Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

SCAI stage reclassification at 24 h predicts outcome of cardiogenic shock: Insights from the Altshock-2 registry.

BACKGROUND: Cardiogenic shock (CS) includes several phenotypes with heterogenous hemodynamic features. Timely prognostication is warranted to identify patients requiring treatment escalation. We explored the association of the updated Society for Cardiovascular Angiography and Interventions (SCAI) stages classification with in-hospital mortality using a prospective national registry. METHODS: Between March 2020 and February 2022 the Altshock-2 Registry has included 237 patients with CS of all etiologies at 11 Italian Centers. Patients were classified according to their admission SCAI stage (assigned prospectively and independently updated according to the recently released version). In-hospital mortality was evaluated for association with both admission and 24-h SCAI stages. RESULTS: The overall in-hospital mortality was 38%. Of the 237 patients included and staged according to the updated SCAI classification, 20 (8%) had SCAI shock stage B, 131 (55%) SCAI stage C, 61 (26%) SCAI stage D and 25 (11%) SCAI stage E. In-hospital mortality stratified according to the SCAI classification at 24 h was 18% for patients in SCAI stage B, 27% for SCAI stage C, 63% for SCAI stage D and 100% for SCAI stage E. Both the revised SCAI stages on admission and at 24 h were associated with in-hospital mortality, but the classification potential slightly increased at 24-h. After adjusting for age, sex, lactate level, eGFR, CVP, inotropic score and mechanical circulatory support [MCS], SCAI classification at 24 h was an independent predictor of in-hospital mortality. CONCLUSIONS: In the Altshock-2 registry the utility of SCAI shock stages to identify risk of in-hospital mortality increased at 24 h after admission. Escalation of treatment (either pharmacological or with MCS) should be tailored to achieve prompt clinical improvement within the first 24 h after admission. Registration: http://www. CLINICALTRIALS: gov; Unique identifier: NCT04295252.

Ethylene glycol poisoning requiring veno-arterial ECMO: A case report.

Supportive care is the cornerstone of the poisoned patient's treatment, waiting for eventual antidotes to act. We recently treated a case of a severe Ethylene Glycol intoxication with early-onset veno-arterial ECMO. The patient was taken to our Emergency Department with the suspicion of acute cerebrovascular accident, since he was found unconscious at home. The arterial blood gas and blood tests showed a severe metabolic acidosis with high serum lactates and creatinine levels. The cerebral Computed Tomography was negative. The rapid increase in serum lactates suggested Ethylene Glycol intoxication. Although the patient was not in shock yet, arterial and venous introducers were placed in to the femoral vessels so that when the patient showed the first signs of cardiogenic shock, veno-arterial ECMO could be initiated in a very short time. The hemodynamic state progressively improved and V-A ECMO was removed after 16 h of support with complete recovery.

Right ventricular time intervals - Comparison between pulsed wave Doppler and tissue Doppler imaging.

BACKGROUND: Cardiac time intervals are used as indices of systolic and diastolic function. Echocardiographic assessment of these intervals is based on either pulsed wave Doppler (PWD) or tissue Doppler imaging (TDI). We investigated the agreement between the two techniques in the evaluation of right ventricular (RV) time intervals in healthy adults. METHODS: In 123 healthy volunteers we used both PWD and TDI to assess RV time intervals (filling time - RVFT, ejection time - RVET), heart rate-corrected intervals (total filling time - t-FT, total ejection time - t-ET) and RV performance indices (total isovolumic time - t-IVT, myocardial performance index - MPI). Intraclass correlation coefficient (ICC) and Pearson analysis (r coefficient) were used to evaluate the agreement and correlation between the two techniques. RESULTS: PWD and TDI had excellent agreement and correlation in measuring RVFT (ICC 0.94 [95% CI 0.85 - 0.97], r 0.91) whereas a good agreement was found for RVET (ICC 0.63[95% CI - 0.14 - 0.84]; r 0.68). Good agreement and strong correlation were found for both t-FT (ICC 0.67 [95% CI 0.36 - 0.82]; r 0.59) and t-ET (ICC 0.71 [95% CI - 0.06-0.88]; r 0.74). The two methods had lower agreement in assessing RV t-IVT (ICC 0.52 [95% CI 0.3187-0.6622]; r 0.57) and MPI (ICC 0.36 [95% CI - 0.05-0.43]; r 0.50). CONCLUSION: In healthy adults, PWD and TDI are interchangeable in measuring RVFT, RVET, RV t-FT and RV t-ET. Lower agreement between the two techniques was found for RV t-IVT and MPI.

Cardiogenic shock diagnosis and management in general intensive care: a nationwide survey.

BACKGROUND: the epidemiology of cardiogenic shock has evolved over the years: in the last decades an increasing prevalence of cardiogenic shock related to acute decompensated heart failure was observed. Therefore, treatment bundles should be updated according to the underlying pathophysiology. No data exist regarding the diagnostic/therapeutic strategies in general intensive care units. METHODS: A 27-questions survey was spread through the GiViTi (Italian Group for the Evaluation of Interventions in Intensive Care Medicine). The results were then divided according to level of hospitals (1st-2nd versus 3rd). RESULTS: Sixty-nine general intensive care units replied to the survey. The shock team is present in 13% of institutions; Society for Cardiovascular Angiography and Interventions shock classification is applied only in 18.8%. Among the ICUs, 94.2% routinely use a cardiac output monitoring device (pulmonary artery catheter more frequently in 3rd level centers). The first-line adrenergic drug are vasopressors in 27.5%, inotrope in 21.7% or their combination in 50.7%; 79.7% applies fluid challenge. The first vasopressor of choice is norepinephrine (95.7%) (maximum dosage tolerated higher than 0.5 mcg/kg/min in 29%); the first line inotrope is dobutamine (52.2%), followed by epinephrine in 36.2%. The most frequently used mechanical circulatory supports are intra-aortic balloon pump (71%), Impella (34.8%) and VA-ECMO (33.3%); VA-ECMO is the first line strategy in refractory cardiogenic shock (60.8%). CONCLUSIONS: According to this survey, there is no standardized approach to cardiogenic shock amongst Italian general intensive care units. The application of shock severity stratification and the treatment bundles may play a key role in improving the outcome.

Echocardiographic assessment of right ventricular performance in COVID-19 related acute respiratory distress syndrome: the importance of systo-diastolic interaction.

BACKGROUND: The cardiac manifestations of COVID-19 have been described in patients with acute respiratory distress syndrome (ARDS) admitted to intensive care unit (ICU). The presence and impact of right ventricular (RV) diastolic function and performance has not been studied in this population yet. We describe the prevalence of RV diastolic dysfunction, assessed by the pulmonary valve pre-ejection A wave (PV A wave), and the RV systo-diastolic interaction, using the RV total isovolumic time (t-IVT), in COVID-19 ARDS. RESULTS: Prospective observational study enrolling patients with moderate to severe COVID-19 ARDS admitted to ICU who underwent a transthoracic echocardiogram within 24 h of ICU admission and at least a second one during the ICU stay. Respiratory, hemodynamic and biochemistry parameters were collected. 163 patients (age 61.0 ± 9.3 years, 72% males) were enrolled. 36 patients (22.1%) had RV dysfunction, 45 (27.1%) LV systolic dysfunction. 73 patients (44.7%) had PV A wave. The RV t-IVT correlated with TAPSE at ICU admission (p < 0.002; r - 0.61), presence of PV A wave (p < 0.001; r 0.78), peak inspiratory pressure (PIP) (p < 0.001; r 0.42), PEEP (p < 0.001; r 0.68), dynamic driving pressure (DDP) (p < 0.001; r 0.58), and PaO2/FiO2 ratio (p < 0.01; r - 0.35). The presence of PV A wave was associated with higher PIP (p < 0.001; r 0.45), higher PEEP (p < 0.001; r 0.56), higher DDP (p < 0.01, r 0.51), and lower PaO2/FiO2 ratio (p < 0.001; r - 0.49). CONCLUSIONS: RV t-IVT and the presence of PV A wave are non-invasive means to describe a significant RV diastolic dysfunction and may be consider descriptive signs of RV performance in COVID-19 ARDS.

Endogenous Catecholamine Release in COVID-19 Related Acute Respiratory Distress Syndrome: Link between Enhanced Sympathetic Stimulation, Cardiac Dysfunction and Outcome.

The aim of this study was to measure the serum levels of catecholamines in patients admitted to intensive care unit (ICU) with COVID-19-related acute respiratory distress syndrome (ARDS) and describe their relation with clinical, inflammatory and echocardiographic parameters. Serum levels of endogenous catecholamines (norepinephrine, epinephrine and dopamine) were measured at ICU admission. We enrolled 71 patients consecutively admitted to ICU due to moderate to severe ARDS. 11 patients (15.5%) died during the admission in ICU. Serum levels of endogenous catecholamines were significantly elevated. Norepinephrine levels were higher in those with RV and LV systolic dysfunction, higher CRP, and higher IL-6. Patients with higher mortality rate were those with norepinephrine values ≥ 3124 ng/mL, CRP ≥ 17.2 mg/dL and IL-6 ≥ 102 pg/mL. Univariable analysis by Cox proportional hazards regression modelling showed that norepinephrine, IL-6 and CRP had the highest risk of acute mortality. Multivariable analysis showed that only norepinephrine and IL-6 retained in the model. Marked increase of serum catecholamine levels is present during acute phase of critically ill COVID-19 and it is associated with inflammatory and clinical parameters.

Safety and Effectiveness of Veno-Venous Extracorporeal Membrane Oxygenation Combined With Continuous Renal Replacement Therapy.

Patients receiving extracorporeal membrane oxygenation (ECMO) often suffer from acute kidney injury (AKI), requiring continuous renal replacement therapy (CRRT). In our clinical practice, we connected the inlet line of a CRRT machine to the postoxygenator Luer port and the outlet line to the inlet Luer port of the oxygenator. In this case series, we analyzed the interaction between the two machines. Between December 31, 2017, and December 31, 2019, we enrolled 15 patients from the ICU of the San Matteo Hospital, Pavia, Italy. All of them suffered from severe acute respiratory distress syndrome and AKI stage 3. We analyzed 570 hours of CRRT combined with venovenous ECMO and collected 261,751 CRRT data. No discontinuation of CRRT occurred before 48 hours. Most of the alarms occurred within 24 hours of the connection: 22/10,831 (0.2%) showed an outranged inlet pressure, 11/10831 (0.11%) showed an outranged transmembrane pressure, 14/10,831 (0.13%) showed an outranged inlet pressure, and 138/10,831 (1.27%) an outranged effluent pressure. The rate per minute set for the ECMO circuit was correlated with the inlet (ß = 5.38; CI, 95% 1.42-9.35; p = 0.008), transmembrane (ß = 4.6; CI, 95% 1.97-7.24; p = 0.001), effluent (ß = 3.02; CI, 95% 1.15-4.90; p = 0.002), and outlet pressures (ß = 597; CI, 95% 2.31-9.63; p = 0.001) of the CRRT circuit. We reported that our configuration could be safe and effective, however well-designed studies would be beneficial for determining the potential risks and benefits.

Differences between cardiogenic shock related to acute decompensated heart failure and acute myocardial infarction.

AIMS: The present analysis from the multicentre prospective Altshock-2 registry aims to better define clinical features, in-hospital course, and management of cardiogenic shock complicating acutely decompensated heart failure (ADHF-CS) as compared with that complicating acute myocardial infarction (AMI-CS). METHODS AND RESULTS: All patients with AMI-CS or ADHF-CS enrolled in the Altshock-2 registry between March 2020 and February 2022 were selected. The primary objective was the characterization of ADHF-CS patients as compared with AMI-CS. In-hospital length of stay and mortality were secondary endpoints. One-hundred-ninety of the 238 CS patients enrolled in the aforementioned period were considered for the present analysis: 101 AMI-CS (80% ST-elevated myocardial infarction and 20% non-ST-elevated myocardial infarction) and 89 ADHF-CS. As compared with AMI-CS, ADHF-CS patients were younger [63 (IQR 59-76) vs. 67 (IQR 54-73) years, P = 0.01], but presented with higher creatinine [1.6 (IQR 1.0-2.6) vs. 1.2 (IQR 1.0-1.4) mg/dL, P < 0.001], bilirubin [1.3 (IQR 0.9-2.3) vs. 0.6 (IQR 0.4-1.1) mg/dL, P = 0.01], and central venous pressure values [14 mmHg (IQR 8-12) vs. 10 mmHg (IQR 7-14),P = 0.01]. Norepinephrine was the most common catecholamine used in AMI-CS (79.3%), whereas epinephrine was used more commonly in ADHF-CS (65.5%); 75.8% vs. 46.6% received a temporary mechanical support in AMI-CS and ADHF-CS, respectively (P < 0.001). Length of hospital stay was longer in the latter [28 (IQR 13-48) vs. 17 (IQR 9-29) days, P = 0.001]. Heart replacement therapies were more frequently used in the ADHF-CS group (heart transplantation 13.5% vs. 0% and left ventricular assist device 11% vs. 2%, P < 0.01 and 0.01, respectively). In-hospital mortality was 41.1% (38.6% AMI-CS vs. 43.8% ADHF-CS, P = 0.5). CONCLUSIONS: ADHF-CS is characterized by a higher prevalence of end-organ and biventricular dysfunction at presentation, a longer hospital length of stay, and higher need of heart replacement therapies when compared with AMI-CS. In-hospital mortality was similar between the two aetiologies. Our data warrant development of new management protocols focused on CS aetiology.

Pulmonary artery acceleration time accuracy for systolic pulmonary artery pressure estimation in critically ill patients.

BACKGROUND: Estimation of pulmonary pressures is of key importance in acute cardiovascular and respiratory failure. Pulmonary artery acceleration time (PAAT) has emerged as reliable parameter for the estimation of systolic pulmonary artery pressure (sPAP) in cardiological population with preserved right ventricular function. We sought to find whether PAAT correlates with sPAP in critically ill patients with and without right ventricular (RV) systolic dysfunction. METHODS: Observational study. We measured sPAP using continuous-wave Doppler analysis of tricuspid regurgitation velocity peak method and we assessed the validity of PAAT in estimating sPAP in patients admitted to adult intensive care unit (ICU) for acute cardiovascular and respiratory failure. RESULTS: We enrolled 236 patients admitted to cardiothoracic ICU for cardiovascular and respiratory failure (respectively: 129, 54.7% and 107, 45.3%). 114 (48.3%) had preserved RV systolic function (defined as TAPSE ≥ 17 mm), whilst 122 (51.7%) had RV systolic impairment (defined as TAPSE < 17 mm). A weak inverse correlation between PAAT and sPAP (ρ-0.189, p 0.0035) was observed in overall population, which was confirmed in those with preserved RV systolic PAAT and sPAP (ρ-0.361, p 0.0001). In patients with impaired RV systolic function no statistically significant correlation between PAAT and sPAP was demonstrated (p 0.2737). Adjusting PAAT values for log10, heart rate and RV ejection time did not modify the abovementioned correlations. CONCLUSIONS: PAAT measurement to derive sPAP is not reliable in cardiothoracic critically ill patients, particularly in the coexistence of RV systolic impairment.

Heart rate control and haemodynamic improvement with ivabradine in cardiogenic shock patient on mechanical circulatory support.

AIMS: Cardiogenic shock (CS) is a life-threatening condition due to primary cardiac dysfunction. First-line therapy involves drug administration (including inotropes and/or vasopressors) up to mechanical circulatory support. Tachycardia is a frequent compensatory mechanism in response to hypotension and low cardiac output or a side effect related to inotropic drugs. Ivabradine selectively acts on the IKf channel in the sinoatrial node to reduce sinus heart rate without affecting inotropism. Its use, in small non-randomized series of patients with CS without mechanical circulatory support, was safe and well tolerated. METHODS AND RESULTS: We present the use of ivabradine in six patients with CS undertaking veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and a matched cohort of selected patients with similar features who did not receive ivabradine. Data regarding haemodynamic and echocardiographic monitoring, oxygenation, renal function, mechanical circulatory support, inotropes, and vasopressors doses were collected before (t0), at 12 (t1), 24 (t2), and 48 (t3) h after ivabradine administration. Ivabradine administration led to a significant heart rate reduction of 20.83 [95% confidence interval (CI) -27.2 to -14.4] b.p.m. (<0.01). Echo-derived left ventricular native stroke volume (SV) significantly increased by +7.83 (95% CI 4.74-10.93) mL (P < 0.001) with a parallel reduction of VA-ECMO support [-170 (95% CI -225.05 to -114.95)]. Noradrenaline was down-titrated over the observation period in all patients (P = 0.016). CONCLUSION: A significant reduction in heart rate was observed after ivabradine administration. This was associated with a native ventricular SV improvement allowing the reduction of extracorporeal flow support and vasopressors administration.

Mechanical circulatory support in ventricular arrhythmias.

In atrial and ventricular tachyarrhythmias, reduced time for ventricular filling and loss of atrial contribution lead to a significant reduction in cardiac output, resulting in cardiogenic shock. This may also occur during catheter ablation in 11% of overall procedures and is associated with increased mortality. Managing cardiogenic shock and (supra) ventricular arrhythmias is particularly challenging. Inotropic support may exacerbate tachyarrhythmias or accelerate heart rate; antiarrhythmic drugs often come with negative inotropic effects, and electrical reconversions may risk worsening circulatory failure or even cardiac arrest. The drop in native cardiac output during an arrhythmic storm can be partly covered by the insertion of percutaneous mechanical circulatory support (MCS) devices guaranteeing end-organ perfusion. This provides physicians a time window of stability to investigate the underlying cause of arrhythmia and allow proper therapeutic interventions (e.g., percutaneous coronary intervention and catheter ablation). Temporary MCS can be used in the case of overt hemodynamic decompensation or as a "preemptive strategy" to avoid circulatory instability during interventional cardiology procedures in high-risk patients. Despite the increasing use of MCS in cardiogenic shock and during catheter ablation procedures, the recommendation level is still low, considering the lack of large observational studies and randomized clinical trials. Therefore, the evidence on the timing and the kinds of MCS devices has also scarcely been investigated. In the current review, we discuss the available evidence in the literature and gaps in knowledge on the use of MCS devices in the setting of ventricular arrhythmias and arrhythmic storms, including a specific focus on pathophysiology and related therapies.

Coronavirus disease 2019 in critically ill patients: can we re-program the immune system? A primer for Intensivists.

In December 2019, Coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread around the word. The immune response is essential to control and eliminate CoV infections, however, multiorgan damage might be due to direct SARS-CoV2 action against the infected organ cells, as well as an imbalanced host immune response. In effect, a "cytokines storm" and an impaired innate immunity were found in the COVID-19 critically ill patients. In this review, we summarized the virus immune response steps, underlying the relevance of introducing the measurement of plasma cytokine levels and of circulating lymphocyte subsets in clinical practice for the follow-up of critically ill COVID-19 patients and support new therapy.