Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial.

OBJECTIVES: To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management. DESIGN: Single-center, prospective, open-label, randomized controlled trial. SETTING: One thousand two hundred-bed academic medical center. PATIENTS: Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days. INTERVENTIONS: External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours. MEASUREMENTS AND MAIN RESULTS: We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6). CONCLUSIONS: Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

Clinical Practices in Central Venous Catheter Mechanical Adverse Events.

Background: Over 5 million central venous catheters (CVCs) are placed annually. Pneumothorax and catheter malpositioning are common adverse events (AE) that requires attention. This study aims to evaluate local practices of mechanical complication frequency, type, and subsequent intervention(s) related to mechanical AE with an emphasis on catheter malpositioning. Methods: This is a retrospective review of CVC placements in a tertiary hospital setting from 1/2013 to 12/2013. Pneumothorax and CVC positioning were evaluated on post-insertion chest x-ray (CXR). Malposition was defined as unintended placement of the catheter in a vessel other than the intended superior vena cava on CXR. Catheter reposition was defined as radiographic evidence of a new catheter with removal of the old catheter less than 24hrs after initial placement. Data points analyzed included pneumothorax and thoracostomy rate, CVC malposition frequency, catheter reposition rate, catheter duration, and incidence of complications such as catheter associated venous thrombosis. Result: Among 2045 eligible CVC insertions, pneumothoraces occurred in 14 (0.7%; 95%CI 0.38, 1.17) and malpositions were identified in 275 (13.4%; 95% CI 12.3, 15.3). The proportion of pneumothoraces that required tube thoracostomy was 57%. The proportion of CVCs with malposition that were removed or replaced within 24h was 32.7%. "Malpositioned" catheters that were left in place by the clinical team (n = 185) had an average catheter duration of 8.2 days (95% CI 7.2, 9.3) versus 7.2 days (95% CI 6.17, 8.23) for catheters that were replaced after initial malposition (p = 0.14, t test). The incidence of venous thrombosis in repositioned "malpositioned" catheters was 7.8% versus 4.9% for "malpositioned" catheters that were left in place. Conclusions: Clinically significant catheter malposition and pneumothorax after CVC insertion are low. In this study, replaced and non-replaced "malpositioned" catheters had similar catheter duration and rates of complications, challenging the current dogma of CVC malposition practice.

Diagnostic Accuracy of Central Venous Catheter Confirmation by Bedside Ultrasound Versus Chest Radiography in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: We performed a systematic review and meta-analysis to examine the accuracy of bedside ultrasound for confirmation of central venous catheter position and exclusion of pneumothorax compared with chest radiography. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, reference lists, conference proceedings and ClinicalTrials.gov. STUDY SELECTION: Articles and abstracts describing the diagnostic accuracy of bedside ultrasound compared with chest radiography for confirmation of central venous catheters in sufficient detail to reconstruct 2 × 2 contingency tables were reviewed. Primary outcomes included the accuracy of confirming catheter positioning and detecting a pneumothorax. Secondary outcomes included feasibility, interrater reliability, and efficiency to complete bedside ultrasound confirmation of central venous catheter position. DATA EXTRACTION: Investigators abstracted study details including research design and sonographic imaging technique to detect catheter malposition and procedure-related pneumothorax. Diagnostic accuracy measures included pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. DATA SYNTHESIS: Fifteen studies with 1,553 central venous catheter placements were identified with a pooled sensitivity and specificity of catheter malposition by ultrasound of 0.82 (0.77-0.86) and 0.98 (0.97-0.99), respectively. The pooled positive and negative likelihood ratios of catheter malposition by ultrasound were 31.12 (14.72-65.78) and 0.25 (0.13-0.47). The sensitivity and specificity of ultrasound for pneumothorax detection was nearly 100% in the participating studies. Bedside ultrasound reduced mean central venous catheter confirmation time by 58.3 minutes. Risk of bias and clinical heterogeneity in the studies were high. CONCLUSIONS: Bedside ultrasound is faster than radiography at identifying pneumothorax after central venous catheter insertion. When a central venous catheter malposition exists, bedside ultrasound will identify four out of every five earlier than chest radiography.

Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to examine the impact of antipyretic therapy on mortality in critically ill septic adults. DATA SOURCES: Literature searches were implemented in Ovid Medline, Embase, Scopus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, and ClinicalTrials.gov through February 2016. STUDY SELECTION: Inclusion criteria were observational or randomized studies of septic patients, evaluation of antipyretic treatment, mortality reported, and English-language version available. Studies were excluded if they enrolled pediatric patients, patients with neurologic injury, or healthy volunteers. Criteria were applied by two independent reviewers. DATA EXTRACTION: Two reviewers independently extracted data and evaluated methodologic quality. Outcomes included mortality, frequency of shock reversal, acquisition of nosocomial infections, and changes in body temperature, heart rate, and minute ventilation. Randomized and observational studies were analyzed separately. DATA SYNTHESIS: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38°C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation. CONCLUSIONS: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.

Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study.

BACKGROUND: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-ɑ) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-ɑ production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients. METHODS: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1-2, days 3-4, and days 6-8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-ɑ production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection. RESULTS: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3-4 (p = 0.04) and days 6-8 (p = 0.002). The change in HLA-DR from days 1-2 to days 6-8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1-2 to days 3-4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-ɑ production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection. CONCLUSIONS: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-ɑ production in adult medical and surgical critically ill patients.

T cells from patients with Candida sepsis display a suppressive immunophenotype.

BACKGROUND: Despite appropriate therapy, Candida bloodstream infections are associated with a mortality rate of approximately 40%. In animal models, impaired immunity due to T cell exhaustion has been implicated in fungal sepsis mortality. The purpose of this study was to determine potential mechanisms of fungal-induced immunosuppression via immunophenotyping of circulating T lymphocytes from patients with microbiologically documented Candida bloodstream infections. METHODS: Patients with blood cultures positive for any Candida species were studied. Non-septic critically ill patients with no evidence of bacterial or fungal infection were controls. T cells were analyzed via flow cytometry for cellular activation and for expression of positive and negative co-stimulatory molecules. Both the percentages of cells expressing particular immunophenotypic markers as well as the geometric mean fluorescence intensity (GMFI), a measure of expression of the number of receptors or ligands per cell, were quantitated. RESULTS: Twenty-seven patients with Candida bloodstream infections and 16 control patients were studied. Compared to control patients, CD8 T cells from patients with Candidemia had evidence of cellular activation as indicated by increased CD69 expression while CD4 T cells had decreased expression of the major positive co-stimulatory molecule CD28. CD4 and CD8 T cells from patients with Candidemia expressed markers typical of T cell exhaustion as indicated by either increased percentages of or increased MFI for programmed cell death 1 (PD-1) or its ligand (PD-L1). CONCLUSIONS: Circulating immune effector cells from patients with Candidemia display an immunophenotype consistent with immunosuppression as evidenced by T cell exhaustion and concomitant downregulation of positive co-stimulatory molecules. These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy. Development of immunoadjuvants that reverse T cell exhaustion and boost host immunity may offer one way to improve outcome in this highly lethal disorder.

Does Point-of-Care Ultrasound Affect Fluid Resuscitation Volume in Patients with Septic Shock: A Retrospective Review.

Background: Fixed, large volume resuscitation with intravenous fluids (IVFs) in septic shock can cause inadvertent hypervolemia, increased medical interventions, and death when unguided by point-of-care ultrasound (POCUS). The primary study objective was to evaluate whether total IVF volume differs for emergency department (ED) septic shock patients receiving POCUS versus no POCUS. Methods: We conducted a retrospective observational cohort study from 7/1/2018 to 8/31/2021 of atraumatic adult ED patients with septic shock. We agreed upon a priori variables and defined septic shock as lactate ≥4 and hypotension (SBP <90 or MAP <65). A sample size of 300 patients would provide 85% power to detect an IVF difference of 500 milliliters between POCUS and non-POCUS cohorts. Data are reported as frequencies, median (IQR), and associations from bivariate logistic models. Results: 304 patients met criteria and 26% (78/304) underwent POCUS. Cardiac POCUS demonstrated reduced ejection fraction in 15.4% of patients. Lung ultrasound showed normal findings in 53% of patients. The POCUS vs. non-POCUS cohorts had statistically significant differences for the following variables: higher median lactate (6.7 [IQR 5.2-8.7] vs. 5.6], p = 0.003), lower systolic blood pressure (77.5 [IQR 61-86] vs. 85.0, p < 0.001), more vasopressor use (51% vs. 34%, p = 0.006), and more positive pressure ventilation (38% vs. 24%, p = 0.017). However, there were no statistically significant differences between POCUS and non-POCUS cohorts in total IVF volume ml/kg (33.02 vs. 32.1, p = 0.47), new oxygen requirement (68% vs. 59%, p = 0.16), ED death (3% vs. 4%, p = 0.15), or hospital death (31% vs. 27%, p = 0.48). There were similar distributions of lactate, total fluids, and vasopressors in patients with CHF and severe renal failure. Conclusions: Among ED patients with septic shock, POCUS was more likely to be used in sicker patients. Patients who had POCUS were given similar volume of crystalloids although these patients were more critically ill. There were no differences in new oxygen requirement or mortality in the POCUS group compared to the non-POCUS group.

Implementation of ultrasound after central venous catheter insertion: A qualitative study in early adopters.

BACKGROUND: The adoption rate of point of care ultrasound (POCUS) for the confirmation of central venous catheter (CVC) positioning and exclusion of post procedure pneumothorax is low despite advantages in workflow compared to traditional chest X-ray (CXR). To explore why, we convened focus groups to address barriers and facilitators of implementation for POCUS guided CVC confirmation and de-implementation of post-procedure CXR. METHODS: We conducted focus groups with emergency medicine and critical care providers to discuss current practices in POCUS for CVC confirmation. The semi-structured focus group interview guide was informed by the Consolidated Framework for Implementation Research (CFIR). We performed qualitative content analysis of the resulting transcripts using a consensual qualitative research approach (NVivo software), aiming to identify priority categories that describe the barriers and facilitators of POCUS guided CVC confirmation. RESULTS: The coding dictionary of barriers and facilitators consisted of 21 codes from the focus group discussions. Our qualitative analysis revealed that 12 codes emerged spontaneously (inductively) within the focus group discussions and aligned directly to CFIR constructs. Common barriers included provider influences (e.g. knowledge and beliefs about POCUS for CVC confirmation), external network (e.g. societal guidelines, ancillary staff, and consultants), and inertia (habit or reflexive processes). Common facilitators included ultrasound protocol advantage and champions. Time and provider outcomes (cognitive offload, ownership, and independence) emerged as early barriers but late facilitators. CONCLUSION: Our qualitative analysis demonstrates real and perceived barriers against implementation of POCUS for CVC position confirmation and pneumothorax exclusion. Our findings discovered organizational and personal constructs that will inform development of multifaceted strategies toward implementation of POCUS after CVC insertion.