Robert L. Hamlin

The effects of graded doses of epinephrine on regional myocardial blood flow during cardiopulmonary resuscitation in swine

Although epinephrine has been shown to improve myocardial blood flow during cardiopulmonary resuscitation (CPR), the effects of standard as well as larger doses of epinephrine on regional myocardial blood flow have not been examined. In this study we compared the effects of various doses of epinephrine on regional myocardial blood flow after a 10 min arrest in a swine preparation. Fifteen swine weighing greater than 15 kg each were instrumented for regional myocardial blood flow measurements with tracer microspheres. Regional blood flow was measured during normal sinus rhythm. After 10 min of ventricular fibrillation, CPR was begun and regional myocardial blood flow was determined. Animals were then randomly assigned to receive 0.02, 0.2, or 2.0 mg/kg epinephrine by peripheral injection. One minute after drug administration, regional myocardial blood flow measurements were repeated. The adjusted regional myocardial blood flows (ml/min/100 g) for animals given 0.02, 0.2, and 2.0 mg/kg epinephrine, respectively, were as follows: left atrium, 0.9, 67.4, and 58.8; right atrium, 0.3, 46.2, and 38.5; right ventricle, 0.7, 82.3, and 66.9; right interventricular septum, 1.7, 125.5, and 99.1; left interventricular septum, 2.8, 182.8, 109.5; mesointerventricular septum, 16.8, 142.2, and 79.2; left ventricular epicardium, 19.2, 98.5 and 108.7; left ventricular mesocardium, 22.8, 135.0, and 115.8; and left ventricular endocardium, 2.5, 176.1, and 132.9). All comparisons between the groups receiving 0.02 and 0.2 mg/kg epinephrine were statistically significant (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effect of graded doses of epinephrine on regional brain blood flow during CPR in a swine model

Cerebral blood flow (CBF) with conventional closed-chest cardiopulmonary resuscitation (CCPR) has been measured at only 2% to 11% of prearrest values. The purpose of our study was to determine whether the peripheral administration of higher doses of epinephrine than currently recommended during CCPR following a prolonged cardiac arrest improves CBF compared to CCPR using a standard dose of epinephrine. Fifteen swine were randomized to receive CCPR plus 0.02 mg/kg, 0.2 mg/kg, or 2.0 mg/kg epinephrine through a peripheral IV line following a ten-minute cardiopulmonary arrest and three minutes of CCPR. Regional CBF measurements were made by radionuclide microsphere technique during normal sinus rhythm (NSR), CCPR, and following epinephrine administration. The adjusted regional blood flows (in mL/min/100 g) following epinephrine administration for the 0.02-, 0.2-, and 2.0-mg/kg groups were, respectively, left cerebral cortex (3.3, 13.1, 11.8); right cerebral cortex (3.9, 13.8, 12.2); cerebellum (9.2, 32.0, 33.1); midbrain/pons (9.9, 32.1, 32.3); medulla (10.6, 61.5, 54.2); and cervical spinal cord (12.2, 53.8, 35.8). In this swine model, 0.2 mg/kg and 2.0 mg/kg epinephrine significantly increased regional CBF over that seen with standard doses. Because neuronal survival is dependent on flow rates of 10 to 15 mL/min/100 g, this preliminary evidence suggests that these higher doses of epinephrine may help improve neurological outcome in CCPR.

Cognitive, cardiac, and physiological safety studies in ultra high field magnetic resonance imaging.

A systematic analysis of the effect of an 8.0 tesla static magnetic field on physiological and/or cognitive function is presented in the normal volunteer and in the swine. A study of ten human subjects revealed no evidence of detectable changes in body temperature, heart rate, respiratory rate, systolic pressure, and diastolic blood pressure after 1 hour of exposure. In addition, no cognitive changes were detected. Important ECG changes were noted which were related both to the position of the subject in the magnet and to the absolute strength of the magnetic field. As such, the ECG tracing at 8 tesla was not diagnostically useful. Nonetheless, all subjects exhibited normal ECG readings both before and following exposure to the 8 tesla field. Cardiac function was also examined in detail in the swine. No significant changes in body temperature, heart rate, left ventricular pressure, left ventricular end diastollic pressure, time rate of change of left ventricular pressure, myocardial stiffness index, cardiac output, systolic volume, troponin, and potassium levels could be detected following 3 h of exposure to a field strength of 8.0 tesla. It is concluded that no short term cardiac or cognitive effects are observed following significant exposure to a magnetic field of up to 8.0 tesla.

Response of Failing Canine and Human Heart Cells to β2-Adrenergic Stimulation

Background Failing human hearts lose β1- but not β2-adrenergic receptors. In canine hearts with tachypacing failure, the ratio of β2- to β1-adrenergic receptors is increased. The present study was designed to determine whether heart failure increases sensitivity to β2-adrenergic stimulation in isolated canine ventricular cardiomyocytes and to verify that myocytes from failing human ventricles contain functional β2-adrenergic receptors. Methods and Results Myocytes from healthy dogs, dogs with tachypacing failure, and human transplant recipients were loaded with fura 2-AM and subjected to electric field stimulation in the presence of zinterol, a highly selective β2-adrenergic agonist. Zinterol significantly increased [Ca2+]i transient amplitudes in all three groups. The failing canine myocytes were significantly more responsive than normal to β2-adrenergic stimulation. We also measured isotonic twitches, indo-1 fluorescence transients, and L-type Ca2+ currents in healthy canine myocytes. Zinterol (10−5 mol...

Atrial Glutathione Content, Calcium Current, and Contractility

Atrial fibrillation (AF) is characterized by decreased L-type calcium current (ICa,L) in atrial myocytes and decreased atrial contractility. Oxidant stress and redox modulation of calcium channels are implicated in these pathologic changes. We evaluated the relationship between glutathione content (the primary cellular reducing moiety) and ICa,L in atrial specimens from AF patients undergoing cardiac surgery. Left atrial glutathione content was significantly lower in patients with either paroxysmal or persistent AF relative to control patients with no history of AF. Incubation of atrial myocytes from AF patients (but not controls) with the glutathione precursor N-acetylcysteine caused a marked increase in ICa,L. To test the hypothesis that glutathione levels were mechanistically linked with the reduction in ICa,L, dogs were treated for 48 h with buthionine sulfoximine, an inhibitor of glutathione synthesis. Buthionine sulfoximine treatment resulted in a 24% reduction in canine atrial glutathione content, a reduction in atrial contractility, and an attenuation of ICa,L in the canine atrial myocytes. Incubation of these myocytes with exogenous glutathione also restored ICa,L to normal or greater than normal levels. To probe the mechanism linking decreased glutathione levels to down-regulation of ICa, the biotin switch technique was used to evaluate S-nitrosylation of calcium channels. S-Nitrosylation was apparent in left atrial tissues from AF patients; the extent of S-nitrosylation was inversely related to tissue glutathione content. S-Nitrosylation was also detectable in HEK cells expressing recombinant human cardiac calcium channel subunits following exposure to nitrosoglutathione. S-Nitrosylation may contribute to the glutathione-sensitive attenuation of ICa,L observed in AF.

The Relationship Between Arrhythmogenesis and Impaired Contractility in Heart Failure: Role of Altered Ryanodine Receptor Function

AIMS In heart failure (HF), abnormal myocyte Ca(2+) handling has been implicated in cardiac arrhythmias and contractile dysfunction. In the present study, we investigated the relationships between Ca(2+) handling, reduced myocyte contractility, and enhanced arrhythmogenesis during HF progression in a canine model of non-ischaemic HF. METHODS AND RESULTS Key Ca(2+) handling parameters were determined by measuring cytosolic and intra-sarcoplasmic reticulum (SR) [Ca(2+)] in isolated ventricular myocytes at different stages of HF. The progression of HF was associated with an early and continuous increase in ryanodine receptor (RyR2)-mediated SR Ca(2+) leak. The increase in RyR2 activity was paralleled by an increase in the frequency of diastolic spontaneous Ca(2+) waves (SCWs) in HF myocytes under conditions of β-adrenergic stimulation. In addition to causing arrhythmogenic-delayed afterdepolarizations, SCWs decreased the amplitude of subsequent electrically evoked Ca(2+) transients by depleting SR Ca(2+). At late stages of HF, Ca(2+) release oscillated essentially independent of electrical pacing. The increased propensity for the generation of SCWs in HF myocytes was attributable to reduced ability of the RyR2 channels to become refractory following Ca(2+) release. The progressive alterations in RyR2 function and Ca(2+) cycling in HF myocytes were associated with sequential modifications of RyR2 by CaMKII-dependent phosphorylation and thiol oxidation. CONCLUSION These findings suggest that destabilized RyR2 activity due to excessive CaMKII phopshorylation and oxidation resulting in impaired post-release refractoriness is a common mechanism involved in arrhythmogenesis and contractile dysfunction in the failing heart.

Transgenic mice with cardiac-specific expression of activating transcription factor 3, a stress-inducible gene, have conduction abnormalities and contractile dysfunction.

Activating transcription factor 3 (ATF3) is a member of the CREB/ATF family of transcription factors. Previously, we demonstrated that the expression of the ATF3 gene is induced by many stress signals. In this report, we demonstrate that expression of ATF3 is induced by cardiac ischemia coupled with reperfusion (ischemia-reperfusion) in both cultured cells and an animal model. Transgenic mice expressing ATF3 under the control of the alpha-myosin heavy chain promoter have atrial enlargement, and atrial and ventricular hypertrophy. Microscopic examination showed myocyte degeneration and fibrosis. Functionally, the transgenic heart has reduced contractility and aberrant conduction. Interestingly, expression of sorcin, a gene whose product inhibits the release of calcium from sarcoplasmic reticulum, is increased in these transgenic hearts. Taken together, our results indicate that expression of ATF3, a stress-inducible gene, in the heart leads to altered gene expression and impaired cardiac function.

Myocardial oxygen delivery/consumption during cardiopulmonary resuscitation: A comparison of epinephrine and phenylephrine

Our study compared the effect of high-dose epinephrine with the pure alpha-agonist phenylephrine on regional myocardial blood flow (MBF), myocardial oxygen delivery (MDO2), myocardial oxygen consumption (MVO2), and defibrillation rates during CPR. Fifteen swine weighing more than 15 kg were instrumented for measurement of regional MBF using radiolabeled tracer microspheres. Measurements of regional MBF, MDO2, and MVO2 were made during normal sinus rhythm. Ventricular fibrillation was induced and persisted for ten minutes. CPR was begun using a pneumatic compression device. Regional MBF, MDO2, and MVO2 were measured during CPR. Following three minutes of CPR, animals (N = 15) were allocated to one of three groups (n = 5): Group 1, epinephrine 0.2 mg/kg; Group 2, phenylephrine 0.1 mg/kg; or Group 3, phenylephrine 1.0 mg/kg. Measurements of regional MBF, MDO2, and MVO2 were repeated after drug administration. Extraction ratios, defined as MVO2/MDO2, were calculated during normal sinus rhythm, CPR, and after drug administration. Defibrillation was attempted 3 1/2 minutes after drug administration. There was no significant difference in MBF, MDO2, MVO2, and extraction ratio during normal sinus rhythm and CPR for any of the groups. Total MBF following drug administration was 67.2 +/- 49.4 mL/min/100 g for the group receiving epinephrine 0.2 mg/kg; 7.0 +/- 7.1 mL/min/100 g for the group receiving phenylephrine 0.1 mg/kg; and 36.7 +/- 21.1 mL/min/100 g for the group receiving phenylephrine 1.0 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimating the duration of ventricular fibrillation

As the duration of time between the onset of ventricular fibrillation and the application of defibrillation (downtime) increases, the rate of successful resuscitation decreases. Results of recent animal studies suggest that the rate of successful resuscitation may be increased after a prolonged cardiorespiratory arrest when pharmacologic therapy is instituted before defibrillation. An accurate estimation of downtime could be critical in selecting the most appropriate therapeutic intervention. The purpose of our study was to determine whether changes in the frequency or amplitude of the ventricular fibrillation ECG signal during cardiac arrest could be used to estimate downtime. We characterized the dynamics of both total power and frequency distribution of the power in the ECG during ventricular fibrillation in 11 swine to determine whether enough information existed in either parameter to estimate downtime. The median frequency of the power spectrum was used to track power distribution. Both parameters followed a dynamic, repeatable pattern. However, median frequency showed less intersubject variability than did total power. A mathematical model of median frequency was developed and used with data obtained from ten additional swine to estimate downtime. The model estimated downtime to within 1.3 minutes of actual downtime between one and ten minutes of ventricular fibrillation. Our study has identified a new, potentially useful parameter for studying various management strategies in ventricular fibrillation as a function of downtime.

CATEGORIZATION OF COMMON DOMESTIC MAMMALS BASED UPON THEIR VENTRICULAR ACTIVATION PROCESS

According to their time-order of ventricular activation, various mammalian species may be divided into two categories. In category A, with the dog as prototype and including also man, monkey, cat, and rat, the ventricles are excited with three general “fronts” of depolarization:‘ ’ (1) Initial depolarization (during the first 5 to 10 msec. of QRS) of an endocardia1 shell surrounding the apex of the left ventricle (although simultaneously the interventricular septum is excited from right ventricular endocardium toward the left) (FIGURES 1A and 1B). (2) Depolarization of both ventricular free walls (during the next 15 msec. of QRS) from subendocardial terminations of the Purkinje fibers toward the epicardium (FIGURE 2A). (3) Terminal depolarization of the bases of both ventricles and of the interventricular septum (during the last 5 msec. of QRS) in a general apicobasilar direction (FIGURE 3A). I n category B, with the goat as prototype and containing also the horse, cow, pig, and sheep, ventricular activation proceeds with only two general “fronts” of dep~lar iza t ion :~ .~ (1) Initial activation almost identical with “front” 1 of category A (FIGURES 1A and B). (2) Terminal depolarization of the middle and basilar thirds of the interventricular septum (during the final 40 msec. of QRS) in a general apicobasilar direction (although during activation of the middle third, a small volume of myocardium comprising the extreme epicardial base [and one near the apex], of the left ventricle is activated simultaneously in a subepicardial to epicardial direction (FIGURE 2B). At a time confluent with the ending of “front” 1 and the beginning of “front” 2 (approximately 15 msec. after onset of QRS), the major masses of both ventricles are excited with a single “burst” of depolarization “permitted” by more general penetration of the Purkinje fibers into the epicardium of species comprising this category.6 Since this activation occurs without spread in any particular direction (many polarity reversals exist within the free walls of the ventricles), it contributes little, if a t all, to the