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TEACHING IN THE LABORATORY
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri
Address for reprint requests and other correspondence: Mark M. Knuepfer, Dept. of Pharmacological and Physiological Science, St. Louis Univ. School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104 (E-mail: knuepfmm{at}slu.edu)
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Abstract |
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 TOP Abstract IntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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Key words: cardiovascular laboratory; hemodynamics; cardiac contractility; arterial pressure regulation; adrenoceptors; skeletal muscle blood flow regulation; heart rate regulation
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Introduction |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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Students have the opportunity to apply the physiological and pharmacological concepts they learned in the classroom and appreciate the complex, interrelated systems responsible for the control of blood pressure. Specific learning objectives covered in this lab include induction and maintenance of anesthesia, basic surgical technique, cannulation of blood vessels, control of hemorrhage, understanding the measurement and recording of physiological parameters, premortem examination of in situ heart and lungs, direct cardiac massage and induction of ventricular fibrillation, understanding of the autonomic innervation that underlies the baroreceptor reflex, and cardiovascular responses to various pharmacological agents. Agents studied include angiotensin II, endothelium-dependent and -independent vasodilators as well as both 
- and ß-adrenergic agonists and antagonists.
Although attendance is voluntary, this laboratory is always well received by >90% of the medical students who attend. This lab is an integral component of the second-year medical school curriculum, and for the vast majority of these students, this was their first opportunity to participate in an integrative physiology lab using an intact animal model. However, many medical schools have discontinued animal labs due to increasing costs of animals and equipment, shortage of qualified demonstrators, as well as pressure from animal rights activists. Approximately 50 medical schools continue to use such labs, while the majority of medical schools have now turned to alternatives, such as computer simulations and videotapes (6). For a list of medical schools that use animal labs in medical school curriculum, refer to the Physicians Committee for Responsible Medicine website: http://www.pcrm.org/issues/Ethics_in_Medical_Research/ethics_medlab_list. Although these alternatives are valuable supplements to classroom learning, they cannot serve as a substitute for an experience with a living organism (7).
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MATERIALS AND METHODS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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Equipment
The following equipment was used for each animal in this experiment.
An anesthesia machine with anesthesia ventilator (Narkomed AV-E) equipped for medical oxygen and medical air (Reconditioned Narkomed Standard for Veterinary Use) was from North American Drager (Telford, PA).
A Mallinckrodt endotracheal tube (size 6.5 mm ID for most swine 20–25 kg), laryngoscope handle with no. 4 Miller blade, respirator tubing to make circuit system with respirator, standard veterinary mask for anesthesia induction, and isoflurane (general anesthetic) were used.
Polyethylene (PE)-200 tubing was 13 in. long, on a blunt 18-gauge needle for accessing the left femoral artery. The catheter introducer sheath with sideport and adjustable (preferred) hemostasis valve for Millar catheter placement into left carotid artery was 6.0- or 7.0-Fr. A 10-Fr silastic tubing 10-in. long on a 15-gauge blunt needle was used for the right jugular or left femoral vein line. Two three-way stopcocks were used.
Silk ligature 2-0 was used for securing cannulas to vessels and 0 silk or Vicryl suture was used for securing cannulas to skin.
Disposable pressure transducers (pressure monitoring kit) was from Baxter Healthcare (Deerfield, IL). The flow probe, size 5 mm was from Transonics Systems (Cornell Research Park, Ithaca, NY). A catheter (size: 3-Fr diameter, 50-cm length) and transducer control unit was from Millar Instruments (Houston, TX).
The simultrace recorder and monitor (model VR-16) were from Honeywell (Morristown, NJ). ECG patches and leads were used to connect to recorder (3/pig). The chart recorder (model MT46000) was from Astro-Med (West Warwick, RI).
A computer with data acquisition software (WINDAQ) was from DATAQ Instruments (Dayton, OH).
Drugs used were epinephrine, norepinephrine, atropine, isoproterenol, nitroprusside, propranolol, and prazosin.
Surgical equipment used was a scalpel with no. 10 blade, needle drivers, right angle, hemostat, Metzenbaum scissors, DeBakey forceps, bone cutters, Weitlaner retractor, and Finocietto rib spreader.
Hespan plasma expander (500 ml per animal) was used.
Preparation of Animals
The pigs in this experiment were domestic swine and had an average weight of 20–25 kg. In the first year, seven pigs were used. One pig was studied before the first laboratory demonstration so that the protocol and duration could be reviewed and any potential difficulties could be addressed. The remaining six pigs were used for each group of 
25 medical students. Ideally, these groups could be smaller, but limitations on time and equipment prevented us from doing this. Keeping the groups relatively small allowed more students to participate in various aspects of the experiment. Six students volunteered to come 1 h before the beginning of the experiment to assist in the preparation of the animal. This allowed these students to gain some hands-on experience in basic surgical techniques during the preparation of the animal.
First, the pig was anesthetized via a mask induction using respiratory tubing connected to a standard veterinary mask placed over the pig’s snout. A mixture of isoflurane (4–5% initial concentration) and oxygen was given to anesthetize the pig. The animal was then placed in the supine position on the operating table, and its limbs were secured to the table. Once the animal was deeply anesthetized, intubation was performed using a size 6.5 mm ID cuffed endotracheal tube, and correct placement was confirmed by assessing bilateral breath sounds using a stethoscope. The pig was ventilated using a Reconditioned Narkomed Standard for Veterinary Use using 2–3% isoflurane mixed with balanced medical grade oxygen. The respirator was set to deliver 10–15 ml/kg body wt of tidal volume and a peak inspiratory airway pressure of 16–18 cmH2O. The end-tidal CO2 was measured with the use of a capnometer and maintained between 3.7 and 4.0%, as corroborated by blood gases drawn intravenously. The CO2 level was verified by analyzing periodic arterial blood gas samples. The anesthesia level was titrated "to effect," and the level of anesthesia was monitored by testing the corneal reflex, jaw tone, and limb withdrawal. If any of these reflexes were elicited, the concentration of anesthetic was increased until the response subsided. Typically, the level of expired isoflurane varied from 2.8 to 3.0%. The exercise allowed students to observe how much anesthesia was necessary to keep the pig in a relaxed and pain-free status without causing respiratory arrest. This emphasized the humane treatment of experimental animals as well.
If desired, another anesthetic regimen may be used. Etomidate or the combination of ketamine and xylazine as a preanesthetic treatment before isoflurane administration at a lower dose in combination with pentobarbital can be used. These anesthetic regimens may reduce the suppression of baroreflex function associated with isoflurane alone. Any improvement in baroreflex function is likely to make the laboratory more interesting as a teaching experience.
ECG leads were attached to the four limbs of the pig and the ECG was continuously monitored on a computerized data acquisition program as well as a paper chart recorder. Students observed the recorded ECG as they learned to recognize basic arrhythmias and were reminded of their significance.
Subsequently, cannulas were inserted in femoral blood vessels for monitoring of blood pressure and the injection of pharmacological agents. This was an important opportunity for students to recognize the difference between arterial and venous pressures and, consequently, the risk for spontaneous bleeding. When hemorrhage occurred, students were shown how to control bleeding by applying direct pressure. Students also experienced firsthand the difficulty in manipulating vessels as they inserted the cannulas. When they secured each cannula with surgical ligatures, students discovered that a reliable knot halts bleeding, whereas an unreliable knot allowed continued seepage of blood. This experience serves as an introduction to the task of inserting an intravenous cannula in a human.
The cannulas were inserted using a cut-down technique. By starting in the right inguinal area, the students located the femoral pulse, and a 3- to 5-cm midventral skin incision was then made using a scalpel. With the use of a curved hemostat, blunt dissection was performed through the subcutaneous tissues until the femoral artery and vein were located. With the use of a right angle, blunt dissection was performed medial and lateral to each vessel. The vessels were also freed from underlying fascia by hooking the right angle behind the vessel and spreading the ends of the right angle. Care was taken at this step because the vasa vasorum in pig vessels is prominent and the vessels are prone to rupture and bleed with minimal trauma.
Once each vessel was exposed and separated, two 2-0 silk ties were looped around the femoral artery. One silk tie was tied at the distal end of the vessel while the other one was looped but not tied at the proximal end of the vessel. Applying upward pressure on the proximal tie with one hand allows occlusion of blood flow while a small incision is made with Metzenbaum scissors or a smaller variety of surgical scissors. It was imperative to make the incision small such that the tunica media and intima of the vessel were transected on one side and preserved on the other side. This created a small hole in the vessels (1–2 mm in size) that was used to insert the end of the saline-filled cannula. By maintaining upward pressure on the proximal tie with one hand, the cannula was inserted into the small opening in the femoral artery. Slowly, the cannula was advanced proximally until the end of the cannula reached the proximal tie. The proximal tie was then relaxed, and the cannula was advanced past the tie. Once the cannula had been advanced 3–4 cm past the proximal tie it was in the correct position. The proximal tie was then tied to secure the cannula in place inside the vessel. The distal end of the cannula was secured by tying suture around an exposed distal end of the cannula and looping it around the cannula several times before suturing it to the pig’s skin. Thus both proximal and distal ends of the cannula were secured. The other end of the cannula was connected to a pressure transducer after calibrating the amplifier.
The femoral vein was cannulated using a similar approach. Once the femoral vein cannula was secured, the line was flushed with additional heparinized saline (10 U/ml heparin) and connected to a 1.0-liter bag of sterile 0.9% NaCl (saline). Fluids were administered at a rate of 5 ml·kg–1·h–1. In addition to intravenous fluids, pharmacologic agents were administered via this cannula. Once both vessels were cannulated, the skin was closed (leaving space for the cannula to exit) by using several simple interrupted sutures.
On the contralateral side, the femoral vessels were exposed using the cut-down technique described above. Once the femoral artery was exposed, a 5-mm transit time flow probe (Transonics, Ithaca, NY) was placed over this vessel. This was used to measure femoral arterial blood flow as an estimate of skeletal muscle blood flow.
The left carotid artery was also cannulated using the cut-down technique. The carotid pulse was palpated just lateral to the trachea. A skin incision was made, and the vessels were exposed as described above. The carotid sheath was opened and the carotid artery was separated from the jugular vein. An introducer was inserted and used to assist the advancement of the Millar transducer into the left carotid artery and then into the left ventricle to measure ventricular pressure. Due to the anatomy of the pig vasculature, the left carotid artery was used, because swine have a common carotid artery that bifurcates into the left and right carotid arteries. Experience with both approaches showed that it was much easier to introduce the Millar transducer into the left ventricle from the left carotid artery as opposed to the right carotid artery.
At this point, the animal was instrumented fully for the ensuing experiments. To stabilize, the animal was allowed to recover for 20 min, during which time 500 ml of Hespan plasma expander were infused intravenously to support arterial pressure, normally low in anesthetized swine. Concurrently, the remaining students arrived, and the anesthesia induction and surgical preparation were described to those students who did not participate in the surgery.
Experimental Procedure
At this time, the five baseline parameters (Table 1) were noted from continuous recordings using the various equipment and posted on a large dry erase board visible to all attending students.
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Pharmacological manipulations.
Initially, bolus infusions of a series of agonists were performed (appendix a) see Table 2 for dosages). Before each dose of drug was infused intravenously, the animal’s arterial pressure, ventricular pressure, heart rate, and iliac blood flow were measured and written on a large dry erase board so all students could observe and record the values. Students discussed expected responses of each parameter to the agonist and predicted one variable they considered the most likely to change in response to the particular agonist. When the peak change in that particular variable occurred (usually 30–60 s later), the student monitoring the variable would alert the other students recording parameters to ensure that all the data were obtained simultaneously. Values were recorded by students, and the predictions for each parameter were discussed. Meanwhile, the intravenous infusion cannula was carefully flushed with saline after each drug to avoid inadvertent mixing of drugs with subsequent dosing.
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Either propranolol or prazosin was then given (appendix a). Students again predicted responses to agonists allowing them to understand the extent of - and ß-adrenoceptor activity of norepinephrine and epinephrine. In addition, because responses to selective agonists were typically attenuated but not blocked, the concept of competitive receptor antagonism previously discussed in lecture was reviewed. Finally, after all three antagonists were administered, students were asked to predict the effects of several agonists and to predict which agonists should still elicit cardiovascular responses.
During some experiments, the combination of pharmacologic agents produced occasional arrhythmias. When this occurred or, in some cases, was anticipated, lidocaine (1–3 mg/kg body wt) was given during baseline monitoring to ensure a normal sinus rhythm.
Direct Observation of the Heart
Once the pharmacologic experiments were complete (usually 90–120 min later), the students and instructors opened the thoracic cavity using a midsternal thoracotomy. An incision was made along the left border of the sternum using a scalpel. Once the sternum was exposed, bone cutters were used to open the thoracic cage. It was important to not cut too laterally to avoid injury to the internal mammary arteries that lie in close proximity to the sternum. Rib spreaders were used to further open the thoracic cavity and provide better visibility. The heart was exposed by grasping a piece of the pericardium and making an incision with Metzenbaum scissors.
After dissecting gloves and scrubs were made readily available, students were asked to identify the anatomy of organs in the thoracic cavity and the large vessels in the cardiopulmonary circulation. Students were also encouraged to palpate the heart to estimate the strength of the contraction of the heart and to observe the lungs expanding with each breath. Invariably, this experience fascinated the students. For many, this was their first opportunity to manipulate a beating heart or to palpate expanding lungs with their own hands. This experience allowed students to realize the amount of effort needed during cardiopulmonary resuscitation to mimic normal respirations and cardiac contractions.
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RESULTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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The parameters depicted include mean arterial pressure, left ventricular contractility (dP/dt), heart rate, and hindquarters vascular resistance. Students were taught that the arterial pressure and hindquarters blood flow could be used to calculate changes in vascular resistance by Ohm’s law (arterial pressure/hindquarters flow = hindquarters vascular resistance). Changes in the hindquarters vascular resistance were used to approximate vascular responses in skeletal muscle.
Agonists Alone: Epinephrine
Epinephrine is a potent direct agonist of 1-, 2-, ß1-, and ß2-adrenergic receptors (4). At low concentrations (0.5 µg/kg), the ß2-effects predominated over the -effects, and vasodilation of skeletal muscle beds occurred (Fig. 1). At intermediate epinephrine concentrations (0.1 and 0.3 µg/kg), the ß2-effects still predominated, as evidenced by the consistent vasodilation in the hindquarters vasculature. However, the 1-receptors were also stimulated, resulting in vasoconstriction in skin and viscera. In addition, there was a ß1-mediated increase in heart rate and cardiac contractility leading to an increase in arterial pressure. At high concentrations of epinephrine, the 1-effects are evident as a large increase in arterial pressure accompanied by positive inotropic and chronotropic effects on the heart via ß1-receptors. The increasing recruitment of 1-receptors over ß2-receptors was also evident as a reduced vasodilation in the hindquarters vasculature.
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1-, 2-, and ß1-receptors. Compared with epinephrine, norepinephrine showed equal potency at the - and ß1-adrenergic receptors, although epinephrine was 10–50 times more potent than norepinephrine at the ß2-receptor (5). According to current understanding of the pharmacology of norepinephrine, this produced vasoconstriction of skin and viscera vasculature (1-receptor effect) without a significant vasodilation of the skeletal muscle vasculature (ß2-receptor effect). This was evident as a significant increase in arterial pressure with minor changes in hindquarters resistance (Fig. 2). There was also an increased dP/dt (positive inotropic effect) similar in magnitude to that caused by epinephrine (0.3 and 1 µg/kg). However, the tachycardic (positive chronotropic) effect was not as great for norepinephrine compared with epinephrine. This may be due to a larger increase in arterial pressure seen with norepinephrine, which produces a greater reflex vasoconstriction. This, in turn, may have attenuated the tachycardia.
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1-adrenoceptors) seen with epinephrine was not antagonized (Fig. 3).
By inhibiting 1-adrenoceptors, prazosin reduced blood pressure by reducing peripheral vascular resistance. The magnitude of this effect was dependent on the concentration of endogenous catecholamines. Administration of prazosin alone usually had no effect on the heart rate (4). Concepts of passive vasodilation and anesthetic-induced increases in plasma catecholamines were discussed with the students during the demonstration. Addition of prazosin to atropine blocked the vasoconstrictive effect of epinephrine, producing a decrease in mean arterial pressure and hindquarters resistance (Fig. 3) and illustrating the classic phenomenon of "epinephrine reversal." Without propranolol, the ß1-mediated increase in heart rate and contractility caused by epinephrine were preserved. However, when propranolol preceded epinephrine, atropine, and prazosin, these ß1-effects were inhibited and decreases in heart rate and dP/dt were observed.
Effects of Selective Antagonists on Responses to Norepinephrine
Figure 4 illustrates the combined effects of norepinephrine administered after the same set of selective antagonists used with epinephrine. Owing to the pressor effect of norepinephrine via 1- and ß1-effects, arterial pressure decreased following the administration of propranolol as well as after prazosin. Propranolol also produced a decrease in contractility and heart rate. Norepinephrine alone had little effect on hindquarters resistance. However, the addition of propranolol revealed a pronounced 1-mediated vasoconstrictor response. In contrast, the addition of prazosin revealed a small component of norepinephrine-induced ß2-mediated vasodilation.
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-adrenergic receptors. Therefore, isoproterenol induced a ß1-mediated increase in heart rate and contractility as well as a ß2-mediated vasodilation in the absence of any vasoconstrictive effects (4). As shown in Fig. 5, isoproterenol decreased mean arterial blood pressure and peripheral vascular resistance and also exerted direct positive inotropic and chronotropic effects. Propranolol pretreatment attenuated ß1-mediated effects of isoproterenol on the heart, producing decreases in heart rate, contractility, and arterial pressure as well as a ß2-mediated hindquarters vasodilation. As expected, prazosin pretreatment had little effect on these responses to isoproterenol.
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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The measure of success for any teaching tool should include both students’ perception of the exercise and the relative improvement in exam performance in this field. From the perspective of the students, this exercise has rated an average of 3.7 on a scale from 1 (strongly disagree or unacceptable) to 5 (strongly agree or excellent), including 1 yr when it received the highest score of any component of the course. In all years, it was above the average score for the various components of the course. On average, 20.5% of students rated the experience as excellent (5 of 5). In the present year (2004), the exercise was optional and limited to only two pigs. Of the students attending, 43% rated it excellent (5 of 5).
Assessment of the laboratory’s contribution to student assimilation and content mastery is more difficult because we have instituted several changes to improve the understanding of autonomic function. These include adding a 1-h refresher course on autonomic agents covered in the previous year, a 1-h review of the swine laboratory results presented to the entire class, and two patient simulator laboratories (one in the first year and one during this course) to teach and reinforce these fundamental principles. Subjectively, at least, these students are considerably better prepared for examinations.
This exercise is not without limitations. There are substantial costs to house and maintain animals and to purchase and maintain the necessary equipment. In addition, this exercise requires more faculty time to organize and oversee these experiments. However, this exercise is a unique opportunity to effectively teach several important concepts, and the students always rate this experience highly. Another limitation is that a medical school must have faculty with experience in performing nonsurvival surgery and conducting live animal experiments. However, most academic medical centers have clinical faculty that would be willing to assist in this exercise.
This was the first opportunity for many students to perform surgery. The skillful use of both a sharp scalpel as well as blunt dissection using hemostats allowed students to gain practical experience in basic surgical technique. Although this limited experience is not sufficient to master surgical skills, it is an important first experience that often motivated students to explore an interest in surgery.
Faculty members conducting the exercise spent considerable time emphasizing the relationships between pressure, flow, and resistance. This is a fundamental concept in our understanding of cardiovascular function that is often confusing to students (2). With each drug administered, the changes in measured flow and pressure are used to calculate the change in vascular resistance such that the primary concepts are well understood before the end of the experimental protocol.
When the thoracic cavity was opened, students directly observed the correlation between cardiac contractions and the ECG tracing on the monitor. By manually compressing the heart, arrhythmias were produced and students noted how they appeared on the monitor as well as which drug was needed to return the heart to a normal sinus rhythm. Before the animal was euthanized with a bolus of potassium chloride, ventricular fibrillation was manually induced so students could correlate the physiological parameters with the loss of contractile strength seen in the fibrillating myocardium.
This experience also allowed students to manipulate tissues in situ and view anatomy in a live animal. When students dissect a cadaver in anatomy, they do not have the experience of following pulsation to find a blood vessel or facing the threat of sudden hemorrhage if they accidentally transect a vessel. In addition, the color and consistency of different tissues and organs is more apparent in the living flesh than in the cadaver.
This laboratory also allowed students to observe and evaluate the effects of anesthesia. Students noted that normal baroreflexes were suppressed in an anesthetized animal. Because the level of anesthesia changed over time, they had the opportunity to participate in monitoring the depth of anesthesia using multiple indexes. Students later observed these same phenomena in the operating room during their clinical clerkship, and this laboratory served as important introduction to those concepts.
During clinical clerkships, medical students do not have the opportunity to directly administer drugs to patients. Even as residents, it is more common for drugs to be given by nurses once an attending physician has written the order. Thus this lab provided a unique opportunity for students to administer graded doses of powerful pharmacological agents and to observe their immediate direct and reflex effects and the duration of the responses.
In addition, these experiments also involved the administration of specific antagonists to illustrate the mechanism of action of the agonist drugs. During their medical education, students often attempt to learn the mechanism of action of various agents by rote memorization without an appreciation for how this knowledge was acquired. By observing how specific pharmacologic antagonists alter the physiological effects of an agonist, the students gained firsthand experience of how a variety of pathways and receptors are responsible for regulation of blood pressure. This experience provided a more meaningful and lasting understanding of each pharmacologic agent, as well as an appreciation of how these drugs might be used to control blood pressure in a patient. While computer simulations of these experiences are helpful (3), the use of a live animal proved particularly stimulating to the students.
This lab also provided students with the opportunity to collect and analyze experimental data and to present results. These students eventually will read and interpret the medical literature to stay abreast of the latest medical knowledge. By participating in the collection and interpretation of such data, the students will better appreciate the experimental basis of contemporary medical pharmacology. Finally, by critically examining their own results, students learn to evaluate the results of others and to assess the putative significance of published findings.
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APPENDIX A: SEQUENCE OF EXPERIMENTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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GRANTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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Acknowledgments |
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Present address of S. Gupta: Univ. Hospitals of Cleveland, Dept. of Internal Medicine, 11100 Euclid Ave., Cleveland, OH 44106.
Received for publication September 23, 2004. Accepted for publication January 18, 2005.
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REFERENCES |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: SEQUENCE OF...GRANTSREFERENCES |
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