and 27.7 ± 22.0 for very obese). Antimicrobial doses per kg were also different among BMI groups. Crude analysis showed that obese and very obese patients had lower hospital mortality compared to normal weight patients (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.66 to 0.97 for obese and OR 0.61, 95% CI 0.44 to 0.85 for very obese patients). After adjusting for baseline characteristics and sepsis interventions, the association became non-significant (OR 0.80, 95% CI 0.62 to 1.02 for obese and OR 0.69, 95% CI 0.45 to 1.04 for very obese). CONCLUSIONS: The obesity paradox (lower mortality in the obese) documented in other populations is also observed in septic shock. This may be related in part to differences in patient characteristics. However, the true paradox may lie in the variations in the sepsis interventions, such as the administration of resuscitation fluids and antimicrobial therapy. Considering the obesity epidemic and its impact on critical care, further studies are warranted to examine whether a weight-based approach to common therapeutic interventions in septic shock influences outcome.