Left Atrial Intervention
General description of procedure, equipment, technique
Stroke is one of the most feared complications of cardiovascular disease because of its attendant morbidity and mortality. Of the subtypes of ischemic stroke, cardioembolic strokes result in the worst short and intermediate term outcome. This is of particular concern in patients with nonvalvular atrial fibrillation in whom there is a five fold increase in stroke risk.
The relationship between the triad of increasing age, atrial fibrillation, and cardioembolic stroke has been well documented. In this setting of nonvalvular atrial fibrillation, the etiology of stroke is typically a thrombus in the left atrial appendage. This has given rise to the concept of mechanical occlusion of that structure in some patients for stroke prevention, particularly those in whom long-term anticoagulant therapy is not felt to be indicated.
The left atrial appendage arises from the left atrium between the left upper pulmonary vein and the mitral valve. There is great variability in its anatomy: the orifice is asymmetrical and often either oval or elliptical in shape while its length, angulation, and volume vary substantially.
An important consideration relates to the number of lobes: approximately 1/2 of people have two lobes while 1/3 have three or more. The size and location of these lobes has important implications for approaches at occlusion. This anatomic detail affects the specific selection of the guiding catheters used and the trajectory of the device placement within the LAA. A final critical issue relates to the thin wall of the left atrial appendage, which on occasion may be even close to transparent and thus poses the danger for perforation during attempts at instrumentation.
Access to the left atrial appendage is either via a transseptal or transpericardial approach. Two randomized clinical trials and multiple multicenter multinational registries have now been completed, both of which used a transseptal approach.
Transseptal catheterization was initially described in the early 1950's as a means of access to the left-sided cardiac structures. In the early era of hemodynamic assessment, invasive cardiologists were often very skilled in this procedure. Subsequent to the wide spread use of echocardiographic assessment, the technique became much less widely used until the advent of electrophysiologic procedures, which routinely required left atrial access for recording and ablation. With the advent of structural heart disease interventions, including left atrial appendage occlusion, interventionalists have now become reacquainted with this approach.
Approaches to transseptal catheterization vary depending upon specific anatomy and physician experience. The standard approach uses percutaneous right femoral venous access. For safe access, detailed knowledge of the anatomy of the atrial septum is required. The target - the fossa ovalis - is approximately 2 cm in diameter. It is posterior and caudad to the aortic root and superior and posterior to the coronary sinus ostium. These structures and the right atrial free wall must be kept in mind to prevent complications, the most severe of which is entry with the needle and dilator into the ascending aorta. Equally important is the issue of pericardial effusion or tamponade which can often be treated with pericardiocentesis but which may require surgery. Depending on the specific patient and substrate to be treated as well as the device to be used, the location of the trans-septal puncture varies. For left atrial appendage procedures, typically the optimal location for trans-septal puncture is posterior and caudal to optimize entry into the LAA.
A variety of catheters and sheaths are used typically with a long sheath and dilator, with a central lumen for placement of the Brockenborough needle, the latter which is also used for pressure monitoring. The sheath/dilator is advanced over a guidewire to the superior vena cava (SVC).
The dilator is withdrawn to the tip of the sheath to avoid trauma, and then the Brockenborough needle is inserted using fluoroscopic control. Following this, the whole apparatus is withdrawn to the right atrium.
Several approaches can be used to identify correct positioning at the site of the fossa ovalis. In the past, angiographic visualization has been the most common approach relying on biplane views and with placement of an arterial catheter just above the aortic valve for guidance so that the needle does not enter the ascending aorta. Currently, ICE or TEE has become dominant, enhancing specific and optimal locations for entry in the LA. The increasing reliance on ICE and/or TEE relates to the fact that these imaging modalities are needed to identify specific anatomic features of the target; for example, the mitral valve for Mitraclip procedures, or the LAA for LAAC procedures or the pulmonary veins during atrial fibrillation ablation procedures. Selection of the specific approach often depends on operator experience and training. Electrophysiologists often rely on TEE or ICE, whereas interventional cardiologists often rely on angiographic landmarks (vide infra).
Using angiographic guidance, as the dilator is withdrawn from the SVC to the right atrium, there are three "bumps" that can be visualized as rightward movement on the posteroanterior (PA) image - as the catheter enters the right atrium, as it moves below the ascending aorta, and finally as it slides over the limbus of the fossa ovalis.
Continuous measurement of pressure is required through the Brockenborough needle to prevent inadvertent entry into the ascending aorta. After satisfactory position has been identified, the needle is advanced carefully while monitoring pressure continuously.
Some operators inject small amounts of contrast to stain the interatrial septum in a so-called "tent" configuration. When left atrial pressure is documented, the dilator can be advanced over the needle a short distance into the left atrium, and then the sheath advanced while keeping the dilator and needle fixed in space to enter the left atrium. During this maneuver counter-clockwise positioning of the sheath is helpful in that with this manuever, the longer axis of the LA down through the mitral valve into the LV is selected, minimizing the potential for damage to the LA walls.
Care should be taken to avoid trauma to the dome of the left atrium. If the entry into the left atrium is not smooth, the approach should be repeated again after placing the sheath and dilator again in the SVC. The presence of advanced structural heart disease, for example aortic stenosis or mitral valve disease or history of repeated transseptal approaches (for example, repeated electrophysiologic ablations), may distort the anatomy or may result in a fibrous septum which is difficult to cross. In this latter circumstance, special devices such as the Safe-Sept needle may be helpful.
An alternative approach for guidance uses intracardiac echocardiography or TEE, either of which is very helpful in localizing an ideal site for entry into the left atrium. Using this approach, the sheath and dilator can be visualized after entry into the right atrium. The fossa can be clearly seen as well as details of the limbus.
The sheath and dilator can then be torqued until there is contact with the fossa ovalis. As previously mentioned, using this approach, specific sites of entry through the fossa can be identified for specific applications; for example, low posterior fossa entry sites for procedures involving the right inferior pulmonary veins. The fossa can be seen to be tented on the echo images with the advancing needle and then injection of saline or contrast can be used to document left atrial positioning. In some institutions, use of TEE or ICE has replaced angiographic guidance for trans-septal procedures.
Indications and patient selection
A single left atrial appendage catheter (Watchman TM) has been approved in the United States for stroke prevention in patients with NVAF. Another device (Amplatzer Amulet) is undergoing clinical trials. In Europe and globally, several devices are either currently EU approved or are undergoing clinical investigation. The selection criteria vary between the United States (the RCT's and registries) and Europe (clinical practice).
In general, patient selection criteria include:
The presence of nonvalvular atrial fibrillation—paroxysmal, persistent, or permanent
Predicted increased risk of stroke using either CHADS2 or CHA2DS2-VASc scores
Suitable anatomy for transseptal catheterization
Suitable left atrial appendage anatomy for device placement
Exclusion criteria include:
The presence of left atrial appendage thrombus or dense spontaneous echo contrast.
In the United States related to the FDA IFU, inability to take either an antiplatelet or anticoagulant therapy are exclusion criteria. In Europe, an increasing number of patients are treated who have a relative or absolute contraindication to anticoagulant therapy.
Recent stroke within 30 days or active cerebrovascular disease.
Need to take chronic anticoagulant therapy, for example a mechanical heart valve.
Concomitant significant mitral stenosis.
Indications for Use
The IFU in the United States differs from those in Europe, as can be seen mainly by the differences in patient characteristics related to anti-coagulant therapy. In the Unites States, approval for the only device was based on two randomized trials with the Watchman device which mandated that patients had to receive warfarin for 6 weeks until the time of a follow up TEE. This was based on the thought that 6 weeks of anticoagulation would enhance endothelialization of the device. This use of warfarin or any NOAC for 6 weeks is not followed in Europe. In the most recent large European Registry (Ewolution), the majority of patients were not felt to be suitable for anticoagulation and accordingly many patients, following implantation, were treated only with anti-platelet therapy.
Irrespective of differences in anticoagulation, contraindications exist for left atrial appendage occlusion devices.
The presence of thrombus in the LAA is an absolute contraindication to manipulation of the left atrial appendage either from a transvenous, transseptal, or pericardial access approach because of the danger of embolization.
The presence of dense echo contrast documented on transesophageal echocardiography is also a contraindication because it may indicate the presence of a thrombus. Inability to safely perform a transseptal catheterization by virtue of distorted thoracic anatomy also represents a contraindication, although the use of intracardiac echo guidance may help to alleviate or mitigate this problem.
Inability to document stable device placement is another absolute contraindication at least for the transvenous transseptal approaches. Device stability should always be checked before the device is released. If stable placement cannot be achieved, the procedure should be terminated.
For endocardial/epicardial approaches, dense pericardial adhesions are an absolute contraindication, while a history of pericarditis is a relative contraindication. With this combined epicardial/endocardial approach, if the tip of the left atrial appendage is tilted too far cephalad, it may be very difficult to engage and place the suture device; preprocedural computed tomography (CT) assessment can identify this group of patients and in them the procedure should be avoided.
Details of how the procedure is performed
Specific device placement varies. Once the guiding sheath has been advanced into the left atrial appendage and stable position is achieved, typically left atrial appendage angiography is performed to document the anatomy with specific attention to the number and location of lobes and the orientation and size of the ostium. During this time, adjunctive echocardiographic imaging using either transesophageal echocardiography or intracardiac echocardiography is useful.
The device size is selected according to the ostial dimensions and length of the left atrial appendage. The device is then advanced through the guiding sheath. Several important factors must be kept in mind:
Air embolism must be prevented by avoiding entrapment of air. This can be accomplished by continual flushing of the guiding sheath during device advancement.
The guiding catheter needs to be kept very stable at the ostium to avoid trauma to the left atrial appendage.
Upon device entry into the left atrial appendage, care should also continue to be taken to avoid injury to the wall.
Device placement should be performed by withdrawing the guiding sheath while simultaneously leaving the device in place. Once the device has been positioned, the seal of the left atrial appendage should be assessed by either angiography or echocardiographic evaluation.
The device should be positioned at the ostium of the left atrial appendage and should cover all the lobes. Significant protrusion into the left atrium itself should not be accepted. Stability is a crucial issue.
This can be assessed in several ways, depending upon the specific device, including device compression, angiography, and a "tug test" whereby axial force applied to the device does not result in device dislodgement. After satisfactory stable device placement has been confirmed, the device can then be released.
An increasing amount of evidence has become available on endocardial LAAO devices. Specific areas of interest include: 1) procedural and device safety; and 2) longer term efficacy.
This area has been a source of considerable concern. In the initial RCT Protect AF, pericardial effusions and tamponade were the most common significant complications occurring in up to approximately 5% of patients. The second was procedural-related stroke which was found to be the result of air embolism as well as thrombus on the catheters. Both of these have been studied intensely. The largest and most recent data on this issue involved 3,822 patients in the United States who were treated with Watchman Device after FDA approval. In this data set, approximately 50% of the procedures were performed by newly trained operators. In this large group of patients, procedural success was identified in 96.8% of cases. Complication rates have continued to improve compared with the early experience in the RCT’s. Pericardial tamponade occurred in 39 patients (1.02%) and was able to be treated with pericardiocentesis in 24 of these patients. Only 12 required surgery. There were 3 deaths felt secondary to the tamponade (0.078%). Procedure-related stroke occurred in 3 patients (0.078%). Overall procedural mortality with one week was seen in 4 patients. All of these complications were improved compared with the earlier experience.
Another large experience has been reported from a large European Registry (Ewolution) with 1021 patients. In this registry, procedural success was seen in 98.6% of patients. Pericardial tamponade was seen in 0.29% (3 patients) and procedural mortality within one week of the procedure was seen in 4 patients. These two large more real-world registries have in aggregate documented excellent success rates > 96% with very low rates of either cardiac tamponade or procedural mortality with stroke when reported occurring in < .1 % of patients. Accordingly, the early safety hazard has been markedly improved.
Longer term outcome
In the most complete data set on the Watchman Experience, the meta-analysis documented that Watchman implantation compared with the control group of patients treated with conventional warfarin therapy using the primary composite endpoint of overall stroke, ischemic stroke and all case mortality was not inferior to warfarin (HR 0.79 p = 0.22). It documented a dramatic difference in hemorrhagic stroke (HR 0.22 P = 0.004), a significant difference in CV/unexplained death (HR 0.48 p =0.006), and a marked decrease in bleeding beyond the first one week post implant, the latter of which relates to the long-term incremental risk of bleeding with warfarin. In addition, at one year post-implant, approximately 95% of patients were free of warfarin therapy. In the meta-analysis, there was in an increase in ischemic stroke (HR 1.95 p=0.05) but when the early peri-procedural strokes are excluded the difference between Watchman and warfarin decreases markedly. It must be remembered that some of the early strokes in the Watchman experience were related to air embolism or thrombus at the time of the procedure. These complications were markedly less in the most recent data.
There is early and later outcome from Europe on another LAAC device (Amplatzer Cardiac Plug or Amulet). Two large registries have been performed. A multi-center non-randomized registry of 1,047 patients enrolled from 2008 -2013 studied baseline demographics, procedural performance and longer term outcome. The mean CHAD2DS2-VASc score was 4.43 and the mean HAS-BLED score was 3.12. The composite of previous bleeding (either major or minor) and high bleeding risk was seen in 73% of patients. Procedural success with the Amplatzer Cardiac Plug was 97.3%. Major adverse events within 7 days defined as death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention occurred in 4.3%. Mortality was 0.76%, pericardial tamponade in 1.24%, and stroke in 0.86%. Longer term effectiveness was evaluated as the ratio of observed both stroke and bleeding rate versus what had been estimated using the predicted stroke and bleeding risk based on the baseline characteristics of the population. There was a 59% reduction in stroke risk, and a 61% reduction in bleeding risk.
A more recent multicenter Registry used the Amplatzer AMULET device in 1,073 patients treated between 2015 and 2016. A CHA2DS2-VASc score >= 4 was seen in 65% and a HAS-BLED score >= 3 in 58%. 85% were felt to have a contraindication to oral anti-coagulants. In this group procedural success was seen in 98.8%. Device /Procedure related major adverse events were seen in 2.7% and included dear in 0.3%, stroke in 0.3%, and pericardial effusion in 0.5%. At discharge, 14.7% of patients were not on either an antiplatelet or an anticoagulant, 23.8% on one antiplatelet drug and 41.8% on dual antiplatelet therapy. Longer term outcome data is still being accumulated.
Alternative and/or additional procedures to consider
A second approach to left atrial appendage occlusion that is being used involves direct pericardial access. This may be combined with a transseptal approach or in the future may be a stand-alone procedure.
In contrast to transseptal approaches, which involve conventional procedural sedation, more intense sedation or even general anesthesia may be required for direct pericardial access. A subxyphoid approach is used with skin entry approximately 2 cm below the subxyphoid process.
A blunt tipped 18-gauge Tuohy epidural needle with a soft tipped wire is used. The needle is directed posteriorly toward the left shoulder. Using fluoroscopic guidance, the needle is advanced to the cardiac silhouette.
Small volumes of contrast can be injected; after entry into the pericardial space, contrast pools and then with further injection outlines the pericardium. Aspiration free of blood documents that the needle is in the pericardial space and not in a cardiac chamber, such as the right ventricle.
Once the correct positioning has been documented, a soft wire can be advanced, which will then be seen fluoroscopically to wrap around the cardiac silhouette; after needle withdrawal, a sheath can be placed. Through the sheath, a variety of catheters can be advanced.
Once in the pericardial space, when a catheter is advanced laterally and cranially, the first arterial structure encountered is the left atrial appendage. This can be identified by either contrast injections or by electrocardiographic tracings.
Several devices for epicardial left atrial appendage occlusion are being evaluated or tested. There are no randomized clinical trials or well-controlled large clinical trials. The most data available comes from a specific device (LARIAT). This hybrid procedure involves both transseptal and direct pericardial access.
After transseptal catheterization, a magnetic tipped 0.025-inch guidewire is advanced to the tip of the left atrial appendage. While using the direct pericardial approach, a magnetic tipped 0.035-inch guidewire is advanced until the two tips meet.
A snare is then advanced over the epicardial wire and positioned over the left atrial appendage. After confirmation of the correct positioning, the snare is tightened thus excluding the left atrial appendage. With this technique as with a transseptal approach, the presence of thrombus in the left atrial appendage is an absolute contraindication.
As previously mentioned, there are no carefully controlled data on direct pericardial access approaches to left atrial appendage occlusion. The largest dataset involves this hybrid device, which is approved in the United States for "approximating soft tissue."
In a single center study, 79 patients underwent evaluation for a LARIAT snare procedure. Contrast 3D-CT was used for left atrial appendage anatomy. A total of 14 of the 79 patients were excluded because of superior direction of the left atrial appendage or a thrombus in the left atrial appendage. Of the remaining patients, 65 had successful ligation and 60 of 65 had complete closure. There were no device related complications. No long-term data are available in this group.
Complications and their management
The major complications that have been seen with the transvenous/transseptal approach are pericardial effusion and periprocedural stroke.
In the PROTECT AF trial, there was an early safety hazard in patients treated with the Watchman device. The most frequent primary safety event was a serious pericardial effusion which occurred in 22 patients (4.8%). None of these patients died but the hospital course was prolonged.
Of the 22 patients, 15 were able to be treated with pericardiocentesis, while 7 underwent surgical intervention. The second most common serious complication was stroke (0.9%), which was felt to be secondary to air embolization. Subsequent analysis of the continued access registry of 460 patients documented that the rate of pericardial effusion had decreased to 2.2% and that there were no strokes.
Prevention of these complications is essential. Meticulous attention to accessing the left atrial appendage and then very careful placement of the device avoiding damage to the wall of the appendage is required. Enhanced surveillance using echocardiographic guidance is extremely important for early recognition of the complications of pericardial effusion.
Fortunately with early recognition and pericardiocentesis, as well as reversal of anticoagulant therapy, this complication can almost always be managed without the need for surgery. In terms of procedural related stroke, essential preventive approaches include minimizing stasis in the guiding catheters, maintenance of adequate heparinization and prevention of air entrapment during catheter placement.
What’s the evidence?
Holmes, DR, Kar, S, Price, MJ. "Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients with Atrial Fibrillation versus Long-Term Warfarin Therapy Trial (PREVAIL).". J Am Coll Cardiol. vol. 64. 2014. pp. 1-12.(PREVAIL is the second randomized trial and further substantiates this improved safety by documenting low numbers of events in the patients treated with the device and in the control group.)
Holmes, DR, Reddy, VY, Turi, ZG. "Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial.". Lancet. vol. 374. 2009. pp. 534-42.(The single published randomized clinical trial of the Watchman device documenting noninferiority versus warfarin for efficacy in preventing stroke/systemic embolism.)
Jain, AK, Gallagher, S.. "Percutaneous occlusion of the left atrial appendage in non-valvular atrial fibrillation for the prevention of thromboembolism: NICE guidance.". Heart. vol. 97. 2011. pp. 762-5.(Recent guidelines for LAA closure.)
Lee, RJ, Bartus, K, Bednarek, J. "Criteria for success of left atrial appendage ligation by a novel catheter-based suture ligation procedure.". J Am Coll Cardiol. vol. 57. 2011.(Initial experience with the LARIAT device for LAA closure.)
Reddy, VY, Doshi, SK, Sievert, H. "Percutaneous Left Atrial Appendage Closure for Stroke Prophylaxis in Patients With Atrial Fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) Trial.". Circulation. vol. 127. 2013. pp. 720-729.
Reddy, VY, Holmes, D, Doshi, SK. "The safety of percutaneous left atrial appendage closure: results from PROTECT AF and the Continued Access Registry.". Circulation. vol. 123. 2011. pp. 417-424.
Reddy, VY, Möbius-Winkler, S, Miller, MA. "Left Atrial Appendage Closure with the Watchman Device in Patients with a Contraindication for Oral Anticoagulation: ASA Plavix Feasibility Study with Watchman Left Atrial Appendage Closure Technology (ASAP Study).". J Am Coll Cardiol. vol. 61. 2013. pp. 2551-6.(The articles by Reddy et al document that indeed the procedure of left atrial appendage occlusion is able to be performed with increasing safety as experience with the technique has improved. That has important implications for the field. The initial PROTECT AF data included a safety concern which has now been largely mitigated.)
Holmes, DR, Doshi, SK, Kar, S. "Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation – a patient-level meta-analysis.". J Am Coll Cardiol. vol. 65. 2015. pp. 2614-23.(A patient level meta-analysis of the Watchman data on outcome vs warfarin control.)
Price, MJ, Reddy, VY, Valderrabano, M. "Bleeding outcomes after left atrial appendage closure compared with long-term warfarin: A pooled, patient level analysis of the WATCHMAN randomized trial experience.". JACC Cardiovasc Interv. vol. 8. 2015. pp. 1925-32.(Documentation of the long-term benefit of Watchman implantation in reducing hemorrhage compared to long-term warfarin.)
Boersma, LVA, Schmidt, B, Betts, TR. "Implant success and safety of left atrial appendage closure with the Watchman device: peri-procedural outcomes from the EWOLUTION registry.". European Heart J. 2016.(The largest European Watchman registry documenting early safety; also documenting current adjunctive therapy.)
Reddy, VY, Gibson, DN, Kar, S. "Post-FDA Approval, Initial US Clinical Experience with Watchman Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation.". J Am Coll Cardiol.. 2016.(Study of the U.S. experience following device approval. Documentation of continued improving safety.)
Tzikas, A, Shakir, S, Gafoor, S. "Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER cardiac plug.". EuroIntervention. vol. 11. 2016. pp. 1170-91.(Early procedural results of Amplatzer cardiac plug in a large multi-national registry. Documentation of use of antiplatelet alone post-implantation.)
Reddy, VY, Akehurst, RL, Armstrong, SO. "Cost-effectiveness of left atrial appendage closure with the Watchman device for atrial fibrillation patients with absolute contraindications to warfarin.". Europace. vol. 18. 2016. pp. 979-86.(Assessment of cost-effectiveness of Watchman documenting time frame in which device implantation is found to be cost-effective.)
Lakkireddy, D, Afzal, MR, Lee, RJ. "Short and long-term outcomes of percutaneous left atrial appendage suture ligation: Results from a U.S multicenter evaluation.". Heart Rhythm. vol. 13. 2016. pp. 1030-6.(Multicenter registry of the largest data obtained with the LARIAT device; documentation of patient population and early safety.)
Hildick-Smith, D, Camm, J, Diener, HC. "The AMULET Study: A multicenter, prospective registry of the Amulet left atrial appendage closure device for stroke prevention in patients with atrial fibrillation.". LBCT presented at AHA,. 2016..(Most recent data presented on the Amplatzer Amulet device in a large multicenter registry documenting early outcome.)
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
Clinical Pain Advisor Articles
- Comparing the Efficacy of Extended-Release Naltrexone and Buprenorphine-Naloxone on Opioid Relapse
- Reviewing the Effectiveness of Lidocaine for the Management of Chronic Pain
- Case Study: Amnestic Syndrome After Combined Cocaine, Fentanyl Use
- Web-Based CBT Adjunct May Address Aberrant Drug-Related Behaviors in Chronic Pain
- Sleep Quality May Mediate the Association Between Pain and PTSD Symptom Severity in Youth With Chronic Pain
- Injections of Corticosteroids vs Local Anesthetic in Rotator Cuff-Related Shoulder Pain
- Epidural Steroid Injections Associated With Decreased Bone Mineral Density, Increased Risk for Vertebral Fracture
- Physician Suicides: A Public Health Crisis
- Case Study: Amnestic Syndrome After Combined Cocaine, Fentanyl Use
- Pain Specialist Dr Beth Darnall Presented at the World Economic Forum Annual Meeting: Here Are Her Takeaways
- Guidelines on the Perioperative Pain Management of Patients on Buprenorphine Therapy
- Vitamin E May Not Improve Diabetic Peripheral Neuropathy-Associated Symptoms
- Migraines and Risk for Cardiovascular Comorbidities
- Antidepressant Medication Adherence and Long-Term Opioid Cessation
- Benefits of Including Humanities in the Medical Curriculum