Divergence Of The Response Induced By Xenogenic Immunization In The Sepsis Survival Of Rats

We have previously described that boosted natural xenoantibodies in rats cross-react to bacteria by targeting carbohydrate antigens. This type of immunization is associated with reduced survival after cecal ligation and puncture (CLP). In the present study, we investigated further this phenomenon by immunizing Lewis rats with three intraperitoneal injections, every other day, of hamster blood compared to saline-injected control animals. One day after the last injection, CLP was performed to produce a low-grade sepsis. Induction of xenoantibodies was associated with a reduction in animal survival after CLP relative to controls (45% vs. 90%, p<0.01). No bacterial blood load was observed after CLP in this model either with or without xenoantibody enhancement, indicating that the augmented mortality was not mediated by a direct effect of boosted xenoantibodies over blood bacteria. Nevertheless, the xenoimmunization produced a systemic inflammatory response in all rats. Additionally, a lack of weight gain at the time of CLP was present in animals that died after the procedure, which was not observed in surviving rats and controls. The cytokine profile at the time of CLP in animals that died after the procedure was characterized by an increase in the serum level of several cytokines, particularly adipokines. In contrast, the cytokine profile at CLP of xenoimmunized rats that survived the procedure was characterized by a reduction in the level of cytokines. In conclusion, this study failed to show a direct effect of boosted xenoantibodies over blood bacterial isolates as cause for the decreased survival after CLP. However, it evidenced that non-infectious systemic inflammation may lead to a pattern of augmented cytokines, particularly adipokines, which impairs survival after subsequent CLP. Therefore, the profile of cytokines existing before the infectious insult appears more crucial than that resulting from the condition for the outcome of sepsis

Repertoire Of Balb/c Mice Natural Anti-carbohydrate Antibodies: Mice Vs. Humans Difference, And Otherness Of Individual Animals

One of the most common genetic backgrounds for mice used as a model to investigate human diseases is the inbred BALB/c strain. This work is aimed to characterize the pattern of natural anti-carbohydrate antibodies present in the serum of 20 BALB/c mice by printed glycan array technology and to compare their binding specificities with that of human natural anti-carbohydrate antibodies. Natural antibodies (NAbs) from the serum of BALB/c mice interacted with 71 glycans from a library of 419 different carbohydrate structures. However, only seven of these glycans were recognized by the serum of all the animals studied, and other five glycans by at least 80% of mice. The pattern of the 12 glycans mostly recognized by the circulating antibodies of BALB/c mice differed significantly from that observed with natural anti-carbohydrate antibodies in humans. This lack of identical repertoires of natural anti-carbohydrate antibodies between individual inbred mice, and between mice and humans, should be taken into consideration when mouse models are intended to be used for investigation of NAbs in biomedical research

A randomized clinical trial for the timing of tracheotomy in critically ill patients: factors precluding inclusion in a single center study

Introduction: We investigated the potential benefits of early tracheotomy performed before day eight of mechanical ventilation (MV) compared with late tracheotomy (from day 14 if it still indicated) in reducing mortality, days of MV, days of sedation and ICU length of stay (LOS). Methods: Randomized controlled trial (RCT) including all-consecutive ICU admitted patients requiring seven or more days of MV. Between days five to seven of MV, before randomization, the attending physician (AP) was consulted about the expected duration of MV and acceptance of tracheotomy according to randomization. Only accepted patients received tracheotomy as result of randomization. An intention to treat analysis was performed including patients accepted for the AP and those rejected without exclusion criteria. Results: A total of 489 patients were included in the RCT. Of 245 patients randomized to the early group, the procedure was performed for 167 patients (68.2%) whereas in the 244 patients randomized to the late group was performed for 135 patients (55.3%) (P <0.004). Mortality at day 90 was similar in both groups (25.7% versus 29.9%), but duration of sedation was shorter in the early tracheotomy group median 11 days (range 2 to 92) days compared to 14 days (range 0 to 79) in the late group (P <0.02). The AP accepted the protocol of randomization in 205 cases (42%), 101 were included in early group and 104 in the late group. In these subgroup of patients (per-protocol analysis) no differences existed in mortality at day 90 between the two groups, but the early group had more ventilator-free days, less duration of sedation and less LOS, than the late group. Conclusions: This study shows that early tracheotomy reduces the days of sedation in patients undergoing MV, but was underpowered to prove any other benefit. In those patients selected by their attending physicians as potential candidates for a tracheotomy, an early procedure can lessen the days of MV, the days of sedation and LOS. However, the imprecision of physicians to select patients who will require prolonged MV challenges the potential benefits of early tracheotomy

Impact of non-neurological complications in severe traumatic brain injury outcome

Introduction: Non-neurological complications in patients with severe traumatic brain injury (TBI) are frequent, worsening the prognosis, but the pathophysiology of systemic complications after TBI is unclear. The purpose of this study was to analyze non-neurological complications in patients with severe TBI admitted to the ICU, the impact of these complications on mortality, and their possible correlation with TBI severity. Methods: An observational retrospective cohort study was conducted in one multidisciplinary ICU of a university hospital (35 beds); 224 consecutive adult patients with severe TBI (initial Glasgow Coma Scale (GCS) < 9) admitted to the ICU were included. Neurological and non-neurological variables were recorded. Results: Sepsis occurred in 75% of patients, respiratory infections in 68%, hypotension in 44%, severe respiratory failure (arterial oxygen pressure/oxygen inspired fraction ratio (PaO2/FiO(2)) < 200) in 41% and acute kidney injury (AKI) in 8%. The multivariate analysis showed that Glasgow Outcome Score (GOS) at one year was independently associated with age, initial GCS 3 to 5, worst Traumatic Coma Data Bank (TCDB) first computed tomography (CT) scan and the presence of intracranial hypertension but not AKI. Hospital mortality was independently associated with initial GSC 3 to 5, worst TCDB first CT scan, the presence of intracranial hypertension and AKI. The presence of AKI regardless of GCS multiplied risk of death 6.17 times (95% confidence interval (CI): 1.37 to 27.78) (P < 0.02), while ICU hypotension increased the risk of death in patients with initial scores of 3 to 5 on the GCS 4.28 times (95% CI: 1.22 to15.07) (P < 0.05). Conclusions: Low initial GCS, worst first CT scan, intracranial hypertension and AKI determined hospital mortality in severe TBI patients. Besides the direct effect of low GCS on mortality, this neurological condition also is associated with ICU hypotension which increases hospital mortality among patients with severe TBI. These findings add to previous studies that showed that non-neurological complications increase the length of stay and morbidity in the ICU but do not increase mortality, with the exception of AKI and hypotension in low GCS (3 to 5)

Invasive Pulmonary Aspergillosis with Disseminated Infection in Immunocompetent Patient

Invasive pulmonary aspergillosis (IPA) is a rare pathology with increasing incidence mainly in critical care settings and recently in immunocompetent patients. The mortality of the disease is very high, regardless of an early diagnosis and aggressive treatment. Here, we report a case of a 56 yr old previously healthy woman who was found unconscious at home and admitted to the emergency room with mild respiratory insufficiency. In the first 24 hours she developed an acute respiratory failure with new radiographic infiltrates requiring Intensive Care Unit admission. A severe obstructive pattern with impossibility of ventilation because of bilateral atelectasis was observed, requiring emergent venovenous extracorporeal membrane oxygenator device insertion. Bronchoscopy revealed occlusion of main bronchi, demonstrating by biopsy an invasive infection by Aspergillus fumigatus and A. flavus. Despite an aggressive treatment and vital support the patient had a fatal outcome. The forensic study confirms the diagnosis of IPA but also revealed the presence of disseminated aspergillosis

Influence of acute kidney injury on short- and long-term outcomes in patients undergoing cardiac surgery: risk factors and prognostic value of a modified RIFLE classification

Introduction: The development of acute kidney injury (AKI) is associated with poor outcome. The modified RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal failure) classification for AKI, which classifies patients with renal replacement therapy needs according to RIFLE failure class, improves the predictive value of AKI in patients undergoing cardiac surgery. Our aim was to assess risk factors for post-operative AKI and the impact of renal function on short- and long-term survival among all AKI subgroups using the modified RIFLE classification. Methods: We prospectively studied 2,940 consecutive cardiosurgical patients between January 2004 and July 2009. AKI was defined according to the modified RIFLE system. Pre-operative, operative and post-operative variables usually measured on and during admission, which included main outcomes, were recorded together with cardiac surgery scores and ICU scores. These data were evaluated for association with AKI and staging in the different RIFLE groups by means of multivariable analyses. Survival was analyzed via Kaplan-Meier and a risk-adjusted Cox proportional hazards regression model. A complete follow-up (mean 6.9 ± 4.3 years) was performed in 2,840 patients up to April 2013. Results: Of those patients studied, 14% (n = 409) were diagnosed with AKI. We identified one intra-operative (higher cardiopulmonary bypass time) and two post-operative (a longer need for vasoactive drugs and higher arterial lactate 24 hours after admission) predictors of AKI. The worst outcomes, including in-hospital mortality, were associated with the worst RIFLE class. Kaplan-Meier analysis showed survival of 74.9% in the RIFLE risk group, 42.9% in the RIFLE injury group and 22.3% in the RIFLE failure group (P <0.001). Classification at RIFLE injury (Hazard ratio (HR) = 2.347, 95% confidence interval (CI) 1.122 to 4.907, P = 0.023) and RIFLE failure (HR = 3.093, 95% CI 1.460 to 6.550, P = 0.003) were independent predictors for long-term patient mortality. Conclusions: AKI development after cardiac surgery is associated mainly with post-operative variables, which ultimately could lead to a worst RIFLE class. Staging at the RIFLE injury and RIFLE failure class is associated with higher short- and long-term mortality in our population

The Influence of Body Mass Index on Outcomes in Patients Undergoing Cardiac Surgery: Does the Obesity Paradox Really Exist?

Purpose: Obesity influences risk stratification in cardiac surgery in everyday practice. However, some studies have reported better outcomes in patients with a high body mass index (BMI): this is known as the obesity paradox. The aim of this study was to quantify the effect of diverse degrees of high BMI on clinical outcomes after cardiac surgery, and to assess the existence of an obesity paradox in our patients. Methods: A total of 2,499 consecutive patients requiring all types of cardiac surgery with cardiopulmonary bypass between January 2004 and February 2009 were prospectively studied at our institution. Patients were divided into four groups based on BMI: normal weight (18.524.9 kg∙m−2; n = 523; 21.4%), overweight (2529.9kg∙m−2; n = 1150; 47%), obese (≥30≤34.9kg∙m−2; n = 624; 25.5%) and morbidly obese (≥35kg∙m−2; n = 152; 6.2%). Follow-up was performed in 2,379 patients during the first year. Results: After adjusting for confounding factors, patients with higher BMI presented worse oxygenation and better nutritional status, reflected by lower PaO2/FiO2 at 24h and higher albumin levels 48h after admission respectively. Obese patients showed a higher risk for Perioperative Myocardial Infarction (OR: 1.768; 95% CI: 1.0353.022; p = 0.037) and septicaemia (OR: 1.489; 95% CI: 1.2821.997; p = 0.005). In-hospital mortality was 4.8% (n = 118) and 1-year mortality was 10.1% (n = 252). No differences were found regarding in-hospital mortality between BMI groups. The overweight group showed better 1-year survival than normal weight patients (91.2% vs. 87.6%; Log Rank: p = 0.029. HR: 1.496; 95% CI: 1.0622.108; p = 0.021). Conclusions: In our population, obesity increases Perioperative Myocardial Infarction and septicaemia after cardiac surgery, but does not influence in-hospital mortality. Although we found better 1-year survival in overweight patients, our results do not support any protective effect of obesity in patients undergoing cardiac surgery

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves

Background: The two common sialic acids (Sias) in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients. Methods: We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG. Results: Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia linkages revealed Siaa2-3> Siaa2-6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaa2-3> Siaa2-6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express 4-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at 6-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3 +/- 16.9 pmol Sia/mu g protein), with Neu5Ac at 8-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity toward Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts. Conclusions: We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation

A Phase I/II Clinical Trial to evaluate the efficacy of baricitinib to prevent respiratory insufficiency progression in onco-hematological patients affected with COVID19: a structured summary of a study protocol for a randomised controlled trial

Objectives: Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the incidence of severe adverse events associated with baricitinib administration. The primary objective of the randomized phase (baricitinib cohort versus standard of care cohort) is to evaluate the number of patients who did not require mechanical oxygen support since start of therapy until day +14 or discharge (whichever it comes first). The secondary objectives of the study (only randomized phase of the study) are represented by the comparison between the two arms of the study in terms of mortality and toxicity at day+30. Moreover, a description of the immunological related changes between the two arms of the study will be reported. Trial design: The trial is a phase I/II study with a safety run-in cohort (phase 1) followed by an open label phase II randomized controlled trial with an experimental arm compared to a standard of care arm

Non-invasive oxygenation support in acutely hypoxemic COVID-19 patients admitted to the ICU: a multicenter observational retrospective study

Background: Non-invasive oxygenation strategies have a prominent role in the treatment of acute hypoxemic respiratory failure during the coronavirus disease 2019 (COVID-19). While the efcacy of these therapies has been studied in hospitalized patients with COVID-19, the clinical outcomes associated with oxygen masks, high-fow oxy‑ gen therapy by nasal cannula and non-invasive mechanical ventilation in critically ill intensive care unit (ICU) patients remain unclear. Methods: In this retrospective study, we used the best of nine covariate balancing algorithms on all baseline covari‑ ates in critically ill COVID-19 patients supported with>10 L of supplemental oxygen at one of the 26 participating ICUs in Catalonia, Spain, between March 14 and April 15, 2020. Results: Of the 1093 non-invasively oxygenated patients at ICU admission treated with one of the three stand-alone non-invasive oxygenation strategies, 897 (82%) required endotracheal intubation and 310 (28%) died during the ICU stay. High-fow oxygen therapy by nasal cannula (n=439) and non-invasive mechanical ventilation (n=101) were associated with a lower rate of endotracheal intubation (70% and 88%, respectively) than oxygen masks (n=553 and 91% intubated), p<0.001. Compared to oxygen masks, high-fow oxygen therapy by nasal cannula was associated with lower ICU mortality (hazard ratio 0.75 [95% CI 0.58-0.98), and the hazard ratio for ICU mortality was 1.21 [95% CI 0.80-1.83] for non-invasive mechanical ventilation. Conclusion: In critically ill COVID-19 ICU patients and, in the absence of conclusive data, high-fow oxygen therapy by nasal cannula may be the approach of choice as the primary non-invasive oxygenation support strateg