Effectiveness of SplashGuard Caregiver prototype in reducing the risk of aerosol transmission in intensive care unit rooms of SARS-CoV-2 patients: a prospective and simulation study.

BACKGROUND: The contagiousness of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is known to be linked to the emission of bioaerosols. Thus, aerosol-generating procedures (AGPs) could increase the risk of infection among healthcare workers (HCWs). AIM: To investigate the impact of an aerosol protection box, the SplashGuard Caregiver (SGGC) with suction system, by direct analysis of the presence of viral particles after an AGP, and by using the computational fluid dynamics (CFD) simulation method. METHODS: This prospective observational study investigated HCWs caring for patients with SARS-CoV-2 admitted to an intensive care unit (ICU). Rooms were categorized as: SGCG present and SGCG absent. Virus detection was performed through direct analysis, and using a CFD model to simulate the movement dynamics of airborne particles produced by a patient's respiratory activities. FINDINGS: Of the 67 analyses performed, three samples tested positive on quantitative polymerase chain reaction: one of 33 analyses in the SCCG group (3%) and two of 34 analyses in the non-SGCG group (5.9%). CFD simulations showed that: (1) reduction of the gaps of an SGCG could decrease the number of emitted particles remaining airborne within the room by up to 70%; and (2) positioning HCWs facing the opposite direction to the main air flow would reduce their exposure. CONCLUSIONS: This study documented the presence of SARS-CoV-2 among HCWs in a negative pressure ICU room of an infected patient with or without the use of an SGCG. The simulation will help to improve the design of the SGCG and the positioning of HCWs in the room.

Sympathetic activation in heart failure.

Sympathetic activation has been long appreciated exclusively as a fundamental compensatory mechanism of the failing heart and, thus, welcome and to be supported. In the initial clinical phases of heart failure (HF), the sympathetic nervous system overdrive plays a compensatory function aimed at maintaining an adequate cardiac output despite the inotropic dysfunction affecting the myocardium. However, when the sympathetic reflex response is exaggerated it triggers a sequence of unfavourable remodelling processes causing a further contractile deterioration that unleashes major adverse cardiovascular consequences, favouring the HF progression and the occurrence of fatal events. Eventually, the sympathetic nervous system in HF was demonstrated to be a 'lethality factor' and thus became a prominent therapeutic target. The existence of an effective highly specialized intracardiac neuronal network immediately rules out the old concept that sympathetic activation in HF is merely the consequence of a drop in cardiac output. When a cardiac damage occurs, such as myocardial ischaemia or a primary myocardial disorder, the adaptive capability of the system may be overcame, leading to excessive sympatho-excitation coupled with attenuation till to abolishment of central parasympathetic drive. Myocardial infarction causes, within a very short time, both a functional and anatomical remodelling with a diffuse up-regulation of nerve growth factor (NGF). The subsequent nerve sprouting signal, facilitated by a rise in the levels of NGF in the left stellate ganglion and in the serum, triggers an increase in cardiac nerve density in both peri-infarct and non-infarcted areas. Finally, NFG production decreases over time, supposedly as an adaptative response to the prolonged exposure to sympathetic overactivity, leading in the end to a reduction in sympathetic nerve density. Accordingly, NGF levels were markedly reduced in patients with severe congestive heart failure. The kidney is the other key player of the sympathetic response to HF as it indeed reacts to under-perfusion and to loop diuretics to preserve filtration at the cost of many pathological consequences on its physiology. This vicious loop ultimately participates to the chronic and disruptive sympathetic overdrive. In conclusion, sympathetic activation is the natural physiological consequence to life stressors but also to any condition that may harm our body. It is the first system of reaction to any potential life-threatening event. However, in any aspect of life over reaction is never effective but, in many instances, is, actually, life threatening. One for all is the case of ischaemia-related ventricular fibrillation which is, strongly facilitated by sympathetic hyperactivity. The take home message? When, in a condition of harm, everybody is yelling failure is just around the corner.

Adrenergic effects on force-frequency relationship: a pivotal role for the cardiac intrinsic systems.

AIM: The force-frequency relationship (F-FR) is an important intrinsic regulatory mechanism of cardiac contractility. The involvement of autonomic nervous system in this physiological aspect of cardiac control remains unclear. The aim of the study was to evaluate the role of extrinsic and intrinsic cardiac adrenergic innervations on the heart rate (HR)-related positive inotropic response. METHODS: Twenty-four dogs were anesthetized and acutely instrumented to monitor and record ECG, systemic and left ventricular pressures and derivatives, and to pace the heart at 130, 150, 170, 190 and 210 bpm, in order to construct the F-FR curve. Animals were randomly assigned to four groups (n = 6 each): vehicle (V), ganglion-blocked (G-B), ß-blocked (ß-B) and ganglion-blocked plus ß-blocked (G-B + ß-B). RESULTS: Vehicle treated animals presented the classical F-FR. In the ß-B group F-FR was blunted, but never fully suppressed. The G-B treated animals showed a bell-shape response curve of the induced inotropic effect with the zenith at 170 bpm: the first part of the curve resembling the control one, followed by a rapid decline toward baseline value. The co-administration of G-B and ß-B agents reversed the contractile response to HR rise with a curve resembling the negative F-FR curve observed in the failing heart. CONCLUSION: The F-FR appeared to be constituted by two consecutive mechanisms: first depolarization-rate dependent, and a second catecholamine-dependent. The natural consequence of these observations is that the full expression of F-FR needs an intact adrenergic system.

Predictors of medical events and of their competitive interactions in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2).

AIMS: Predictive factors for medical events and interactions between events were not reported in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2). We examined the interactions among death, permanent treatment withdrawals, nonlethal cardiovascular hospitalizations and their own occurrence in a given patient, the treatment received, and baseline variables during CIBIS-2. METHODS AND RESULTS: A Cox model for censored data was used to analyze the relations among baseline variables, medical events, and their interactions with treatment. We used competitive risk analysis to examine the interactions between successive events in a given patient during follow-up. No baseline variable predicted the reduction of mortality with bisoprolol. Withdrawal from bisoprolol therapy was more frequent in patients whose baseline heart rate was in the lower tertile of the distribution (P =.0002) but otherwise was not different between patients randomized to bisoprolol and to placebo. Event history analysis revealed that bisoprolol reduced mortality (P =.0006) and hospitalizations for nonlethal cardiovascular events (P =.003) in patients in whom treatment was not permanently withdrawn. Analysis of survival curves in patients who permanently discontinued treatment showed that bisoprolol did not reduce mortality compared with placebo in this population (relative risk 1.03, 95% CI 0.67-1.59; P =.88). Recurrent nonlethal events were reduced by bisoprolol. CONCLUSION: In CIBIS-2, medical events were significantly influenced by treatment withdrawal. Patients who derive benefit from bisoprolol therapy are those in whom treatment is not permanently withdrawn.

[Physiopathology of the autonomic nervous system activity during sleep]. / Fisiopatologia dell'attività del sistema nervoso autonomo durante il sonno.

Sleep consists of two phases that periodically alternate: the rapid eye movement (REM) phase and the non-REM phase. The non-REM stage is characterized by wide synchronous waves in the electroencephalogram, by a low heart rate and by a decrease in arterial blood pressure and peripheral resistances. This hemodynamic setting is the consequence of the autonomic balance characterized by high vagal activity and low sympathetic activity. Such an autonomic condition is adequately described by the spectral analysis of heart rate variability documenting a prevalence in the high frequency band (the respiratory vagal band). The REM stage of sleep is characterized by asynchronous waves in the electroencephalogram and it is associated with a further increase in the vagal dominance of the autonomic balance resulting in a lower heart rate and decreased peripheral resistances. The REM phase of sleep is, however, also characterized by hemodynamic instability due to sudden bursts of sympathetic activity, associated with the rapid eye movements. These sympathetic bursts cause sudden changes in heart rate and peripheral resistance and may influence cardiac electrical stability both at the atrial and ventricular levels. Additionally, REM sleep may enhance the risk of anginal attacks in coronary artery disease patients. Analysis of the autonomic balance during the different phases of sleep may also help in the identification of autonomic derangements typically associated with myocardial infarction.

Early autonomic and repolarization abnormalities contribute to lethal arrhythmias in chronic ischemic heart failure: characteristics of a novel heart failure model in dogs with postmyocardial infarction left ventricular dysfunction.

OBJECTIVES: Using a model of arrhythmias associated with ischemic left ventricular (LV) dysfunction, this study investigated autonomic and electrophysiologic mechanisms associated with sudden cardiac death (SCD) in chronic heart failure (HF). BACKGROUND: Left ventricular dysfunction from ischemic heart disease is associated with many instances of SCD. Electrophysiologic and autonomic derangements occur in HF, but their contribution to SCD risk is poorly understood. METHODS: Sudden death risk was assessed in 15 dogs with a healed anterior myocardial infarction (MI) during submaximal exercise and brief acute circumflex ischemia. Left ventricular dysfunction was then induced by repetitive circumflex microembolization until LV ejection fraction reached 35%. Before embolization, six dogs were susceptible to SCD, and nine were resistant. RESULTS: Baroreflex sensitivity was lower in susceptible dogs (10 ms/mm Hg +/- 4 ms/mm Hg vs. 20 ms/mm Hg +/- 11 ms/mm Hg, p = 0.04). QT intervals from susceptible dogs were longer after MI (246 ms +/- 26 ms susceptible vs. 231 ms +/- 20 ms resistant, p < 0.001) and prolonged within eight weeks after LV dysfunction was established (from 246 ms +/- 26 ms to 274 ms +/- 56 ms, +11%, p < 0.01). Heart rate in susceptible dogs increased during transient ischemia (+20%) and with progressive LV dysfunction (102 beats/min +/- 28 beats/min baseline to 154 beats/min +/- 7 beats/min LV dysfunction, p = 0.003). All susceptible dogs had spontaneous sustained ventricular tachycardia culminating in SCD. In contrast, QT intervals in resistant dogs prolonged after 24 +/- 6 weeks (from 231 ms +/- 20 ms to 238 ms +/- 15 ms, p < 0.05), and heart rates were unchanged. Only one resistant dog died suddenly with LV dysfunction. CONCLUSIONS: Depressed vagal and elevated sympathetic control of heart rate coupled with abnormal repolarization are associated with high SCD risk when post-MI LV dysfunction develops.

T wave alternans detection during exercise stress test and during dobutamine stress. A comparative study in patients with a recent myocardial infarction.

BACKGROUND: Beat to beat electrical alternans of the T wave (TWA) on the electrocardiogram is a risk marker for the occurrence of life-threatening ventricular tachyarrhythmias. Atrial pacing or exercise are commonly used to increase heart rate to the critical level for TWA detection. However, atrial pacing requires invasive procedures while exercise may cause significant noise on the electrocardiographic recording or may be not performed by a number of patients with cardiac diseases. Dobutamine stress testing is routinely used in post-myocardial infarction patients and may represent an alternative means to detect TWA. However, the comparability of data obtained with exercise and dobutamine needs to be proven. METHODS: We measured TWA during exercise and/or dobutamine stress in 42 patients with a recent myocardial infarction. TWA was detected using a commercially available software while the heart rate was increased to the target range of 105-130 b/min. Each patient performed the two tests in random order with an adequate recovery time in between. RESULTS: The mean level of noise during data acquisition for TWA detection was significantly lower during the dobutamine test than during exercise (1.003 +/- 0.67 vs 1.46 +/- 1.20 microV, p < 0.01). With exercise, 32 (78%) patients had a determinable TWA. Of these, 9 (27%) were TWA positive and 23 TWA negative. In the other patients noise (n = 8) or exercise-induced arrhythmias (n = 1) prevented an appropriate TWA determination. One patient could not exercise. With dobutamine stress, 38 (87%) of the 42 patients studied had a determinable TWA. Arrhythmias prevented TWA determination in the remaining 4 patients. Dobutamine and exercise testing provided comparable proportions of TWA determinability. However, by combining exercise and dobutamine testing, a greater (p = 0.0071) proportion of the patients (41/42, 98% vs 32/42, 76%) had a determinable TWA when compared with exercise alone. A comparative TWA study could be performed in 29 patients who completed both the dobutamine and the exercise stress tests. All 22 patients TWA negative at exercise were so at dobutamine testing also. On the other hand, 5 of the 7 patients TWA positive at exercise were so at dobutamine testing also. Overall, 27 (93%) of the 29 patients in whom internal comparison could be performed showed a concordant result. CONCLUSIONS: Dobutamine testing allows TWA detection with results comparable to those obtained at exercise testing. Combining exercise and dobutamine stress allows TWA determination in most of post-myocardial infarction patients. The present study provides the evidence for a safe and effective TWA determination for risk stratification after myocardial infarction.

Five-minute recording of heart rate variability in severe chronic heart failure: correlates with right ventricular function and prognostic implications.

BACKGROUND: In advanced chronic heart failure (CHF), correlation between heart rate variability (HRV) and parameters of disease severity is still unclear. A reduced HRV has been related to left but not to right ventricular function parameters. Moreover, the prognostic role of spectral measures is not fully defined. We sought to assess HRV by using a short electrocardiographic recording in ambulatory patients with severe CHF to investigate the relation of HRV with clinical neurohormonal and hemodynamic parameters and to determine its predictive prognostic power. METHODS AND RESULTS: HRV was obtained from 5-minute electrocardiographic recordings in 75 ambulatory patients with CHF referred for heart transplantation screening. Standard frequency-domain parameters (total power, low-frequency power, and high-frequency power) were calculated. Prognostic value of these autonomic markers and their correlation with clinical and instrumental parameters were also assessed. A low low-frequency/high-frequency ratio was an independent predictor of cardiac events (P =.015). No correlation was found between New York Heart Association class and HRV, whereas significant correlations were identified between norepinephrine plasma levels, several hemodynamic parameters, and spectral measures (P < or =.03). A reduced HRV, particularly a low-frequency power reduction (P =.000), was highly related to indexes of right ventricular dysfunction. CONCLUSIONS: The current data indicate that spectral analysis of HRV, calculated from short electrocardiographic recordings, may represent a simple but effective means contributing to risk stratification of patients with severe CHF. Autonomic information obtained from this analysis suggests that right ventricular dysfunction may be a critical element determining autonomic imbalance in patients with severe CHF.

Autonomic control of heart rate: pharmacological and nonpharmacological modulation.

The evidence of the predictive value of autonomic markers has generated a growing interest for interventions able to influence autonomic control of heart rate. The hypothesis is that an increase in cardiac vagal activity as detected by an increase in heart rate variability (HRV) or baroreflex sensitivity (BRS) may be beneficial in the ischemic heart. Numerous experimental data support the hypothesis that augmenting vagal activity might be protective against lethal ischemic arrhythmias. Among them is the evidence that ventricular fibrillation during acute myocardial ischemia may be largely prevented by electrical stimulation of the right cervical vagus or by pharmacological stimulation of cholinergic receptors with oxotremorine. There is an inherent danger in the so far unwarranted assumption that modification of HRV or BRS translates directly in cardiac protection. This may or may not be the case. It should be remembered that the true target is the improvement in cardiac electrical stability and that BRS or HRV are just markers of autonomic activity. Low dose scopolamine increases HRV in patients with a prior myocardial infarction. This observation, combined with the evidence that elevated cardiac vagal activity during acute myocardial ischemia is antifibrillatory, has generated the hypothesis that scopolamine might be protective after MI. We tested low dose scopolamine in a clinically relevant experimental preparation for sudden death in which other vagomimetic interventions are effective and found that this intervention does indeed increase cardiac vagal markers but has minimal antifibrillatory effects. This is in contrast to exercise training that in the same experimental model had a marked effect on both BRS and HRV and at the same time provided strong protection from ischemic ventricular fibrillation. Thus, based on the current knowledge it seems appropriate to call for caution before attributing excessive importance to changes in "markers" of vagal activity in the absence of clearcut evidence for a causal relation with an antifibrillatory effect.

Antifibrillatory efficacy of ersentilide, a novel beta-adrenergic and Ikr blocker, in conscious dogs with a healed myocardial infarction.

OBJECTIVES: IKr blockade is ineffective in preventing ventricular fibrillation elicited by the interaction between acute myocardial ischemia and elevated sympathetic activity. This depends in part on the fact that adrenergic activation offsets more than 50% of the action potential prolonging effect of IKr blockade, and thus impairs its primary mechanism of action. This study examined the antifibrillatory effect of ersentilide (CK-3579), a novel antiarrhythmic agent which combines blockade of the rapid component of the delayed rectifier potassium channel (IKr) with relatively weak beta-adrenergic blockade, in a conscious canine model of lethal arrhythmias. METHODS: Ersentilide was tested in 19 dogs with a healed myocardial infarction (MI) undergoing two minutes of circumflex artery occlusion (CAO) during sub-maximal treadmill exercise. Epicardial monophasic action potential duration was measured before and after ersentilide in 8 anesthetized open chest dogs at baseline and during stimulation of the left stellate ganglion at constant paced heart rate. RESULTS: In the control tests 13 of the 19 dogs had ventricular fibrillation (VF) during the exercise and ischemia test, 6 did not. During a subsequent exercise test, ersentilide prevented VF in 85% (11 of 13) of the high risk animals and showed no proarrhythmic effects in the 6 dogs without arrhythmias in the initial test. Ersentilide lowered heart rate at all levels of exercise and during acute myocardial ischemia. The antifibrillatory effect was maintained in 3 of 4 dogs in which heart rate was kept at control levels by atrial pacing. Ersentilide prolonged left ventricular monophasic action potential duration by 30% (from 179 +/- 6 ms to 233 +/- 5 ms, p < 0.001) at a 360 ms cycle length and completely prevented its shortening during sympathetic stimulation. CONCLUSIONS: The combination of IKr and weak beta-adrenergic blockade, using ersentilide, represents a very effective and safe antiarrhythmic intervention able to overcome the limitations present in drugs devoid of any antiadrenergic effect. Such a combination may be very useful in the management of post-myocardial infarction patients at high arrhythmic risk.

Influence of residual ischaemia on heart rate variability after myocardial infarction.

Despite the growing evidence for the positive predictive value of depressed baroreflex sensitivity and/or reduced heart rate variability after myocardial infarction, the mechanisms involved in these autonomic alterations are not fully understood. Specifically, the possible influence of residual ischaemia has not been assessed. To address this problem we studied the spectral analysis of heart rate variability in 21 patients with a first myocardial infarction in whom the only clinical correlate was the presence of residual ischaemia, as documented by the positive response to both an exercise stress test and an echocardiographic stress test. Data from these patients were compared with those obtained in a group of postmyocardial infarction patients similar for several risk factors, age, site of myocardial infarction, but without residual ischaemia. Patients positive for residual ischaemia had lower power in the whole spectrum (1146 +/- 158 vs 1631 +/- 159 ms2, P = 0.032) as well as in the low and high frequency bands of heart rate variability. A nocturnal increase in high frequency was observed in those without residual ischaemia (from 167 +/- 35 to 242 +/- 51 ms2, +45%, P = 0.034), but not in those with residual ischaemia (from 111 +/- 19 to 141 +/- 29 ms2, +27%, ns). Thus, residual ischaemia reduces heart rate variability after myocardial infarction. The autonomic effects of residual ischaemia probably contribute to its negative prognostic value after myocardial infarction.

Muscarinic effects on action potential duration and its rate dependence in canine Purkinje fibers.

Studies of the autonomic influence on action potential duration (APD) in the ventricles show direct effects of muscarinic stimulation on epicardial, but not endocardial, APD and conflicting results regarding direct vagal effects on the conduction system. In canine Purkinje fibers, we analyzed the action of the M2 agonist oxotremorine (OXO, 0.1 microM) on APD and on its cycle length (CL) dependence. Fibers were impaled with glass microelectrodes and superfused with Tyrode's solution. APD90 was measured after 3 minutes of drive at CL between 0.3 and 5 seconds. The best fit for the APD/CL relationship at steady state was a hyperbole: APD = APDmax*CL/(CL+CL50), where APDmax (APD at infinite CL) is a rate independent measure of APD, and CL50 (CL at which 50% APDmax is reached) is an index of the rate dependence of APD. In five fibers, OXO reduced APD at all CL (P < 0.05), APDmax was also reduced to 377 +/- 41 ms from 447 +/- 34 ms (P < 0.05), while CL50 was unchanged (405 +/- 46 ms from 437 +/- 28 ms). No effects of OXO on APD and APDmax were seen in two fibers obtained from dogs pretreated with pertussis toxin (PTX). In conclusion, stimulation of M2 receptors in intact, and not PTX treated, Purkinje fibers affects APD but not its CL dependence. This may reflect the activation of a rate independent, background current through a GTP binding protein-linked pathway, such as, IK,ACh. These data differ from those obtained in endocardial and epicardial muscle, stressing the regional differences in vagal modulation of ventricular electrophysiological properties.

K+ channel blockade in the prevention of ventricular fibrillation in dogs with acute ischemia and enhanced sympathetic activity.

The value of K+ channel blockade in preventing lethal arrhythmias, and specifically those triggered by acute myocardial ischemia and sympathetic hyperactivity, remains unproven. To address this issue, we tested the antifibrillatory effect of d-sotalol, and Ikr blocker, d,l-sotalol, its racemic compound which blocks Ikr, and beta-adrenoreceptors, and propranolol. Ten dogs with a healed anterior myocardial infarction (MI) had ventricular fibrillation (VF) during a 2-min occlusion of the circumflex coronary artery performed toward the end of a submaximal exercise stress test. In successive trials in the same animals, d-sotalol (three injections of 8 mg/kg, one every 12 h), d,l-sotalol (8 mg/kg), and propranolol (1 mg/kg) were tested. All three interventions significantly reduced heart rate (HR) response to exercise, but only d,l-sotalol and propranolol also blunted the reflex HR increase during acute myocardial ischemia. With d-sotalol, HR at 30 s of coronary occlusion was similar (253 +/- 28 beats/min) to that observed in the control tests (259 +/- 35 beats/min). d-Sotalol prevented recurrence of VF in only 1 of 10 dogs tested. One dog was lost to the continuation of the study after occurrence of VF with d-sotalol. Six of 9 dogs (67%) tested with d,l-sotalol and 5 (56%) of the same 9 dogs tested with propranolol were protected from VF. d-Sotalol does not reduce risk of VF during acute myocardial ischemia associated with sympathetic hyperactivity, and lethal events can be prevented by antiadrenergic interventions.