Discuss the production, detection and prevention of microemboli

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Detection of Microemboli

There are different methodologies that have evolved to detect and quantify embolism in relation to cardiopulmonary bypass; they can be divided into in vivo and in vitro methods. In vitro methods include processing of blood samples, end organ histopathology, and direct visual and optical methods. Radiographic, computer-assisted tomography, particle sizing using resistance or laser devices are also some form of detection techniques and have advantages and disadvantages over one another.

Histopathology

The brain is more likely to reflect functional changes due to multiple scattered microemboli than other organs. Functional measurements of kidney, liver, and heart are not sufficiently sensitive to detect microemboli phenomena. Histological techniques have been utilised in response to emboli detection in cardiopulmonary bypass, in brain histology isolated areas of perivascular and focal subarachnoid hemorrhage, neuronal swelling, and axonal degeneration are seen with higher frequency in the brains of patients dying after cardiac surgery then after a non-cardiopulmonary bypass or major vascular surgery. After surgery using unfiltered cardiopulmonary circuits, fibrin and platelet emboli and calcific and atheromatous debris are seen frequently in small arterioles and capillary beds during histological examination. Once the specimen is stained with a specialised vascular stain which is for alkaline phosphatase (AP), an endogenous enzyme that is localized in the endothelium of capillaries, arterioles and small arteries but not in veins and venules; it turns it into a brown-black lead sulphide deposit that reveal vasculature against an almost clear celloidin background. In AP-stained section of the brain tissue the microemboli appear as small (10-40µm) capillary and arteriolar dilatations, which are lightly stained swellings in the darkly stained vessels. The microvasculature could be seen in three dimensions, and many emboli could be seen at the bifurcation of the vessels blocking the supply of blood. The composition of the microemboli could also be determined by various staining techniques, although not characterised the emboli have a basic lipid composition with small birefringent particles containing aluminum or silicone. Histological techniques are gold standard for detection of emboli caused by cardiopulmonary bypass however it is only possible after the end organ damage has occurred.

In another study by Hill and colleagues examination of 133 patients brains who died after an open heart surgery, fat embolism was the most common finding and occurred nearly in all patients. Non-fat emboli majority of which were composed of platelets and fibrin were found in 31% of the patients.

Blood sampling

Screen filtration method to detect emboli during cardiopulmonary bypass has been well known in practice. The degree of micro-aggregate formation was assessed by the screen filtration method described by Swank, this techniques measures the peak pressure necessary to force 2cc. of blood through a metal filter with square 20 microns holes at a constant rate of 0.2cc./sec. This method has been shown to an effective means of detecting aggregation of cellular elements in blood. Prolonged circulation of blood in a pump oxygenator is associated with a marked rise in the screen filtration pressure (SPF) and wide spread clumping of platelets. This method appears to be very sensitive to the presence of particulate matter in water solutions. The particles partially or totally occlude a certain number of pores through which they are forced. This reduces the cross sectional area of the micro-pores and increases the pressure required to force blood at a given flow rate through a screen filter of given pore size. Although this is not a direct method for the detection of microemboli, the residual debris on the filter is found to give description of microaggregate presence. Although being a cumbersome and lengthy process for emboli detection, there was certainly a place for it cardiopulmonary bypass in early days. This process only detected particulate microaggregate and was unable to detect the gaseous emboli.

Another method of for the detection of emboli in vitro is with the use of a coulter counter principle, albeit being a well-proven technique for particle determination has been used very little for the detection and characterization of emboli in cardiac surgery. In a coulter counter instrument, a tube with a small aperture on the wall is immersed into a beaker that contains particles suspended in a low concentration electrolyte. Two electrodes, one inside the aperture tube and one outside the aperture tube but inside the beaker; are placed and a current path is provided by the electrolyte when an electric field is applied. The impedance between the electrodes is then measured. The aperture creates a "sensing zone". Particles in low concentration, suspended in the electrolyte, can be counted by passing them through the aperture. As a particle passes through the aperture, a volume of electrolyte equivalent to the immersed volume of the particle is displaced from the sensing zone. This causes a short-term change in the impedance across the aperture. This change can be measured as a voltage pulse or a current pulse. The pulse height is proportional to the volume of the sensed particle. If constant particle density is assumed, the pulse height is also proportional to the particle mass. A typical measurement using coulter counter instruments takes less than a minute, as counting and sizing rates of up to 10,000 particles per second are possible. The accuracy of the size measurements can be better than 1%. Aperture size typically ranges from 15 to 2000 µm. Each aperture can be used to measure particles within a size range of 2 to 60% of its nominal diameter. Therefore, the overall particle size range of 0.4 to 1200 µm is feasible. However, the ability of the technology to analyze particles is limited to those particles that can be suitably suspended in an electrolyte solution. The upper limit therefore may be 500 µm for sand but only 75 µm for tungsten carbide particles. Moreover, the lower size limit is restricted by electronic noise generated mainly within the aperture itself. The selection of the most suitable aperture size is dependent upon the particles to be measured. If the sample to be measured is composed of particles largely within a 30:1 diameter size range, the most suitable aperture can be chosen. For example, a 30 µm aperture can measure particles from about 0.6 to 18 µm in diameter. A 140 µm aperture can measure particles from about 2.8 to 84 µm. If the particles to be measured cover a wider range than a single aperture can measure, two or more apertures have to be used and the test results can be overlapped to provide a complete particle size distribution. Once agin this process is invitro and have not been utilised in cardiac surgery effectively as particulate emboli presence become evident after lengthy process making patient susceptible to neurological damage.

These techniques detect the presence of microemboli however, both microaggregates and gaseous microbubbles are inherently unstable entities in the blood and can be altered by foreign surfaces; hence any manipulation of blood samples for measurement has a high probability of altering such emboli.

Other in vivo techniques of bulk Compressibility, fluorescein angiography and ultrasonography are used for detection of microemboli during cardiopulmonary bypass. Intraoperative fluorescein retinal angiography has demonstrated that extensive retinal microvascular embolization occurs during CPB. This technique is used to examine the circulation of retina using the dye tracing method, it involves the injection of sodium fluorescein into the systemic circulation and then angiogram is obtained by photographing the fluorescein emitted after illumination of the retina with blue light at a wavelength of 490 nanometres. The incidence and extent of retinal obstruction are much greater with bubble than with membrane oxygenators, despite use of 40-µm arterial line filters. However, eye is very sensitive to microemboli, this organ receives only a miniscule percentage of the cardiac output and therefore occurrence of microemboli is subjected to serious sampling errors. On the other hand cerebral function tests before and after bypass have shown small changes postoperatively, the studies have usually shown measurable changes in cerebral function during first few days after operation, but few changes after weeks and months later. Again these techniques provide substantial evidence about microembolic events; however they are able to quantify microemboli and are only evident after end organ damage.

Transoesophageal Echocardiography (TEE):

TEE is a non-invasive ultrasonography imaging system has been shown very effective in evaluating gaseous microemboli. These devices enable localization of microemboli within their respective acoustic fields. Echocardiography works on the principle of ultrasound physics, where sound waves are produced by piezoelectric crystals. These sound waves once directed into the body are reflected by the interfaces between the tissues of different acoustic impedance such as myocardium, valves and blood. Blood reflects little sound so it appears relatively hypoechoic compared with myocardium which appears to hyperechoic.

There are two modes of echocardiography are diagnostically used to produce real-time images of heart. In M-mode (motion mode), the crystal is stationary and the beam produced is a pencil beam of sound. The signal is produced almost continuously, and the echoes are displayed on the Y-axis, with time displayed on the X-axis. This produces almost continuous image of the position of the cardiac chamber and cardiac structures which are in line with the beam. This mode has been found to permit some degree of quantification of emboli, as the X-axis represents time making relative counts possible. On the other hand B-Mode (two-dimensional mode) enables the operator to view emboli within the chambers of the heart; it is produced by multiple beams along a single plane. Phased array transducers which consists of multiple transducer elements, each having its own circuitry and thin crystals, produce sound waves and the summation of these waves produces the 2D picture. Over all 2D TEE mode has been effective identifying the gaseous emboli. TEE has been used in many studies to evaluate the air emboli in the heart after de-clamping the aorta especially in patients having valve surgery. Study done by (Zanatta et al. 2008) on microbubble detection report that TEE monitoring is a useful strategy in monitoring microemboli activity during bypass. They found that retained intracardiac air can be seen without difficulty by TEE, most of air was observed primarily in right superior pulmonary vein, left atrium, apex of left ventricle and the right coronary sinus of Valsalva. A technical advance in the TEE has also made possible viewing of not only air emboli but particle matter as well.

TEE can also be used in direct evaluation of atherosclerosis of aorta at the time of cannulation for cardiopulmonary bypass. Particulate matter arising from the cannulation of atherosclerotic aorta has long been a major risk factor for neurological injury during CPB. More than 60% of emboli occur during periods of manipulation of heart or aorta. The sensitivity of digital palpation of the aorta to detect atherosclerosis is low, with 30% to 50% of significant plaques undetected. However epi-aortic scanning is an invasive method and requires expertise, it's done by using a hand-held probe and high frequency ultrasound making it a portable, immediate and easy to use tool in evaluating generation of micro emboli during cannulation and cross clamping of aorta.

Computerized tomography (CT) and clinical magnetic resonance imaging (MRI) are widely used in detecting the organ ischemia and the evaluation of cerebral vascular disease. However their role as monitoring emboli during cardiopulmonary bypass is not well established. In studies of brain injury during CPB, 60% to 70% of clinically apparent neurological events correlate with abnormal CT scan results. A pediatric study comparing oxygenator types showed reduced brain masses in some patients after use of a bubble oxygenator despite no clinically apparent neurologic deficit. In another study acute infracts on CT were seen in patients under gone CPB who were asymptomatic. A review of clinical MRI after CPB also show similar variations in findings, with new abnormalities reported in 0% to 50% of cases. This is apparent from the discussion that CT and MRI techniques can be employed in detection of injury caused by microemboli creation during cardiac surgery, however there importance comes into effect post cardiopulmonary bypass.

Near-infrared Spectroscopy (NIRS)

This techniques monitors cerebral oxygenation and indirectly measures cerebral blood flow. The principles are similar to that of pulse oximetry; NIRS light is capable of passing through up to 8cms of tissue, including skin, soft tissue, and bone. It is absorbed by specific chemicals chromophores, notable HbO2, deoxyhemoglobin, and cytochrome oxidase (CytO2). Changes in intensity of reflected near-infrared light represents change in the concentration of the chromophores, thereby detect changes in intravascular and intracellular oxygenation, respectively. The sum of HbO2 and deoxyhemoglobin gives total cerebral blood volume, which correlates if the microemboli are intentionally introduced in the circuit during laboratory experiments and similar decrease in oxygenation is seen in tissues blocked by microemboli. Thus NIRS offers a continuous, non invasive, portable, and compact method of monitoring that is easy to use. However its role during CPB for the detection of microemboli needs to be fully validated by further experimentation. The results need to be quantified, and level of oxygenation at which neuronal damage occurs needs to be defined. Despite these limitations NIRS remains an exciting tool that may have use in CPB.

Light-Scattering microemboli detector (LSMD)

The ability of the LSMD to detect thromboemboli in whole blood is based on a principle of differential light scattering. An incident beam of light that is directed through a translucent conduit carrying blood, is scattered by the red cells (and by platelets and white blood cells, but their contribution is insignificant due to their relatively small numbers in conjunction with small size), and by thromboemboli. The scattered light is captured by detectors placed at specific angles to the incident beam. Based on the fact that the scattering from thromboemboli is distinct from that of the red cells, a light scattering microemboli detection system was conceived by Reynolds and Simon and latter improved by Brigham Young University to study various thromboembolic phenomena in undulated whole blood. LSMD has been used in studying platelet aggregation and thromboembolic phenomena induced by the surface contacting agents used in cardiopulmonary bypass. One study demonstrated the synergistic contributions of secondary flows and surface-induced activation of platelets which is prime cause of microemboli formation due to activation of blood formed elements. In this study blood was directed in a single pass through 3/8" PVC tubing containing a "flow cell" consisting of alternating abrupt expansions and contractions. Thromboemboli released form the flow cell was detected continuously by the LSMD. Experiment indicated that significantly more emboli were directed downstream of the flow cell then were directed upstream, indicating flow cell was the primary source.

Another study reported a link between flow fluctuations (caused by varied CPB pump activity) and thromboembolic events. Sudden increases in flow rate were found to associate with incidents of thromboembolism, confirming the important role of fluid mechanics in dynamics of thromboembolism during cardiopulmonary bypass. Over all the light scattering micro emboli detectors have evolved into a relatively inexpensive yet versatile tool for assessment of thromboembolic phenomena. The ability of continuously and noninvasively detecting and quantifying thromboemboli in whole blood offers a new and innovative approach to assess (1) the thrombogenic potential of blood contacting surfaces in CPB and efficacy of existing and emerging anti-thrombogenic regimen in a manner not possible until now. Another advancement of differentiating between microemboli based on their composition and ration of light scattered at 5` and 20` deg angles is in progress, this capability once incorporated will increase the diagnostic power and enable user to distinguish between gaseous emboli and thromboemboli during cardiopulmonary bypass.

In vivo methods use either ultrasound or observation and imaging of microcirculation. Clinically and in research ultrasonography devices are most commonly used to detect emboli, this ability is due to the change in the reflected Doppler energy. On-line detection of echogenic material in the tubing of the extracorporeal circuit was first reported by Austen and Howry in 1965. Early research using embolus detection via ultrasound during cardiac surgery established the occurrence of high frequency signals; these have been verified in the laboratory through the use of microspheres and other particulate matter and are considered to reflect the presence of emboli. Doppler ultrasound device emits a sound signal from piezoelectric crystal, this sound signal reflects from moving blood cells. The frequency of the reflected signals differs from that of the transmitted signal in proportion to the blood velocity. This results form the difference in sound frequency between the ultrasonography beams transmitted into the tissue, and that returned by reflection from red blood cells. The resultant Doppler shift allows the velocity of the blood to be determined through Doppler principle. Thus ultrasonography devices allow non-invasive differentiation of circulating particles from the background blood flow.

A long-lasting study showed it was possible to reduce the average aggregate number of high-intensity transient signals per case of artery bypass graft from 10 000 to 86 over 8 years by using TCD. The utility of TCD was also demonstrated by a report showing an association between the numbers of emboli detected intraoperatively and neurobehavioral outcome. Also, the presence of more than 50 microemboli signals per hour in the early postoperative period can predict the development of focal cerebral ischemia.

TCD has found increased use in port-access procedures and endovascular clamping, allowing the assessment of blood flow from the aorta to the innominate artery and ensuring that the endovascular clamp has not occluded innominate artery flow. A retrospective evaluation of 1058 patients undergoing carotid surgery in two medical centers showed four TCD variables to be independently associated with perioperative stroke: embolism during dissection, embolism during wound closure, a drop in the MCA flow velocity at cross-clamping of more than 90%, and an increase of 100% or more in the pulsatility index at clamp release. Also, in pediatric cardiac surgery examples from the recent literature show that TCD technology can be particularly useful in assessing cerebral perfusion of children during CPB by providing clinicians with a real-time evaluation of CBF. This suggests a good correlation between changes in cerebral blood flow and MCA blood-flow velocity.

TCD has some valuable advantages as a monitoring tool. It is a noninvasive, continuous monitor of cerebral perfusion that allows detection of clinically significant microembolization. It also allows recognition of instantaneous changes in CBF which are of great importance in carotid and cardiac surgery, especially when selective cerebral perfusion is needed or congenital cardiac defects have to be repaired. Limitations of TCD use in clinical practice include that it is operator-dependent and that 10% of patients cannot be assessed through the temporal window. There can be difficulties with reproducibility, especially at low blood flow, and there is an absence of signal during times of low flow and during deep hypothermic cardiac arrest

A major problem, particularly when recording during operative interventions, is the failure of conventional TCD equipment to differentiate between gaseous and solid emboli. This is important as the neurological consequences of solid emboli are far greater then injury due to tiny microbubbles. Due to this TCD use has severely been limited in situations where both gaseous and solid emboli can occur. Also early studies demonstrated that mean intensity increases with gaseous emboli are higher than with solid emboli including platelet aggregation and thrombi. However signal intensity increases with emboli size, if neither size nor composition is known accurate classification is impossible. Furthermore, although using intensity alone allowed gaseous emboli to be discriminated off line with specificity and specificity of 90% this is insufficient in clinical practice. During many situations when gaseous emboli occur, many hundreds or thousands may be produced; therefore unless specificity is near 100%, a significant number will be misclassified as more clinically significant solid emboli.

Recent a new method using dual-frequency transducer has been developed. This novel system uses a dual frequency

Transcranial Doppler ultrasound (TCD) is a sensitive, real-time monitor of cerebral blood flow velocity (CBFV) and emboli during cardiopulmonary bypass. Currently available instruments use pulsed-wave ultrasound at 2 MHz frequency that is range-gated, emits a power of 100 mW, and has a sample volume length of up to 15 mm. A display of the frequency spectrum of Doppler signals is easily interpreted, and peak systolic and mean flow velocities, in cm/s, are displayed, as well as a pulsatility index that is equal to the peak velocity minus the end-diastolic velocity, divided by the mean velocity. As with cardiac ultrasound, the advantage of pulsed-wave Doppler ultrasound is that a precise sample volume can be selected which insonates only the arteries of interest without contamination from other sources.

The most consistent and reproducible technique for clinical use in patients of all ages is to monitor the middle cerebral artery (MCA) through the temporal window, which can usually be found just above the zygoma and just anterior to the tragus of the ear. Several transducer probes are available, ranging from very small disk probes suitable for infants and children, to larger, heavier probes for adolescents and adults. The depth of the sample volume and angle of insonation is adjusted until the bifurcation of the MCA and the anterior cerebral artery (ACA) is detected. This is heralded by a maximal antegrade signal (positive deflection, toward the transducer) from the MCA, accompanied by a retrograde signal from the ACA (negative deflection, away from the transducer) of the same or very similar velocity and wave form as the MCA flow.

In infants, an alternative site for monitoring is through the anterior fontanelle, using a hand-held pencil-type probe, placing the probe over the lateral edge of the fontanelle, and aiming caudally, at a greater depth than for the temporal window, at the internal carotid artery. These normal velocities were determined in awake children without cardiovascular disease, under perfect examination conditions. Lesions producing large diastolic runoff (e.g., large patent ductus arteriosus) will decrease diastolic blood flow to the brain. Hemodynamic instability, less than optimal probe positioning, and general anaesthesia may reduce these velocities in clinical practice. Typically the clinician must accept a stable baseline for the individual patient and use it as the basis for comparison. Fixation of the probe in the optimal position is problematic. There are several commercial devices available for fixation in larger patients but in practice it is often simpler to affix a small disk Doppler probe with a clear adhesive dressing and clear tape over the temporal window of infants and children, assuring access and some mobility to the probe for the frequent adjustments that may be necessary.

Doppler ultrasound has the unique ability to detect emboli as they pass through the circulation. Due to increased scattering and reflection of ultrasound from the embolus, compared with the surrounding red blood cells, an embolus appears as a short duration high intensity signal within the Doppler flow spectrum. It has been appreciated since the 1960s that gas bubbles can be detected using ultrasound, and the technique has been applied to both decompression sickness and cardiopulmonary bypass to detect gaseous emboli. However, it was only in 1990 that it was appreciated that solid emboli, composed of thrombus or platelet aggregates, could also be detected. While recording during carotid endarterectomy for air emboli introduced during the operation, Spencer and colleagues noted that similar embolic signals occurred prior to arterial opening, i.e. before any air could be introduced into the system. They deduced these must be solid emboli dislodged from the carotid plaque during surgical manipulation.

Although there was initial scepticism, subsequent in vitro and in vivo studies have demonstrated that the technique is highly sensitive and specific. Embolic signals have been detected in patients with a wide variety of potential embolic sources including carotid artery stenosis, atrial fibrillation, and valvular heart disease. Conventionally, recordings are made from the middle cerebral artery. The low frequency transducer used for TCD increases the embolic to background blood signal ratio and, therefore, makes them easier to detect. In addition, prolonged recording can be performed using simple headpieces. Good interobserver reproducibility in identifying embolic signals has been reported and recent consensus criteria have been developed for applying this technique in clinical practice. Most work has been performed in carotid artery stenosis. Asymptomatic embolic signals are surprisingly frequent and are usually detected in 20-50% of patients with symptomatic carotid stenosis if recordings are performed for an hour. Their presence has been shown to correlate with known markers of increased risk including symptomatic status, time since last symptoms, and plaque ulceration determined either histologically or on angiography. Recently, small studies have suggested that asymptomatic embolization may be an independent predictor of future stroke risk and this is being tested in larger multicentre studies. Asymptomatic embolic signal detection has a number of potential uses. It may allow identification of individuals at high risk of stroke for targeted pharmacological or surgical therapy. For example, operating on an asymptomatic carotid stenosis has a poor risk-benefit ratio. Eighty-five patients have to be operated on to prevent one stroke over a one-year period. Identifying a high-risk group of individuals would improve both cost-benefit and risk-benefit ratios. Embolic signal detection may also be useful in monitoring the effectiveness of antithrombotic therapy in individuals. It may also be useful m monitoring during interventional procedures. For example, it has been demonstrated that embolic signals during the dissection phase of carotid endarterectomy (before arterial opening) correlate with both new peri-operative MRI infarcts and neuropsychological decline. Intra-operative use of the technique may aid the surgeon in reducing embolization. Furthermore, embolization in the postoperative period has been associated with early postoperative stroke and TLA risk. It has been suggested that the technique may allow the identification of individuals in this setting who require more aggressive postoperative antithrombotic measures such as a Dextran infusion. Embolic signal detection may also prove useful in evaluating new antithrombotic and antiplatelet therapies. Currently, these are evaluated in large expensive clinical trials with an endpoint of stroke. For example, the recent CAPRIE trial recruited approximately 20,000 patients and only just achieved a significant result. There is a wide gulf between ex vivo assessment of platelet function and clinical effectiveness, and animal models are not always truly representative of the situation occurring in man. Because asymptomatic embolic signals are much more frequent than stroke and TLA, they provide a surrogate endpoint which can be used to

Zanatta, P, Bosco, E, Salandin, V, Salvador, L, Valfre, C & Sorbara, C 2008, 'Microbubbles detection during cardiopulmonary bypass with transoesophageal echocardiography: a case report', Cases Journal, vol. 1, no. 1, p. 141.

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