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BACKGROUND: Unplanned intensive care unit (ICU) admissions from medical/surgical floors and increased boarding times of ICU patients in the emergency department (ED) are common; approximately half of these are associated with adverse events. We explore the potential role of a tele-critical care consult service (TC3) in managing critically ill patients outside of the ICU and potentially preventing low-acuity unplanned admissions and also investigate its design and implementation needs. METHODS: We conducted a qualitative study involving general observations of the units, shadowing of clinicians during patient transfers, and interviews with clinicians from the ED, medical/surgical floor units and their ICU counterparts, tele-ICU, and the rapid response team at a large academic medical center in St. Louis, Missouri, United States. We used a hybrid thematic analysis approach supported by open and structured coding using the Consolidated Framework for Implementation Research (CFIR). RESULTS: Over 165 hours of observations/shadowing and 26 clinician interviews were conducted. Our findings suggest that a tele-critical care consult (TC3) service can prevent avoidable, lower acuity ICU admissions by offering a second set of eyes via remote monitoring and providing guidance to bedside and rapid response teams in the care delivery of these patients on the floor/ED. CFIR-informed enablers impacting the successful implementation of the TC3 service included the optional and on-demand features of the TC3 service, around-the-clock availability, and continuous access to trained critical care clinicians for avoidable lower acuity (ALA) patients outside of the ICU, familiarity with tele-ICU staff, and a willingness to try alternative patient risk mitigation strategies for ALA patients (suggested by TC3), before transferring all unplanned admissions to ICUs. Conversely, the CFIR-informed barriers to implementation included a desire to uphold physician autonomy by floor/ED clinicians, potential role conflicts with rapid response teams, additional workload for floor/ED nurses, concerns about obstructing unavoidable, higher acuity admissions, and discomfort with audio-visual tools. To amplify these potential enablers and mitigate potential barriers to TC3 implementation, informed by this study, we propose two key characteristics-essential for extending the delivery of critical care services beyond the ICU-underlying a telemedicine critical care consultation model including its virtual footprint and on-demand and optional service features. CONCLUSION: Tele-critical care represents an innovative strategy for delivering safe and high-quality critical care services to lower acuity borderline patients outside the ICU setting.
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Telemedicina , Humanos , Cuidados Críticos , Unidades de Terapia Intensiva , Centros Médicos Acadêmicos , Serviço Hospitalar de EmergênciaRESUMO
BACKGROUNDSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients generally relies on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision.METHODSAn ex vivo whole-blood enzyme-linked immunosorbent spot (ELISpot) assay for cellular production of interferon γ (IFN-γ) was evaluated in 107 septic and 68 nonseptic patients from 5 academic health centers using blood samples collected on days 1, 4, and 7 following ICU admission.RESULTSCompared with 46 healthy participants, unstimulated and stimulated whole-blood IFN-γ expression was either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole-blood IFN-γ expression was significantly reduced on ICU days 1, 4, and 7 (all P < 0.05), due to both significant reductions in total number of IFN-γ-producing cells and amount of IFN-γ produced per cell (all P < 0.05). Importantly, IFN-γ total expression on days 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6, and procalcitonin. Septic patients with low IFN-γ expression were older and had lower ALCs and higher soluble PD-L1 and IL-10 concentrations, consistent with an immunosuppressed endotype.CONCLUSIONSA whole-blood IFN-γ ELISpot assay can both identify septic patients at increased risk of late mortality and identify immunosuppressed septic patients.TRIAL REGISTRYN/A.FUNDINGThis prospective, observational, multicenter clinical study was directly supported by National Institute of General Medical Sciences grant R01 GM-139046, including a supplement (R01 GM-139046-03S1) from 2022 to 2024.
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Interferon gama , Sepse , Humanos , Interferon gama/metabolismo , Imunoadsorventes/uso terapêutico , Estudos Prospectivos , BiomarcadoresRESUMO
BACKGROUND: Sepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients has generally relied on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision. METHODS: An ex vivo whole blood enzyme-linked immunosorbent (ELISpot) assay for cellular production of interferon-γ (IFN-γ) was evaluated in 107 septic and 68 non-septic patients from five academic health centers using blood samples collected on days 1, 4 and 7 following ICU admission. RESULTS: Compared with 46 healthy subjects, unstimulated and stimulated whole blood IFNγ expression were either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole blood IFNγ expression was significantly reduced on ICU days 1, 4 and 7 (all p<0.05), due to both significant reductions in total number of IFNγ producing cells and amount of IFNγ produced per cell (all p<0.05). Importantly, IFNγ total expression on day 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6 and procalcitonin. Septic patients with low IFNγ expression were older and had lower ALC and higher sPD-L1 and IL-10 concentrations, consistent with an immune suppressed endotype. CONCLUSIONS: A whole blood IFNγ ELISpot assay can both identify septic patients at increased risk of late mortality, and identify immune-suppressed, sepsis patients.
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Fever is a recognized protective factor in patients with sepsis, and growing data suggest beneficial effects on outcomes in sepsis with elevated temperature, with a recent pilot randomized controlled trial (RCT) showing lower mortality by warming afebrile sepsis patients in the intensive care unit (ICU). The objective of this prospective single-site RCT was to determine if core warming improves respiratory physiology of mechanically ventilated patients with coronavirus disease 2019 (COVID-19), allowing earlier weaning from ventilation, and greater overall survival. A total of 19 patients with mean age of 60.5 (±12.5) years, 37% female, mean weight 95.1 (±18.6) kg, and mean body mass index 34.5 (±5.9) kg/m2 with COVID-19 requiring mechanical ventilation were enrolled from September 2020 to February 2022. Patients were randomized 1:1 to standard of care or to receive core warming for 72 hours through an esophageal heat exchanger commonly utilized in critical care and surgical patients. The maximum target temperature was 39.8°C. A total of 10 patients received usual care and 9 patients received esophageal core warming. After 72 hours of warming, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) ratios were 197 (±32) and 134 (±13.4), cycle thresholds were 30.8 (±6.4) and 31.4 (±3.2), ICU mortalities were 40% and 44%, 30-day mortalities were 30% and 22%, and mean 30-day ventilator-free days were 11.9 (±12.6) and 6.8 (±10.2) for standard of care and warmed patients, respectively (p = NS). This pilot study suggests that core warming of patients with COVID-19 undergoing mechanical ventilation is feasible and appears safe. Optimizing time to achieve febrile-range temperature may require a multimodal temperature management strategy to further evaluate effects on outcome. ClinicalTrials.gov Identifier: NCT04494867.
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COVID-19 , Hipotermia Induzida , Sepse , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , COVID-19/terapia , Respiração Artificial , Projetos Piloto , OxigênioRESUMO
OBJECTIVES: In mechanically ventilated patients, awareness with paralysis (AWP) can have devastating consequences, including post-traumatic stress disorder (PTSD), depression, and thoughts of suicide. Single-center data from the emergency department (ED) demonstrate an event rate for AWP factors higher than that reported from the operating room. However, there remains a lack of data on AWP among critically ill, mechanically ventilated patients. The objective was to assess the proportion of ED patients experiencing AWP and investigate modifiable variables associated with its occurrence. DESIGN: An a priori planned secondary analysis of a multicenter, prospective, before-and-after clinical trial. SETTING: The ED of three academic medical centers. PATIENTS: Mechanically ventilated adult patients that received neuromuscular blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All data related to sedation and analgesia were collected. AWP was the primary outcome, assessed with the modified Brice questionnaire, and was independently adjudicated by three expert reviewers. Perceived threat, in the causal pathway for PTSD, was the secondary outcome. A total of 388 patients were studied. The proportion of patients experiencing AWP was 3.4% ( n = 13), the majority of whom received rocuronium ( n = 12/13; 92.3%). Among patients who received rocuronium, 5.5% ( n = 12/230) experienced AWP, compared with 0.6% ( n = 1/158) among patients who did not receive rocuronium in the ED (odds ratio, 8.64; 95% CI, 1.11-67.15). Patients experiencing AWP had a higher mean ( sd ) threat perception scale score, compared with patients without AWP (15.6 [5.8] vs 7.7 [6.0]; p < 0.01). CONCLUSIONS: AWP was present in a concerning proportion of mechanically ventilated ED patients, was associated with rocuronium exposure in the ED, and led to increased levels of perceived threat, placing patients at greater risk for PTSD. Studies that aim to further quantify AWP in this vulnerable population and eliminate its occurrence are urgently needed.
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Estado Terminal , Serviço Hospitalar de Emergência , Adulto , Estado Terminal/terapia , Humanos , Paralisia/epidemiologia , Estudos Prospectivos , RocurônioRESUMO
BACKGROUND: Survival rates following in-hospital cardiac arrest (IHCA) are lower during nights and weekends (off-hours), as compared to daytime on weekdays (on-hours). Telemedicine Critical Care (TCC) may provide clinical support to improve IHCA outcomes, particularly during off-hours. OBJECTIVE: To evaluate the association between hospital availability of TCC and IHCA survival. METHODS: We identified 44,585 adults at 280 U.S. hospitals in the Get With The Guidelines® - Resuscitation registry who suffered IHCA in an Intensive Care Unit (ICU) or hospital ward between July 2017 and December 2019. We used 2-level hierarchical multivariable logistic regression to investigate whether TCC availability was associated with better survival, overall, and during on-hours (Monday-Friday 7:00 a.m.-10:59p.m.) vs. off-hours (Monday-Friday 11:00p.m.-6:59 a.m., and Saturday-Sunday, all day, and US national holidays). RESULTS: 14,373 (32.2%) participants suffered IHCA at hospitals with TCC, and 27,032 (60.6%) occurred in an ICU. There was no difference between TCC and non-TCC hospitals in acute resuscitation survival rate or survival to discharge rates for either IHCA occurring in the ICU (acute survival odds ratio [OR] 1.02, 95% CI 0.92-1.15; survival to discharge OR 0.94 [0.83-1.07]) or outside of the ICU (acute survival OR 1.03 [0.91-1.17]; survival to discharge OR 0.99 [0.86-1.12]. Timing of cardiac arrest did not modify the association between TCC availability and acute resuscitation survival (P =.37 for interaction) or survival to discharge (P =.39 for interaction). CONCLUSIONS: Hospital availability of TCC was not associated with improved outcomes for in-hospital cardiac arrest.
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Reanimação Cardiopulmonar , Parada Cardíaca , Telemedicina , Adulto , Cuidados Críticos , Parada Cardíaca/terapia , Hospitais , HumanosRESUMO
OBJECTIVE: Temperature abnormalities are recognized as a marker of human disease, and the therapeutic value of temperature is an attractive treatment target. The objective of this synthetic review is to summarize and critically appraise evidence for active temperature management in critically ill patients. DATA SOURCES: We searched MEDLINE for publications relevant to body temperature management (including targeted temperature management and antipyretic therapy) in cardiac arrest, acute ischemic and hemorrhagic stroke, traumatic brain injury, and sepsis. Bibliographies of included articles were also searched to identify additional relevant studies. STUDY SELECTION: English-language systematic reviews, meta-analyses, randomized trials, observational studies, and nonhuman data were reviewed, with a focus on the most recent randomized control trial evidence. DATA EXTRACTION: Data regarding study methodology, patient population, temperature management strategy, and clinical outcomes were qualitatively assessed. DATA SYNTHESIS: Temperature management is common in critically ill patients, and multiple large trials have been conducted to elucidate temperature targets, management strategies, and timing. The strongest data concerning the use of therapeutic hypothermia exist in comatose survivors of cardiac arrest, and recent trials suggest that appropriate postarrest temperature targets between 33°C and 37.5°C are reasonable. Targeted temperature management in other critical illnesses, including acute stroke, traumatic brain injury, and sepsis, has not shown benefit in large clinical trials. Likewise, trials of pharmacologic antipyretic therapy have not demonstrated improved outcomes, although national guidelines do recommend treatment of fever in patients with stroke and traumatic brain injury based on observational evidence associating fever with worse outcomes. CONCLUSIONS: Body temperature management in critically ill patients remains an appealing therapy for several illnesses, and additional studies are needed to clarify management strategies and therapeutic pathways.
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Unidades de Terapia Intensiva , Temperatura , HumanosRESUMO
OBJECTIVES: Deep sedation in the emergency department (ED) is common, increases deep sedation in the ICU, and is negatively associated with outcome. Limiting ED deep sedation may, therefore, be a high-yield intervention to improve outcome. However, the feasibility of conducting an adequately powered ED-based clinical sedation trial is unknown. Our objectives were to assess trial feasibility in terms of: 1) recruitment, 2) protocol implementation and practice change, and 3) safety. Patient-centered clinical outcomes were assessed to better plan for a future large-scale clinical trial. DESIGN: Pragmatic, multicenter ( n = 3), prospective before-after pilot and feasibility trial. SETTING: The ED and ICUs at three medical centers. PATIENTS: Consecutive, adult mechanically ventilation ED patients. INTERVENTIONS: An educational initiative aimed at reliable ED sedation depth documentation and reducing the proportion of deeply sedated patients (primary outcome). MEASUREMENTS AND MAIN RESULTS: Sedation-related data in the ED and the first 48 ICU hours were recorded. Deep sedation was defined as a Richmond Agitation-Sedation Scale of -3 to -5 or a Sedation-Agitation Scale of 1-3. One thousand three hundred fifty-six patients were screened; 415 comprised the final population. Lighter ED sedation was achieved in the intervention group, and the proportion of deeply sedated patients was reduced from 60.2% to 38.8% ( p < 0.01). There were no concerning trends in adverse events (i.e., inadvertent extubation, device removal, and awareness with paralysis). Mortality was 10.0% in the intervention group and 20.4% in the preintervention group ( p < 0.01). Compared with preintervention, the intervention group experienced more ventilator-free days [22.0 (9.0) vs 19.9 (10.6)] and ICU-free days [20.8 (8.7) vs 18.1 (10.4)], p < 0.05 for both. CONCLUSIONS: This pilot trial confirmed the feasibility of targeting the ED in order to improve sedation practices and reduce deep sedation. These findings justify an appropriately powered clinical trial regarding ED-based sedation to improve clinical outcomes.
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Unidades de Terapia Intensiva , Respiração Artificial , Adulto , Serviço Hospitalar de Emergência , Estudos de Viabilidade , Humanos , Hipnóticos e Sedativos/uso terapêutico , Projetos Piloto , Estudos Prospectivos , Respiração Artificial/métodosRESUMO
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.
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COVID-19 , Hipertermia Induzida , Sepse , Adulto , Estado Terminal/terapia , Antígenos HLA-DR , Humanos , Projetos Piloto , Estudos Prospectivos , SARS-CoV-2 , Sepse/terapiaRESUMO
OBJECTIVES: Telemedicine critical care is associated with improved efficiency, quality, and cost-effectiveness. As of 2010, fewer than 5% of U.S. hospitals had telemedicine critical care, and fewer than 10% of ICU beds were covered. We evaluated recent telemedicine critical care implementation and bed coverage rates in the United States and compared characteristics of hospitals with and without telemedicine critical care. DESIGN: Cross-sectional study of 2018 American Hospital Association Annual Survey Database. SETTING: U.S. hospitals. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We obtained data regarding telemedicine critical care implementation, ICU capability (defined as ≥ 1 ICU bed), other hospital characteristics, and the Herfindahl-Hirschman Index, a measure of ICU market competition based on hospital referral regions. Among 4,396 hospitals (response rate 71%), 788 (17.9%) had telemedicine critical care, providing potential coverage to 27,624 (28% of total) ICU beds. Among 306 hospital referral regions, 197 (64%) had a respondent hospital with telemedicine critical care. Telemedicine critical care implementation was associated with being a nonprofit (odds ratio, 7.75; 95% CI, 5.18-11.58) or public (odds ratio, 4.16 [2.57-6.73]) compared with for-profit hospital; membership in a health system (odds ratio, 3.83 [2.89-5.08]; stroke telemedicine presence (odds ratio, 6.87 [5.35-8.81]); ICU capability (odds ratio, 1.68 [1.25-2.26]); and more competitive ICU markets (odds ratio per 1,000-point decrease in Herfindahl-Hirschman Index 1.11 [1.01-1.22]). Notably, rural critical access hospitals had lower odds of telemedicine critical care implementation (odds ratio, 0.49 [0.34-0.70]). Teaching status, geographic region, and rurality were not associated with telemedicine critical care implementation. CONCLUSIONS: About one fifth of respondent hospitals had telemedicine critical care by 2018, providing potential coverage of nearly one third of reported ICU beds. This represents a substantial increase in telemedicine critical care implementation over the last decade. Future expansion to include more rural hospitals that could benefit most may be aided by addressing hospital financial and market barriers to telemedicine critical care implementation.
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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.
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STUDY OBJECTIVE: Awareness with paralysis is a devastating complication for patients receiving mechanical ventilation and risks long-term psychological morbidity. Data from the emergency department (ED) demonstrate a high rate of longer-acting neuromuscular blocking agent use, delayed analgosedation, and a lack of sedation depth monitoring. These practices are discordant with recommendations for preventing awareness with paralysis. Despite this, awareness with paralysis has not been rigorously studied in the ED population. Our objective is to assess the prevalence of awareness with paralysis in ED patients receiving mechanical ventilation. METHODS: This was a single-center, prospective, observational cohort study on 383 mechanically ventilated ED patients. After extubation, we assessed patients for awareness with paralysis by using the modified Brice questionnaire. Three expert reviewers independently adjudicated awareness with paralysis. We report the prevalence of awareness with paralysis (primary outcome); the secondary outcome was perceived threat, a mediator for development of posttraumatic stress disorder. RESULTS: The prevalence of awareness with paralysis was 2.6% (10/383). Exposure to rocuronium at any point in the ED was significantly different between patients who experienced awareness with paralysis (70%) versus the rest of the cohort (31.4%) (unadjusted odds ratio 5.1; 95% confidence interval 1.30 to 20.1). Patients experiencing awareness with paralysis had higher mean values on the threat perception scale, denoting a higher degree of perceived threat, compared with patients who did not experience awareness with paralysis (13.4 [SD 7.7] versus 8.5 [SD 6.2]; mean difference 4.9; 95% confidence interval 0.94 to 8.8). CONCLUSION: Awareness with paralysis occurs in a significant minority of ED patients who receive mechanical ventilation. Potential associations of awareness with paralysis with ED care and increased perceived threat warrant further evaluation.
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Conscientização , Paralisia/psicologia , Respiração Artificial/psicologia , Adulto , Idoso , Anestesia Geral/efeitos adversos , Anestesia Geral/psicologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Respiração Artificial/efeitos adversos , Inquéritos e QuestionáriosRESUMO
Sepsis initiates simultaneous pro- and anti-inflammatory processes, the pattern and intensity of which vary over time. The inability to evaluate the immune status of patients with sepsis in a rapid and quantifiable manner has undoubtedly been a major reason for the failure of many therapeutic trials. Although there has been considerable effort to immunophenotype septic patients, these methods have often not accurately assessed the functional state of host immunity, lack dynamic range, and are more reflective of molecular processes rather than host immunity. In contrast, ELISpot assay measures the number and intensity of cytokine-secreting cells and has excellent dynamic range with rapid turnaround. We investigated the ability of a (to our knowledge) novel whole blood ELISpot assay and compared it with a more traditional ELISpot assay using PBMCs in sepsis. IFN-γ and TNF-α ELISpot assays on whole blood and PBMCs were undertaken in control, critically ill nonseptic, and septic patients. Whole blood ELISpot was easy to perform, and results were generally comparable to PBMC-based ELISpot. However, the whole blood ELISpot assay revealed that nonmonocyte, myeloid populations are a significant source of ex vivo TNF-α production. Septic patients who died had early, profound, and sustained suppression of innate and adaptive immunity. A cohort of septic patients had increased cytokine production compared with controls consistent with either an appropriate or excessive immune response. IL-7 restored ex vivo IFN-γ production in septic patients. The whole blood ELISpot assay offers a significant advance in the ability to immunophenotype patients with sepsis and to guide potential new immunotherapies.
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ELISPOT/métodos , Sepse/imunologia , Imagem Corporal Total/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Imunidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Sepse/diagnóstico , Sepse/mortalidade , Análise de SobrevidaRESUMO
A defining feature of protracted sepsis is development of immunosuppression that is thought to be a major driving force in the morbidity and mortality associated with the syndrome. The immunosuppression that occurs in sepsis is characterized by profound apoptosis-induced depletion of CD4 and CD8 T cells and severely impaired T cell function. OX40, a member of the TNF receptor superfamily, is a positive co-stimulatory molecule expressed on activated T cells. When engaged by OX40 ligand, OX40 stimulates T cell proliferation and shifts the cellular immune phenotype toward TH1 with increased production of cytokines that are essential for control of invading pathogens. The purpose of the present study was to determine if administration of agonistic Ab to OX40 could reverse sepsis-induced immunosuppression, restore T cell function, and improve survival in a clinically relevant animal model of sepsis. The present study demonstrates that OX40 agonistic Ab reversed sepsis-induced impairment of T cell function, increased T cell IFN-γ production, increased the number of immune effector cells, and improved survival in the mouse cecal ligation and puncture model of sepsis. Importantly, OX40 agonistic Ab was not only effective in murine sepsis but also improved T effector cell function in PBMCs from patients with sepsis. The present results provide support for the use of immune adjuvants that target T cell depletion and T cell dysfunction in the therapy of sepsis-induced immunosuppression. In addition to the checkpoint inhibitors anti-PD-1 and anti-PD-L1, OX40 agonistic Ab may be a new therapeutic approach to the treatment of this highly lethal disorder.
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Anticorpos/uso terapêutico , Terapia de Imunossupressão , Receptores OX40/agonistas , Sepse/tratamento farmacológico , Sepse/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Ceco/patologia , Estado Terminal , Feminino , Granulócitos/metabolismo , Humanos , Hipersensibilidade Tardia/imunologia , Interferon gama/metabolismo , Ligadura , Contagem de Linfócitos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Punções , Receptores OX40/metabolismo , Análise de Sobrevida , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the virus SARS-CoV-2, is spreading rapidly across the globe, with little proven effective therapy. Fever is seen in most cases of COVID-19, at least at the initial stages of illness. Although fever is typically treated (with antipyretics or directly with ice or other mechanical means), increasing data suggest that fever is a protective adaptive response that facilitates recovery from infectious illness. OBJECTIVE: To describe a randomized controlled pilot study of core warming patients with COVID-19 undergoing mechanical ventilation. METHODS: This prospective single-site randomized controlled pilot study will enroll 20 patients undergoing mechanical ventilation for respiratory failure due to COVID-19. Patients will be randomized 1:1 to standard-of-care or to receive core warming via an esophageal heat exchanger commonly utilized in critical care and surgical patients. The primary outcome is patient viral load measured by lower respiratory tract sample. Secondary outcomes include severity of acute respiratory distress syndrome (as measured by PaO2/FiO2 ratio) 24, 48, and 72 hours after initiation of treatment, hospital and intensive care unit length of stay, duration of mechanical ventilation, and 30-day mortality. RESULTS: Resulting data will provide effect size estimates to guide a definitive multi-center randomized clinical trial. ClinicalTrials.gov registration number: NCT04426344. CONCLUSIONS: With growing data to support clinical benefits of elevated temperature in infectious illness, this study will provide data to guide further understanding of the role of active temperature management in COVID-19 treatment and provide effect size estimates to power larger studies.
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Temperatura Corporal , COVID-19/fisiopatologia , COVID-19/terapia , Ventiladores Mecânicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-É£ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-É£ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-É£ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.