In this issue:

Review: Baseline Pharmacology in Cardiac Arrest

Research Brief--Vasopressin

Warning! Dr. Smith, Warning!

Look---No Hands!

Holiday Eating-Portion Size Reminder

A Test for You: Choosing Great Leaders

Cool Web Sites

Quotable Quotes

ERDOCS e-mail group (listserv)

Financial sponsorship statement & How to contact us

Review: Baseline Pharmacology in Cardiac Arrest

The following is an interpretive summary of a review article entitled "The Pharmacology of Acute Cardiac Resuscitation" released in early 1999 and reviewed in October 2000. The full article is written by Mark D. Tasch, M.D., a Clinical Associate Professor at the Department of Anesthesia, Indiana University School of Medicine in Indianapolis, Indiana.

The complete article, with individual studies cited (some 123 different reviews and studies), is available at Anesthesiology Online and is available for up to 1.5 AMA PRA category 1 CME. If interested in viewing the entire text, or obtaining the CME (currently available at no cost), please go to http://www.anesthesiologyonline.com/navigation.cfm on the worldwide web.

Note: this article might more appropriately be entitled "Baseline Pharmacology of Acute Cardiac Resuscitation" since the discussion does not extend to antiarrhythmics or a variety of confounding special situations that may be needed to be addressed during resuscitation. It should also be noted that this article (having been initially authored in 1999) does not strictly conform to the guidelines of the most recently-released AHA Guidelines on Emergency Cardiac Care (August 2000). It does, however, provide a good historical overview of the research into a variety of agents in cardiac arrest management, particularly those that, on theory, might be useful but, in many cases, have not actually worked.

As evidence-based medicine becomes a mainstay in resuscitation guidelines, many theoretical, traditional, and animal study-based interventions are being more carefully reviewed and reclassified. To date, however, the only major impact that has held up consistently in 35 years of modern cardiac resuscitation, has been defibrillation.

Coronary Perfusion
Both clinical and laboratory studies, alike, suggest coronary perfusion pressure is the primary factor determining the success of the initial cardiac resuscitation. For example, ten years ago, a study looked at 100 cardiac arrest patients The first measured coronary perfusion pressure (defined as aortic diastolic minus right atrial pressure) was 13.4±8.5 mmHg in those who attained return of spontaneous circulation, vs. 1.6±8.5 mmHg in those who did not. Spontaneous circulation was restored in 24 of 42 patients with maximal coronary perfusion pressures of at least 15 mmHg, vs. 0 of 58 patients whose coronary perfusion pressures never reached 15 mmHg. (No patient, however, survived to be discharged from the hospital). Alpha-mediated vasoconstriction appears to be critical in increasing coronary perfusion pressure, which, in turn, can facilitate "meaningful cardiac activity." Alpha stimulation appears to enhance this perfusion the best through peripheral vasoconstriction. Beta-2 stimulation appears to "preferentially dilate larger coronary vessels" suggesting that blood is diverted from the "imperiled" sub-endocardium and shunted instead to the outer myocardium. Beta-1 stimulation increases myocardial oxygen demand and increases intraventricular pressures (furthering hindering perfusion of the subendocardium). Such activity may depress myocardium to an extent that "in canine studies of ventricular fibrillation, myocardial contractility following defibrillation was less in epinephrine-treated dogs than in dogs given phenylephrine or no drug at all."

Cerebral Perfusion
"Following normothermic circulatory arrest, cerebral oxygen supply and consciousness are both lost within 20 seconds. Cerebral glucose and ATP are depleted within 5 minutes, causing cellular membrane pump functions to fall. If perfusion is restored to the brain, further cellular injury results from chemical cascades of free radicals, ionic calcium, excitatory amino acids, and other substances. Meaningful cerebral survival requires, of course, the prompt restoration of cerebral perfusion, in the range of 10-15 ml/min/100g in both clinical and animal studies. Unfortunately, cardiopulmonary resuscitation (CPR), alone, or with standard-dose epinephrine (0.01-0.02 mg/kg), has been shown to provide the cerebral cortex with only 1-2 ml/min/100g of blood flow. This is associated with the finding of profoundly decreased cerebral perfusion pressures in humans during CPR with standard-dose epinephrine." While b-adrenergic stimulation does not appear to be a factor in initial cardiac resuscitation, there is some evidence that b-2-mediated vasodilation improves cerebral microvascular blood flow. Circulation to and within the brain is affected by both alpha and beta receptor stimulation. Alpha-adrenergic stimulation seems to affect the blood flow into the brain (extracerebral), while beta receptors seem to have a greater affect within the brain (intracerebral vessels). Alpha-mediated vasoconstriction is thought to increase carotid artery pressures and may divert blood flow from extracerebral to intracerebral arteries. Despite this, a combined alpha-beta agonist, such as epinephrine does not have any clear evidence of benefit from its beta properties.

Amplitude of Ventricular Fibrillation
Beta stimulation may affect electrical defibrillation. It has been suggested that "coarsening" or increasing the amplitude of ventricular fibrillation may facilitate electrical conversion. Conflicting results regarding the reliability of amplitude in determining success or failure in defibrillation added to the fact that epinephrine does not seem to improve the chances of successful defibrillation or reduce the energy requirements for countershocks, cloud the likelihood that beta stimulation enhances this aspect of resuscitation. Tang et al., in a 1995 study of ventricular fibrillation in rats, reported that "the number of counter­shocks required for ROSC was significantly greater for epinephrine-treated animals when compared with phenylephrine-treated animals and with animals treated with epinephrine combined with esmolol" although all treatment regimens produced similar increases in coronary perfusion pressure. Animal studies have identified epinephrine-treated animals had a "significantly greater" number of countershocks required (than an alpha agonist only, or epi with beta-blocker) to get return to spontaneous circulation, the greatest depression in myocardial contractility following return of spontaneous circulation, shortest duration of survival, and in some cases roughly quintupled both myocardial oxygen consumption and delivery.

Going with the Flow
Based on several studies, most researchers now agree that critical issues in successful resuscitation (beyond defibrillation) are based on establishing and maintaining sufficient coronary and cerebral blood flow.

Catecholamines and Adrenergic Receptors
In selecting a resuscitative agent, it should first be determined whether alpha only, beta only, or mixed adrenergic stimulation is most conducive to cardiac and cerebral survival. If a combined alpha and beta agonist is to be used, there remains the question of which agent is best, in what situations, and in what dose. This now includes a hard look at an "old" standard of resuscitation-epinephrine.

The pharmacology of acute cardiac resuscitation initially focuses upon using catecholamines and targeting adrenergic receptors. Alpha 1 and 2 (a-1 and a-2) postsynaptic receptor sites stimulate constriction of vascular smooth muscle. Some research suggests that the a-2 sites may be more accessible for catecholamines during low-flow (cardiac arrest-cpr) states. Beta 1 (b-1) sites increase myocardial contractility when stimulated and beta 2 (b-2) sites cause bronchial and vascular smooth muscle relaxation when stimulated.

Epinephrine stimulates all four of these receptor sites, while norepinephrine stimulates alpha sites and b-1, but a relatively weak b-2 agonist effect. Isoproterenol is a purely b-adrenergic agonist, while phenylephrine and methoxamine selectively stimulate a-1 receptors. While epinephrine has been the catecholamine most commonly used in acute cardiac resuscitation, it has been challenged for a variety of reasons, some cited within this article; other agents have been (and are being) considered.

Methoxamine
Results in limited rat and dog studies have been promising, but when applied to porcine subjects (considered to more closely model human cardiac vasculature and electrophysiology) and in human studies, the results have been disappointing. This might be due to dosing (dogs often received 20mg, while human subjects typically got 5-10 mg).

Phenylephrine
No demonstrated advantage over epinephrine (online article expounds upon this)

Dopamine
No demonstrated advantage over epinephrine (online article expounds upon this)

Norepinephrine
Conflicting study conclusions. Among them, In swine with ventricular fibrillation, ROSC occurred in 7 of 7 given norepinephrine, vs. 6 of 7 given epinephrine. Epinephrine provided significantly more rapid resuscitation in the asystolic swine, while norepinephrine was much more rapidly effective in the fibrillating animals. Additional research is needed.

High-Dose Epinephrine
No demonstrated long-term benefits. Initial studies concerning high dose epinephrine concluded that there appeared to increase coronary perfusion pressure and the incidence of return of spontaneous circulation, but without improving long-term survival. They suggested that "it is possible that higher doses of epinephrine may be physiologically detrimental in the postresuscitation period." In findings that followed, detrimental effects have been noted resulting in a post-resuscitative state of decreased cardiac output and increased peripheral vascular resistance, as well as complications in neurological recovery. Increases in improved outcomes have not been observed (vs. standard dose epinephrine).

Non-catecholamines
Aminophylline
Mixed results in animal ventricular fibrillation studies, single study and anecdotal evidence only in human asystole/PEA; more research needed.

Aminophylline has a possible therapeutic benefit based on two proposed mechanisms. One explanation for aminophylline's pharmacologic effects was the inhibition of phosphodiesterase, which would slow the degradation of cyclic AMP, the intracellular effector whose synthesis is promoted by catecholamines. In this fashion, aminophylline might be synergistic with epinephrine or other adrenergic agents administered for resuscitation. Aminophylline is also said to be a direct, perhaps weak, competitive antagonist of adenosine. "This antagonism could be either beneficial or detrimental. Cardiac adenosine receptors have been classified as types A1, found in the myocardium, and A2, located in vascular smooth muscle. Stimulation of A1 receptors limits the cardiac responses to catecholamines, and depresses the chronotropy, automaticity, and conduction velocity of the heart's electrical system. These mechanisms could inhibit the desired resuscitative effects of catecholamine administration, but could also protect the myocardium from the hazards of undesirable and excessive metabolic demands. Alpha-2 receptors can affect coronary vasodilation, which could promote either myocardial perfusion or coronary steal. When myocardial oxygen supply is deficient, myocardial adenosine concentrations have been found to rise."

In an animal study, Adenosine substantially reduced coronary perfusion pressure during ventricular fibrillation. However, the adenosine-treated subjects were actually more likely to be successfully resuscitated than were control animals. "Either via metabolic suppression or coronary dilation, adenosine appeared to protect the fibrillating heart from the hazards of lower perfusion pressures. Inhibition of adenosine's effects might, therefore, be inadvisable in this setting."

Angiotensin II
In a porcine study, doses of 50 mcg/kg led to increases in diastolic arterial pressure and both cerebral and myocardial perfusion during CPR. In one small sudy, this angiotensin II was found to significantly increase the number of animals in whom spontaneous circulation could be restored, when compared to placebo. Angiotensin II receptors in arteriolar beds can facilitate release of endogenous catecholamines and stimulate significant peripheral vasoconstriction. Further investigation needed.

Naloxone
Despite promise in hemorrhagic and septic shock, two follow-up canine fibrillation studies failed to show any benefit.

Vasopressin
Promising anecdotal, small, retrospective, and animal studies; large multi-center trial underway. In animal studies (primarily porcine) comparing epinephrine to vasopressin---the vasopressin-treated subjects collectively showed significantly higher increases in myocardial blood flow (75-200%); and compared to high-dose epinephrine (0.2 mg/kg), vasopressin was superior in increasing left ventricular myocardial perfusion, coronary diastolic pressure, total cerebral blood flow (up to twice as much), cerebral oxygenation, as well as greater increases in peripheral vascular resistance in the early post-resuscitation period

One study also reported on the effectiveness of identical doses given intravenous and endobronchial routes, having similar increases in coronary perfusion pressure and both "facilitating" successful resuscitation, compared to placebo.

In oft-cited research, studies on 60 prehospital cardiac arrest patients found that plasma concentrations of both arginine vasopressin and adrenocorticotropic hormone were significantly greater, both before and after epinephrine administration, in short-term survivors than in nonsurvivors. The authors then administered vasopressin 40 U to 8 patients who had failed defibrillation following standard CPR and epinephrine administration. Resumption of spontaneous circulation was promptly achieved after subsequent defibrillation in all 8 non-responders to standard-dose epinephrine, with 3 of the 8 discharged neurologically intact.

Glucose, Insulin, and Potassium
A anecdotal evidence, additional studies underway. An older concept revisited; while hyperglycemia and ischemia speed anaerobic metabolism and brain injury, the concurrent administration of glucose and insulin has been proposed to improve myocardial output. A glucose-insulin combination may accelerate the synthesis of myocardial high-energy phosphates, improving the inotropic status of the heart. To counteract the glucose-insulin-driven shift of potassium from the extracellular to the intracellular compartment, a glucose-insulin-potassium (GIK) combination has been advocated. GIK has been reported anecdotally to correct refractory ventricular fibrillation.

Calcium
The administration of calcium was, for many years, was a conventional component of acute cardiac resuscitation. Most studies, however, have failed to justify such a role. Excessive intracellular [Ca++] is said to provoke myocardial "stunning" or contracture and necrosis. In perfusing patients, calcium has induced tachyarrhythmias , coronary vasospasm and ventricular ectopy. Such problems have led to the rejection of the routine use of calcium in cardiac arrest management.

Pulseless electrical activity (PEA) in the presence of a widened QRS complex may be an area where calcium may have a role in the future; at least one study suggests that more pulses returned in test subjects, (but no increase in longterm survivors was noted). Further research needs to clarify this.

Calcium is currently indicated in resuscitation cases with demonstrated hypocalcemia or hyperkalemia, or with excessive calcium channel blockade.

Magnesium
Anecdotally (with higher doses-eg., 4g) may be helpful, controlled studies fail to suggest improvement. "Magnesium ion would theoretically have both useful and detrimental properties in acute cardiac resuscitation. Magnesium stabilizes myocardial cell membranes, suppressing ventricular ectopy and tachyarrhythmias. Magnesium also antagonizes intracellular calcium, potentially averting such events as cerebral vasospasm, myocardial ischemic contracture, and reperfusion injuries. Hypomagnesemia can reportedly be found in 10-20% of hospitalized patients, and in up to 50% of those with hypokalemia. (Chronic diuretic therapy is considered to increase the likelihood of this problem.) On the other hand, magnesium's vasodilating properties can decrease cerebral and coronary perfusion pressures, impeding resuscitation or producing post-resuscitation hypotension." The routine use of magnesium in acute cardiac resuscitation cannot be supported by currently available data. Hypomagnesic states and Torsades de pointes are the only current conditions where magnesium is a recommended agent.

Summary
What really hasn't seemed to work: high dose-epinephrine, phenylephrine, metaraminol, methoxamine, mephentermine, dopamine, naloxone, and isuproterenol. Routine use of magnesium and calcium are not recommended. Since the original authoring of this article, the efficacy of standard dose epinephrine has been officially challenged and it is now classified as a Class Indeterminate intervention, by the American Heart Association] and there is inconclusive evidence regarding aminophylline, GIK, and norepinephrine, such that additional research is needed. Most promising agents include angiotensin II and vasopressin, though additional higher-level multi-center trials are necessary for validation and reliability.

Research Brief
Vasopressin improves survival after cardiac arrest in hypovolemic shock

Voelckel WG, Lurie KG, Lindner KH, Zielinski T, McKnite S, Krismer AC, Wenzel V. Cardiac Arrhythmia Center, Cardiovascular Division, Department of Medicine at the University of Minnesota, Minneapolis 55455.

"Survival after hypovolemic shock and cardiac arrest is dismal with current therapies. We evaluated the potential benefits of vasopressin versus large-dose epinephrine in hemorrhagic shock and cardiac arrest on vital organ perfusion, and the likelihood of resuscitation."

Using 18 pigs, one-third of their blood volume was removed over 15 minutes; ventricular fibrillation was induced 5 minutes later. After four minutes in cardiac arrest, standard CPR was initiated for an additional four minutes. Seven pigs were then given high dose (200 mcg/kg) of epinephrine, seven others received 0.8 units/kg of vasopressin, and the remaining four received a saline placebo. Two and one-half minutes later defibrillation was attempted. Subjects were observed for an additional one hour without intenvention. Spontaneous circulation was restored in all pigs receiving medication (except one that had been given epinephrine) and none of the pigs that received the saline placebo. Researchers noted that the vasopressin-treated group had less acidosis, better organ perfusion and greater prolonged survival.

Warning! Dr. Smith, Warning!

The patient lay unconscious on a Baltimore hospital operating table as The doctor in charge (Dr. Louis Kavoussi) sat in a convention hall booth 700 miles away in Chicago, at a computer console and video screen directing a remote-controlled robotic arm inside the patient's abdomen.

The abdominal surgery was taking place at Johns Hopkins Bayview Medical Center in Baltimore, assisted by Dr. Thomas Jarrett at the patient's side. The two physicians communicated via a microphone during the the hour-long operation.

Since his first procedure about four years ago, Kavoussi has operated long-distance from Baltimore to Thailand, Singapore, Rome and Austria. In September, from the library of his Maryland home, he helped do Robotic varicose vein surgery on a patient in Brazil.

Among the unique costs are the phone bills, since several phone lines arerequired for the computer hookups. A three-hour surgery done in Austria in1996 cost $3,500 in phone charges alone. Such costs have since dropped somewhat--the phone bill for the Singapore surgery two years later was under $2,000.

Transmission delays over phone lines are minimal; Kavoussi reported a delay of one second when he operated "remotely" from the U.S. to southeast Asia.

Look---No Hands!

At the annual clinical congress of the American College of Surgeons in October, surgeons from East Carolina University's School of Medicine in Greenville, North Carolina, said they were able to perform "keyhole" operations on the heart's mitral valve through three tiny intercostal incisions, using a three-armed computer-assisted robotic device. Similar technology has been used for years in repairs involving the knee, gall bladder and shoulder.

"With the robot, you can drive a tiny camera into the left ventricle of the heart and see and repair the subvalvular apparatus, which includes all the muscles and cords that hold the valve and the valve leaflets in place," Wiley Nifong, an assistant professor at ECU, said. "We can do very complex operations on the mitral valve and repair 75 to 80 percent of the valves we previously had to replace."

During the surgery, the robot is at the patient's side at the operating table while the surgeon sits at a computer, controlling the robot's arms. The arms have flexible mechanical wrists eqquipped with tiny instruments such as needle holders, microscissors and tissue graspers at the tips. A tiny camera-equipped arm is inserted in an incision and provides the surgeon with images of the heart.

The da Vinci Surgical System won Food and Drug Administration approval in July for general surgery and has been used in several abdominal operations. Mitral valve repairs using robotic technology have been done only in Europe, until now.

The minimally invasive surgery was done on ten patients since May, and has shortened recovery time in the intensive care unit and overall stay in the hospital by almost 50 percent. This makes this approach less expensive (by approximately 33 percent) and less invasive than conventional open-heart surgery.

Results are being forwarded to the FDA; as other studies follow, some are predicting the FDA will approve robotics for general cardiac use within the next five years.

More than 70,000 heart valve operations are done each year.

For further information: http://www.intusurg.com and the American Telemedicine Association at http://www.atmeda.org/

Holiday Eating-Portion Size Reminder
(From the American Dietetic Association)

Recommended Serving Sizes
3 ounces of meat--Deck of cards
1 cup fruit or yogurt--Baseball
½ cup veg. or fruit or pasta--Tennis Ball
1 medium potato--Computer mouse
1 tsp. Butter--Thumb tip
1 ounce of cheese--Four small dice

A Test for You: Choosing Great Leaders

Here's a test for you: It's fairly simple---the following are thumbnail sketches of three candidates, one of whom you need to choose for our leader; which would you choose? [Hint: All of them are actual historical figures and all lived in the same era. The answer is at the end of the next section]

Candidate A: Associates with corrupt bosses and consults with astrologists. He has had two mistresses. He also chain smokes and drinks eight to ten martinis a day.

Candidate B: Was kicked out of office twice. Typically sleeps until noon. Used opium in college. Drinks a quart of brandy every evening.

Candidate C: Is a decorated war hero. He eats a vegetarian diet and doesn't smoke. He drinks an occasional beer. He hasn't had any extramarital affairs.

Cool Web Sites

CLOUDS
http://www.lookitsa.com

This site is devoted to empowering your imagination with clouds. For children, clouds are magical and inspirational. This site is an invitation to daydream, and you don't even need to be near a window. It features dozens of photos of cloud formations, with new selections added each week. Click on a tiny cloud photo and it blows up to full screen proportions, complete with commentary by the person who submitted it. There's even a Grow Your Own Cloud kit!

TRAVEL SITE
http://www.concierge.com/

Conde' Nast has a free travel site called "Concierge.com" at The site is a one-stop collection of travel resources, from cruise guides to travel deals to bed & breakfast finders. If it has to do with travel, you'll find it at Concierge.com.

PLAYTIME
http://www.sodaplay.com

There are no practical uses for this site, but it's strangely addictive. To use an already overused phrase--you just have to see it to believe it. Sodaplay is like an animated set of virtual TinkerToys. You can build virtual wireframe models using a simple toolkit. Then you can make your creation bounce, roll, and walk by adding "springs," which can be set to move almost like muscles. It's a tedious process, and it takes some practice to create a workable model, so get ready to become addicted (or frustrated!). If you aren't that ambitious, then simply load an existing model, let it wander around and mesmerize you for a while, and then start to alter it and see what happens. You can adjust gravity, its shape, and the movement of its springs. And the best part is after you're done, you don't have to clean up your room.

Answers to section above "Choosing a Leader"
Candidate A: Franklin D. Roosevelt
Candidate B: Winston Churchill
Candidate C: Adolph Hitler

Quotable Quotes

"The true meaning of life is to plant trees, under whose shade you do not expect to sit."
Nelson Henderson

"Kind words can be short and easy to speak, but their echoes are truly endless."
Mother Teresa

"Great thoughts speak only to the thoughtful mind, But great actions speak to all mankind."
Emily P. Bissell

"Preach the gospel at all times. If necessary, use words."
Saint Francis of Assisi, Apocrypha

ERDOCS e-mail group (listserv)

As a Clinician providing acute and emergency medical care, you are invited to visit and participate in our new ERDOCS group at eGroups, a free, easy-to-use email group service! You have plenty of experiences to share, questions to ask, concerns and opinions to voice, suggestions, news to post, tips to offer, etc.and can do so within this framework. this is a versatile system for posting things to be sent to a group to peruse, respond to, or simply be aware of. It eliminates conventional mail delays and allows you to review and post at your leisure. (We still have the more open-ended [any visitor can observe/post] discussion group at the ACUTE CARE, INC. web site). Our goal is to give you a variety of feedback and communication tools.

The manager/moderator for this ERDOCS egroup is the webmaster for the ACUTE CARE, INC. website (www.acutecare.com), Paul Hudson. You can subscribe by sending an e-mail indicating your wish to be included to Paul at paul@acutecare.com

As this site grows, it will feature news, calendars, links to references, resources, and other useful features. We hope you will support this effort to foster ongoing communication amongst EM providers.