Kinetics of C-reactive protein during extracorporeal membrane oxygenation.

BACKGROUND: The exposure of blood to the artificial circuit during extracorporeal membrane oxygenation (ECMO) can induce an inflammatory response. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation. METHODS: In this retrospective observational study, we analyzed results of daily plasma CRP measurements in 110 critically ill patients, treated with ECMO. We compared CRP levels during the first 5 days of ECMO operation, between different groups of patients according to ECMO configurations, Coronavirus disease 2019 (COVID-19) status, and mechanical ventilation parameters. RESULTS: There was a statistically significant decrease in CRP levels during the first 5 days of veno-venous (VV) ECMO (173 ± 111 mg/L, 154 ± 107 mg/L, 127 ± 97 mg/L, 114 ± 100 mg/L and 118 ± 90 mg/L for days 1-5 respectively, p < 0.001). Simultaneously, there was a significant reduction in ventilatory parameters, as represented by the mechanical power (MP) calculation, from 24.02 ± 14.53 J/min to 6.18 ± 4.22 J/min within 3 h of VV ECMO initiation (p < 0.001). There was non-significant trend of increase in CRP level during the first 5 days of veno arterial (VA) ECMO (123 ± 80 mg/L, 179 ± 91 mg/L, 203 ± 90 mg/L, 179 ± 95 mg/L and 198 ± 93 for days 1-5 respectively, p = 0.126) and no significant change in calculated MP (from 14.28 ± 8.56 J/min to 10.81 ± 8.09 J/min within 3 h if ECMO initiation, p = 0.071). CONCLUSIONS: We observed a significant decrease in CRP levels during the first 5 days of VV ECMO support, and suggest that the concomitant reduction in ventilatory MP may have mitigated the degree of alveolar stress and strain that could have contributed to a decrease in the systemic inflammatory process.

Inhaled Exosomes Genetically Manipulated to Overexpress CD24 (EXO-CD24) as a Compassionate Use in Severe ARDS Patients.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a major global health concern with a significant unmet need. EXO-CD24 is delivered via inhalation-reduced cytokines and chemokine secretion and lung injury in ARDS and improved survival in mice models of ARDS, influenza, and sepsis. OBJECTIVES: This clinical paper aims to evaluate the potential of EXO-CD24, a novel immunomodulatory treatment, in the compassionate care of critically ill, intubated patients with post-infection-induced acute respiratory distress syndrome (ARDS). METHODS: Eleven critically ill patients diagnosed with post-infection ARDS (10 with COVID-19 and one with an adenovirus-associated infection) were administered EXO-CD24 in four medical centers across Israel. The patients had multiple co-morbidities, including cancer, hypertension, diabetes, and ischemic heart disease, and met the criteria for severe ARDS according to the Berlin classification. EXO-CD24 was administered via inhalation, and adverse events related to its use were carefully monitored. MEASUREMENTS AND MAIN RESULTS: The administration of EXO-CD24 did not result in any recorded adverse events. The median hospitalization duration was 11.5 days, and the overall mortality rate was 36%. Notably, patients treated at the Tel Aviv Medical Center (TASMC) showed a lower mortality rate of 12.5%. The WBC and CRP levels decreased in comparison to baseline levels at hospitalization, and rapid responses occurred even in patients with kidney transplants who were off the ventilator within a few days and discharged shortly thereafter. The production of cytokines and chemokines was significantly suppressed in all patients, including those who died. Among the patients at TASMC, four had kidney transplants and were on immunosuppressive drugs, and all of them fully recovered and were discharged from the hospital. CONCLUSIONS: EXO-CD24 holds promise as a potential therapeutic agent for all stages of ARDS, even in severe intubated cases. Importantly, EXO-CD24 demonstrated a favorable safety profile without any apparent side effects with promising efficacy. Furthermore, the potential of EXO-CD24 as a platform for addressing hyper-inflammatory states warrants exploration. Further research and larger-scale clinical trials are warranted to validate these preliminary findings.

Inhaled CD24-Enriched Exosomes (EXO-CD24) as a Novel Immune Modulator in Respiratory Disease.

Acute Respiratory Distress Syndrome (ARDS) is a major health concern with urgent unmet need for treatment options. There are three million new ARDS cases annually, and the disease's mortality rate is high (35-46%). Cluster of differentiation 24 (CD24), a long-known protein with multifaceted functions, is a small, heavily glycosylated, membrane-anchored protein which functions as an immune checkpoint control. CD24 allows for immune discrimination between Damage-Associated Molecular Patterns and Pathogen-Associated Molecular Patterns derived from pathogens. Exosomes are intraluminal vesicles which play an important role in intercellular communication. Exosomes offer the advantage of targeted delivery, which improves safety and efficacy. The safety and efficacy of EXO-CD24 is promising, as was shown in >180 ARDS patients in phase 1b/2a, phase 2b, and compassionate use. CD24 binds Damage-associated molecular patterns (DAMPs) and inhibits the activation of the NF-ĸB pathway, a pivotal mediator of inflammatory responses. In contrast to anti-inflammatory therapies that are cytokine-specific or steroids that shut down the entire immune system, EXO-CD24 acts upstream, reverting the immune system back to normal activity. Herein, the safety and efficacy of mEXO-CD24 is shown in murine models of several pulmonary diseases (sepsis, allergic asthma, Chronic Obstructive Pulmonary Disease(COPD), fibrosis). EXO CD24 can suppress the hyperinflammatory response in the lungs in several pulmonary diseases with a significant unmet need for treatment options.

Central catheter tip migration in critically ill patients.

OBJECTIVES: Chest X-ray (CXR) is routinely required for assessing Central Venous Catheter (CVC) tip position after insertion, but there is limited data as to the movement of the tip location during hospitalization. We aimed to assess the migration of Central Venous Catheter (CVC) position, as a significant movement of catheter tip location may challenge some of the daily practice after insertion. DESIGN AND SETTINGS: Retrospective, single-center study, conducted in the Intensive Care and Cardiovascular Intensive Care Units in Tel Aviv Sourasky Medical Center 'Ichilov', Israel, between January and June 2019. PATIENTS: We identified 101 patients with a CVC in the Right Internal Jugular (RIJ) with at least two CXRs during hospitalization. MEASUREMENTS AND RESULTS: For each patient, we measured the CVC tip position below the carina level in the first and all consecutive CXRs. The average initial tip position was 1.52 (±1.9) cm (mean±SD) below the carina. The maximal migration distance from the initial insertion position was 1.9 (±1) cm (mean±SD). During follow-up of 2 to 5 days, 92% of all subject's CVCs remained within the range of the Superior Vena Cava to the top of the right atrium, regardless of the initial positioning. CONCLUSIONS: CVC tip position can migrate significantly during a patient's early hospitalization period regardless of primary location, although for most patients it will remain within a wide range of the top of the right atrium and the middle of the Superior Vena Cava (SVC), if accepted as well-positioned.

Changes in mean systemic filling pressure as an estimate of hemodynamic response to anesthesia induction using propofol.

BACKGROUND: Even a small change in the pressure gradient between the venous system and the right atrium can have significant hemodynamic effects. Mean systemic filling pressure (MSFP) is the driving force of the venous system. As a result, MSFP has a significant effect on cardiac output. We aimed to test the hypothesis that the hemodynamic instability during induction of general anesthesia by intravenous propofol administration is caused by changes in MSFP. METHODS: We prospectively collected data from 15 patients undergoing major surgery requiring invasive hemodynamic monitoring. Hemodynamic parameters, including MSFP, were measured before and after propofol administration and following intubation, using venous return curves at a no-flow state induced by a pneumatic tourniquet. RESULTS: A significant decrease in MSFP was observed in all study patients after propofol administration (median (IQR) pressure 17 (9) mmHg compared with 25 (7) before propofol administration, p = 0.001). The pressure gradient for venous return (MSFP - central venous pressure; CVP) also decreased following propofol administration from 19 (8) to 12 (6) mmHg, p = 0.001. Central venous pressure did not change. CONCLUSIONS: These results support the hypothesis that induction of anesthesia with propofol causes a marked reduction in MSFP. A possible mechanism of propofol-induced hypotension is reduction in preload due to a decrease in the venous vasomotor tone.

Low FXIII activity levels in intensive care unit hospitalized COVID-19 patients.

BACKGROUND: COVID-19 infection is associated with a hypercoagulable state. Severe COVID-19 patients present with high plasma fibrinogen levels, continuous deposition of fibrin and the presence of microthrombi in their lungs, accompanied by significant fibrinolysis, resulting in high D-dimer levels. Due to the role of FXIII in fibrin crosslinking and clot stabilization, we analyzed its activity levels and dynamics in COVID-19 patients hospitalized in the intensive care unit (ICU). METHODS: FXIII levels were measured in thirty four COVID-19 patients hospitalized in the ICU and in fourteen non-severe COVID-19 patients. FVIII levels were measured for comparison. Laboratory data and clinical variables were recorded. RESULTS: The average FXIII activity level in 34 ICU hospitalized COVID-19 patients was 69.9±33 %, significantly lower compared to an average of 120±20.9 % FXIII activity in 14 non-severe COVID-19 patients. FXIII activity levels were below the low normal value (< 79 % FXIII activity) in 74 % of the ICU hospitalized COVID-19 patients. In contrast, high FVIII activity was measured among all severe COVID-19 patients. Consecutive measurements, performed in fourteen ICU hospitalized COVID-19 patients, pointed to a significant decrease in FXIII activity from the average of 85.7±28.2 %, (which is in the normal range), to an average of 68.0±20.4 %, below the low normal range, within 6.4±3.4 days of ICU hospitalization. Liver functions did not differentiate between patients with low and normal FXIII activity. No inhibitor to FXIII activity was found in the plasma of severe COVID-19 patients. Levels of FXIII-A antigen correlated with FXIII activity, and were low in severe COVID-19 patients. CONCLUSIONS: Low FXIII activity levels were found in COVID-19 patients hospitalized in the ICU, with gradual decline during their hospitalization. A mechanism of consumption may account for the low FXIII activity in these patients.

Correction to: Lung ultrasound predicts clinical course and outcomes in COVID-19 patients.

The original article can be found online.

Lung ultrasound predicts clinical course and outcomes in COVID-19 patients.

PURPOSE: Information regarding the use of lung ultrasound (LUS) in patients with Coronavirus disease 2019 (COVID-19) is quickly accumulating, but its use for risk stratification and outcome prediction has yet to be described. We performed the first systematic and comprehensive LUS evaluation of consecutive patients hospitalized with COVID-19 infection, in order to describe LUS findings and their association with clinical course and outcome. METHODS: Between 21/03/2020 and 04/05/2020, 120 consecutive patients admitted to the Tel Aviv Medical Center due to COVID-19, underwent complete LUS within 24 h of admission. A second exam was performed in case of clinical deterioration. LUS score of 0 (best)-36 (worst) was assigned to each patient. LUS findings were compared with clinical data. RESULTS: The median baseline total LUS score was 15, IQR [7-20]. Baseline LUS score was 0-18 in 80 (67%) patients, and 19-36 in 40 (33%) patients. The majority had patchy pleural thickening (n = 100; 83%), or patchy subpleural consolidations (n = 93; 78%) in at least one zone. The prevalence of pleural thickening, subpleural consolidations and the total LUS score were all correlated with severity of illness on admission. Clinical deterioration was associated with increased follow-up LUS scores (p = 0.0009), mostly due to loss of aeration in anterior lung segments. The optimal cutoff point for LUS score was 18 (sensitivity = 62%, specificity = 74%). Both mortality and need for invasive mechanical ventilation were increased with baseline LUS score > 18 compared to baseline LUS score 0-18. Unadjusted hazard ratio of death for LUS score was 1.08 per point [1.02-1.16], p = 0.008; Unadjusted hazard ratio of the composite endpoint (death or need for invasive mechanical ventilation) for LUS score was 1.12 per point [1.05-1.2], p = 0.0008. CONCLUSION: Hospitalized patients with COVID-19, at all clinical grades, present with pathological LUS findings. Baseline LUS score strongly correlates with the eventual need for invasive mechanical ventilation and is a strong predictor of mortality. Routine use of LUS may guide patients' management strategies, as well as resource allocation in case of surge capacity.

Outcomes of prolonged mechanical ventilation in patients who underwent bedside percutaneous dilatation tracheostomy in intermediate care units - A single center study.

BACKGROUND: The number of chronic critical illness (CCI) patients requiring prolonged mechanical ventilation (PMV) is increasing worldwide, mandating health professionals to discuss interventions while considering disease trajectory. The aim of this study was to analyze the survival of CCI patients who underwent percutaneous dilatational tracheostomy (PDT) within intermediate care units. METHODS: We carried out a retrospective study of all patients who underwent PDT in our intermediate care units from 2009 to 2015. Based on their survival statuses at different time points, patients were categorized into groups of survival at one week, one month, and one year following the procedure. RESULTS: This study included 254 patients. The mean age was 77.7 (±11.8) years. Out of the 254 patients included, 213 patients (84.2%) were defined as nursing care dependent. In-hospital mortality was 38.2% (97 patients). Seven patients (2.7%) were discharged to their homes. Overall survival rates at one week, one month, and one year following PDT were 88.6%, 66.1%, and 29.5%, respectively. Upon multivariate analyses, higher creatinine levels and resuscitation prior to the procedure were associated with increased mortality rates at one week and one month following tracheostomy. Higher creatinine and low albumin levels were associated with increased mortality at one year following tracheostomy. CONCLUSION: The prognosis of CCI patients in intermediate care units is generally poor. Identified risk factors for complications and survival should be presented to patients and their surrogates when discussing courses of action and future treatments.

Outcome and survival following tracheostomy in patients ≥ 85 years old.

PURPOSE: To evaluate percutaneous dilatational tracheostomy in patients ≥ 85 years old: its complication rate and possible risk factors. In addition, to assess prognostic factors for short, intermediate and long term survival following the procedure. METHODS: A retrospective case-control study of 72 patients ≥ 85 years who received percutaneous dilatation tracheotomy (PTD), compared to a control group of younger patients (n = 182). Demographics, clinical and laboratory data were collected. Survival and risk for complications were analyzed. RESULTS: The study group's mean age was 89 ± 4. Twelve patients had complications, three (4.2%) were major. No significant difference was found in overall complication rates between the groups. Cerebrovascular disease with neurologic deficits and pre-procedure albumin levels were significantly associated with complications. Survival rates did not differ in 1 week and 1 month following procedure between study and control group. There was a significant difference in the 1-year survival rates between the patients ≥ 85 years and the control groups (18.1% vs. 34.4%, p = 0.01, respectively). Congestive heart failure, a frailty score > 0.27 and failure to wean from a cannula were associated with reduced 1-year survival. CONCLUSION: PTD is safe for patients ≥ 85 years. Complication risk factors and reduced survival should be discussed with patients and families before conducting tracheostomies. LEVEL OF EVIDENCE: 3b.

Evaluation and Predictors for Nasogastric Tube Associated Pressure Ulcers in Critically Ill Patients.

BACKGROUND: Nasal device-related pressure ulcers are scarcely addressed in the literature. OBJECTIVES: To assess the prevalence and severity of cutaneous and mucosal nasogastric tube (NGT)-associated pressure ulcers (PU) in critically ill patients and to define predictors for their formation. METHODS: A single center observational study of intensive care unit patients with a NGT for more than 48 hours was conducted. Nasal skin was evaluated for PU. Ulcers were graded according to their depth. Consenting patients underwent a nasoendoscopic examination to evaluate intranasal mucosal injury. RESULTS: The study comprised 50 patients, 17 of whom underwent nasoendoscopic examination. Mean time of NGT presence in the nose was 11.3 ± 6.17 days. All patients had some degree of extranasal PU, 46% were low grade and 54% were high grade. Predictors for high grade extranasal PU compared to low grade PU were higher peak Sepsis-related Organ Failure Assessment (SOFA) scores (11.52 vs. 8.87, P = 0.009), higher peak C-reactive protein (CRP) levels (265.3 mg/L vs. 207.58, P = 0.008), and bacteremia (33.3% vs. 8.7%, P = 0.037). The columella was the anatomical site most commonly involved and the most severely affected. The number of intranasal findings and their severity were significantly higher in the nasal cavity containing the NGT compared to its contralateral counterpart (P = 0.039 for both). CONCLUSIONS: NGTs cause injury to nasal skin and mucosa in critically ill patients. Patients with bacteremia, high CRP, and high SOFA scores are at risk for severe ulcers, warranting special monitoring and preventive measures.

Bedside percutaneous dilatational tracheostomy in patients outside the ICU: a single-center experience.

PURPOSE: To assess the safety of medical-ward bedside percutaneous dilatational tracheostomy (GWB-PDT). MATERIALS AND METHODS: A retrospective study of all patients who underwent elective GWB-PDT between 2009 and 2015. A joint otolaryngology-ICU team performed all GWB-PDTs. The patients were followed until decannulation, discharge or death. Complications were divided into early (within 24 h) and late, and into minor and major. RESULTS: Two hundred and fifty six patients were included in the study. The mean age was 77.7 ±â€¯11.8 Medical history included cardiac comorbidities (42.6%) and cerebrovascular accidents (34.4%). Overall, 48 patients (18.9%) had 60 complications, of which 70% (42/60) were minor (13 early; 29 late complications). Fifteen patients (5.9%) had major complications. Eight patients had early major complications (loss of airway - two patients [0.8%], pneumothorax - two patients [0.8%], resuscitation - one patient [0.4%], and a single patient (0.4%) died within 24 h following PDT). Two additional patients (0.8%) underwent conversion to an open tracheostomy. Seven patients had late complications (airway complications in six patients [2.3%] and major bleeding in a single patient [0.4%]). Of the seven patients with late major complications, three had two major complications. Half of the complications occurred by POD 3. CONCLUSION: GWB-PDT is a feasible and safe solution for tracheostomies in general-ward ventilated patients.

Feasibility of a single-stage tracheostomy decannulation protocol with endoscopy in adult patients.

OBJECTIVES/HYPOTHESIS: Gradual decrease in tube size and tube capping are considered the standard of care for tracheostomy decannulation. Both of these actions result in increased airway resistance. Immediate decannulation may offer a more tolerable approach. OBJECTIVE: To assess the feasibility of immediate tracheostomy decannulation compared with the traditional decannulation methods. METHODS: This study is a single institute, case-control retrospective study of patients between the years 2009 to 2014. The study group included all patients who underwent immediate decannulation, whereas the control group comprised patients who underwent traditional staged decannulation. An immediate decannulation protocol included admission to the intensive care unit, a comprehensive evaluation, decannulation, 24 hours of monitoring, and observation until discharge. RESULTS: Twenty-nine patients were included in the study group and 20 in the control group. No significant statistical difference was found between the two groups in the patients' medical history and tracheostomy data, except for the Acute Physiology and Chronic Health Evaluation II score and duration of the deflated cuff, which were significantly higher in the control group. A significant difference was found in the complication rate between the groups. In the staged decannulation group, four patients failed decannulation and required reinsertion of the tracheostomy cannula, whereas there were no such failures in the immediate decannulation group. Hospitalization duration after decannulation of the study group patients was significantly shorter than that of the control group. CONCLUSION: Immediate decannulation may offer a safe alternative for weaning from tracheostomy. It may also reduce the duration of the weaning process and hospitalization. LEVEL OF EVIDENCE: 3b Laryngoscope, 126:2057-2062, 2016.

Effect of physical therapy on muscle strength, respiratory muscles and functional parameters in patients with intensive care unit-acquired weakness.

OBJECTIVES: The aim of this study was to evaluate the effect of an intensive physical therapy protocol in patients who contract 'intensive care unit-acquired weakness' (ICUAW), in terms of muscle strength, breathing and functional indices. METHODS: This was a prospective, single-blinded study in a general hospital intensive care unit (ICU). Patients who required mechanical ventilation longer than 48 h and who were expected to remain mechanically ventilated for at least another 48 h were randomly divided into two intervention groups: group I (n = 9) - the routine care group, received physical therapy according to our daily custom protocol; and group II (n = 9) - the intensive treatment group, were treated by the same protocol twice a day. The main outcome measures included the Medical Research Council (MRC) physical strength examination, maximal inspiratory pressure (MIP), hand grip dynamometer and sitting balance test. RESULTS: Significant strength improvement from first (T1) to second (T2) measurements was demonstrated for variables MIP and MRC physical strength examination in favor of the intensive treatment group (P < 0.05). The intensive treatment group also required shorter intensive care length of stay than the routine care group (P = 0.043). CONCLUSIONS: It is possible that an intensive therapy protocol may facilitate the initial recovery process in patients who suffer from ICUAW.

Vipera aspis venom reduces lethality and down-regulates tumor necrosis factor-alpha in a rat model of LPS-induced sepsis.

OBJECTIVES: Sepsis and septic shock are major causes of morbidity and mortality in critically-ill patients. Sepsis constitutes the systemic response to infection, that is predominantly mediated by the pro-inflammatory cytokines TNF-alpha and IL-1beta. Hence, cytokine modulation provides a promising target for the treatment of sepsis. In this work we evaluated the effect of a low-dose Vipera aspis venom (VAV) vaccine on survival and cytokine serum levels in a rat model of lipopolysaccharide (LPS)-induced septic shock. METHODS: Adult male Wistar rats were given either VAV vaccine or saline, and 2 weeks later half of each group received LPS challenge, and were monitored for mortality, cytokine levels, blood count and chemistry. RESULTS: Survival rate was significantly higher in venom-treated, compared to non-vaccinated septic rats. Furthermore, VAV treatment significantly reduced LPS-associated TNF-alpha and LDH, without affecting IL-6 and IL-10 levels, and modified WBC and platelet counts. CONCLUSIONS: Our data suggest that sub-toxic doses of VAV have a protective effect against LPS-induced septic shock that may be mediated, at least partially, by the modulated TNF-alpha activity. This study thus offers a novel therapeutic approach for the attenuation of bacteremia-induced septic shock through the modulation of a central pro-inflammatory cytokine by VAV vaccination in mammals.