Medicine
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Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine
Chapters
Summary July 7th, 2016
We have developed a swine model for the target delivery of pharmacological agents within the pericardial space/fluid. Using this approach, the relative benefits of administered agents on induced atrial fibrillation, relative refractory periods and/or ischemic protection can be investigated.
Transcript
The overall goal of the following experiment is to identify pharmacological agents delivered to the pericardial space that may reduce side effects during surgical procedures, or improve transplant outcomes. Pacing leads are placed in the right atrium and right ventricle in order to determine the refractory period. A pulse electrical stimulation study on the programmer determines the refractory period of the atria, atrial-ventricular node, and the ventricles.
A shock is delivered to the left atrial appendage in order to induce atrial fibrillation in order to determine the AF burden. The drug is delivered to the pericardial space. The refractory period and AF burden is taken at 30 minutes and 60 minutes after pericardial delivery to be compared to baseline.
Next, cardioplegia is administered via an aortic route cannula, and the heart is arrested. Thus, various pharmacological agents that may decrease the incidence of cardiac arrhythmias, and/or eschemic damage can be assessed for their practicality during both cardiac surgery and transplantation. The choice of swine has several advantages.
It allows for placement of multiple sensing catheters and pacing leads. The swine's cardiac anatomy mimics that of an adult human. A surgical pericardial cradle is easy to form in the animals, and their pericardial fluid volumes hemodynamic behavios and electrophysiologic properties are similar to those of humans.
Various clinical procedures could benefit from the pericardial delivery of therapeutics, including delivery, cardiac surgical procedures and organ recovery for transplantation. This method can also help answer important clinical questions relative to cardiac diagnosis and treatments, such as what agents are most efficacious for pericardial delivery in order to reduce AF burden and/or prevent associated arrhythmias with cardiac procedures. A 70 to 80 kilogram swine is anesthetized and intubated isofluorine is delivered in a combination of house air and oxygen.
Before proceeding, ensure the swine is in a deep plane of anesthesia by checking for the absence of jaw tone. Begin the surgery by carefully accessing the right external jugular and carotid artery with cautery and blunt dissection. Once exposed, put an 8.5 french swan ganz catheter into the external jugular and inflate the balloon to 1.5 CCs.
Then, traverse the catheter though the right atrium into the ventricle through the pulmonic valve and down the pulmonary artery until a wedge pressure is felt. At this point, deflate the balloon and leave the catheter in this position. Record the right atrial pressure and pulmonary artery pressure using the balloon.
Next, place a five french balloon pressure catheter in the external jugular, and feed it into the right ventricle. Place another 5F balloon pressure catheter in the carotid artery, prolapse it through the aortic valve, and position it in the left ventricle. Then, flush all the pressure catheters with 20 units per milliliter of hepronized saline, and record all the pressure data from the left ventricle, right ventricle, pulmonary artery pressure, and right atrial pressure.
The next step is to carefully access the left external jugular. Once accessed, place two 11 french hemostasis introducers in the jugular and secure them with suture. Then, position steerable catheters into the introducers.
Now, start using fluoroscopic guidance. Place active fixation leads in the right atrial appendage, and the apex of the right ventricle. Connect the analyzer cables to the implanted leads, and using a programmer to test for capture.
Set the parameters to eight folds, 0.25 milliseconds, and set the pace 10 beats per minute higher than the intrinsic rate at that time, or even higher. Then, record the relative impedence for each lead. Next, make a medial incision from the xyphoid process to near the insertion point of the sternocleidomastoid muscles.
Then, make a shear cut through the remaining portions of sternal bone structure, and to retract the sternum, dissect the sternal-pericardial ligament. With the sternum retracted, make a blunt dissection to separate the pericardium from the pleural linings. Next, make a three to five centimeter medial-saggital incision in the pericardium, and create a pericardial cradle with four square knot sutures at each corner.
Finally, place a temporary bipolar lead in the apical region of the left ventricle, and place a unipolar plunge temporary pacing lead into the left atrial appendage. To begin, start a PES study. First program a burst induction of the PES study parameters to wait paces at either 400 or 300 milliseconds.
Next, program a minimum of 300 milliseconds pacing, and reduce pacing until the heart chambers fail to contract. Which is noted by the sensing of the pacing leads, and determines the relative refractory period. Next, attach the grass stimulator to the left atrial appendage via the plunge pacing lead.
Set it to deliver two second pulses at four hertz. Check those settings with an oscilloscope. Now, deliver a single pulse to the left atrial appendage to reduce atrial fibrillation, or AF.To determine the relative AF burden, use the grass stimulator once per minute up to 10 times, until an AF is sustained for one minute.
Then, allow the animal to remain in AF for up to 10 minutes. This time length represents the AF burden. If the heart hasn't stopped fibrillating after 10 minutes, shock the atria with direct paddles at five joules to resynchronize the heart.
Initiate the pericardial delivery of the potentially protected pharmaceutical agent. The refractory period and AF burden are determined again at 30 minutes and 60 minutes after the pericardial delivery of the pharmaceutical agent. To explant the heart, first implant the aortic route cannula.
Carefully dissect the pericardial tissue around the ascending aorta and remove the pericardium. Then, secure the cannula with 2.0 ethibond sutures in the ascending aorta, about two to three centimeters apart. After attaching the sutures, administer 30, 000 units of heprin intravenously.
Then, suture the aortic route cannula to the aorta. With the delivery system pressurized, remove stylet bevel, and place a clamp on the cannula to stop the flow. Next, prepare cold Saint Thomas cardiopalegia to deliver at 150 millimeters of mercury.
Secure an irrigation catheter to the pressurized cardiopalegia with a three-way stopcock. Then, secure the stopcock to the aortic route cannula. Now, performa a cross-clamp.
And flush the heart with cardiopalegia toward the aortic valve, thus closing the valve and perfusing the coronaries. To prevent the heart from being overpressurized, make an incision in the pulmonary artery. Once the heart is stopped, excise it, and transfer into cold Krebs henseleit buffer.
To reanimate the heart, cannulate the grade vessels using visible heart methods. Once the perfused heart is within five degrees of 37 degrees Celsius, restore a native sinus rhythm using 34 joule shocks to the ventricles via epicardial patch electrodes. Monitor the cardiac function for an hour via the same pressures measured in situ.
Every five minutes, take a one CC sample from the coronary sinus. Every 10 minutes, calculate the ventricular wall thickness and ejection fractions. Using the described protocol, a notable increase in the ventrical effective refractory periods was seen following a DHA infusion in situ.
Measuring the maximum pressure after reanimation showed an increase in left ventricular pressure of DHA treated hearts compared to controls. The left ventricular pressure in the treated hearts was significantly higher at several time points. This technique allows for the assessment of target-delivered therapeutic agents that could be used translationally for patients undergoing cardiac procedures, including surgery, or for the recovery of hearts for transplantation.
Employing this experimental approach may pave the way for surgeons and researchers to explore novel agents and treatment strategies that mitigate atrial fibrillation, reduce myocardial damage, and reduce associated reprofusion injury.
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