A Novel Heart Failure Diagnostic Risk Score Using a Minimally Invasive Subcutaneous Insertable Cardiac Monitor.

BACKGROUND: The authors tested the hypothesis that physiological information from sensors within a minimally invasive, subcutaneous, insertable cardiac monitor (ICM) could be used to develop an ambulatory heart failure risk score (HFRS) to accurately identify heart failure (HF) patients, across the ejection fraction spectrum, at high risk of an impending worsening heart failure event (HFE). OBJECTIVES: The purpose of this study was to examine performance of ICM-based, multiparameter, dynamic HFRS to predict HFEs in patients with NYHA functional class II/III HF. METHODS: In 2 observational cohorts, HF patients were implanted with an ICM; subcutaneous impedance, respiratory rate, heart rate and variability, atrial fibrillation burden, ventricular rate during atrial fibrillation, and activity duration were combined into an HFRS to identify the probability of HFE within 30 days. Patients and providers were blinded to the data. HFRS sensitivity and unexplained detection rate were defined in 2 independent patient population data sets. HFEs were defined as hospitalization, observation unit, or emergency department visit with a primary diagnosis of HF, and intravenous diuretic treatment. RESULTS: First data set (development): 42 patients had 19 HFE; second data set (validation): 94 patients had 19 HFE (mean age 66 ± 11 years, 63% men, 50% with LVEF ≥40%, 80% NYHA functional class III). Using a high-risk threshold = 7.5%, development and validation data sets: sensitivity was 73.7% and 68.4%; unexplained detection rate of 1.4 and 1.5 per patient-year; median 47 and 64 days early warning before HFE. CONCLUSIONS: ICM-HFRS provides a multiparameter, integrated diagnostic method with the ability to identify when HF patients are at increased risk of heart failure events. (Reveal LINQ Evaluation of Fluid [REEF]; NCT02275923, Reveal LINQ Heart Failure [LINQ HF]; NCT02758301, Algorithm Using LINQ Sensors for Evaluation and Treatment of Heart Failure [ALLEVIATE-HF]; NCT04452149).

Inspiratory impedance threshold device effects on hypotension in heat-stroked swine.

INTRODUCTION: Heat stroke is still an epidemiologically relevant disease with overall mortality rates as high as 15-33%. In heat stroke, hypotension is caused by relative central hypovolemia. We performed a feasibility study to determine if an inspiratory impedance threshold valve (ITDTM) set to open at -12 cm H2O would reverse systemic hypotension by enhancing venous return in hyperthermic, hypotensive, but spontaneously breathing animals. METHODS: Seven anesthetized pigs weighing 30 +/- 2 kg were warmed with a heating device until a mean rectal temperature of 44 degrees C was reached, and mean arterial blood pressure (MAP) was < or = 60 mmHg. The animals were then treated with the ITD. An intravenous bolus of 200 cc of 4 degrees C normal saline was delivered 20 min after the ITD was placed, and external cooling was started. RESULTS: Heat stroke criteria were achieved within 105 +/- 15 min. MAP had decreased from 105 +/- 5 to 57 +/- 5 mmHg, and respiratory rates had increased from 33 +/- 2 to 101 +/- 13 breaths/min. Addition of the ITD significantly improved MAP to 85 +/- 4 mmHg, and reduced respiratory rate to 54 +/- 6 breaths/min within 2 min. The effect was sustained until fluid replacement and external cooling were delivered 20 min later. At that point, MAP returned to baseline within 30 min, and 6/7 animals survived for an additional 30 min. CONCLUSIONS: Use of an inspiratory impedance threshold device resulted in an immediate rise in blood pressure in animals in heat stroke and preserved blood pressure for at least 20 min prior to cooling and fluid replacement.

Treatment of hypotension in pigs with an inspiratory impedance threshold device: a feasibility study.

OBJECTIVE: An inspiratory impedance threshold device was evaluated in spontaneously breathing animals with hypotension to determine whether it could help improve systemic arterial pressures when fluid replacement was not immediately available. DESIGN: Prospective, randomized. SETTING: Animal laboratory. SUBJECTS: Thirty-nine female farm pigs (weight, 28-33 kg). INTERVENTIONS: A total of 39 anesthetized spontaneously breathing pigs were treated with an impedance threshold device, with cracking pressures from 0 to -20 cm H2O. Four separate experimental protocols were performed: protocol A, in which the hemodynamics of seven pigs were examined during application of an impedance threshold device at various levels of inspiratory impedance (-5, -10, -15, and -20 cm H(2)O), both before and after a severe, controlled hemorrhage to a systolic blood pressure of 50 - 55 mm Hg; protocol B, in which nine pigs bled to systolic blood pressure of 50 -55 mm Hg were treated with an impedance threshold device set at -12 cm H2O and were compared with nine others treated with a sham device; protocol C, in which the effects of the impedance threshold device on mixed venous gases were measured in seven hemorrhaged pigs; and protocol D, in which the effects of the impedance threshold device on cardiac output in seven hemorrhaged pigs were measured. METHODS AND MAIN RESULTS: During initial studies with both normovolemic and hypovolemic pigs, sequential increases in inspiratory impedance resulted in a significant increase in systolic blood pressure, whereas diastolic left ventricular and right atrial pressures decreased significantly and proportionally to the level of impedance. When comparing the sham vs. active impedance threshold device (-12 cm H(2)O) in hypotensive pigs, systolic blood pressure (mean +/- sem) with active impedance threshold device treatment increased from 70 +/- 2 mm Hg to 105 +/- 4 mm Hg (p <.01). Pressures in the control group remained at 70 +/- 4 mm Hg (p <.01). Cardiac output increased by nearly 25% (p <.01) with the active impedance threshold device when calculated using the mixed gas equation and when determined by thermodilution. CONCLUSIONS: These studies demonstrate that it is feasible to use a device that creates inspiratory impedance in spontaneously breathing normotensive and hypotensive pigs to increase blood pressure and enhance cardiopulmonary circulation in the absence of immediate fluid resuscitation. Further studies are needed to evaluate the potential long-term effects and limitations of this new approach to treat hypovolemic hypotension.

Feasibility and effects of transcutaneous phrenic nerve stimulation combined with an inspiratory impedance threshold in a pig model of hemorrhagic shock.

OBJECTIVE: Intrathoracic pressure changes are of particular importance under hypovolemic conditions, especially when central venous blood pressure is critically low. Accordingly, the purpose of this study was to assess the feasibility of transcutaneous phrenic nerve stimulation, used in conjunction with an inspiratory impedance threshold, on hemodynamic variables during hemorrhagic shock. DESIGN: Prospective, randomized laboratory investigation using a porcine model for measurement of hemodynamic variables, left and right ventricular diameter, and transmitral, transpulmonary, and transaortic blood flow employing transesophageal echo-Doppler technique. SETTING: University hospital laboratory. SUBJECTS: Thirteen female pigs weighing 28-36 kg. INTERVENTIONS: The anesthetized pigs were subjected to profound hemorrhagic shock by withdrawal of 55% of estimated blood volume over 20 mins. After a 10-min recovery period, the diaphragm was stimulated with a prototype transcutaneous phrenic nerve stimulator at a rate of ten per minute while the airway was intermittently occluded with an inspiratory threshold valve between positive pressure ventilations. Hemodynamic variables were monitored for 30 mins. MEASUREMENTS AND MAIN RESULTS: Phrenic nerve stimulation in combination with the inspiratory threshold valve significantly (p <.001) improved right and left ventricular diameter compared with hypovolemic shock values by 34 +/- 2.5% and 20 +/- 2.5%, respectively. Moreover, phrenic nerve stimulation together with the inspiratory threshold valve also increased transaortic, transpulmonary, and transmitral valve blood flow by 48 +/- 6.6%, 67 +/- 13.3, and 43 +/- 8.2%, respectively (p <.001 for comparisons within group). Mean +/- sem coronary perfusion and systolic aortic blood pressures were also significantly (p <.001) higher compared with values before stimulation (30 +/- 2 vs. 20 +/- 2 mm Hg, and 37 +/- 2 vs. 32 +/- 3 mm Hg, respectively). CONCLUSIONS: This feasibility study suggests that phrenic nerve stimulation with the inspiratory threshold valve may improve cardiac preload and, subsequently, key hemodynamic variables in porcine model of severe hemorrhagic shock.

Evaluation of a prototypic inspiratory impedance threshold valve designed to enhance the efficiency of cardiopulmonary resuscitation.

OBJECTIVE: Assess a prototype inspiratory impedance threshold valve (ITV) designed to enhance vital organ circulation during standard and active compression/decompression cardiopulmonary resuscitation (CPR). BACKGROUND: The ITV attaches to commonly used airway assist devices and decreases intrathoracic pressure during the decompression (chest recoil) phase of CPR by creating a vacuum within the thorax, which increases venous blood flow to the heart and thus increases coronary perfusion pressure and blood flow to the brain. METHODS: The evaluation included laboratory bench testing, according to American Society for Testing and Materials (ASTM) and International Standards Organization (ISO) guidelines, and performance testing with pigs in cardiac arrest. A vacuum pull test was developed to determine the inspiratory impedance under various inspiratory flow conditions. RESULTS: The valve passed all minimum ASTM and ISO performance tests. During cardiac arrest in pigs the ITV decreased intrathoracic pressures by 6-8 mm Hg during the decompression phase. The vacuum pull test demonstrated that the prototype ITV functioned as intended. CONCLUSIONS: The prototype ITV passed all performance testing recommended by international guidelines and functioned effectively as intended for use. The animal study results, when combined with recent clinical data, suggest that an ITV inspiratory cracking pressure of 12 cm H(2)O should be sufficient to decrease intrathoracic pressure during the decompression phase of standard CPR. Clinical studies are now underway.

Combination drug therapy with vasopressin, adrenaline (epinephrine) and nitroglycerin improves vital organ blood flow in a porcine model of ventricular fibrillation.

There is increasing evidence that the combination of epinephrine (adrenaline) with vasopressin may be superior to either epinephrine or vasopressin alone for treatment of cardiac arrest. However, the optimal combination, and dosage of cardiovascular drugs to minimize side effects, and to improve outcome has yet to be found. We therefore evaluated whether the combination of vasopressin plus epinephrine plus nitroglycerin (EVN), would improve vital organ blood flow during cardiopulmonary resuscitation (CPR) when compared with epinephrine (EPI) alone. After 4 min of ventricular fibrillation (VF) and 4 min of standard CPR, pigs were randomized to the combination of epinephrine (45 microg/kg) plus vasopressin (0.4 U/kg) plus nitroglycerin (7.5 microg/kg; n=12), or epinephrine (40 microg/kg; n=12) alone. Cerebral and myocardial blood flow was measured with radiolabeled microspheres. Defibrillation was attempted after 19 min of VF including 15 min of CPR. Mean+/-SEM coronary perfusion pressures were significantly (P < 0.01) higher 5 min after EVN vs. EPI alone (34+/-3 vs. 24+/-3 mmHg, respectively). At the same time, mean+/-SEM left ventricular, and global cerebral blood flow was also significantly (P < 0.05) higher after EVN vs. EPI alone (0.78+/-0.11 vs. 0.48+/-0.08 ml/min/g; and 0.37+/-0.05 vs. 0.22+/-0.0 3 ml/min/g, respectively). Spontaneous circulation was restored in 11 of 12 animals in the EVN group vs. 6 of 12 swine after EPI alone (P = N.S.). In conclusion, the combination of EVN significantly improved vital organ blood flow during CPR compared with EPI alone. Addition of nitroglycerin to the combination of low dose epinephrine with vasopressin during cardiac arrest may be beneficial.

Effects of epinephrine and vasopressin in a piglet model of prolonged ventricular fibrillation and cardiopulmonary resuscitation.

OBJECTIVE: We recently demonstrated that vasopressin alone resulted in a poorer outcome in a pediatric porcine model of asphyxial cardiac arrest when compared with epinephrine alone or with epinephrine plus vasopressin in combination. Accordingly, this study was designed to differentiate whether the inferior effects of vasopressin in pediatrics were caused by the type of cardiac arrest. DESIGN: Prospective, randomized laboratory investigation that used an established porcine model for measurement of hemodynamic variables and organ blood flow. SETTING: University hospital laboratory. SUBJECTS: Eighteen piglets weighing 8-11 kg. INTERVENTIONS: After 8 mins of ventricular fibrillation and 8 mins of cardiopulmonary resuscitation, either 0.4 units/kg vasopressin (n = 6), 45 microg/kg epinephrine (n = 6), or a combination of 45 microg/kg epinephrine with 0.8 units/kg vasopressin (n = 6) was administered. Six minutes after drug administration, a second respective bolus dose of 0.8 units/kg vasopressin, 200 microg/kg epinephrine, or a combination of 200 microg/kg epinephrine with 0.8 units/kg vasopressin was given. Defibrillation was attempted 20 mins after initiating cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: Mean +/- sem left ventricular myocardial blood flow 2 mins after each respective drug administration was 65 +/- 4 and 70 +/- 13 mL x min(-1) x 100 g(-1) in the vasopressin group; 83 +/- 42 and 85 +/- 41 mL x min(-1) x 100 g(-1) in the epinephrine group; and 176 +/- 32 and 187 +/- 29 mL x min(-1) x 100 g(-1) in the epinephrine-vasopressin group (p <.006 after both doses of epinephrine-vasopressin vs. vasopressin and after the first dose of epinephrine-vasopressin vs. epinephrine, respectively). At the same times, mean +/- sem total cerebral blood flow was 73 +/- 3 and 47 +/- 5 mL x min(-1) x 100 g(-1) after vasopressin; 18 +/- 2 and 12 +/- 2 mL x min(-1) x 100 g(-1) after epinephrine; and 79 +/- 21 and 41 +/- 8 mL x min(-1) x 100 g(-1) after epinephrine-vasopressin (p <.025 after both doses of vasopressin and epinephrine-vasopressin vs. epinephrine). Five of six vasopressin-treated, two of six epinephrine-treated, and six of six epinephrine-vasopressin treated animals had return of spontaneous circulation (nonsignificant). CONCLUSIONS: In this pediatric porcine model of ventricular fibrillation, the combination of epinephrine with vasopressin during cardiopulmonary resuscitation resulted in significantly higher levels of left ventricular myocardial blood flow than either vasopressin alone or epinephrine alone. Both vasopressin alone and the combination of epinephrine with vasopressin, but not epinephrine alone, improved total cerebral blood flow during cardiopulmonary resuscitation. In stark contrast to asphyxial cardiac arrest, vasopressin alone or in combination with epinephrine appears to be of benefit after ventricular fibrillation in the pediatric porcine model.

Augmentation of ventricular preload during treatment of cardiovascular collapse and cardiac arrest.

Despite aggressive measures for the treatment of cardiovascular collapse and cardiac arrest, the hypotension associated with these malignant processes usually leads to profound vital-organ ischemia and death. A fundamental therapeutic challenge of such life-threatening processes is the restoration of adequate blood flow to the heart and the brain. However, to maintain adequate forward blood flow out of the heart, venous blood return must be drawn back into the heart. With the exception of administration of exogenous fluid replacement, there are limited ways to enhance blood flow back to the heart during prolonged hypotension. This article describes the potential value of a new impedance threshold valve for the treatment of cardiac arrest and hypotension. The valve was designed to create a vacuum within the thorax during the decompression phase of cardiopulmonary resuscitation or during inhalation. By transiently blocking inspiratory gas exchange during the decompression phase of cardiopulmonary resuscitation, after phrenic nerve-stimulated gasping, or during spontaneous ventilation, the impedance-valve concept may have clinical value in the treatment of patients in cardiac arrest, hemorrhagic shock, and cardiovascular collapse secondary to a number of life-threatening clinical processes.

Effects of active compression-decompression cardiopulmonary resuscitation with the inspiratory threshold valve in a young porcine model of cardiac arrest.

Active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) with the inspiratory threshold valve (ITV) has been recently recommended by the American Heart Association for treatment of adults in cardiac arrest (class IIb: alternative, useful intervention), but this new technique has never been used in a pediatric population. Thus, this study was designed to evaluate ACD + ITV CPR in a young porcine model of cardiac arrest. After 10 min of ventricular fibrillation, and 8 min of standard CPR, ACD + ITV CPR was performed in seven 4- to 6-wk-old pigs (8-12 kg); defibrillation was attempted 8 min later. Within 2 min after initiation of ACD + ITV CPR, mean (+/- SEM) coronary perfusion pressure increased from 18 +/- 2 to 24 +/- 3 mm Hg (p = 0.018). During standard versus ACD + ITV CPR, mean left ventricular myocardial and total cerebral blood flow was 59 +/- 21 versus 126 +/- 32 mL.min(-1).100 g(-1), and 36 +/- 7 versus 60 +/- 15 mL.min(-1).100 g(-1), respectively (p = 0.028). Six of seven animals were successfully defibrillated, and survived >15 min. In conclusion, the combination of ACD + ITV CPR significantly increased both coronary perfusion pressure and vital organ blood flow after prolonged standard CPR in this young porcine model of ventricular fibrillation.

Use of an inspiratory impedance valve improves neurologically intact survival in a porcine model of ventricular fibrillation.

BACKGROUND: This study evaluated the potential for an inspiratory impedance threshold valve (ITV) to improve 24-hour survival and neurological function in a pig model of cardiac arrest. METHODS AND RESULTS: Using a randomized, prospective, and blinded design, we compared the effects of a sham versus active ITV on 24-hour survival and neurological function. After 6 minutes of ventricular fibrillation (VF), followed by 6 minutes of cardiopulmonary resuscitation (CPR) with either a sham or an active valve, anesthetized pigs received 3 sequential 200-J shocks. If VF persisted, they received epinephrine (0.045 mg/kg), 90 seconds of CPR, and 3 more 200-J shocks. A total of 11 of 20 pigs (55%) in the sham versus 17 of 20 (85%) in the active valve group survived for 24 hours (P<0.05). Neurological scores were significantly higher with the active valve; the cerebral performance score (1=normal, 5=brain death) was 2.2+/-0.2 with the sham ITV versus 1.4+/-0.2 with the active valve (P<0.05). A total of 1 of 11 in the sham versus 12 of 17 in the active valve group had completely normal neurological function (P<0.05). Peak end-tidal CO2 (PETCO2) values were significantly higher with the active valve (20.4+/-1.0) than the sham (16.8+/-1.5) (P<0.05). PETCO2 >18 mm Hg correlated with increased survival (P<0.05). CONCLUSIONS: Use of a functional ITV during standard CPR significantly improved 24-hour survival rates and neurological recovery. PETCO2 and systolic blood pressure were also significantly higher in the active valve group. These data support further evaluation of ITV during standard CPR.