Laser thrombolysis is an interventional procedure that removes clot by delivering microsecond pulses via a fluid core catheter. The removal of the clot results in a restoration of blood flow while maintaining vascular integrity.
This following has been adapted from the introduction of the Ph.D. thesis of Ujwal Sathyam
Cardiovascular disease occurs when arteries and veins become occluded with atherosclerotic plaque and clot cutting off blood supply to vital organs. This can lead to potentially fatal conditions such as heart attacks, strokes, and pulmonary embolism.
To cause injury to tissue with light, the tissue has to absorb the energy. The amount of energy absorbed by the tissue depends on the wavelength of the light. The absorption by thrombus is significantly higher than that by arterial tissue in the visible region of the electromagnetic spectrum. This allows lasers to selectively remove thrombus without injuring the vessel wall by using a wavelength in this region. Current investigations of laser thrombolysis use tunable pulsed-dye lasers operating in the visible region with pulse lengths of 1-2µs. The absorption of light by the thrombus leads to the explosive vaporization of part of the clot and the formation of rapidly expanding and collapsing vapor bubbles. The dynamics of the vapor bubbles generate pressure transients that disrupt the clot.
Laser thrombolysis was first used to treat acute myocardial infarctions caused by thrombosed native coronary arteries that supply the heart muscles. Preclinical and early clinical studies have demonstrated effective removal of thrombus and restoration of blood flow. Pulsed lasers have also been used to remove clots in occluded bypass grafts and femoral arteries. Recently, there has been considerable interest in using this technique to remove cerebral clots in the arteries of the brain. This can be an important step towards the treatment of stroke that can be caused by occlusions in the brain arteries.
The use of lasers to remove tissue was suggested soon after the development of the first laser in 1960. Some of the clinical applications of lasers to ablate tissue are bone removal, cartilage smoothing, corneal reshaping, burn treatment, and laser angioplasty. Laser angioplasty targets the plaque that is usually present along with clot in diseased arteries. The use of optical fibers capable of delivering light to previously inaccessible places in the body has made the medical laser particularly attractive for many minimally invasive techniques.
The development of a safe and effective laser system for arterial recanalization is a complex task involving the selection of optimal laser parameters and delivery of the energy. Early enthusiasm for laser angioplasty and laser thrombolysis was tempered by unacceptable failure rates. Some of this was due to poor designs of laser and delivery systems and a lack of understanding of the ablation mechanism. The last ten years have seen progress in the design of the system and have rejuvenated the interest in laser-assisted recanalization techniques.
The broad goal of the research at the Oregon Medical Laser Center is to make laser thrombolysis a safe and rapid procedure, so that it may be accepted as a standard treatment modality for vascular disease. Both basic research into the physical ablation phenomena and clinical trials are required to achieve this. This thesis addresses some of the questions regarding the basic physical processes during laser thrombolysis. With a better understanding of the ablation process, it may be possible to specify optimal parameters for the design of the laser and delivery systems.
Vascular disease is the major cause of death and disability in the United States. More health care dollars are spent on the treatment of various types of vascular disease than any others. One cause of vessel disease is the accumulation of plaque and thrombus (clot) in the arteries resulting in reduction and/or cessation of blood flow to vital organs. Another related cause is thromboembolism where a piece of a clot formed elsewhere breaks off and floats downstream blocking blood flow to a vital organ.
Coronary artery thrombosis resulting in myocardial infarction occurs in over 1.5 million people in the United States, and over 500,000 will die as a consequence [fuster 1992, fuster 1992a]. Thrombosis of coronary artery bypass grafts is the major cause of bypass graft closure at a rate of about 200,000 cases per year [chesebro 1992]. Thrombosis can also occur in cerebral arteries and lead to strokes. Over 80% of strokes are ischemic in nature and are attributed to thrombosis and embolism [stroke 1995]. Venous thrombosis can lead to pulmonary embolism where a piece of the clot detaches and embolizes downstream in the lung.
Normally, blood constituents do not interact with intact vascular endothelium that is a thin layer of cells lining the insides of vessels. However, the exposure of flowing blood to disrupted vasculature or to cardiovascular devices initiates complex mechanisms leading to thrombosis. There is rapid deposition of platelets, insoluble fibrin, leukocytes, and entrapped erythrocytes [davies 1994]. Clots can also form when the blood flow slows down as in most cases of venous thrombosis.
Not all clots are created equal. The etiology and characteristics of the thrombus, and therefore its preferred treatment modality depend on where it is formed. Vascular occlusions can occur almost anywhere in the vascular system including in the coronary arteries, bypass grafts, cerebro-vasculature, and in the peripheral blood vessels. Arterial flow conditions give rise to platelet-rich ``white'' thrombi, and static venous flow yields ``red'' thrombi rich in fibrin and red blood cells.
The mainstay of thrombus management is a regimen of pharmacological therapy that includes thrombolytics to dissolve the clot and anticoagulants to prevent clotting. Streptokinase, urokinase, and tPA are examples of thrombolytics, and heparin is an anticoagulant. The use of these drugs has been shown to improve cardiac function [debono 1992, gusto 1993]. Alternate approaches to vascular recanalization are balloon angioplasty, rotoblader atherectomy, and aspiration devices [goudreau 1991, ivanhoe 1992, rosenblum 1992, grines 1992]. In balloon angioplasty a balloon is inflated inside the vessel to mechanically re-mold the lumen. When all else fails or if the thrombus burden is too large, bypass surgery may be performed.
Acute coronary thrombosis is common to the pathogenesis of myocardial infarction and of unstable angina. Fissuring or rupture of an atherosclerotic plaque plays a fundamental role in the formation of coronary artery thrombosis [badimon 1992]. When the injury to the vessel is mild, the thrombogenic stimulus is relatively limited, and the resulting occlusion is transient as in unstable angina. The endothelium is denuded with thrombi adherent to the surface of the plaque. Deep vessel injury results in persistent thrombotic occlusion and myocardial infarction. Major plaque disruption exposes the lipid core to the lumen. Blood enters the core and thrombus forms within the plaque expanding its volume rapidly. The intraplaque component of the thrombus is very rich in platelets. The intraluminal part forms as the last stage of the occlusion and is rich in fibrin and red cells.
Thrombolytic therapy with pharmacological agents is paramount in myocardial infarction, but it is less effective in unstable angina [debono 1994]. The reduction in mortality associated with the use of thrombolytic agents is impressive [isis 1992, gusto 1993]. The most feared complication of thrombolytic therapy is intracranial hemorrhage since fatality rates in such cases can range from 44% to 75% [gore 1995]. Some patients have contra-indications to the drugs and cannot receive them due to bleeding disorders, recent strokes, etc. Also, the thrombus burden is usually not removed completely. Residual thrombus is very thrombogenic acting as substrate for additional clot formation. Re-occlusion of the artery is therefore a problem.
Percutaneous interventional techniques like balloon angioplasty and atherectomy were initially used as a secondary treatment to keep the vessel open after thrombolytic therapy. Angioplasty has now evolved as a primary intervention for patients who have shown contra-indications to thrombolytics. Acute results of balloon angioplasty are promising with a relatively low rate of abrupt vessel closure (~5%) [linkoff 1992]. Drawbacks, however, appear in the short-term follow-up phases where vessel closure rates of 30-50% within six months have been reported [ellis 1989, hirshfeld 1991]. This has been largely attributed to the damage incurred by the vessel wall during inflation of the balloon.
The last line of defense is bypass surgery where a piece of a vein from the leg is grafted around the occlusion to re-establish blood flow. This is an open chest procedure and involves severe trauma to the patient. There is also an increased risk of re-occlusion due to thrombosis of the vein graft.
The term ``stroke'' is used to describe a number of brain disorders with a common feature of a defect in the cerebral vasculature. Strokes are classified according to whether they are ischemic or hemorrhagic. Most strokes are due to arterial occlusion with brain ischemia (oxygen deprivation) leading to cerebral infarction or transient ischemic attacks [stroke 1995].
Similar to the pathogenesis of acute coronary syndromes, thrombosis over a disrupted plaque can play a key role in cerebrovascular occlusions [badimon 1992]. However, intracranial hemorrhage and embolism may also be involved; common sources for the thrombus embolus are the heart and the carotid arteries. Transient ischemic attacks result from progressive narrowing of the vessel leading to reduction of blood flow or from a transient occlusion by a thrombus. Cerebral infarction arises from total occlusions.
Early studies of therapies for acute stroke show benefit at a high price [langhorne 1994]. It is clear that cerebral perfusion has to be re-established within 3-6 hours to restore normal neurological function. The treatment is to infuse the patient with thrombolytics and agents that dissolve thrombus and increase cerebral perfusion. This treatment modality is not always successful, and sometimes the occlusion is not cleared in time. The thrombolytic tPA has recently been approved by the Food and Drug Administration for the treatment of embolic stroke. Mechanical intervention has not been tried on large scale due to difficult access to the occlusion via the tortuous bends in the arteries. Also, the arteries of the brain are more fragile, increasing the risk of vascular injury and vasospasm. A major problem in the treatment of stroke is the recurrence of stroke. This is particularly true of strokes that are embolic in nature. In such cases the underlying cause of the stroke has to be treated where possible.
Claudication is the clinical term for pain in the muscles of the leg due to insufficient delivery of oxygen resulting from a proximal obstruction to blood flow. Peripheral arterial disease is frequently asymptomatic for long periods and often occurs together with coronary artery disease. The risk of a leg amputation is relatively low (~5%); however, life expectancy is generally reduced [verhaeghe 1992]. A large number of patients die of cardiovascular causes.
Smokers demonstrate a higher incidence of fibrous, calcified, and ulcerated plaques in the aorta and in the iliofemoral circulation [badimon 1992]. Diabetes is also commonly associated with disease of the iliofemoral and distal arteries of the leg. Major acute arterial occlusion is often due to fibrin-rich emboli arising from the heart or occasionally from venous thromboembolism through a patent foramen ovale (an abnormal communication between chambers in the heart). Microemboli causing digital infarction may arise from cardiac sources or from fragmentation of a proximal thrombus during vascular intervention.
In most patients with intermittent claudication, conservative therapy is usually lifestyle advice to exercise regularly and to reduce smoking. In acute cases the primary treatments are reconstructive surgery and catheter recanalization procedures. Arterial bypass grafts and percutaneous transluminal angioplasty are the most common procedures performed [wholey 1993]. Systemic thrombolysis with drugs has a low success rate and a significant risk of bleeding. Local thrombolysis delivers drugs via a catheter and has a higher success rate. Nevertheless, the use of thrombolytics is frequently not the treatment of choice for peripheral arterial disease.
Bypass surgery is generally performed for diffuse atherosclerotic disease resulting from a chronic build-up or when there has already been a previous intervention. It is also done when arterial disease develops at multiple sites. Basically, a piece of the saphenous vein in the leg is grafted and implanted to bypass the occlusion.
A problem plaguing bypass surgery is thrombosis of the vein graft cutting off blood flow again. Disease of vein grafts is a form of accelerated atherosclerosis that begins with acute vascular injury, mural thrombosis, and proliferation of smooth muscle cells in the vessel wall. Injury to the vein graft results from procurement of the vein from the leg, surgical handling, delays before insertion, and from the increased shear forces of the pulsatile arterial system. There is platelet deposition and secretion of growth factors for smooth muscle cells and white cells. Recent bypass procedures have used a graft from the internal mammary artery that is more protected from generalized injury and platelet deposition. This is probably due to previous adaption to arterial shear forces.
There is no satisfactory treatment for thrombosed vein grafts. Mechanical intervention like angioplasty is not preferred because of problems and embolization at lesions to distal coronary arteries [defeyter 1988}. Thrombolytics ease the thrombus burden in about 50% of the cases, but the re-occlusion rate is around 30% [chesebro 1992, gavaghan 1991]. Because platelet deposition starts as soon as blood flows through the vein graft, perioperative antithrombotic therapy is critical.
Deep vein thrombosis is a common and potentially dangerous complication of a primary illness in hospitalized patients. It may lead to pulmonary embolism that can be fatal. When venous thrombi dislodge, they can reach the pulmonary arterial circulation and may adhere to the bifurcation of the pulmonary artery. The thrombus generally forms in post-operative patients who are under extensive bed rest. It is also common in people who spend extended periods of time in a sedentary position.
Venous thrombosis develops when stasis in the deep veins of the legs occurs at times of increased coagulability of the blood [badimon 1992]. This combination leads to local generation of thrombin that is the crucial event in the pathogenesis of the disease. Since the clot forms under static conditions of blood flow more red blood cells are trapped and the clot appears red. Vessel wall injury is less likely to be involved. Deep vein thrombosis can also go undetected for some time, and they can be several weeks old before turning symptomatic.
Prevention of deep vein thrombosis is a critical part of post-operative care. This involves elimination of stasis and fighting blood coagulation. Although anticoagulant therapy is highly effective, two thirds of the patients who die from pulmonary embolism succumb abruptly or before the therapy can take effect. Thrombolytic therapy is generally more rapid than anticoagulants in thrombus removal. Contra-indications again appear in the form of bleeding.
Surgical intervention for venous thrombosis consists of either thrombectomy or venous interruption. The role of thrombectomy remains controversial. There are several techniques for the interruption of the inferior vena cava that is the main blood vessel carrying blood from the legs back to the heart. One example is a variety of external clips designed to partially compress the vein so that emboli floating in the stream are filtered [kakkar 1994]. However, compromised cardiac output due to inadequate venous return led to low acceptance of these techniques in clinical practice.
The disadvantages of current techniques to rapidly clear large thrombus burden in occluded arteries led to the search for an alternative method that did not endanger the vessel wall. The potential for laser energy to remove atherosclerotic obstructions (plaque) was described as early as 1963 [mcguff 1963]. Since then most investigations have concentrated on the removal of plaque in a technique called laser angioplasty [grundfest 1985}. In 1983 Lee et al. used an argon laser to vaporize human thrombus in vitro [lee 1983]. If the arterial occlusions is a combination of plaque and thrombus, it is essential to remove both for effective therapy.
Early studies of both laser angioplasty and laser thrombolysis used continuous wave laser to remove the arterial obstruction. Crea and Abela attempted to recanalize thrombosed coronary arteries in dogs using an argon ion laser [crea 1985}. The wavelengths used were 488nm and 514nm, and the laser energy was transmitted via 140 or 200µm cleaved silica fibers. The results were not encouraging with recanalization reported in only 1 of 19 dogs. Perforation of the arterial lumen was observed in 7 of 9 dogs. Minimal thrombus was removed and there was evidence of charring at the laser delivery sites.
The results of several subsequent studies have demonstrated the limitations of both continuous laser energy and delivery by hard silica fibers [choy 1982, choy 1984, abela 1982, abela 1985]. Irradiation by a continuous wave laser does not confine the heat produced to the target area. The diffusion of heat out of the target area can result in thermal necrosis and even charring in the surrounding tissue. These factors also lead to intense vasospasm and thrombosis [ginsberg 1985]. It has been reported recently that accelerated intimal hyperplasia can be attributed to thermal injury [douek 1992]. Intimal hyperplasia is a condition where the smooth muscle cells in the vessel wall proliferate and cause closure of the vessel.
Bare silica fibers are generally stiff and have sharp edges. Tortuous bends in the vascular system are difficult to navigate and therefore limit access to the occlusion. The sharp edges of the fiber pose considerable hazards to the vessel wall, and arterial perforations and fracture of fibers have been reported in animal trials. The fiber tip was then covered with a metal cap (``hot-tip'') in an attempt to reduce the sharp profile of the fiber [hussein 1986, welch 1987a, lecarpentier 1988, labs 1991, tomaru 1992b]. While results from animal trials were promising, an unacceptable number of thermal injuries during angioplasty in human coronary arteries were reported. Consequently, most attempts at laser angioplasty and thrombolysis using continuous-wave lasers were abandoned.
Srinivasan et al. reported their experience using ultrashort excimer laser pulses to produce precise cuts in polymers without adjacent thermal effects [srinivasan 1982]. This approach of using pulsed lasers to limit thermal effects can also be be used to ablate tissue. The limiting pulse length would be determined by the thermal relaxation time of the material. This is the time for heat to diffuse out of the irradiated volume and is determined by the thermal diffusivity of the tissue and the dimensions of the volume. When laser energy is deposited in pulses shorter than the thermal relaxation time, heat accumulates and high temperatures are achieved. The ablative event can then occur before the heat diffuses out of irradiated volume. This confinement of heat can reduce the thermal damage incurred by adjacent tissue [jacques 1993b, jacques 1993].
For vascular structures the thermal relaxation time is of the order of milliseconds, so lasers with pulse durations less than 1ms are likely to produce little thermal injury [linsker 1984, anderson 1983]. Pulsed lasers from the ultraviolet [grundfest 1985a, isner 1985, pettit 1993, deckelbaum 1985, litvack 1990], visible [prince 1986, prince 1986a, lamuraglia 1988b, lamuraglia 1990, gregory 1990a, gregory 1994], and infrared [kopchok 1990, geschwind 1991, knopf 1992] have been investigated for both angioplasty and thrombolysis. Notable among these are the excimer (308nm, 351nm, 100-200ns), tunable pulsed-dye (400-600nm, 1µs), and the Ho:YAG (2.1µm, 250µs) lasers. The excimer and holmium lasers are popular because of the potential for a single laser system to treat both plaque and thrombus. The excimer laser targets the tissue proteins, while the holmium energy is absorbed by tissue water. Both these chromophores are present in both plaque and thrombus.
Excimer nm light in 100-200ns pulses are being tested for thrombus removal in animal and clinical trials [pettit 1993]. These systems were designed for and have had extensive evaluation for the treatment of atherosclerotic obstructions.
The laser energy is delivered via a catheter made of bundles of 50-100µm core diameter fused silica fibers circumferentially arranged around a central guidewire lumen. Conventional angioplasty guidewires are pushed through the thrombus into the distal part of the vessel. The laser catheter is brought over the guidewire to the thrombus, and pulse energies of 40-50mJ/sq mm are delivered at a repetition rate of 10-30Hz. Balloon angioplasty immediately after the laser procedure is generally required to open the vessel further.
Ultraviolet light of 308nm is strongly absorbed by the tissue protein in the clot; the depth of penetration is about 30µm. This would theoretically allow for precise etching of clot similar to that demonstrated in atherosclerotic tissue and polymers. However, the results have been conflicting [rosenfield 1992, estella 1992]. The clinical excimer laser is configured to principally treat plaque. Refining the laser and delivery systems, technique, and case selection specifically for treatment of thrombi may improve the efficacy of the excimer laser for thrombolysis. However, ultraviolet photons have sufficient energy to break certain carbon bonds and may result in unwanted photochemical reactions.
One feature that was noted was that the ablative event was different from previous continuous-wave ablation studies. Ablation was initiated by explosive vaporization of the tissue and the subsequent formation of a vapor bubble. The dynamics of this rapidly expanding and collapsing bubble exert mechanical forces on the clot leading to removal of more clot. This bubble formation occurs almost always when tissue is ablated under a liquid with a pulsed laser. The removal of thrombus under these conditions is usually more efficient but less controlled.
Holmium/thulium:YAG lasers emitting 2.1µm radiation have been successfully used for angioplasty and are now being tested for thrombolysis [kopchok 1990]. Other applications include cutting bone and intervertebral discs. The pulse duration is 250µs in the free running mode and 1µs in a Q-switched mode. Water has an absorption peak at 2.1µm, and the penetration depth of the holmium radiation in water-containing tissues is about 300µm.
The holmium laser is a solid state device and is favored for its smaller size and ease of operation. The clinical laser for angioplasty and thrombolysis is configured to emit 250µs pulses. The energy is delivered to coronary artery thrombi via a catheter similar in design to the one for the excimer laser. The catheter is 1.4-1.7mm in diameter and delivers 250-600mJ pulses at a repetition rate of 5Hz.
The results of holmium laser thrombolysis are fair. In one study the majority of the thrombus was cleared and the residual stenosis was less than 30% in all cases [topaz 1993]. No acute adverse procedural complications were reported. However, balloon angioplasty was still required as a follow-up procedure.
There is some reservation regarding the holmium laser for thrombolysis. Stress wave effects and the formation of vapor bubbles have been shown to induce damage to adjacent tissue [delatorre 1992a]. Hassenstein et al. reported formation of thrombotic occlusions during holmium laser angioplasty [hassenstein 1991]. Another potential disadvantage is the inability of the holmium laser to selectively target thrombus without ablating the vessel wall. Since water is present in roughly the same proportions in all tissues, the holmium laser does not discriminate between an arterial occlusion and healthy vessel wall. This presents the danger of perforations caused by inadvertent ablation of arterial tissue.
A laser system capable of selectively targeting the thrombus is therefore desirable. This capability is offered by lasers emitting in the ultraviolet and visible regions, where the absorption by thrombus is much higher than that by artery. The principal chromophore of thrombus in the visible waveband is hemoglobin present in the red blood cells. Since higher absorption coefficients require less energy per unit area to achieve ablation, the ablation threshold for artery is higher than that for clot. Pulsed lasers operating in this waveband at radiant exposures between the thresholds for artery and clot can therefore selectively remove clot.
Prince et al. reported that differential absorption of light of selected wavelengths between plaque and arterial wall resulted in differences in ablation thresholds [prince 1985a, prince 1985b, prince 1986}. LaMuraglia et al. conducted spectrophotometric studies to determine the absorption spectra of thrombus and normal arterial tissue in the 400-600nm waveband [lamuraglia 1990]. An increase in absorption of nearly two orders of magnitude between clot and artery due to the presence of hemoglobin was observed.
Based on these tissue spectrophotometric studies, a pulsed-dye laser system was developed. The wavelength of emission is tunable between 400-600nm, and the pulse duration is 1-2µs. A longer pulse could potentially work as long as it stayed below the thermal relaxation time of tissue (~1ms). The lasers currently configured in clinical settings operate at 480nm with pulse widths of 1-2µs [gregory 1994, lamuraglia 1988a]. The ablation thresholds for acute arterial thrombus and normal arterial tissue measured with this laser in vivo and in vitro were approximately 15mJ/sq.mm and 1500mJ/sq.mm respectively [gregory 1989, gregory 1990a].
Light delivery is achieved with a fluid-core light guide, that is essentially a tubing of low refractive index filled with an optically transparent fluid of higher refractive index [gregory 1989, gregory 1990b]. Light propagation is similar to that of a regular optical fiber. The light is launched from the laser into an optical fiber contained within the fluid catheter. The fiber in turn launches the light into the optical fluid that finally delivers it to the target. Further, the catheter is open-ended at the distal end allowing the fluid to flow out of the catheter. The advantages over delivery by regular optical fibers are:
The laser catheter is fitted with a Y-adapter. The optical fiber is inserted into the catheter tubing through one leg of the adapter. The distal end of the fiber is kept about 20cm from the distal part of the catheter. A fluid injector injects the contrast media through the other leg of the Y-adapter. The catheter can be inserted into the femoral artery in the leg and advanced to the occlusion in the coronary artery over a monorail guidewire.
The initial pulse energy at the output end of the fiber is approximately 80mJ. The transmission through the optically clear fluid is about 75% resulting in an output energy of 60mJ. The internal diameter of the optical channel is 1.1mm that results in a laser spot diameter of similar dimensions. The pulse repetition rate is 3Hz. The fluid injector maintains the contrast flow between 0.3-0.5ml/sec that provides adequate light transmission up to 1cm from the tip of the catheter. The tip of the catheter is marked with a gold band for visualization during fluoroscopy.
The pulsed-dye laser thrombolysis technique was tested on a canine model with promising results [gregory 1989]. Coronary artery thrombi were removed in all of 22 dogs without perforation, vasospasm, or other untoward incidents. All thrombi were removed within 600 pulses. The patency rate of the vessels 90 minutes after the procedure was 80%.
Based on these favorable animal studies of laser thrombolysis and approval from the Food and Drug Administration, a pilot study of laser thrombolysis in acute myocardial infarction in humans was performed. The criteria for patient selection was contra-indications to or failure of thrombolytic drugs. The procedures were performed at St. Vincent Hospital, Portland, Oregon and at St. Joseph's Hospital, Atlanta, Georgia. Effective thrombus removal was demonstrated in 16 of 18 patients [gregoryclinical].
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