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.

Economic Evaluation of Ultrasound-guided Central Venous Catheter Confirmation vs Chest Radiography in Critically Ill Patients: A Labor Cost Model.

INTRODUCTION: Despite evidence suggesting that point-of-care ultrasound (POCUS) is faster and non-inferior for confirming position and excluding pneumothorax after central venous catheter (CVC) placement compared to traditional radiography, millions of chest radiographs (CXR) are performed annually for this purpose. Whether the use of POCUS results in cost savings compared to CXR is less clear but could represent a relative advantage in implementation efforts. Our objective in this study was to evaluate the labor cost difference for POCUS-guided vs CXR-guided CVC position confirmation practices. METHODS: We developed a model to evaluate the per patient difference in labor cost between POCUS-guided vs CXR-guided CVC confirmation at our local urban, tertiary academic institution. We used internal cost data from our institution to populate the variables in our model. RESULTS: The estimated labor cost per patient was $18.48 using CXR compared to $14.66 for POCUS, resulting in a net direct cost savings of $3.82 (21%) per patient using POCUS for CVC confirmation. CONCLUSION: In this study comparing the labor costs of two approaches for CVC confirmation, the more efficient alternative (POCUS-guided) is not more expensive than traditional CXR. Performing an economic analysis framed in terms of labor costs and work efficiency may influence stakeholders and facilitate earlier adoption of POCUS for CVC confirmation.

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.

Adverse events related to ultrasound-guided regional anesthesia performed by Emergency Physicians: Systematic review protocol.

The use of ultrasound-guided regional anesthesia for pain management has become increasingly prevalent in Emergency Medicine, with studies noting excellent pain control while sparing opioid use. However, the use of ultrasound-guided regional anesthesia may be hampered by concern about risks for patient harm. This systematic review protocol describes our approach to evaluate the incidence of adverse events from the use of ultrasound-guided regional anesthesia by Emergency Physicians as described in the literature. This project will also seek to document the scope of ultrasound-guided regional anesthesia applications being performed in Emergency Medicine literature, and potentially serve as a framework for future systematic reviews evaluating adverse events in Emergency Medicine.

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.

Protocol for DRAUP: a deimplementation programme to decrease routine chest radiographs after central venous catheter insertion.

INTRODUCTION: Avoiding low value medical practices is an important focus in current healthcare utilisation. Despite advantages of point-of-care ultrasound (POCUS) over chest X-ray including improved workflow and timeliness of results, POCUS-guided central venous catheter (CVC) position confirmation has slow rate of adoption. This demonstrates a gap that is ripe for the development of an intervention. METHODS: The intervention is a deimplementation programme called DRAUP (deimplementation of routine chest radiographs after adoption of ultrasound-guided insertion and confirmation of central venous catheter protocol) that will be created to address one unnecessary imaging modality in the acute care environment. We propose a three-phase approach to changing low-value practices. In phase 1, we will be guided by the Consolidated Framework for Implementation Research framework to explore barriers and facilitators of POCUS for CVC confirmation in a single centre, large tertiary, academic hospital via focus groups. The qualitative methods will inform the development and adaptation of strategies that address identified determinants of change. In phase 2, the multifaceted strategies will be conceptualised using Morgan's framework for understanding and reducing medical overuse. In phase 3, we will locally implement these strategies and assess them using Proctor's outcomes (adoption, deadoption, fidelity and penetration) in an observational study to demonstrate proof of concept, gaining valuable insights on the programme. Secondary outcomes will include POCUS-guided CVC confirmation efficacy measured by time and effectiveness measured by sensitivity and specificity of POCUS confirmation after CVC insertion.With limited data available to inform interventions that use concurrent implementation and deimplementation strategies to substitute chest X-ray for POCUS using the DRAUP programme, we propose that this primary implementation and secondary effectiveness pilot study will provide novel data that will expand the knowledge of implementation approaches to replacing low value or unnecessary care in acute care environments. ETHICS AND DISSEMINATION: Approval of the study by the Human Research Protection Office has been obtained. This work will be disseminated by publication of peer-reviewed manuscripts, presentation in abstract form at scientific meetings and data sharing with other investigators through academically established means. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier, NCT04324762, registered on 27 March 2020.

Point-of-care Ultrasound-guided Central Venous Catheter Confirmation in Ultrasound Nonexperts.

OBJECTIVE: Emerging evidence suggests that chest radiography (CXR) following central venous catheter (CVC) placement is unnecessary when point-of-care ultrasound (POCUS) is used to confirm catheter position and exclude pneumothorax. However, few providers have adopted this practice, and it is unknown what contributing factors may play a role in this lack of adoption, such as ultrasound experience. The objective of this study was to evaluate the diagnostic accuracy of POCUS to confirm CVC position and exclude a pneumothorax after brief education and training of nonexperts. METHODS: We performed a prospective cohort study in a single academic medical center to determine the diagnostic characteristics of a POCUS-guided CVC confirmation protocol after brief training performed by POCUS nonexperts. POCUS nonexperts (emergency medicine senior residents and critical care fellows) independently performed a POCUS-guided CVC confirmation protocol after a 30-minute didactic training. The primary outcome was the diagnostic accuracy of the POCUS-guided CVC confirmation protocol for malposition and pneumothorax detection. Secondary outcomes were efficiency and feasibility of adequate image acquisition, adjudicated by POCUS experts. RESULTS: Twenty-six POCUS nonexperts collected data on 190 patients in the final analysis. There were five (2.5%) CVC malpositions and six (3%) pneumothoraxes on CXR. The positive likelihood ratios of POCUS for malposition detection and pneumothorax were 12.33 (95% confidence interval [CI] = 3.26 to 46.69) and 3.41 (95% CI = 0.51 to 22.76), respectively. The accuracy of POCUS for pneumothorax detection compared to CXR was 0.93 (95% CI = 0.88 to 0.96) and the sensitivity was 0.17 (95% CI = 0.00 to 0.64). The median (interquartile range) time for CVC confirmation was lower for POCUS (9 minutes [8.5-9.5 minutes]) compared to CXR (29 minutes [1-269 minutes]; Mann-Whitney U, p < 0.01). Adequate protocol image acquisition was achieved in 76% of the patients. CONCLUSION: Thirty-minute training of POCUS in nonexperts demonstrates adequate diagnostic accuracy, efficiency, and feasibility of POCUS-guided CVC position confirmation, but not exclusion of pneumothorax.

Current Practices in Central Venous Catheter Position Confirmation by Point of Care Ultrasound: A Survey of Early Adopters.

PURPOSE: Although routine chest radiographs (CXR) to verify correct central venous catheter (CVC) position and exclude pneumothorax are commonly performed, emerging evidence suggests that this practice can be replaced by point of care ultrasound (POCUS). POCUS is advantageous over CXR because it avoids radiation while verifying correct placement and lack of pneumothorax without delay. We hypothesize that a knowledge translation gap exists in this area. We aim to describe the current clinical practice regarding POCUS alone for CVC position confirmation and pneumothorax exclusion as compared with chest radiography. METHODS: We used a modified Dillman technique to conduct a brief web-based survey to Critical Care Medicine and Emergency Medicine physicians (targeted group of early adopters) evaluating the current practice related to CVC position confirmation and PTX exclusion via CXR or POCUS. RESULTS: Of 200 post-training clinicians contacted, 136 (68%) responded to the survey. For routine CVC confirmation and PTX evaluation, 50.7% of Critical Care Medicine physicians and 65.4% of Emergency Medicine physicians reported using CXR alone while 49.3% and 33.1% respectively reported using CXR and ultrasound together. Though 84.6% of clinicians use ultrasound for CVC insertion "most of the time" or "always," none use ultrasound alone for CVC position confirmation, and only 1% has used ultrasound alone for PTX exclusion. CONCLUSIONS: Though data support its utility and advantages for POCUS as a sole modality for CVC position confirmation and PTX evaluation, POCUS is rarely used for this indication. We identified several perceived barriers toward widespread utilization suggesting areas for dissemination and implementation strategy development that will benefit patient care practices.

Discrepancies in measuring bladder volumes with bedside ultrasound and bladder scanning in the intensive care unit: A pilot study.

OBJECTIVE: Intensive care unit patients are at risk for catheter-associated urinary tract infection. Earlier removal of catheters may be possible with accurate measurement of bladder volume. The purpose was to compare measured bladder volumes with bedside ultrasound, bladder scanner, and urine volume. DESIGN: Prospective correlational descriptive study. SETTING: Surgical/trauma intensive care unit and medical intensive care unit. PATIENTS: Renal dialysis patients with less than 100 ml of urine in 24 h prior to urinary catheter removal and patients with suspected catheter obstruction. MEASUREMENTS AND MAIN RESULTS: A physician trained in ultrasound and an advanced practice registered nurse trained in bladder scanning measured bladder volume; each blinded to the other's measurement. Device used first (ultrasound or bladder scanner) alternated daily. The intensive care unit team determined need for intermittent catheterization or treatment for suspected obstruction. Fifty-one measurements from 13 patients were obtained with results reported in milliliters. Ultrasound measurements were a mean volume of 72.1 ± 127 (range: 1.7-666) and the bladder scanner measurements were 117 ± 131 (0-529). On six occasions in five dialysis patients, urine volume measurement was available. The mean difference in ultrasound-urine volume mean difference was 0.5 ± 37.8 (range: -68 to 38.2) and the bladder scanner-urine volume was 132 ± 167 (-72 to 397). Two patients with suspected catheter obstructions had ultrasound, bladder scanner, urine volume measurements, respectively: (1) 539, 51, >300 (began voiding before catheter replaced); (2) 666, 68, 1000 with catheter replacement. Conditions leading to greatest differences were obesity, indwelling catheter and ascites. CONCLUSIONS: These results demonstrate the inaccuracy of the bladder scanner. Ultrasound measurements appear more accurate. To remove urinary catheters in patients with minimal to low urine output, serial ultrasound measurements can be used to monitor bladder volumes and return of renal function.

Monocyte Function and Clinical Outcomes in Febrile and Afebrile Patients With Severe Sepsis.

INTRODUCTION: Absence of fever is associated with higher mortality in septic patients, but the reason for this is unknown. Immune dysfunction may be a potential link between failure to mount a fever and poor outcomes. The purpose of this study was to evaluate monocyte function and clinical surrogates of immunity (i.e., mortality and acquisition of secondary infections) in febrile and afebrile septic patients. METHODS: Single-center, prospective cohort study of 92 critically ill septic patients. Patients were categorized into febrile (≥38.0°C) and afebrile (<38.0°C) groups based on temperature measurements within 24 hours of sepsis diagnosis. HLA-DR expression and LPS-induced TNF-α production were quantified on days 1-2, days 3-4, and days 6-8 after sepsis diagnosis. A repeated measures mixed models analysis was used to compare these markers between the two groups. RESULTS: Forty-four patients (47.8%) developed a fever within 24 h of sepsis diagnosis. There were no significant differences in HLA-DR expression or LPS-induced TNF-α production between febrile and afebrile patients at any individual time point. However, HLA-DR expression significantly increased between days 1-2 and days 6-8 (median difference 8118 [IQR 1,662, 9,878] antibodies/cell, P = 0.002) in febrile patients, but not in afebrile patients (median difference 403 [-3,382, 3,507] antibodies/cell, P = 0.25). Afebrile patients demonstrated higher 28-day mortality (37.5% vs 18.2%) and increased acquisition of secondary infections (35.4% vs. 15.9%). CONCLUSIONS: Absence of fever is associated with suppressed HLA-DR expression over time, a finding suggestive of monocyte dysfunction in sepsis, as well as worse clinical outcomes.

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.

Sub-acute Tamponade and the Value of Point-of-Care Ultrasound for Rapid Diagnosis: A Case Report.

Minoxidil is a strong oral vasodilator that is used to treat patients with hypertension refractory to first-line medications. We report a case of minoxidil-associated subacute cardiac tamponade diagnosed by point-of-care ultrasound (POCUS) in a hypertensive patient. A 30-year-old male with a past medical history of poorly controlled hypertension (treated with minoxidil) and chronic kidney disease presented with 2-3 days of chest pain and shortness of breath with markedly elevated blood pressures. A point-of-care transthoracic echocardiogram revealed a massive pericardial effusion with sonographic tamponade physiology. We review the risk factors for developing pericardial effusions that progress to cardiac tamponade, the utility of diagnosing these patients by POCUS, and the incidence of patients who present with sonographic signs of cardiac tamponade without hypotension.

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.

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.