1 Department of Neurology and 2 Department of Internal Medicine, University of Münster, Münster, Germany
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Abstract |
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Methods. The study cohort consisted of 24 long-term dialysis patients undergoing haemodialysis (n=21) and online-haemodiafiltration (n=3), respectively. The subclavian vein downstream to the venous access was investigated during different phases of the procedure using a 2-MHz pulsed ultrasound device.
Results. In all periods investigated (connection, dialysis, disconnection), numerous microembolic signals (MES) were found in the subclavian vein. The numbers of MES detected during haemodiafiltration (314709 MES per 10 min) were higher than during haemodialysis (081 MES per 10 min).
Conclusions. The composition (gaseous or solid) and origin (pump, tubing system or shunt) of the microemboli detected remains unclear. Chronic microembolization may be one cause of pulmonary complications of haemodialysis and haemodiafiltration. The detection method described in this article will help us to better understand this process and to determine what role microemboli might play in pulmonary and central nervous system disorders. It may also help to optimize the devices and techniques used.
Keywords: dialysis; microemboli; ultrasonography
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Introduction |
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Subjects and methods |
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Haemodialysis and haemodiafiltration
Twenty-two of the 25 patients underwent haemodialysis, while five patients were treated by online-haemodiafiltration using different devices by Gambro Medizintechnik (München, Germany), Fresenius Medical Care (Bad Homburg, Germany), or B. Braun Melsungen AG (Melsungen, Germany) (Table 1). In the 22 haemodialysis patients, a low-flux hollow fibre dialyser (Hemoflow F6HPS, Fresenius Medical Care) was used, while haemodiafiltration was performed with a high-flux hollow fibre dialyser (Hemoflow F60 Highflux, Fresenius Medical Care, Bad Homburg, Germany) for patients 11, 19 and 24. The dialyser membrane material for the filters was polysulphone. In 20 of the 25 cases (patients 1, 39, 1114, 1620, 22 and 23), two needles were used for vascular access (Diacan V17G/A17G, diameter and length of the cannula 1.5 and 20 mm, respectively; B. Braun Melsungen AG), while five patients (patients 2, 10, 15, 21 and 24) were on single needle dialysis (Bionic 652T 1.6 mm, Bionic Medizintechnik, Friederichsdorf, Germany). In all but one patient, the site of vascular access was the forearm, elbow, or upper arm. Only native fistulas were used. Patient 25 was dialysed using a Sheldon catheter (Dualyse-Cath 32/11, Vygon, Aachen, Germany) placed in the right jugular vein. In all 22 patients on dialysis, a bicarbonate-containing dialysis bath was used.
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Blood flow was set at a mean of 213 ml/min (200280 ml/min) and 20008000 I.U./h of heparin were constantly infused. The haemodialysis and haemodiafiltration was well tolerated, although two patients had minor hypotensive events with vertigo and dizziness and one patient suffered from nausea.
Ultrasound investigations
In patients 124, the subclavian vein downstream to the arteriovenous fistula was investigated during dialysis in the infraclavicular fossa with a hand-held multidepth-2-MHz probe. All studies were performed by the same investigator (K.K.) using the same pulsed Doppler ultrasound device (TC4040, Nicolet-EME, Kleinostheim, Germany). An axial width of the small sample volume of 4 mm in length and a low gain provided a setting guaranteeing optimal embolus discrimination from the background spectrum [12]. Power was 10 mW/cm2. The insonation depths of the 4-gate probe were arranged over a length of 1 cm according to the following sequence: channel 1 (deep), channel 2 (4 mm more distally), channel 3 (8 mm more distally), and channel 4 (10 mm more distally). This setting was maintained unchanged throughout the recordings. A detection threshold of 5 dB was used for all studies. The audio Doppler signal of all the four channels was continuously recorded onto an 8-channel digital audio tape-deck recorder (TA-88, TEAC Corporation, Tokyo, Japan) with normal speed. Further details of the technique have been described previously [13].
Ultrasound recordings during extracorporeal therapy were done as follows: (i) Due to a scheduling problem, in 14 patients it was only possible to record during the period of connecting the tubes to the patients and starting the dialysis. This period lasted from 7 to 13 min in the individual patients. (ii) After a treatment period of 10 min, we recorded the 24 patients for 10 min. (iii) After a second break, we performed another 10 min ultrasound recording. In a randomized way, oxygen was applied at a dose of 6 l/min by a loosely-fitted facial mask either during the first 10 min or during the second 10 min of the recording times previously mentioned [7]. This second break was used as a washout period after instances of oxygen application. In the remaining one of these two 10-min periods and during the rest of the haemodialysis or haemodiafiltration period the patients breathed normal air. (iv) In all 24 patients, it was possible to record for the period of tube disconnection from the patients (3.512 min in the individual patients). (v) After disconnection, we waited for 10 min, and then investigated the subclavian vein for another 10 min. In patients 2 and 9, these investigations were not performed immediately following dialysis, but on the following day.
For intensity quantification of the MES, each recording period was separated into five sections. At the end of each section, the MES was measured automatically by the software yielding four relative intensity values for each period. The mean of these four values was entered into the statistical analysis for each patient to avoid repeated measures.
In patient 25, and during a second haemodialysis procedure in patients 10 and 14, both middle cerebral artery main stems were simultaneously investigated for 30 min through the temporal window using an elastic head ribbon with a probe holder. Two sample volumes were placed in each middle cerebral artery separated by 1 cm. Instrumentation settings and the microembolus detection procedure were as described above except for the instrument's power, which was adjusted to achieve an adequate skull penetration. In these three patients that were investigated transtemporally, a test for the presence of cardiac or pulmonary right-to-left shunting was performed following the microembolus detection [14]. Microcavitation saline contrast was generated by agitating a mixture of 10 ml of normal saline and 1 ml of air between two 12 ml syringes connected by a three-way stopcock. Once the contrast fluid was prepared, 10 ml were immediately injected as a bolus into one of the access needles. The Valsalva manoeuvre started 5 s after the beginning of the injection with deep inspiration followed by pressing against the closed glottis and expiration 10 s after the beginning of the injection.
Statistics
Besides descriptive statistics, the numbers of MES with and without oxygen inhalation were compared using the non-parametric Wilcoxon test. Statistical significance was declared at the 0.05 level. Using the same test, the relative intensity increases of MES were compared across the following periods: (i) connection period vs the haemodialysis/haemodiafiltration period without oxygen application, (ii) disconnection period vs haemodialysis/haemodiafiltration period without oxygen application, and (iii) the period following haemodialysis/haemodiafiltration vs the haemodialysis/haemodiafiltration period without oxygen application. Because not all patients had measurements made during all phases of the study, for each single comparison only the patients with data were considered. Statistical significance was declared at the 0.0125 level, having corrected for multiple comparisons.
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Results |
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The relative intensity increase of MES during connection was 19.1±3.0 dB (mean±SD; range 14.824.0), during haemodialysis/haemodiafiltration without the application of oxygen 14.0±9.2 dB (range 5.048.7), during haemodialysis/haemodiafiltration with the application of oxygen 10.7±4.3 dB (range 5.519.5), during disconnection 16.0±5.1 dB (range 7.829.5), and following the procedure 8.4±3.6 dB (range 5.015.88). Only the difference in relative intensity increase between the connection and the haemodialysis/haemodiafiltration period without application of oxygen was significant (P=0.003).
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Discussion |
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The composition of these microemboli remains unclear. Their high relative intensity increase makes a gaseous composition very likely [13]. However, a strong signal can be due to a gaseous microembolus or to a large solid embolus. On the other hand, their number was not significantly reduced by oxygen inhalation. In patients with a mechanical cardiac valve, oxygen inhalation reduced the number of MES originating from cavitation bubbles by replacing the blood's physically dissolved nitrogen with oxygen, which has a lower tendency to form gaseous bubbles [7]. Unfortunately, it is not yet possible to distinguish solid from gaseous microemboli and to assess the size of the microemboli by their pattern or intensity characteristics. In the present study, either the microemboli were large gas bubbles that needed some time to dissolve into blood, or they were of solid composition. There may even be a coexistence of gaseous and solid microemboli. These microemboli may correspond to air bubbles already in the haemodialysis/ haemodiafiltration device before the procedure, or those entering the blood system during connection and disconnection of the device. The formation of gas bubbles may also be caused by cavitation due to the pressure gradients inside the device or the shunt. In addition there may be solid particles such as plastic or rubber originating from the device, especially from the pump segment of the tubing system. A third possibility would be microthrombi previously formed in the machine or the tubing system [15]. The persistence of a low number of MES even after haemodialysis/ haemodiafiltration raises additional questions. Some microemboli from the procedure may still remain in the veins and appear in the subclavian vein later on. There may also be ongoing thrombus formation within the fistula. In patient 14, four MES were detected even on the day following haemodialysis, favouring the latter hypothesis.
In the literature, there are reports on pulmonary damage such as pulmonary fibrosis and calcification in patients undergoing chronic haemodialysis [16,17]. In an autopsy study, the most common acute diseases were pulmonary infections (pneumonia, lung abscess, empyema) and fluid overload. The most common chronic process was interstitial pulmonary fibrosis. Other relatively common chronic diseases included pleural fibrosis and/or pleuritis as well as pulmonary arteriosclerosis, haemorrhage, thromboembolism and calcification [1]. In a recent study atelectasis, cardiomegaly, pleural effusion, vascular congestion, parenchymal consolidation, parenchymal scarring/fibrosis, and lymphadenopathy were the most common CT findings in long-term haemodialysis patients [18]. The authors attributed these findings mainly to infectious diseases. Macroembolization with overt pulmonary embolism may occur, especially from thrombi generated at the surface of the in-dwelling catheter [1921]. Ongoing massive microembolization into the pulmonary vasculature as described in this report may be another possible explanation for the high pulmonary morbidity in long-term dialysis patients.
The brain is particularly vulnerable to embolization. The three patients in our study who also underwent transcranial Doppler monitoring did not show any MES, and they did not have a right-to-left shunt. This may be different in patients with such a shunt, especially with a large atrial septal defect [22,23]. Paradoxical embolism may not only cause acute stroke, but may also result in slowly evolving cognitive deficits, which are common in patients on long-term haemodialysis. Similar to patients with mechanical cardiac valves or those undergoing cardiothoracic surgery with cardiopulmonary bypasses, chronic microembolization in the cerebral vasculature in dialysis patients with a right-to-left shunt may cause occlusion of cerebral capillaries, thereby giving rise to cognitive deficits [24,25].
In conclusion, the detection method described in this article may help to optimize the devices and techniques used in haemodialysis and haemodiafiltration to avoid chronic massive microembolization in the lungs or the brain.
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Notes |
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References |
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