James Ashton

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.

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)

A model for regional blood flow measurements during cardiopulmonary resuscitation in a swine model.

Recent reports examining regional blood flow during cardiopulmonary resuscitation (CPR) have been criticized for several reasons: (1) cardiac arrest times of 5 min or less are not reflective of the prehospital setting, (2) anesthetic agents may significantly influence autonomic control of regional blood flow, (3) canine cardiac anatomy and coronary blood supply are not reflective of humans and (4) precise validation data for blood flow measurements have not been reported. This study presents a methodology and model for measuring regional blood flow during CPR after a prolonged cardiac arrest. Fifteen swine weighing 15-25.4 kg were instrumented for regional blood flow measurements using tracer microspheres. Regional cerebral and myocardial blood flow were measured during normal sinus rhythm (NSR) and during CPR following a 10-min cardiopulmonary arrest. Regional blood flow (ml/min/100 g) to the cerebral cortices averaged less than 3% of baseline flow (NSR: right cortex = 41.2 +/- 13.8; left cortex = 41.2 +/- 12.2; CPR: right cortex = 1.3 +/- 1.2; left cortex = 1.3 +/- 1.3). Total myocardial blood flow averaged less than 5% of baseline flow (NSR = 211.5 +/- 104.9; CPR = 9.5 +/- 14.9). The flow data demonstrates minimal cardiac and cerebral perfusion with standard CPR following a 10-min arrest. The variability in the pilot data may be used in determining sample sizes for future studies.

The effect of norepinephrine versus epinephrine on myocardial hemodynamics during CPR

Alpha-adrenergic agonists improve myocardial blood flow during CPR by increasing aortic diastolic pressure. Adrenergic agonists with beta-2 properties may enhance peripheral vasodilation and may prove less beneficial during CPR. The purpose of this study was to compare epinephrine (E), an alpha-1,2; beta-1,2 agonist, versus norepinephrine, an alpha-1,2; beta-1 agonist, on myocardial hemodynamics during CPR. Twenty swine were instrumented for pressure, arterial and coronary sinus oxygen content (CAO 2 and CCSO 2 , respectively), and myocardial blood flow measurements using tracer microspheres. CAO 2 , CCSO 2 , myocardial blood flow, myocardial oxygen delivery (MDO 2 ) and myocardial oxygen consumption (MVO 2 ), extraction ratio, and aortic diastolic pressure were determined during normal sinus rhythm and during CPR following a ten-minute arrest. After three minutes of CPR, the animals were allocated to receive either norepinephrine 0.08 mg/kg (n = 5), norepinephrine 0.12 mg/kg (n = 5), norepinephrine 0.16 mg/kg (n = 5), or epinephrine 0.20 mg/kg (n = 5). One minute after drug administration, all hemodynamic parameters were again determined. Three and one half minutes after drug administration defibrillation was attempted. A Newman-Keuls multiple comparison procedure was used to compare differences following drug administration. During CPR, aortic diastolic pressure averaged less than 13 mm Hg, and myocardial blood flow averaged less than 6 mL/min/100 g. All doses of norepinephrine and epinephrine improved all hemodynamic parameters over those seen during CPR. The two highest doses of norepinephrine significantly improved extraction ratio compared with norepinephrine 0.08 mg/kg ( P = .04). Epinephrine 0.20 mg/kg, norepinephrine 0.12 mg/kg, and 0.16 mg/kg significantly improved aortic diastolic pressure ( P = .007) and coronary perfusion pressure ( P = .012) compared with norepinephrine 0.08 mg/kg. With the two largest doses of norepinephrine, myocardial blood flow averaged 94 to 101 mL/min/100 g; average myocardial blood flow with epinephrine 0.20 mg/kg was 69 mL/min/100 g, and myocardial blood flow with norepinephrine 0.08 mg/kg was 35 mL/min/100 g. All the animals were defibrillated successfully with norepinephrine 0.12 and 0.16 mg/kg, 80% with epinephrine, and 40% with norepinephrine 0.08 mg/kg. Although equipressor doses of epinephrine 0.20 mg/kg and norepinephrine 0.16 mg/kg produced statistically similar hemodynamics, a trend toward improved myocardial blood flow and successful defibrillation rates was noted with norepinephrine 0.16 mg/kg. This trend also was noted with norepinephrine 0.12 mg/kg. Thus, alpha-adrenergic agonists such as norepinephrine, which lack beta-2 agonist properties, may be hemodynamically more beneficial during CPR than alpha-adrenergic agonists such as epinephrine with beta-2 activity.

The effect of norepinephrine versus epinephrine on regional cerebral blood flow during cardiopulmonary resuscitation

alpha-Adrenergic drugs improve cerebral blood flow (CBF) during cardiopulmonary resuscitation (CPR), in part, by reversing carotid artery collapse and by shunting blood from extracerebral to intracerebral vascular structures. Adrenergic drugs with beta 2-agonist properties may cause peripheral vasodilation, and thus may be less beneficial in this setting. The purpose of this study was to compare epinephrine (E), an alpha 1,2, beta 1,2-agonist, with norepinephrine (NE), an alpha 1,2, beta 1-agonist, on CBF during CPR. Twenty swine each weighing greater than 15 kg were instrumented for regional CBF measurements using tracer microspheres. Regional CBF was measured during normal sinus rhythm (NSR). Animals were then placed into ventricular fibrillation (VF). After ten minutes of VF, the animals received closed-chest CPR using a mechanical thumper. Regional CBF was measured during CPR. After three minutes of CPR, the animals were allocated to receive either E, 0.20 mg/kg (N = 5); NE, 0.08 mg/kg (N = 5); NE, 0.12 mg/kg (N = 5); or NE, 0.16 mg/kg (N = 5). Regional blood flows were again measured following drug administration. CBFs following drug administration were compared using an analysis of covariance adjusting for baseline differences during CPR. A Newman-Keuls multiple comparison was used to follow-up significant (P less than or equal to .05) differences. Statistical significance was considered at P less than or equal to .05. There was a clinically significant improvement in cerebral cortical flow with NE, 0.12 mg/kg, and NE, 0.16 mg/kg, compared with NE, 0.08 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of direct mechanical ventricular assistance on myocardial hemodynamics during ventricular fibrillation

Direct mechanical ventricular assistance (DMVA) is a method of biventricular circulatory support that employs a pneumatic device to apply both systolic and diastolic forces directly to the ventricular myocardium. This study investigated the effects of DMVA on myocardial hemodynamics when applied after a prolonged cardiopulmonary arrest. Seven swine weighting 28.3 +/- 2.5 kg were instrumented for regional myocardial blood flow (MBF) measurements using tracer microspheres. Ventricular fibrillation was then induced. After 10 min of ventricular fibrillation, CPR was initiated for 3 min. DMVA was then applied through median sternotomy. Defibrillation was attempted after 3.5 min of DMVA. If unsuccessful, DMVA was instituted for another 17.5 min and a subsequent defibrillation attempt was made. Arterial oxygen content (CaO2), coronary sinus oxygen content (CcSO2), myocardial oxygen delivery/consumption (mDO2/mVO2), extraction ratio (ER), and endocardial/epicardial blood flow ratio (EN/EP) were determined during CPR, during the initial application of DMVA (DMVA1), and after the subsequent 17.5 min of DMVA in those animals not initially defibrillated (DMVA2). Three of the seven animals were successfully defibrillated during DMVA1. After the additional 17.5 min of DMVA, only one other animal was defibrillated. There was a significant improvement in CaO2, CcSO2, MBF, mDO2, mVO2, ER, and EN/EP after DMVA1 compared to CPR. Only mVO2 and ER improved significantly after DMVA2. These findings support the concept that physical diastolic augmentation may improve myocardial hemodynamics when DMVA is applied during cardiac arrest.

Statistical reasoning in clinical trials: hypothesis testing

Hypothesis testing is based on certain statistical and mathematical principles that allow investigators to evaluate data by making decisions based on the probability or implausibility of observing the results obtained. However, classic hypothesis testing has its limitations, and probabilities mathematically calculated are inextricably linked to sample size. Furthermore, the meaning of the p value frequently is misconstrued as indicating that the findings are also of clinical significance. Finally, hypothesis testing allows for four possible outcomes, two of which are errors that can lead to erroneous adoption of certain hypotheses: 1. The null hypothesis is rejected when, in fact, it is false. 2. The null hypothesis is rejected when, in fact, it is true (type I or alpha error). 3. The null hypothesis is conceded when, in fact, it is true. 4. The null hypothesis is conceded when, in fact, it is false (type II or beta error). The implications of these errors, their relation to sample size, the interpretation of negative trials, and strategies related to the planning of clinical trials will be explored in a future article in this journal.

The effect of UK14,304-18 (an alpha-2 adrenergic agonist) on myocardial blood flow during cardiopulmonary resuscitation☆

Several recent studies have suggested that adrenergic drugs with peripheral postsynaptic alpha-2 agonist properties increase aortic diastolic pressure (ADP), and thus in the setting of CPR, may improve myocardial blood flow (MBF). This preliminary study investigated the effect of UK14,304-18, a postsynaptic alpha-2 adrenergic agonist on ADP, MBF, myocardial oxygen delivery/utilization (MDO2/MVO2), endocardial/epicardial blood flow ratio (EN/EP), coronary sinus oxygen content (CcsO2) and extraction ratio (ER) during CPR. Five swine were instrumented for MBF measurements using tracer microspheres. Catheters were also placed to measure arterial oxygen content (CaO2) and CcsO2. ADP, MBF, MDO2/MVO2, EN/EP, ER, CaO2 and CcsO2 were measured during normal sinus rhythm (NSR), and during CPR following a 10-min cardiorespiratory arrest. Following this, each animal received 2.0 mg/kg of UK14,304-18 through a right atrial line. ADP, MBF, MDO2/MVO2, EN/EP, ER, CaO2 and CcsO2 were again determined. Defibrillation was then attempted. To determine whether UK14,304-18 improved ADP, MBF and MDO2 over MVO2, compared to CPR alone, results were compared using a paired Student t-test. Statistical significance was considered at the P less than or equal to 0.05 level. No significant improvement in ADP, MBF, MDO2 or ER was noted following the administration of UK14,304-18. The lack of improvement in ADP and MBF may be secondary to a centrally acting postsynaptic alpha-2 agonist effect because of disruption of the blood brain barrier following a prolonged cardiac arrest or because of pharmacologically or structurally distinct populations of peripheral postsynaptic alpha-2 adrenoreceptors that develop in this setting.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effect of Norepinephrine Versus Epinephrine on Myocardial Hemodynamics During CPR

Alpha-adrenergic agonists improve myocardial blood flow during CPR by increasing aortic diastolic pressure. Adrenergic agonists with beta-2 properties may enhance peripheral vasodilation and may prove less beneficial during CPR. The purpose of this study was to compare epinephrine (E), an alpha-1,2; beta-1,2 agonist, versus norepinephrine, an alpha-1,2; beta-1 agonist, on myocardial hemodynamics during CPR. Twenty swine were instrumented for pressure, arterial and coronary sinus oxygen content (CAO2 and CCSO2, respectively), and myocardial blood flow measurements using tracer microspheres. CAO2, CCSO2, myocardial blood flow, myocardial oxygen delivery (MDO2) and myocardial oxygen consumption (MVO2), extraction ratio, and aortic diastolic pressure were determined during normal sinus rhythm and during CPR following a ten-minute arrest. After three minutes of CPR, the animals were allocated to receive either norepinephrine 0.08 mg/kg (n = 5), norepinephrine 0.12 mg/kg (n = 5), norepinephrine 0.16 mg/kg (n = 5), or epinephrine 0.20 mg/kg (n = 5). One minute after drug administration, all hemodynamic parameters were again determined. Three and one half minutes after drug administration defibrillation was attempted. A Newman-Keuls multiple comparison procedure was used to compare differences following drug administration. During CPR, aortic diastolic pressure averaged less than 13 mm Hg, and myocardial blood flow averaged less than 6 mL/min/100 g. All doses of norepinephrine and epinephrine improved all hemodynamic parameters over those seen during CPR. The two highest doses of norepinephrine significantly improved extraction ratio compared with norepinephrine 0.08 mg/kg (P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)