SARS-Cov-2 fulminant myocarditis: an autopsy and histopathological case study.

The coronavirus disease 2019 (COVID-19), due to SARS-CoV-2, is primarily a respiratory disease, causing in most severe cases life-threatening acute respiratory distress syndrome (ARDS). Cardiovascular involvement can also occur, such as thrombosis or myocarditis, generally associated with pulmonary lesions. Little is known about SARS-CoV-2-induced myocarditis. We report the case of a 69-year-old man suffering from a refractory cardiogenic shock, without significant lung involvement. Prior to death, several nasopharyngeal swabs and distal bronchoalveolar lavage were sampled in order to perform RT-PCR analyses for SARS-CoV-2-RNA, which all gave negative results. Autopsy showed coronary atherosclerosis, without acute complication. Microscopic examination of the heart revealed the existence of an intense multifocal inflammatory infiltration, in both ventricles and septum, composed in its majority of macrophages and CD8+ cytotoxic T lymphocytes (CD4/CD8 ratio: 0.11). Immunohistochemistry for anti-SARS nucleocapsid protein antibody was strongly positive in myocardial cells, but not in lung tissue. RT-PCR was realized on formalin-fixed paraffin-embedded lung and heart tissue blocks: only heart tissue was positive for SARS-CoV-2 RNA. In conclusion, this exhaustive post-mortem pathological case study of fulminant myocarditis demonstrates the presence of SARS-CoV-2 RNA in heart tissue, without significant lung involvement. Immunohistochemistry showed that the virus was specifically localized in cardiomyocytes and induced a strong cytotoxic T cells inflammatory response. This case report thus gives new insight in the pathogenesis of SARS-CoV-2-induced myocarditis and emphasizes on the importance and reliability of post-mortem analyses in order to better understand the physiopathology of this worldwide spreading new viral disease.

Profile of the risk of death after septic shock in the present era: an epidemiologic study.

OBJECTIVES: To investigate mortality of ICU patients over a 3-month period after an initial episode of septic shock and to identify factors associated with mortality. DESIGN: Prospective multicenter observational cohort study. SETTING: Fourteen ICUs from 10 French nonacademic and university teaching hospitals. PATIENTS: All consecutive adult patients with septic shock admitted between October 2009 and September 2011 were eligible. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Multivariable analyses were performed using a Cox proportional hazard model and a flexible extension of the Cox model. In total, 1,495 of 10,941 patients (13.7%) had septic shock and 1,488 patients (99.5%) were included. Median age was 68 years (range, 58-78 yr). The majority of admissions (84%) were medical. Median (interquartile range) Simplified Acute Physiological Score II and Sequential Organ Failure Assessment were, respectively, 56 (45-70) and 11 (9-14). ICU and hospital mortality were, respectively, 39.4% and 48.6%. At 3 months, 776 patients (52.2%) had died. Factors significantly associated with increased risk of death in the multivariable Cox model were older age, male sex, comorbidities (immune deficiency, cirrhosis), Knaus C/D score, and high Sequential Organ Failure Assessment score. Flexible analyses indicated that the impact of Sequential Organ Failure Assessment score was greatest early after septic shock, while the onset of the effect of age, nosocomial infection, and cirrhosis was later. CONCLUSIONS: This is the most recent large-scale epidemiological study to investigate medium-term mortality in nonselected patients hospitalized in the ICU for septic shock. Advances in early management have improved survival at the initial phase, but risk of death persists in the medium term. Flexible modeling techniques yield insights into the profile of the risk of death in the first 3 months.

Factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients.

INTRODUCTION: A rational use of antibiotics is of paramount importance in order to prevent the emergence of multidrug resistant bacteria that can lead to therapeutic impasse, especially in intensive care units (ICUs). A de-escalation strategy is therefore naturally advocated as part of better antibiotics usage. However, the clinical impact of such a strategy has not been widely studied. We aimed to assess the feasibility and the clinical impact of a de-escalation strategy in a medical ICU and to identify factors associated when de-escalation was possible. METHODS: We performed a retrospective study of patients hospitalized in a medical ICU over a period of six months. Independent factors associated with de-escalation and its clinical impact were assessed. RESULTS: Two hundred and twenty-nine patients were included in the study. Antibiotics were de-escalated in 117 patients (51%). The appropriateness of initial antibiotic therapy was the only independent factor associated with the performance of de-escalation (OR = 2.9, 95% CI, 1.5-5.7; P = 0.002). By contrast, inadequacy of initial antibiotic therapy (OR = 0.1, 0.0 to 0.1, P <0.001) and the presence of multidrug resistant bacteria (OR = 0.2, 0.1 to 0.7, P = 0.006) prevented from de-escalation. There were no differences in terms of short (ICU) or long-term (at 1 year) mortality rates or any secondary criteria such as ICU length of stay, duration of antibiotic therapy, mechanical ventilation, incidence of ICU-acquired infection, or multi-drug resistant bacteria emergence. CONCLUSIONS: De-escalation appears feasible in most cases without any obvious negative clinical impact in a medical ICU.

The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study.

INTRODUCTION: To provide up-to-date information on the prognostic factors associated with 28-day mortality in a cohort of septic shock patients in intensive care units (ICUs). METHODS: Prospective, multicenter, observational cohort study in ICUs from 14 French general (non-academic) and university teaching hospitals. All consecutive patients with septic shock admitted between November 2009 and March 2011 were eligible for inclusion. We prospectively recorded data regarding patient characteristics, infection, severity of illness, life support therapy, and discharge. RESULTS: Among 10,941 patients admitted to participating ICUs between October 2009 and September 2011, 1,495 (13.7%) patients presented inclusion criteria for septic shock and were included. Invasive mechanical ventilation was needed in 83.9% (n=1248), inotropes in 27.7% (n=412), continuous renal replacement therapy in 32.5% (n=484), and hemodialysis in 19.6% (n=291). Mortality at 28 days was 42% (n=625). Variables associated with time to mortality, right-censored at day 28: age (for each additional 10 years) (hazard ratio (HR)=1.29; 95% confidence interval (CI): 1.20-1.38), immunosuppression (HR=1.63; 95%CI: 1.37-1.96), Knaus class C/D score versus class A/B score (HR=1.36; 95%CI:1.14-1.62) and Sepsis-related Organ Failure Assessment (SOFA) score (HR=1.24 for each additional point; 95%CI: 1.21-1.27). Patients with septic shock and renal/urinary tract infection had a significantly longer time to mortality (HR=0.56; 95%CI: 0.42-0.75). CONCLUSION: Our observational data of consecutive patients from real-life practice confirm that septic shock is common and carries high mortality in general ICU populations. Our results are in contrast with the clinical trial setting, and could be useful for healthcare planning and clinical study design.

Combination biomarkers to diagnose sepsis in the critically ill patient.

RATIONALE: Although the outcome of sepsis benefits from the prompt administration of appropriate antibiotics on correct diagnosis, the assessment of infection in critically ill patients is often a challenge for clinicians. In this setting, simple biomarkers, especially when used in combination, could prove useful. OBJECTIVES: To determine the usefulness of combination biomarkers to diagnose sepsis. METHODS: Three hundred consecutive patients were enrolled to construct a biologic score that was next validated in an independent prospective cohort of 79 critically ill patients from another center. MEASUREMENT AND MAIN RESULTS: Plasma concentrations of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and procalcitonin (PCT) were assayed, and the expression of the high-affinity immunoglobulin-Fc fragment receptor I (FcγRI) CD64 on neutrophils (polymorphonuclear [PMN] CD64 index) in flow cytometry was measured. A "bioscore" combining these biomarkers was constructed. Serum concentrations of PCT and sTREM-1 and the PMN CD64 index were higher in patients with sepsis compared with all others (P < 0.001 for the three markers). These biomarkers were all independent predictors of infection, the best receiver-operating characteristic curve being obtained for the PMN CD64 index. The performance of the bioscore, better than that of each individual biomarker, was externally confirmed in the validation cohort. CONCLUSIONS: This prospective study, including inceptive and validation cohorts of unselected intensive care unit patients, demonstrates the high performance of a bioscore combining the PMN CD64 index together with PCT and sTREM-1 serum levels in diagnosing sepsis in the critically ill patient.

The relationship between CD4+CD25+CD127- regulatory T cells and inflammatory response and outcome during shock states.

INTRODUCTION: Although regulatory T lymphocytes (Tregs) have a pivotal role in preventing autoimmune diseases and limiting chronic inflammatory conditions, they may also block beneficial immune responses by preventing sterilizing immunity to certain pathogens. METHODS: To determine whether naturally occurring Treg cells have a role in inflammatory response and outcome during shock state we conducted an observational study in two adult ICUs from a university hospital. Within 12 hours of admission, peripheral whole blood was collected for the measurement of cytokines and determination of lymphocyte count. Sampling was repeated at day three, five and seven. Furthermore, an experimental septic shock was induced in adult Balb/c mice through caecal ligation and puncture. RESULTS: Forty-three patients suffering from shock (26 septic, 17 non septic), and 7 healthy volunteers were included. The percentage of Tregs increased as early as 3 days after the onset of shock, while their absolute number remained lower than in healthy volunteers. A similar pattern of Tregs kinetics was found in infected and non infected patients. Though there was an inverse correlation between severity scores and Tregs percentage, the time course of Tregs was similar between survivors and non survivors. No relation between Tregs and cytokine concentration was found. In septic mice, although there was a rapid increase in Treg cells subset among splenocytes, antibody-induced depletion of Tregs before the onset of sepsis did not alter survival. CONCLUSIONS: These data argue against a determinant role of Tregs in inflammatory response and outcome during shock states.

Physicochemical stability of an admixture of lidocaine and ketamine in polypropylene syringe used in opioid-free anaesthesia.

Objectives: Opioid-free anaesthesia is a treatment strategy of pain management based on the use of drugs such as lidocaine, ketamine and dexmedetomidine that do not interact significantly with opioid receptors. In particular, these drugs are used by anaesthesiologists to ensure adequate levels of analgesia during surgical procedures for burn patients such as daily wound dressings and graft surgeries. Furthermore, for hypothermia prevention and wound-healing purposes, ambient temperature must be kept high for these patients, usually between 27°C and 30°C. To facilitate the use of this technique, clinicians want to mix lidocaine and ketamine in the same syringe. No stability data is available to determine the feasibility of this admixture and at this temperature. The objective was to study the physicochemical stability of lidocaine 20 mg/mL with ketamine 2.5 mg/mL diluted with 0.9% sodium chloride (0.9% NaCl) stored at 28°C in polypropylene syringe for 48 hours. Methods: Physical stability was evaluated by visual examination and by measuring turbidity with a spectrophotometer. Chemical stability was determined after preparation and after 6, 24 and 48 hours of conservation with a high performance liquid chromatography and pH measurements. The method was validated according to International Conference on Harmonisation Q2(R1) guidelines. Results: Both lidocaine (99.98%±1.44%) and ketamine (100.70%±0.95%) retained more than 95% of their initial concentration after 48 hours storage. pH measurements remained stable over the course of the study (less than 0.21 point of variation). No signs of physical instability were observed after visual and subvisual inspections. Conclusions: The physicochemical stability of lidocaine 20 mg/mL and ketamine 2.5 mg/mL diluted with 0.9% NaCl in a polypropylene syringe stored at 28°C protected from light was demonstrated for 48 hours. This infusion technique is therefore feasible from a pharmaceutical point of view in burn-unit settings.

Management of severe thermal burns in the acute phase in adults and children.

OBJECTIVES: To provide recommendations to facilitate the management of severe thermal burns during the acute phase in adults and children. DESIGN: A committee of 20 experts was asked to produce recommendations in six fields of burn management, namely, (1) assessment, admission to specialised burns centres, and telemedicine; (2) haemodynamic management; (3) airway management and smoke inhalation; (4) anaesthesia and analgesia; (5) burn wound treatments; and (6) other treatments. At the start of the recommendation-formulation process, a formal conflict-of-interest policy was developed and enforced throughout the process. The entire process was conducted independently of any industry funding. The experts drew up a list of questions that were formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes). Two bibliography experts per field analysed the literature published from January 2000 onwards using predefined keywords according to PRISMA recommendations. The quality of data from the selected literature was assessed using GRADE® methodology. Due to the current paucity of sufficiently powered studies regarding hard outcomes (i.e. mortality), the recommendations are based on expert opinion. RESULTS: The SFAR guidelines panel generated 24 statements regarding the management of acute burn injuries in adults and children. After two scoring rounds and one amendment, strong agreement was reached for all recommendations. CONCLUSION: Substantial agreement was reached among a large cohort of experts regarding numerous strong recommendations to optimise the management of acute burn injuries in adults and children.

Metformin-associated lactic acidosis in an intensive care unit.

INTRODUCTION: Metformin-associated lactic acidosis (MALA) is a classic side effect of metformin and is known to be a severe disease with a high mortality rate. The treatment of MALA with dialysis is controversial and is the subject of many case reports in the literature. We aimed to assess the prevalence of MALA in a 16-bed, university-affiliated, intensive care unit (ICU), and the effect of dialysis on patient outcome. METHODS: Over a five-year period, we retrospectively identified all patients who were either admitted to the ICU with metformin as a usual medication, or who attempted suicide by metformin ingestion. Within this population, we selected patients presenting with lactic acidosis, thus defining MALA, and described their clinical and biological features. RESULTS: MALA accounted for 0.84% of all admissions during the study period (30 MALA admissions over five years) and was associated with a 30% mortality rate. The only factors associated with a fatal outcome were the reason for admission in the ICU and the initial prothrombin time. Although patients who went on to haemodialysis had higher illness severity scores, as compared with those who were not dialysed, the mortality rates were similar between the two groups (31.3% versus 28.6%). CONCLUSIONS: MALA can be encountered in the ICU several times a year and still remains a life-threatening condition. Treatment is restricted mostly to supportive measures, although haemodialysis may possess a protective effect.

High-mobility group box 1 protein plasma concentrations during septic shock.

OBJECTIVE: To investigate plasma high-mobility group box 1 protein (HMGB1) concentration and its relationship with organ dysfunction and outcome in septic shock patients. DESIGN AND SETTING: Prospective, noninterventional study. Medical adult intensive care unit at a university hospital in France. PATIENTS: 42 critically ill patients with septic shock. METHODS: Arterial blood was drawn within 12 h of admission for the measurement of plasma HMGB1 concentration by ELISA. Repeated sampling was performed on days 3, 7, and 14. RESULTS: Median HMGB1 concentration was 4.4 ng/ml (IQR 1.2-12.5) at admission, with no difference between survivors and nonsurvivors. A positive correlation was observed between HMGB1 and SOFA score and lactate, and procalcitonin concentrations. There was a progressive but statistically nonsignificant decline in HMGB1 concentration among the survivors, while nonsurvivors showed an increase in HMGB1 level between days 1 and 3. SOFA score and lactate and procalcitonin concentrations did not vary significantly between days 1 and 3. When measured on day 3, HMGB1 discriminated survivors from nonsurvivors with 66% sensitivity and 67% specificity, and concentration greater than 4 ng/ml was associated with an odds ratio of death of 5.5 (95% CI 1.3-23.6).

Growth arrest-specific protein 6 plasma concentrations during septic shock.

INTRODUCTION: The product of growth arrest-specific gene 6 (Gas6) is a vitamin K dependent protein that is secreted by leucocytes and endothelial cells in response to injury and participates in cell survival, proliferation, migration and adhesion. Our purpose was to investigate plasma Gas6 concentration and its relation to organ dysfunction in patients with septic shock. METHODS: Forty-five patients with septic shock admitted to a medical adult intensive care unit were enrolled. Plasma Gas6 concentration was determined using enzyme-linked immunosorbent assay at days 1, 3, 7 and 14. RESULTS: The median (interquartile range) Gas6 concentration was 51 (5 to 95) pg/ml at admission. A positive correlation (Spearman rank-order coefficient [rs] = 0.37, P = 0.01) was found between Gas6 level and Sepsis-related Organ Failure Assessment score. Patients requiring renal support had higher Gas6 concentration that those without need for haemofiltration (76.5 [52 to 164] pg/ml versus 10.5 [1.5 to 80.5] pg/ml; P = 0.04). Moreover, there was a positive correlation between Gas6 and aspartate transaminase (rs = 0.42, P = 0.006) and between Gas6 and prothrombin time (rs = 0.45, P = 0.02). Although there was a progressive decline in Gas6 concentration in survivors (analysis of variance, P = 0.01), nonsurvivors exhibited persistently elevated Gas6. However, the two populations diverged only after day 7 (P = 0.04). CONCLUSION: Plasma concentrations of Gas6 correlate with disease severity, especially with renal and hepatic dysfunction, in septic shock.

Randomized clinical trials with levosimendan.

There are important unmet needs in the treatment of acute heart failure syndromes (AHFS). The unique dual mechanism of action of levosimendan suggests that this new agent may help fill some of these unmet needs. A review of randomized, controlled clinical trials with levosimendan demonstrated that it is well tolerated, and its use results in significantly reduced pulmonary capillary wedge pressure (PCWP) and increased cardiac output. Effects of levosimendan on PCWP and cardiac output are more pronounced than those observed with dobutamine. Levosimendan treatment is also associated with significantly improved clinical symptoms. Moreover, data from 3 trials indicate that levosimendan treatment was associated with improved 6-month survival compared with dobutamine treatment or placebo. Emerging data suggest that levosimendan is beneficial for patients with acute myocardial ischemia. Thus, early clinical indicators suggest that levosimendan may help prevent myocardial injury during hospitalization for AHFS and may be well suited for first-line therapy for AHFS.

Host response biomarkers in sepsis: overview on sTREM-1 detection.

The diagnosis of sepsis, and especially its differentiation from sterile inflammation, may be challenging. TREM-1, the triggering receptor expressed on myeloid cells-1, is an amplifier of the innate immune response. Its soluble form acts as a decoy for the natural TREM-1 ligand and dampens its activation. In this chapter, we review the numerous studies that have evaluated the usefulness of sTREM-1 concentration determination for the diagnosis and the prognosis evaluation of sepsis or localized infection. Nowadays, sandwich ELISA kits are available and the assay is described.

Pharmacological inhibition of the triggering receptor expressed on myeloid cells-1 limits reperfusion injury in a porcine model of myocardial infarction.

AIMS: Limitation of ischemia/reperfusion injury is a major therapeutic target after acute myocardial infarction (AMI). Toll-like receptors are implicated in the inflammatory response that occurs during reperfusion. The triggering receptor expressed on myeloid cells (TREM)-1 acts as an amplifier of the immune response triggered by toll-like receptor engagement. We hypothesized that administration of a TREM-1 inhibitory peptide (LR12) could limit reperfusion injury in a porcine model of AMI. METHODS AND RESULTS: AMI was induced in 15 adult minipigs by a closed-chest coronary artery occlusion-reperfusion technique. Animals were randomized to receive LR12 or vehicle before reperfusion (LR12 n = 7, vehicle n = 8), and were monitored during 18 h. AMI altered hemodynamics and cardiac function, as illustrated by a drop of mean arterial pressure, cardiac index, cardiac power index, ejection fraction, and real-time pressure-volume loop-derived parameters. TREM-1 inhibition by LR12 significantly improved these dysfunctions (P < 0.03) and limited infarct size, as assessed by lower creatine phosphokinase and troponin I concentrations (P < 0.005). Pulmonary, renal, and hepatic impairments occurred after AMI and were attenuated by LR12 administration as assessed by a better PaO2 to FiO2 ratio, a less positive fluid balance, and lower liver enzymes levels (P < 0.05). CONCLUSION: Inhibition of the TREM-1 pathway by a synthetic peptide limited myocardial reperfusion injury in a clinically relevant porcine model of AMI.

Impact of the administration of probiotics on mortality in critically ill adult patients: a meta-analysis of randomized controlled trials.

BACKGROUND: The objective of this study was to systematically review and quantitatively synthesize all randomized controlled trials (RCTs) that have compared important outcomes in critically ill patients who received an administration of probiotics. METHODS: A systematic literature search of PubMed, Scopus, and the Cochrane Central Register of Controlled Trials was conducted using specific search terms. Eligible studies were RCTs that compared the effect of prebiotics, probiotics, or synbiotics administration with control on ICU and hospital mortality rates in critically ill adult patients. Weighted mean differences (WMDs), pooled ORs, and 95% CIs were calculated using the Mantel-Haenszel fixed- and random-effects models. RESULTS: Thirteen trials with 1,439 patients were analyzed. Probiotics did not significantly reduce ICU (OR, 0.85; 95% CI, 0.63-1.15) or hospital (OR, 0.90; 95% CI, 0.65-1.23) mortality. By contrast, probiotics administration reduced the incidence of ICU-acquired pneumonia (OR, 0.58; 95% CI, 0.42-0.79) and was associated with a shorter stay in the ICU (WMD, -1.49 days; 95% CI, -2.12 to -0.87 days). Finally, probiotics use was not associated with a shorter duration of mechanical ventilation (WMD, -0.18 days; 95% CI, -1.72-1.36 days) or a shorter hospital length of stay (WMD, -0.45 days; 95% CI, -1.41-0.52 days). CONCLUSIONS: The present meta-analysis suggests that the administration of probiotics did not significantly reduce ICU or hospital mortality rates but did reduce the incidence of ICU-acquired pneumonia and ICU length of stay.

Effects of a TREM-like transcript 1-derived peptide during hypodynamic septic shock in pigs.

The objective of this study was to determine the effects of a TREM (triggering receptor expressed on myeloid cells 1)-like transcript 1-derived peptide (LR12) administration during septic shock in pigs. Two hours after induction of a fecal peritonitis, anesthetized and mechanically ventilated adult male minipigs were randomized to receive LR12 (n = 6) or its vehicle alone (normal saline, n = 5). Two animals were operated and instrumented without the induction of peritonitis and served as controls (sham). Resuscitation was achieved using hydroxyethyl starch (up to 20 mL/kg) and norepinephrine infusion (up to 10 µg/kg per minute). Hemodynamic parameters were continuously recorded. Gas exchange, acid-base status, organ function, and plasma cytokines concentrations were evaluated at regular intervals until 24 h after the onset of peritonitis when animals were killed under anesthesia. Peritonitis induced profound hypotension, myocardial dysfunction, lactic acidosis, coagulation abnormalities, and multiple organ failure. These disorders were largely attenuated by LR12. In particular, cardiovascular failure was dampened as attested by a better mean arterial pressure, cardiac index, cardiac power index, and S(v)O(2), despite lower norepinephrine requirements. LR12, a TREM-like transcript 1-derived peptide, exhibits salutary properties during septic shock in adult minipigs.

Triggering receptor expressed on myeloid cell 1.

Sepsis is a common cause of morbidity and mortality in intensive care units. There is no gold standard for diagnosing sepsis because clinical and laboratory signs are neither sensitive nor specific enough and microbiological studies often show negative results. The triggering receptor expressed on myeloid cell 1 (TREM-1) is a member of the immunoglobulin superfamily. Its expression is upregulated on phagocytic cells in the presence of bacteria or fungi. This article reports on the potential usefulness of the assessment of the soluble form of TREM-1 in biologic fluids in the diagnosis of infection.