Contribution of the bronchial circulation to lung preservation.

Short preservation time still severely limits lung transplantation. To determine the effect of bronchial arterial flush preservation, we studied 54 dogs using the isolated perfused working lung model. After baseline measurements, lungs were flushed with lactated Ringer's solution (60 ml/kg at 8 degrees C) by one of three methods: pulmonary artery perfusion, bronchial artery perfusion through a 15 cm closed aortic segment, or simultaneous pulmonary-bronchial artery perfusion. These groups were further subdivided and tested after 0, 4, and 17 hours of storage at 4 degrees C (n = 6 each). Lungs were ventilated (flow rate 140 ml/kg/min; inspired oxygen fraction 0.21) and continuously reperfused with normothermic deoxygenated autologous blood in a closed loop. Measured variables were hemodynamics, aerodynamics, and leukocytes in bronchoalveolar lavage. Survival time was determined from initial reperfusion to failure of the lung to oxygenate. After 0 and 4 hours of storage, there was no significant difference in survival times. After 17 hours, lungs subjected to pulmonary-bronchial artery perfusion survived longer than those perfused via either the pulmonary or bronchial arteries alone (120 +/- 24 versus 38 +/- 14 or 52 +/- 16 minutes; p less than 0.01). Pulmonary artery pressure and resistance in all groups except at failure were never different from baseline values in the intact animal. Shunts in the pulmonary-bronchial artery perfusion groups were closest to baseline at onset (8% +/- 4%) and remained lower throughout reperfusion than in the groups subjected to pulmonary or bronchial artery perfusion alone. After 17 hours, static compliance of pulmonary artery-perfused lungs was worse than baseline (1.1 +/- 0.2 x 10(-2) versus 3.2 +/- 0.7 x 10(-2) L/cm H2O/sec; p less than 0.05), whereas compliance in the pulmonary-bronchial artery perfusion groups remained constant (3.6 +/- 1.5 x 10(-2) L/cm H2O/sec). Elastic work performed by lungs subjected to pulmonary-bronchial artery flushing at onset was significantly lower when these lungs were reperfused immediately (201 +/- 14 versus 295 +/- 35 gm-m/min for pulmonary artery-flushed lungs) or after 4 hours of storage (229 +/- 30 versus 290 +/- 24 gm-m/min for pulmonary artery-flushed lungs). Bronchoalveolar lavage after 17 hours in the group subjected to pulmonary bronchial artery flushing demonstrated leukocyte counts similar to those of intact lungs (45 +/- 5 versus 29 +/- 8/mm3) and significantly less than in lungs subjected to pulmonary or bronchial artery flushing (137 +/- 18 or 82 +/- 10/mm3, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Living-related lobar lung transplantation in beagle puppies.

Unilateral lung transplantation has provided effective short-term therapy in adults with end-stage lung disease. Rejection continues to be the most common cause of transplant failure. Living-related lung transplantation may decrease the recipient immune response. The purpose of this study is to test the technical and physiological feasibility of living-related lobar lung transplantation from adult beagles into beagle puppies in a chronic model. Twenty purebred adult beagle donors underwent left thoracotomy with harvest of the left lower lobe using cold perfusion of the pulmonary artery and cold immersion. Twenty recipient purebred beagle puppies from the same colony underwent left thoracotomy, left pneumonectomy, and implantation of the donor adult lobe. Anastomoses were performed in sequence: pulmonary vein to left atrium, bronchus, pulmonary artery. Postoperative immunosuppression was with Cyclosporine. Respiratory function of the implanted lobe was evaluated by pulmonary angiography and during balloon occlusion of the right pulmonary artery with arterial blood gases 1 month after transplantation. Ten recipient puppies died of rejection (4), infection (3), or bronchial dehiscence (3) prior to angiography. Seventeen pulmonary angiograms in 10 surviving animals showed normal left pulmonary arterial blood flow (2), diminished left pulmonary arterial flow (5), and occluded left pulmonary artery (3). In two recipients balloon occlusion of the right pulmonary artery was performed and respiratory function was maintained solely by the transplanted lobe for 2 days in one recipient and for 30 minutes at 1 month and 2 months postimplant in a second recipient. Living-related lung transplantation of adult beagle lobes into pneumonectomized beagle puppies is technically feasible. High mortality rates in a chronic model are related to infection and rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

New uses of the laser in thoracic and cardiovascular surgery.

Lasers have been accepted in general thoracic surgery as resectional tools which allow precise hemostasis and maximal salvage of normal lung tissue. Used endoscopically, with or without associated photodynamic therapy, we have provided acceptable palliation in some patients with obstructing tumors of the tracheobronchial tree and esophagus. Cardiovascular uses of the laser have been under extensive investigation at our medical center for many years. We have demonstrated that laser-assisted anastomosis of small vessels is possible, that early tensile strength and patency are excellent, but that long-term aneurysm formation is excessive. In addition, CO2 laser injury of the arterial intima leads to a marked increase in atheromata formation in animal models of atherosclerosis; this may be eliminated with the excimer laser. We have begun using the excimer laser to open obstructed peripheral and coronary arteries. New technology is emerging which allows dual fiber catheters which allow identification of tissue in an artery, ie calcium, atheromata, clot, media, etc. and instantaneous computer sensing/integration which initiates "fire" or "no fire" signals in the enclosed laser system, thus decreasing the chance of vessel perforation. These technologies, in association with balloon angioplasty, intravascular stents, and atherectomy devices are offering exciting alternate therapy for patients with obstructing atherosclerosis.

Clinical experience with portable cardiopulmonary bypass in cardiac arrest patients.

To evaluate the use of portable cardiopulmonary bypass as a resuscitative tool and its impact on long-term survival of patients in cardiac arrest, we reviewed the results of 32 consecutive patients resuscitated by cardiopulmonary bypass for cardiac arrest or severe hemodynamic compromise at Northwestern Memorial Hospital over a 2-year period. Overall survival was 12.5%. Only 1 (3.4%) of the 29 patients who had cardiac arrest survived and left the hospital. All 3 patients who had severe hemodynamic compromise but not cardiac arrest were long-term survivors. Our study suggests that portable cardiopulmonary support systems used as a resuscitative tool do not prolong the survival of most cardiac arrest patients but may be useful for patients with shock due to mechanical causes and for those with profound hemodynamic compromise due to ischemia or myocardial infarction. Portable heart-lung machines can provide patients with excellent hemodynamic support; however, neurological or cardiac recovery is unlikely once cardiac arrest occurs.

Aggressive blood conservation in coronary artery surgery: impact on patient care.

Data on 100 consecutive non-emergency coronary artery bypass (CABG) patients were analyzed retrospectively. Sixty-nine patients received no homologous blood (Group I). Thirty-one patients received a total of 118 units of blood products averaging 2.23 units of red cells (Group II). The average red cell transfusion rate for all patients was 0.7 units per patient. The median age for Group I was 61 and Group II was 68 years (p less than 0.05). The average number of grafts was the same for both (3 per patient) with 75% of Group I and 58% of Group II receiving internal mammary artery (IMA) grafts (p less than 0.05). Twelve of the Group II patients who received intraoperative transfusions on cardiopulmonary bypass to maintain adequate hemoglobin levels were older and had lower admission hematocrits: 36 +/- 0.8% compared to 41 +/- 0.5% for all other patients (p less than 0.05). Average postoperative blood loss was 889 +/- 38 ml for Group I and 1077 +/- 104 ml for Group II (p less than 0.05). Increased hemorrhage was correlated with bypass time and IMA use but not with preoperative heparin administration, pre-existing risk factors (diabetes, hypertension, etc.), bleeding time, post-bypass clotting time, age or number of grafts. Two patients in Group II and none in Group I required exploration for excessive postoperative hemorrhage. Mortality rate was 2% (both in Group II, neither transfusion related). Discharge hematocrits were the same for all at 29.4 +/- 0.4%. Among anemia-related postoperative symptoms, only sinus tachycardia was significantly higher in Group I (20%) compared to Group II (6.5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Interposition of the thymus as a pedicled flap in tracheal reconstructive surgery.

Thymus was interposed in six patients following tracheal reconstruction: three tracheo-innominate fistula repairs, two resections for stenosis, and one repair of a membranous tear during esophagectomy. The two resections for stenosis were elective; the others were emergent repairs. This gland, readily accessible in the upper mediastinum, is easily dissected from the pleura and pericardium and separated into two lobes. Pedicles based at the thoracic inlet measure between 15 and 20 cm by 4 cm. Each lobe receives independent arterial blood supply and venous drainage which remains intact even if the innominate vein must be divided to effect tracheal repair. All patients survived the perioperative period. The patient with the tracheo-innominate fistula died 1 month later. No patient had evidence of further vascular complications or tracheal anastomotic leak even though one patient developed a long segment of necrotic trachea. Reinforcement following tracheal reconstruction is important in preventing complications from anastomotic leak or vascular erosion. The pedicled thymus gland is an excellent, readily available interposition flap for emergent or elective tracheal reconstruction.

Implications of prosthetic valve implantation: an 8-year follow-up of patients with porcine bioprostheses.

Nurses in cardiovascular critical care settings routinely care for patients with implanted valvular prostheses. The presence of an artificial valve substitutes a new disease state for the preexisting valvular disease. Five hundred nine patients who underwent cardiac valve replacement with porcine bioprostheses and who were followed for a total of 1633 patient-years provide the data base for discussion of long-term survival, functional capacity, and morbidity associated with valvular prostheses. Seventy-two percent of patients survived 5 years after operation. New York Heart Association functional class was improved in 84%. Three major types of morbidity were documented: thromboembolism, endocarditis, and valve failure. Cardiovascular nurses should be familiar with the implications of valvular prostheses to provide appropriate patient education and to facilitate the prompt detection and treatment of valve-related complications.

Laser-assisted parenchyma-sparing pulmonary resection.

The neodymium:yttrium-aluminum-garnet laser is an excellent tool for removing lesions while sparing surrounding normal tissue. Local excision of 32 pulmonary lesions in 26 patients was performed with the Nd:YAG laser. Fourteen patients had moderate to severe impairment of pulmonary function: average forced vital capacity = 2.2 +/- 0.3 L and forced expiratory volume in 1 second = 1.3 +/- 0.3 L. Limited thoracotomy was used in the last 23 patients. The resected lesions included 16 primary malignant tumors: nine adenocarcinomas, five squamous carcinomas, and two large cell carcinomas. Eight of these lesions were classified as T1 N0, seven were T2 N0; and one was T1 N2. There were 10 metastatic lesions: three lymphomas, two adenocarcinomas, two leiomyosarcomas, and one case each of melanoma, squamous cell carcinoma, and renal cell carcinoma. There were six benign lesions: three granulomas, two hamartomas, and one carcinoid. Twelve lesions were deep seated, could not have been removed by wedge resection or segmentectomy, and would have necessitated lobectomy without this technique. With the laser, the lesion could be precisely excised with minimal loss of lung parenchyma. Mean operating time was 80 +/- 20 minutes; laser resection time was 15 +/- 8 minutes. Resection necessitated 10,000 to 20,000 J. Total blood loss was minimal (less than 100 ml). Chest tubes were always used and remained in place 5 +/- 2 days. The mean hospitalization time was 10 +/- 2 days. Pulmonary function testing, perform 6 weeks to 6 months after discharge, showed no significant difference from preoperative levels. To date, there have been no local recurrences (longest follow-up 2 years). The Nd:YAG laser is an excellent adjunct for pulmonary resection in patients who have marginal pulmonary function or who have deep parenchymal lesions not amenable to wedge resection. The operative technique for laser resection is presented.

Pulmonary venous anastomosis in lung transplantation without donor left atrium. Experimental and clinical results.

Single lung transplantation now is a therapeutic option for some patients with end-stage lung disease. Cyclosporine immunosuppression and refinements in bronchial anastomosis have been responsible for recent successes. Since 1953, the usual pulmonary venous anastomosis, both in experimental animals and in humans, has been an atrium-to-atrium connection. This technique may limit the availability of usable donor lungs, since the donor heart, along with the atrium, is usually harvested for another recipient. Although techniques can be developed to allow both transplant teams to harvest atrial tissue, this study was undertaken to determine if, in fact, anastomosis with donor left atrium is necessary. Twenty-four dogs were anesthetized and a left thoracotomy performed. After heparinization (3 mg/kg), the pulmonary artery and left atrium were occluded. One of four different pulmonary venous anastomoses was performed at 3.5x magnification: superior pulmonary vein end to end (group I), inferior pulmonary vein end to end (group II), superior pulmonary vein implantation into left atrium (group III), and left atrium-to-left atrium anastomosis as control (group IV). Everting mattress sutures of 7-0 polypropylene were used in groups I, II, and III and 6-0 in group IV. Average crossclamp time for group I, group II, and group IV was 20 minutes. The average crossclamp time for group III was 10 minutes. All anastomoses were patent at the time of 1-week reevaluation. Gross and microscopic examination demonstrated establishment of an intimal lining; organized nonocclusive thrombus was present in only one anastomosis. We conclude that atrium-to-atrium anastomosis is not necessary for a successful single lung transplantation, and that transplantation of a single lobe is feasible. The best alternative is implantation of the pulmonary vein into the left atrium, which will easily allow use of the heart and both lungs from a single donor to different recipients. We have used this anastomosis in one patient without difficulty.

Early reexploration for excessive postoperative bleeding lowers wound complication rates in open heart surgery.

Clinical reviews of sternal wound infections following open heart surgery indicate many predisposing factors including diabetes, low cardiac output, use of bilateral internal mammary grafts, and reoperation for excessive postoperative bleeding. This study was undertaken to determine the role of mediastinal re-exploration in the development of sternal wound complications. From a series of 2,271 patients undergoing median sternotomy for open-heart surgery between 1979 and 1984, 71 (3.1%) were re-explored for excessive bleeding. Nine of these patients died in the early postoperative period of noninfectious complications. The remaining patients were divided into two groups. Group 1 (54 patients) were re-explored without subsequent problems. Group 2 (8 patients) developed sternal and costochondral wound complications. Comparison of age, intercurrent and pre-existing disease, total bypass time, crossclamp time, and postoperative hemodynamic status showed no statistical difference. All patients bled an average rate of 247 ml/hr. However, the average time before re-exploration was 7.6 hours in group 1 compared to 13.8 hours in group 2 (P less than 0.001). Sternal wound complications may be minimized by a policy of early re-exploration for excessive postoperative bleeding (greater than 200 ml/hr for 4 hours).

Pulmonary procedures assisted by optosurgical and electrosurgical devices: comparison of damage potential.

Electrosurgical devices have been used widely in thoracic surgery to assist in dissection and to reduce hemorrhage. Recent experimental data have shown that lasers may be used to resect and control small air leaks while conserving normally functioning lung. This investigation quantitates the amount of damage produced by the electrosurgical unit (ESU), the carbon dioxide laser (CO2), and the neodymium: YAG laser (YAG) compared to standard suture (SU) techniques. Six dogs were anesthetized, intubated, and ventilated. The left chest was opened and the lower lobe exposed, where four sets of lesions were created using each device. All lesions were visually similar to those lesions that would be created for sealing at the time of a pulmonary resection. The lesions were harvested immediately following wounding as well as at 1, 3, and 6 week intervals. They were examined histologically and ranked from least to most damage produced at each interval. A grading system (0-4+) was also devised to compare the injury to simultaneously harvested normal lung. Immediately following injury, histologic ranking was: CO2 (2+), suture (2+), ESU (3+), YAG (4+). By 6 weeks, the suture damage had become minimal and the ranking was: suture (1+), CO2 (2+), YAG (4+), ESU (4+). The ESU consistently produced more extensive damage than any other device. It appears that the most suitable long-term adjunctive devices to assist in pulmonary surgery are suture and the CO2 laser. The YAG laser may have specific indications in circumstances when significant blood loss may be encountered. ESU usage should be minimized when attempting to preserve functioning lung tissue.

Partial splenectomy with the CO2 laser: an alternative technique.

Because total splenectomy has been shown to affect immunocompetence in children, partial splenectomy is advocated as an alternative to total splenectomy in traumatic injury as well as in treatment of benign cysts. Present techniques include elaborate hemostatic techniques and extensive suture repair which has led to the development of massive abdominal adhesions. We have investigated CO2 laser sealing of splenic wounds to obviate the need for extensive repair and to minimize intraabdominal reaction. Five dogs underwent partial splenectomy with a scalpel. Hemostasis was obtained with CO2 laser coagulation; a defocused laser beam at 8 W (power density 30-50 W/cm2). After 3 weeks, the laser sealed splenic tissue was amputated and, on this occasion, hemostasis was obtained using a standard suture technique of Teflon pledget-bolstered chromic sutures. Three weeks later the dogs were explored and the sutured splenic tissue was removed. Gross findings on the first exploration demonstrated no signs of hemorrhage and minimal adhesions of the laser sealed spleens. In contrast, exploration after suture repair revealed dense adhesions containing the spleen, omentum, mesentery, and small and large bowel. Microscopic examination of the laser sealed spleen showed a zone of injury only 2-3-mm thick. Excellent hemostasis of the cut surface of the spleen can be accomplished using the CO2 laser. In addition, the minimal depth of injury and the absence of foreign material in the peritoneal cavity make this an attractive alternative to conventional methods.

Comparative study of warfarin versus antiplatelet therapy in patients with a St. Jude Medical valve in the aortic position.

To determine the necessity of long-term warfarin anticoagulation after St. Jude Medical aortic valve replacement in adults, we evaluated the risks of thromboembolism, valve thrombosis, anticoagulant hemorrhage, and sudden cardiac death in two groups of patients. Group I consisted of 41 patients treated with conventional long-term warfarin therapy. Forty-two patients in Group II were treated primarily with antiplatelet therapy (aspirin, dipyridamole, or both); 17 of these patients received warfarin for a short time postoperatively and seven others received it intermittently during the study period. The groups were similar with respect to age, sex, associated cardiovascular disease, and length of follow-up (mean 29 months per patient). In the warfarin-treated group, three late sudden deaths occurred, one of which was preceded by a cerebrovascular accident, for a cardiac mortality of 2.7% per patient-year. There were eight major nonfatal complications (7.3% per patient-year), of which four were hemorrhagic and four embolic. In Group II, there was one sudden cardiac death (1.1% per patient-year) and four major complications occurred (3.2% per patient-year). Two of the complications were embolic and two were episodes of valve thrombosis, both necessitating reoperation. Although the incidence of serious morbidity in the warfarin-treated group was twice that of patients treated with antiplatelet therapy, there were no statistically significant differences in the rates of sudden death or major complications. These data suggest that antiplatelet therapy may be as effective as warfarin in preventing embolism from the St. Jude Medical valve in the aortic position. Valve thrombosis occurred in two patients, both receiving antiplatelet therapy (2.2% per patient-year). Whether this type of valve failure can be prevented by warfarin remains in question.

An eight-year experience with porcine bioprosthetic cardiac valves.

A total of 589 porcine bioprostheses were implanted in 509 patients from January, 1976, through December, 1983. Of the valves implanted, 390 were Hancock and 199 were Carpentier-Edwards. A total of 1,633 patient-years was accrued, with a mean follow-up of 38 months per patient. Two hundred eight patients had aortic valve replacement, 209 had mitral valve replacement, and 79 had multiple valve replacements, of which 46 were aortic and mitral replacements. The mortality for isolated aortic valve replacement was 5.8%; for isolated mitral replacement, 8.6%, and for all patients, 10.9%. Late mortality was 3.9% per patient-year. The actuarial survival rate at 5 years was 79% for aortic, 68% for mitral, and 76% for aortic-mitral valve replacement. There were 12 thromboembolic events (0.73% per patient-year). Two episodes occurred in patients with an aortic bioprosthesis, nine in patients with a porcine mitral valve, and one in a patient with mitral and tricuspid bioprosthetic valves. The probability of remaining free of thromboembolism at 5 years was 99% for the group having aortic valve replacement, 93% for those having mitral replacement, and 100% for the group having aortic-mitral valve replacements. Thirteen episodes of endocarditis occurred (0.8% per patient-year). Seven of the 13 patients died as a direct result of endocarditis. The probability of remaining free of prosthetic endocarditis at 5 years was 97% for the aortic valve replacement group, 95% for the mitral group, and 97% for the aortic-mitral group. There were 20 instances of xenograft failure (1.2% per patient-year). The probability of remaining free of valve failure at 5 years was 96% for the aortic valve replacement group, 93% for the mitral group, and 93% for the aortic-mitral replacement group. Primary tissue failure of a prosthesis occurred in seven patients, all with Hancock valves (0.43% per patient-year). As yet there has been no primary tissue failure of the Carpentier-Edwards prosthesis. There also appears to be a lower incidence of thromboembolism (Edwards, 0.3% per patient-year; Hancock, 0.8% per patient-year) and endocarditis (Edwards, 0.6% per patient-year; Hancock, 1.0% per patient-year). The low incidence of complications with the porcine bioprosthetic valve, especially the Carpentier-Edwards, encourages us to recommend its continued use, especially in situations in which anticoagulation is contraindicated.

Remote skin injury: a protean complication of open heart surgery.

In the 12-month period ending August, 1984, 14 adult patients (2.9%) developed within 24 hr following open heart surgery skin defects of varying magnitude remote from the incision site. Electrical injury secondary to a grounding defect was documented in two patients and suspected in one. Four patients' injuries were caused by the roller device when transfering from operating room table to intensive care unit bed. The remaining eight patients all had skin loss at sites of pressure on either the head, back, buttocks, or arm. Retrospective analysis showed no correlation with mean pressure during cardiopulmonary bypass (CPB), depth of cooling, length of time to rewarm, or the use vasoactive drugs. Subsequently, core temperature plus ten surface temperatures were monitored during and following CPB in ten patients. The data showed that during active cooling and rewarming, skin temperature actually lagged behind the core temperature (4 C). Thus, the skin appears to develop a relative oxygen debt during CPB which may decrease the threshold for skin injury particularly in older patients who may have other predisposing factors, such as obesity, generalized atherosclerosis, diabetes, or friable skin. Pressure points during positioning and subsequent skin trauma must be meticulously avoided in any patient undergoing CPB.

Vascular anastomoses with laser energy.

Laser-assisted arterial and venous anastomoses are now feasible. A microscope-guided CO2 laser was used to deliver 60 to 100 mW to anastomose end to end 44 rabbit carotid arteries (1.5 to 2.0 mm) and 27 rabbit vena cavae (4 to 6 mm). These were compared with control arteries repaired with interrupted suture technique. Anastomoses were examined from between 24 hours and 19 weeks. Laser carotid anastomoses yielded 93% patency (41 of 44) and 9% aneurysms (4 of 44), whereas hand-sewn carotid anastomoses produced 91% patency (40 of 44) and no aneurysms. In the vena cava, 26 of 27 laser anastomoses were patent (96%) compared with 19 of 20 (95%) sutured controls. Venous aneurysmal dilatation was seen in 2 of 27 laser (7%) and in 3 of 20 (15%) hand-sewn anastomoses. Histologic examination of laser-assisted anastomoses showed local full-thickness thermal injury. Repair was by fibroblast and myofibroblast proliferation, and luminal cell coverage was complete by 14 days in both laser and sutured repairs. Laser arterial and venous anastomoses are attractive because of their simplicity and rapidity of performance. Their patency is comparable to sutured anastomoses, but arterial aneurysms remain a hazard despite use of extremely low laser energy.

New applications of the laser in pulmonary surgery: hemostasis and sealing of air leaks.

In thoracic surgery, the laser has been used primarily as a destructive instrument (e.g., for extirpation of endobronchial lesions and for skin incisions). Previously, the carbon dioxide laser was used for its scalpel-like action but not for sealing. The neodymium:yttrium aluminum garnet (Nd:YAG) laser not only cuts but also seals blood vessels and bronchi. We have modified the CO2 laser technique to seal vessels and bronchi up to 3 mm on a cut surface by using low power in a defocused mode, and have evaluated the method in 12 dogs. Matched lesions in the lingula were sealed with each type of laser and compared with lesions closed by suture technique. These lesions were then evaluated at biweekly intervals up to 6 weeks following operation. All lesions demonstrated substantial air leak and bleeding prior to sealing. There was no bleeding or air leak (40 cm H2O of pressure) at any time after sealing (laser or suture). The CO2 laser sealing consistently produced the least damage both macroscopically and microscopically. However, this technique requires a relatively bloodless field. The Nd:YAG laser produced the deepest tissue destruction but functioned well under conditions of poor hemostasis. Suture closure produced large early injuries, which subsided gradually to approach the amount of damage seen with the CO2 laser. These studies demonstrate that the laser may be a useful adjunct to maximally preserve normal lung tissue and to seal bleeding, leaking, raw lung surfaces. Results of early clinical trials are also detailed.