Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

BACKGROUND: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. METHODS: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. RESULTS: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). CONCLUSION: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Myocardial edema in paroxysmal permeability disorders: The paradigm of Clarkson's disease.

PURPOSE: Paroxysmal Permeability Disorders (PPDs) comprise a variety of diseases characterized by recurrent and transitory increase of endothelial permeability. Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a rare PPD that leads to an abrupt massive shift of fluids and proteins from the intravascular to the interstitial compartment. In some cases, tissue edema may involve the myocardium, but its role in the development of shock has not been elucidated so far. MATERIALS AND METHODS: Assessment of cardiac involvement during ten life-threatening ISCLS episodes admitted to ICU. RESULTS: Transthoracic echocardiographic examination was performed in eight episodes, whereas a poor acoustic window prevented cardiac ultrasound assessment in two episodes. Myocardial edema was detected by echocardiography in eight episodes and marked pericardial effusion in one-episode. Cardiac magnetic resonance showed diffuse myocardial edema in another episode. In one case, myocardial edema caused fulminant left ventricular dysfunction, which required extracorporeal life support. The mean septum thickness was higher during the shock phase compared to the recovery phase [15.5 mm (13.1-21 mm) vs. 9.9 mm (9-11.3 mm), p = .0003]. Myocardial edema resolved within 72 h. CONCLUSIONS: During early phases of ISCLS, myocardial edema commonly occurs and can induce transient myocardial dysfunction, potentially contributing to the pathogenesis of shock.

Current and emerging biologics for the treatment of hereditary angioedema.

INTRODUCTION: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients. AREAS COVERED: This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed. EXPERT OPINION: The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.

Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction.

BACKGROUND: Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes. OBJECTIVE: Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation. METHODS: Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10') and 75-degrees-head-up tilt (10'). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively. RESULTS: HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01). CONCLUSIONS: Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.

Primary PCI is associated with different cardiac autonomic patterns in relation to the site of myocardial infarction.

AIM: Reflex alterations of cardiac autonomic modulation have been described after acute myocardial infarction (AMI). The non-homogeneous autonomic innervation of the heart gives reason of different patterns of autonomic modulation depending upon the site of AMI. Conflicting data are available on cardiac autonomic modifications after primary percutaneous coronary intervention (pPCI). We evaluated cardiac autonomic changes in patients with ST-elevation myocardial infarction (STEMI) after pPCI, either within 24h after revascularization (T0) and at clinical stability (T1, 6±2days), taking into account the site of infarction. METHODS AND RESULTS: We enrolled 33 consecutive patients with STEMI treated with pPCI (25 males, mean age 61±12.1yr); 15 had an anterior wall STEMI (ANT) and 18 had an inferior wall STEMI (INF). ECG and respiration were recorded at T0 and at T1. Cardiac autonomic modulation was evaluated by means of symbolic analysis of heart rate variability. At T0, At T0, 0V% (marker of sympathetic modulation) was higher in INF compared to ANT [31% (18-43) vs 18% (7-32), p=0.014]. Moreover, ANT had a higher 2LV%, index of vagal modulation, compared to INF [8% (7-15) vs 5% (2-8), p=0.006]. CONCLUSION: After pPCI, these preliminary results suggest that patients with INF were characterized by a sympathetic predominance, while ANT by a predominant vagal modulation. Our data suggest that pPCI can be associated with specific autonomic patterns, which are different for ANT and INF STEMI, according to the different autonomic innervation. Future ad hoc studies are needed to confirm these preliminary observations.

Salvage therapy with bortezomib and dexamethasone in elderly patients with relapsed/refractory multiple myeloma.

Bortezomib-dexamethasone (bort-dex) is effective for relapsed/refractory (R/R) multiple myeloma, but few data are available for elderly patients. The aim of this study was to evaluate efficacy and toxicity of bort-dex in elderly R/R MM patients. We evaluated 81 R/R MM patients treated with bort-dex. Eight of them had light-chain disease. The median age of the patients was 73 years (range 65-89 years). All patients were R/R MM patients and had been treated with melphalan and prednisone with or without thalidomide or bortezomib in the first line or with lenalidomide and dexamethasone in the second line. The median number of previous lines was 2. Thirty-nine (48%) patients received bortezomib intravenously and 42 (52%) patients received bortezomib subcutaneously. The median number of bort-dex cycles was 6 (range 1-11). Fifty-three (65.4%) patients achieved at least a partial response, including eight (11%) patients with complete response and nine (12.5%) patients with very good partial responses. The median duration of response, time to next therapy and treatment-free intervals were 8, 11 and 5 months. Duration of response was significantly longer for patients achieving complete response/very good partial response than for those achieving partial response (7.3 vs. 3.8 months, P=0.03). After a median follow-up of 24 months, 78 patients showed disease progression and 70 died. The median time to progression, progression-free survival and overall survival were 8.9, 8.7 and 22 months, respectively. Peripheral neuropathy occurred in 38 (47%) patients. Our data highlight that bort-dex is effective and tolerable in fit elderly patients, thus justifying the efforts for deeper responses. However, awareness of short-lived responses to bort-dex should lead to a thorough evaluation of the need for maintenance.

Modulation of sympathetic activity and heart rate variability by ivabradine.

AIMS: Bradycardic agents are currently used in the treatment of angina and heart failure; direct information on their effects on cardiac sympathetic nerve activity (SNA) may be relevant to their chronic use. The present study evaluates the effect of pacemaker inhibition on SNA; direct nerve recordings and indirect autonomic indexes are compared. METHODS AND RESULTS: Experiments were performed in 18 anaesthetized rats. SNA (direct nerve recording) and heart rate variability (HRV) indexes were evaluated in parallel. All parameters were recorded 10 min before to 60 min after administration of the If blocker ivabradine (IVA; 2 mg/kg, i.v.; n = 8) or vehicle (VEH; n = 5). IVA-induced RR interval (RR) prolongation (at 60 min +15.0 ± 7.1%, P < 0.01) was associated with decreased diastolic arterial pressure (DAP; -17.3 ± 8.4%, P < 0.05) and increased SNA (+51.1 ± 12.3%, P < 0.05). These effects were accompanied by increased RR variance (RRσ(2)), which showed strong positive correlation with RR. Frequency-domain HRV indexes (in normalized units) were unchanged by IVA. After baroreceptor reflexes had been eliminated by sino-aortic denervation (n = 5), similar IVA-induced RR prolongation (at 60 min +14.3 ± 5.9%, NS vs. intact) was associated with a larger DAP reduction (-30.9 ± 4.1%, P < 0.05 vs. intact), but failed to affect SNA. CONCLUSIONS: (i) IVA-induced bradycardia was associated with increased SNA, resulting from baroreceptor unloading; if this applied to chronic IVA use in humans, it would be of relevance for therapeutic use of the drug. (ii) Whenever mean HR is concomitantly changed, time-domain HRV indexes should not be unequivocally interpreted in terms of autonomic balance.

Differential Diagnosis and Management Issues of Idiopathic Angiooedema and their Resolution.

Angiooedema is a local and self-limiting swelling of the subcutaneous and sub mucosal tissues, produced by vasoactive peptides that temporary increase the vascular permeability. It is recognized that recurrent angiooedema exposes patients to the risk of fatalities and reduced quality of life, being in some circumstances associated with a critical condition. Angiooedema can occur with or without wheals. The first symptom is urticaria, the second is a distinct nosologic entity. In absence of an identifiable cause, recurrent angiooedema without wheals can be defined as idiopathic and marked"idiopathic histaminergic angiooedema" when it is responsive to anti histamine treatment, and "idiopathic non-histaminergic angiooedema" when it is not. Furthermore, idiopathic non-histaminergic angiooedema can be diagnosed as hereditary or sporadic by family history. In this review, we summarize the approaches to diagnose and treat different forms of idiopathic angiooedema.

One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians.

BACKGROUND: Sleep loss is associated with increased cardiovascular morbidity and mortality. It is known that chronic sleep restriction affects autonomic cardiovascular control and inflammatory response. However, scanty data are available on the effects of acute sleep deprivation (ASD) due to night shifts on the cardiovascular system and its capability to respond to stressor stimuli. The aim of our study was to investigate whether a real life model of ASD, such as "one night on-call", might alter the autonomic dynamic response to orthostatic challenge and modify the immune response in young physicians. METHODS: Fifteen healthy residents in Internal Medicine were studied before and after one night on-call at Rest and during a gravitational stimulus (head up-tilt test, HUT). Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were analyzed during Rest and HUT before and after ASD. Plasmatic hormones (epinephrine, norepinephrine, cortisol, renin, aldosterone, ACTH) and tissue inflammatory cytokines were measured at baseline and after ASD. RESULT: HRV analysis revealed a predominant sympathetic modulation and a parasympathetic withdrawal after ASD. During HUT, the sympathovagal balance shifted towards a sympathetic predominance before and after ASD. However, the magnitude of the autonomic response was lower after ASD. BPV and BRS remained unchanged before and after ASD as the hormone levels, while IFN-γ increased after ASD compared to baseline. CONCLUSION: In summary, one night of sleep deprivation, at least in this real-life model, seems to affect cardiovascular autonomic response and immune modulation, independently by the activation of the hypothalamic-pituitary axis.