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Current Medical Research Programs

 

Hypothermic Reperfusion after Ischemia Improves Ventricular Myocyte Contractility and Intracellular Ca2+ Dynamics 

An energy-sparing effect of hypothermia has been described, such that lowering the temperature may lead to increases in cardiac work without increases in energy cost. We have recently reported improved myocardial function with hypothermia following resuscitation from cardiac arrest. In the present investigation, we hypothesized that reductions in reperfusion temperature from 37°C to 30°C after 10 minutes of ischemia would minimize the decreases in myocyte contractility and intracellular Ca2+ transients. Results: Hypothermic reperfusion following ischemia improved myocyte contractility. Increased myocyte intracellular Ca2+ dynamics during hypothermia accounted for the greater cell contractility.

 

 

Hypothermia Improves Ventricular Myocyte Sensitivity to Extracellular Ca2+

We have previously reported that hypothermia minimizes the impairment of myocyte contractility following ischemia. In the present study, we investigated the mechanisms accounting for these reduced impairments in contractility. We hypothesized that hypothermia would increase myocyte sensitivity to extracellular Ca2+ under conditions of normal perfusion and following reperfusion after ischemia. Results: Hypothermia increased myocyte sensitivity to extracellular Ca2+ content, and this accounted for greater contractility. Hypothermic reperfusion after ischemia maintained greater responsiveness of myocyte contractility to extracellular Ca2+ content, in comparison to normothermic reperfusion.

 

 

Current-Based Impedance Compensation Outperformed Duration-Based Technique in Defibrillation Efficacy in a High Impedance Pig Model

Transthoracic impedance (TI) for defibrillation varies widely in patients with a median value of approximately 95-100 ohms. High impedance patients are more difficult to defibrillate. The modern generation of external defibrillators therefore adjusts defibrillation output based on patient impedance measurement prior to shock delivery (impedance compensation). Commercial external defibrillators use different impedance compensation methods (ICM). Defibrillator A (DefA, rectilinear biphasic waveform) controls current with maximum E=200 Joules; Defibrillator B (DefB, truncated exponential waveform) increases shock duration with maximum E=360 Joules. The purpose of the study is to assess the effect of two ICM on defibrillation success for TI>100ohms. Results: For TI greater than average, the current-based compensation technique was much more efficient than the duration-based technique; higher defibrillation current, not higher energy from extending shock duration resulted in higher defibrillation success.

 

 

Nasopharyngeal Cooling Improves Coronary Perfusion Pressure and Amplitude Spectrum Area during CPR in Comparison to Systemic Cold Saline Infusion in a Porcine Model of Prolonged Cardiac Arrest

 

We have previously demonstrated that nasopharyngeal cooling (NPC) initiated during CPR improves the success of resuscitation. In the present study, we compared the effects of NPC with cold saline infusion (CSI) on hemodynamics, amplitude spectrum area (AMSA) during CPR and ultimate resuscitation outcome in a porcine model of prolonged cardiac arrest. We hypothesized that NPC would yield better resuscitation outcome when compared to CSI when both were initiated during CPR. Results: In this model, NPC improved hemodynamics and AMSA during CPR and this was associated with increases in the success of resuscitation.

 

 

 

Resuscitation Blanket during CPR for “Hands-on” Defibrillation

Uninterrupted chest compression has been recognized as a important factor for improving cardiopulmonary resuscitation (CPR) outcomes. We therefore introduced a resuscitation blanket made from insulating material which allows for uninterrupted chest compressions during shock delivery. We hypothesized that the resuscitation blanket used during CPR is safe, feasible and efficient to protect the rescuer from the risk of receiving current during defibrillation and therefore allowing performance of continuous chest compressions during CPR. Results: The resuscitation blanket allows for continuous precordial compression without interruption for delivering a defibrillation shock. It therefore minimizes the hands-off interruptions of chest compression and improves hemodynamics prior to delivering of an electrical shock and ultimately increases the defibrillation success.

Table.  Measurements from 15 Hand-on Shocks During External Defibrillation

Shock energy(J)

(n=5)

Voltage delivered(V) (n=5)

Current

delivered  (A) (n=5)

Voltage above the blanket(V)

(n=5)

Mean leakage current(μA) (n=5)

150

1610

32.2

42.0 ± 5.4†

1.1 ± 0.2‡

200

1835

36.7

56.6 ± 21.8†

1.4 ± 0.5‡

360

1995

39.9

105.0 ± 35.1†

3.3 ± 0.6‡

 Values expressed as mean ± SD. P<0.01 compared to “voltage delivered”; P<0.01 compared to “current delivered”;

 

 

Mild hypothermia minimized the adverse effects of epinephrine 

Epinephrine is administered during cardiac arrest to increase coronary perfusion and therefore favor return of spontaneous circulation (ROSC).  Experimentally, the a1 and b adrenergic actions of epinephrine increase the severity of post resuscitation myocardial dysfunction and thereby reduce the duration of post resuscitation survival. We have previously demonstrated that therapeutic hypothermia after ROSC improves both post resuscitation myocardial and neurological function. In the present study, we investigated the combined effects of epinephrine and hypothermia. We hypothesized that hypothermia minimizes the detrimental effects of epinephrine on post resuscitation myocardial dysfunction and favors survival. Results: Except for one control animal, all were resuscitated. Post resuscitation (PR) ejection fraction (EF), neurological deficit scores (NDS) and survivals were significantly greater after both epinephrine and hypothermia. These findings provide evidence that mild hypothermia minimized the adverse effects of epinephrine on post-resuscitation neurological and myocardial functions and favored better survival.

EF, %

Baseline

PR1hrs      

PR2hrs      

PR4hrs

Control

75

51±6*#     

38±11*#     

32±6*#

EPI

76

42±15*#   

45±9*#       

36±6*#

C+H

75

66±5*       

65±6*         

59±8*

EPI+H

76

75±4

75±3           

71±4

Survival            

72hrs

1month

24hrsNDS

48hrsNDS

Control

37*#   

1/5*#       

228(3)*#     

231*#

EPI

23*#   

1/5*#       

185(1)         

115

C+H

>72    

4/5*

123*            

69

EPI+H

>72   

5/5

63

30

*p<0.05 vs EPI+H, #p<0.05 vs C+H.

 

 

 

Hypothermia initiated during cardiac arrest and CPR also reduced myocardial ischemic injury

Therapeutic hypothermia following return of spontaneous circulation (ROSC) improves neurological outcome and survival. In the present study, we examined the effects of therapeutic hypothermia initiated during cardiac resuscitation on the severity of global myocardial ischemic injury. We hypothesized that therapeutic hypothermia decreases myocardial ischemic injury and thereby further improves the outcomes of CPR. Results: Significantly better echocardiographically measured cardiac output (CO) and myocardial performance index (MPI) were observed in the hypothermia group.  The magnitude of ST segment elevation and the incidence of recurrent VF (8±6 vs 0.6±0.5, p<0.05) were significantly reduced in comparison with normothermic animals  and resulted in significantly higher 7 day survival rates (1/5 vs 5/5, p<0.01). We conclude that therapeutic hypothermia initiated during cardiac arrest and CPR also reduced myocardial ischemic injury and thereby contributed to improved survival.

MPI

Baseline

PR1hrs      

PR4hrs

PR24hrs

NT

0.62±.06

1.13±.07*

1.4±.32*

1.18±.2*

H

0.60±.09

0.85±.1

0.9±.06

0.85±.1

CO, ml/min

 

 

 

NT

114±17         

61±9*        

  81±15*      

  67±15*

H

112±13

81±12      

102±9        

106±26

ST segment

 

 

 

NT

 

0.06±.01*

0.08±.02*

 

H

 

0.04±.01  

0.05±.01

 

  *p<0.05 vs H. PR= postresuscitation

 

Comparison between Invasive and Noninvasive Assessment of Myocardial Function in A Rat Model of Cardiac Arrest and CPR

Placement a pressure catheter into the left ventricle for monitoring myocardial function is a standard technique in animal models of cardiac arrest and CPR. However, this technique is invasive and time-limited. We therefore sought to compare this approach with the noninvasive echocardiographic assessment for monitoring myocardial function in rat model of cardiac arrest and CPR. We hypothesized that echocardiographically assessed myocardial function would be correlated to the invasive left ventricular function measurements. Results: All animals were successfully resuscitated. Both dP/dt40 and EF were significantly decreased after resuscitation (P < 0.05). The noninvasive assessed EF was highly correlated to dP/dt40 (R=0.75, P<0.01).  The echocardiographically assessed myocardial function is significantly correlated with the standard invasive monitoring measurements in a rat model of cardiac arrest and CPR.

 

 

AMSA is decreased during cardiac arrest and CPR, in rats with chronic ischemic heart

Ventricular fibrillation (VF) waveform features are altered in instance of acute myocardial ischemia and chronic coronary heart disease. Amplitude Spectrum Area (AMSA), in particular, have been investigated under conditions of electrical induced cardiac arrest or under condition of acute myocardial ischemia. However, no data on AMSA values during cardiac arrest in heart suffering of chronic ischemia have been previously investigated. In the present study we sought to investigate AMSA during VF induced in rats with chronic myocardial ischemia in comparison to that observed in rats with normal myocardium. Results: AMSA values are significantly decreased in rats with chronic ischemic heart in comparison to those assessed in rat with not ischemic heart. 

 

 

Apoptosis is not involved in the mechanisms of postresuscitation myocardial dysfunction in a rat model of cardiac arrest and CPR

Postresuscitation myocardial dysfunction (PRMD) has been recognized as the main cause of early death after successful resuscitation from cardiac arrest. However, the mechanisms of PRMD remain controversial. Since myocyte apoptosis plays an important role in myocardial dysfunction following ischemia/reperfusion, it has also been proposed as a potential mechanism of PRMD. We therefore investigated the presence of apoptosis during either cardiac arrest/cardiopulmonary resuscitation (CPR) or myocardial ischemia/reperfusion and related it to the severity of postresuscitation myocardial dysfunction. Results: Myocardial function was significantly impaired after both resuscitation from cardiac arrest and reperfusion from LAD occlusion (P<0.01). There was no difference in percentage of apoptotic cells between CPR animals and sham operated animals. However, greater apoptosis (P<0.05) was observed in animals subjected to LAD occlusion. Apoptosis, therefore, was not involved in the mechanism of postresuscitation myocardial dysfunction. both resuscitation from cardiac arrest and reperfusion from LAD occlusion (P<0.01). There was no difference in percentage of apoptotic cells between CPR animals and sham operated animals. However, greater apoptosis (P<0.05) was observed in animals subjected to LAD occlusion. Apoptosis, therefore, was not involved in the mechanism of postresuscitation myocardial dysfunction.

 

 

 

Comparison of myocardial function between global myocardial ischemia of cardiac arrest and regional myocardial ischemia in rats

Both global myocardial ischemia following cardiac arrest (CA) and regional myocardial ischemia induced by left anterior descending coronary artery (LAD) occlusion lead to myocardial dysfunction following reperfusion. We therefore sought to compare myocardial function during the reperfusion interval following resuscitation from cardiac arrest or reperfusion from LAD occlusion. We hypothesized that myocardial dysfunction would be more severe in animals resuscitated from cardiac arrest in comparison to animals subjected to LAD ligation. Results: Myocardial dysfunction was significantly more severe following global myocardial ischemia even though the duration of ischemia was significantly short.

 *, P<0.05 vs LAD group; **, p<0.01 vs LAD group. ISC= ischemia

 

 

 

The effects of waveform duration on efficacy of a dual time constant biphasic truncated exponential defibrillation waveform

The effects of the first and the second phase durations of a biphasic truncated exponential (BTE) waveform on defibrillation success were evaluated in a guinea pig model of ventricular fibrillation (VF). We hypothesized that the waveform duration, and especially the first phase duration, plays the main role for defibrillation efficacy in comparison to energy, current and voltage, when a dual time constant BTE shock is employed. Results: For dual time constant BTE waveforms, an intermediate first phase duration,   yielded the best defibrillation efficacy with less energy, current, and voltage compared to shorter or longer durations.

 

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