Cardiovasc Intervent Radiol DOI 10.1007/s00270-014-0842-0
LABORATORY INVESTIGATION
Wireless Blood Pressure Monitoring with a Novel Implantable Device: Long-Term In Vivo Results Nina J. Cleven • Peter Isfort • Tobias Penzkofer Anna Woitok • Benita Hermanns-Sachweh • Ulrich Steinseifer • Thomas Schmitz-Rode
•
Received: 26 September 2013 / Accepted: 22 December 2013 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2014
Abstract Purpose Devices constantly tracking the blood pressure (BP) of hypertensive patients are highly desired to facilitate effective patient management and to reduce hospitalization. We report on experiences gathered in a pilot study that was designed to evaluate the prototype of a newly developed, minimally invasive implantable sensor system for long-term BP monitoring. Methods The device was implanted in the femoral artery (FA) of 12 sheep via standard FA catheterization under fluoroscopic control. Accuracy of the recorded blood pressure was determined by comparison with a reference catheter, which was positioned in the contralateral FA immediately after implantation. Regular follow-up included angiography, computed tomography (CT), and control of functionality and position of the BP sensor. Animals were euthanized after 6 months. FA segments with in situ
pressure sensor underwent macroscopic and histopathologic examinations. Results All implantations of the novel sensor device in the FA were successful and uneventful. High-quality BP recordings were documented. Bland–Altman plots indicate very good agreement. Comparison with measurements taken from the reference sensor revealed mean differences and standard deviations of -0.56 ± 0.85, 0.29 ± 1.44, and 0.85 ± 2.27 mmHg (diastolic, systolic, and pulse pressure, respectively) after exclusion of one outlier. CT uncovered deficiencies in cable stability that were addressed in a redesign. No thrombus formation, necrosis, or apoptosis were detected. Conclusions The pilot study proved the technical feasibility of wireless BP measurement in the FA via a novel miniature sensor device.
N. J. Cleven (&) U. Steinseifer T. Schmitz-Rode Department of Cardiovascular Engineering, Institute of Applied Medical Engineering, Helmholtz-Institute, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany e-mail: [email protected]
T. Penzkofer Surgical Planning Laboratory, Department of Radiology, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, USA e-mail: [email protected]
U. Steinseifer e-mail: [email protected] T. Schmitz-Rode e-mail: [email protected] P. Isfort T. Penzkofer Department of Diagnostic and Interventional Radiology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany e-mail: [email protected] T. Penzkofer e-mail: [email protected]
A. Woitok Institute for Laboratory Animal Science, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany e-mail: [email protected] B. Hermanns-Sachweh Institute of Pathology, RWTH Aachen University Hospital, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany e-mail: [email protected]
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N. J. Cleven et al.: Implantable Blood Pressure Sensor Fig. 1 Wireless blood pressure monitoring system. A Fullyimplantable, battery-less sensor system. B External readout unit for wireless communication (inner diameter of aerial coil: 6 cm)
Keywords Hypertension Intravascular blood pressure monitoring Implantable device Wireless measurement Pilot study Introduction Hypertension is a major risk factor for arteriosclerosis, cerebrovascular disease, heart disease, retinal damage, and kidney failure. According to latest statistics, 51 % of all cerebrovascular disease and 45 % of all ischemic heart disease deaths globally are contributed to high systolic blood pressure (BP) [1– 3]. Thus, being a major cause for cardiovascular disease with high hospitalization and mortality rates, a superior medical treatment of hypertension is mandatory to improve the general health situation and reduce future total health costs [1–6]. In cases where a lower BP cannot be achieved by lifestyle changes (diet, body weight, physical activity, etc.), a frequent surveillance combined with personalized drug treatment is the cornerstone of care. Recent studies confirm that long-term BP monitoring enables hypertensive patients to optimize therapy more effectively, improve symptoms, and reduce hospitalization time [7–10]. Implantable devices in particular could facilitate the long-term tracking of hemodynamic changes over time and improve hypertension treatment by reducing the need for patient compliance, recording accurate measures automatically and providing personalized feedback to the physician based on the recorded data [11, 12]. The purpose of this study was to evaluate the feasibility of implantation and long-term performance of a novel implantable and batteryless sensor system, which could serve as a wireless BP monitoring device for patients with hypertension [13]. We present our results and the lessons learned from this long-term in-vivo evaluation in the femoral artery (FA) of 12 sheep.
Methods BP Monitoring System The prototype of the BP monitoring system used consists of an implantable, miniature pressure sensor system (Fig. 1A)
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and an external communication unit (Fig. 1B) (company A, company B, company C, company D). The custom-developed blood pressure sensor (BPS) comprises two functional elements: the sensor tip—a capsule made of stainless steel embodying the capacitive pressure sensor—and the telemetric transducer, which communicates with the external readout unit. Both elements are connected via a data cable of 1 mm [3-French (F)] diameter. The full length of the BPS system amounts to 20 cm, including the 13 mm length of the sensor tip and the 18 mm length/diameter of the telemetric unit. Antithrombogenic coating (BaymedixTM CH 320 from Bayer Material Science, Pittsburgh, PA) was applied to the cable to prevent thrombus formation. The telemetric unit features three eyelets for subcutaneous fixation and enables wireless communication via inductive signal and energy coupling over a resonance circuit. It is batteryless and holds no data storage. The external readout unit communicates with the implant at a transmission frequency of 133 kHz and a sampling rate of 30 Hz while consuming up to 300 lW. It visualizes BP measurements online and automatically saves the recorded data, which can be easily transferred to an evaluation unit. The sensor measures the pressure with an accuracy of ±1.0 mmHg over the relative pressure range of 30–300 mmHg. For a detailed description of the BP monitoring system please refer to Cleven et al. [13]. Study Design The study was approved by the state committee on animal affairs. The BPS system is designed for minimally invasive implantation into the FA. To evaluate the system, an animal study with 12 female sheep was conducted. Percutaneous implantation was performed under angiographic guidance. After implantation, patency of the FA was assessed via conventional angiography and contrastenhanced computed tomography (ceCT). Invasive hemodynamic measurements were performed immediately after implantation. For direct comparison, reference measurements were obtained simultaneously in the contralateral FA. Follow-up hemodynamic assessments over a period of
N. J. Cleven et al.: Implantable Blood Pressure Sensor
6 months (daily in the first week after implantation, weekly from then on) as well as ceCT (directly after implantation, 1 week after implantation, two-monthly from then on) were performed to assess functionality and position of the BPS. Final ceCTs of all animals were performed before euthanization. For regular control measurements, sheep were gently held by a veterinary assistant while BP recordings were performed for up to 60 s. The antenna was therefore placed on the fur of the sheep right above the telemetric unit. Holding the antenna within a range with a mean of 10 cm was sufficient for data transmission. No sedation was necessary for the measurements. Animals A total of 12 adult female sheep (average body weight of 59 ± 9 kg) were included in this study. After intramuscular premedication with 100 mg of atropinsulfate 1 % (Atropinsulfat 1 %, Dr. Franz-Ko¨hler Chemie GmbH, Bensheim, Germany), 0.2–0.3 mg/kg xylazin 2 % (Xylazinhydochlorid, medistar, Ascheberg, Germany) anesthesia was induced by intravenous injection of diluted propofol 1 % (Propofol 1 %, Fresenius Kabi, Bad Homburg v.d.H., Germany). All animals were orotracheally intubated and mechanically ventilated with an oxygen-air mixture containing 1.5 vol% isoflurane (Isofluran Forene, Abbott, USA) at a respiratory rate of 14–18 breaths/min adjusted to the weight of the animal. For pain management, 2 ml/h of morphine (Fentanylcitrat, Rotexmedica GmbH, Trittau, Germany) was administered intravenously. A single-shot prophylactic antibiotic (Cefuroxime 1,500 mg, Fresenius Kabi, Bad Homburg v.d.H., Germany) was injected intravenously. Heparin, 1,000 I.E./10 ml, was administered (Heparin-Natrium-25000, Ratiopharm, Ulm, Germany) intra-arterially once during catheterization. At approximately 6 months (mean 6.5 months), postimplantation animals were euthanized by lethal barbiturate injection (Narcoren, Pentobarbital-Natrium, Merial, Hallbergmoos, Germany).
sensors were initially calibrated in the lab and adjusted for zero offset after sensor placement to rectify for errors induced by the implantation process, i.e., mechanical stress, and the intrinsic properties of blood, which could not be depicted during calibration in the laboratory setting. To validate the measurements of the implanted system, reference measurements were conducted with established invasive monitoring catheters (CPMS, Mammendorfer Institut fu¨r Physik und Medizin, Mammendorf, Germany) in the same segment of the contralateral FA immediately after implantation. Follow-up ceCT were performed with a dual-source CT scanner (Somatom Definition, Siemens, Forchheim, Germany). For contrast enhancement, 123 ml of iopromide (Ultravist 370, Bayer Medical, Berlin, Germany) followed by a 30 ml of saline bolus was injected via an ear vein at a flow rate of 3.3 ml/s. The image data were transferred to an external workstation equipped with a dedicated software tool (OsiriX PRO, aycan Digitalsysteme GmbH). Histopathology Animals were euthanized after a mean of 6.5 months. The implants were carefully excised en bloc together with the surrounding tissue including the FA and fixed in a 4 % buffered formalin solution. After macroscopic investigation, the specimens were divided into segments at defined spots. The cross-sections were embedded in paraffin and stained routinely in hematoxylin-eosin (H&E) and Elastica-van-Gieson (EvG) or were embedded in Technovit 7200 VLC in case of macroscopically conspicuous findings. Plastic embedded sections of 100 lm were obtained and stained with blue O-Tolouidin after dewatering for analysis with reflected-light microscopy. Histopathologic investigations for inflammation, foreign body reaction, connective tissue proliferation, fibrosis, intimal proliferation, luminal narrowing or occlusion, apoptosis, necrosis, or thrombus formation were performed. Statistical Analysis
Interventional Procedure All interventions were performed with a C-arm-based angiography system (Angiostar, Siemens, Forchheim, Germany). The animals were positioned supine on the angiography table. The right FA was percutaneously punctured with a standard 18-gauge (G) Terumo SURFOÒ catheter; thereafter a 4F peel-away sheath introducer set (PASIS) was inserted [12]. The sensor unit was then introduced via the sheath, and the telemetric unit was placed in a small subcutaneous pocket and fixed to the subcutaneous tissue using nonabsorbable sutures. All
BP measurements in form of BP waveforms were recorded for 1–2 min during each control measurement. Mean values of systolic and diastolic BP were calculated. Reference measurement with duration of 15 s was used to calculate the mean value of systolic, diastolic, and pulse pressure. Bland–Altman-plots, which allow the assessment of systematic bias, magnitude of deviation, as well as systematic trends and outliers, were used to compare BP readings of the novel implant and reference BP readings [14]. Data were analyzed using MedCalc 12.3.0 (MedCalc Software bvba, Mariakerke, Belgium).
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Fig. 2 Implanted blood pressure sensor (BPS). A 3D-reconstructed CT data of BPS in the right FA. B Selective angiography showing unimpaired FA blood flow
Results Preclinical Data The device was implanted successfully into the right FA of all 12 (100 %) animals. Delivery and introduction of the BPS via the PASIS was feasible. Fluoroscopy and selective angiography observation assured accurate implant position (Fig. 2). The average overall procedure time was 68 ± 17 min (range 30–93 min). Although no complications occurred during the implantation procedure, four devices had to be excluded from further evaluation (sensor performance and histopathology). One animal suffered from caseous lymphadenitis, which was not associated with the implantation of the sensor device. In another case, a wound infection and wound healing deficit made early euthanization necessary. The damage of the BPS, in one case during the implantation process and in the other through intense hind leg movements very early after implantation, led to the exclusion of two further devices. FA pressures could be obtained easily from the eight remaining implants. The communication distance was limited to 10 cm (distance between the internal telemetric unit and the external readout coil), which presents a comfortable reading distance above the implantation site. In the case of an unsuccessful connection buildup, the readout unit gave an acoustic warning and the measurement had to be restarted. Agreement between BP readings of the novel implant and reference BP readings is visualized in the Bland–Altman-plots in Fig. 3 comparing simultaneous diastolic, systolic, and pulse FA pressures from the implant and reference catheter directly after implantation [14]. Mean differences between implant and reference sensor
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recordings of -0.56, 0.29, and 0.85 mmHg (diastolic, systolic, and pulse pressures, respectively) indicate a low average error and, thus, a high accuracy. Standard deviations of 0.85, 1.44, and 2.27 mmHg (diastolic, systolic, and pulse pressures, respectively), in turn, result in low limits to agreement, indicating a small random error, equivalent to sufficient precision for a diagnostic conclusion. Moreover, the Bland–Altman-plot did not reveal any systematic trend based on the data. Because of its constant measurement failure from the very beginning, one sensor was excluded from Bland–Altman analysis. Table 1 gives an overview on the devices used in the in-vivo trials. Figure 4A shows a representative measurement series for over 3 months. Each measuring point displays the mean value, the minimum, and the maximum of the BP measurement, which was taken during the day. The series demonstrates good measurement stability of the BPS system with no systematic error and no drift over time. Moreover, the series reflects postural change and anesthesia captured by the BPS. Figure 5 shows BP curves of a measurement series over a time period of 197 days. This sensor measured equivalent BPs compared with the reference sensor after implantation but suffered from distinct offset drift over time. Control CTs revealed that the cable stiffness of the BPS was inadequate for the test environment, particularly the FA of an ovine animal. The intense leg movements caused the cable to dislocate gradually out of the artery and form loops in a subcutaneous position causing high mechanical stress on the system (Fig. 6). Subcutaneous tunneling of the cable before vessel entrance did not result in better local stability. For the last four trials, the stiffness of the cable was enhanced by insertion of a metal mesh into the outer cable sheathing. Dislocation did no longer occur from then on. In the histopathological examinations, no thrombus formation in the FA surrounding the intravascular part of the sensor cable was observed. Moderate to focally pronounced intimal proliferation occurred predominantly in central sections (Fig. 7A, B). Furthermore, connective tissue and intimal proliferation surrounding the sensor cable was observed close to the vascular entry point in some cases. The accumulated tissue growth amounted to approximately twice the thickness of the vascular wall of the FA (Fig. 7C). Accumulations of macrophages and lymphocytes appeared in the vascular wall and in the soft tissue surrounding the telemetric unit, indicating a normal foreign-body reaction to an intravascular implant. In three of the eight cases, great accumulations of granulocytes indicating an acute, fluoride inflammation reaction in the peri-implant tissue also was observed. No necrosis or apoptosis was detected.
N. J. Cleven et al.: Implantable Blood Pressure Sensor Fig. 3 Bland-Altman comparison of BP measurement with novel BPS and reference sensor (X-ray). Diastolic BP, systolic BP, and pulse pressure in FA
Table 1 Summary of all devices used in the in vivo trials No.
Sensor readout (days)
Test period (days)
Failures occurred
1
104
170
2
–
193
3 4
162 175
209 202
5
–
183
Caseous lymphadenitisa,b
6
–
187
Measurement failure from day 1c
7
–
187
Sensor damage during implantationb
8
–
100
Wound infectiona,b
9
175
225
10 11
197 71
226 196
12
264
280
Heavy cable dislocationb
a
Not device related
b
Excluded from Bland–Altman analysis and histopathology
c
Excluded from Bland–Altman analysis
Discussion Wireless home monitoring of vital signs has the potential to substantially improve the treatment, management, and
quality of life of patients with cardiovascular diseases. A major advantage of implantable devices is the ability to track measurements longitudinally and automatically, regardless of the patient’s compliance. Furthermore, they enable patients to manage their treatment more readily using customized alerts and instructions based on the sensor readings [18]. Implantable devices designed for long-term monitoring of hemodynamics therefore may help to reduce cardiovascular morbidity, hospitalization, and overall healthcare costs by reducing or preventing further aggravation of cardiovascular disease symptoms [6]. At the same time, numerous criteria need to be fulfilled by implantable sensor systems, such as small size, ease of implantation, biocompatibility, long-term functionality, user friendliness, and safety. The novel sensor system for long-term BP monitoring presented in this study has several advantages. Primarily, it was designed for minimally invasive implantation, an aspect that plays a vital role in obtaining acceptance. The cable diameter amounts to 3F and device implantation can be performed easily via a small surgical procedure very similar to a port-a-cath implantation. The intervention requires an 18-G needle arterial puncture and a small subcutaneous incision to implant the telemetric unit. This technique allows the implantation to be performed with local anesthesia on an outpatient basis. Moreover, energy as well as data transmission are supplied via wireless
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Fig. 4 a Intravascular BP measurement series with novel BPS. b Reference measurement directly after Implantation. * Measurement was done while sheep was narcotized (after implantation or CT). ** Measurement was done while sheep was turned on its backside
Fig. 5 Intravascular BP measurement with novel BPS over time. Parallel intravascular BP measurement with novel BPS (solid black line) and reference sensor (solid red line) directly after implantation while sheep was narcotized, intravascular BP measurement with
novel BPS 1 day after implantation (dashed black line), intravascular BP measurement with novel BPS 197 days after implantation (dotted black line)
magnetic telemetry. Hence, the patient is not affected by the monitoring system in everyday life, because no battery or transcutaneous cable feed-through is required.
Implantable hemodynamic monitoring systems which have been developed so far are mostly designated to assist chronic patient management for patients with congestive
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heart failure (ChronicleÒ IHM, Medtronic, Inc.; CardioMEMS HFI, CardioMEMS, Inc.; HeartPOD, SavacorÒ, Inc./St. Jude Medical; ImPressureTM, Remon Medical TechnologiesTM/Boston Scientific Corp.; ISSYS IHM, Integrated Sensing Systems, Inc.) [15–24]. These fully implantable systems also incorporate pressure sensors and use wireless technology for data transmission. They are placed in the pulmonary artery, the right heart, the right atrium across the septum, or the apex of the left ventricle,
Fig. 6 Bent sensor cable. Dislocation 13 days after implantation
and some of the devices rely on energy input via battery. Data transfer is either implemented via acoustic energy or radiofrequency telemetry. Several of the devices have already been tested in clinical studies or are still under evaluation but have not been FDA approved yet. In contrast to these devices, the system presented in this study is supposed to monitor hypertension patients. Therefore, the implantation site (peripheral arterial system) as well as the measurement range (30-300 mmHg) involving the recording of systemic BP pulsatility differ considerably. The goal of our pilot in vivo study was to evaluate the proposed device regarding measurement accuracy, longterm functionality, communication performance with the readout device, as well as histopathological alterations using an ovine animal model. Moreover, the evaluation of the FA as a vascular access point for minimally invasive implantation of the BPS was an aim of this study. The BPS communicated with the external readout station without any problems for a period of 6 months. Reference measurements and follow-up hemodynamic assessments revealed high accordance between BPS and reference sensor but also varying degrees of drift amongst all tested systems. Figure 4A, for example, shows a measurement series of a likely drift-free sensor. The measured values are constant in a typical range. Figure 5 shows that
Fig. 7 Histopathological sections of the FA. A Area were sensor tip was positioned (sensor tip removed). B FA directly behind the sensor tip (cable removed). C FA, 2 cm before vessel entering (cable removed). IP intimal proliferation, FBR foreign body reaction, M macrophages
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not every sensor we tested was drift-free. Due to the pilot nature of this study, the manual way in which the BPS was built may have contributed to the drift observed. In the future, an automated production process needs to ensure high reproducibility. Further on, invasion of humidity into the system or mechanical damage by cable fracture might have contributed to errors. The incident of sensor damage suggests that, although vessel sizes in human and sheep are in a fairly similar dimension, an ovine animal model may not be optimal for testing the wireless BPS. The absence of fat tissue on the upper leg of a sheep necessitated the fixation of the telemetric unit on a thin tissue layer close to the fasciae. The sensor system was hence directly exposed to leg and hip joint movement. Although the movements of sheep and patients with severe hypertension may differ significantly it is undeniable that the danger of cable withdrawal and damage also exists for the use of the device in humans. A further miniaturization of the system is supposed to counteract these shortcomings and, further on, allows implantation of the BPS at other sites than the FA, such as brachial or radial artery. Histopathological analysis indicated that the antithrombogenic coating prevented thrombus formation on the intravascular part of the cable and sensor. However, inflammation and foreign body reactions in the periimplant tissue as well as vascular luminal narrowing caused by connective tissue and intimal proliferation were observed. The biomechanics of the sheep may have contributed to these results by benefitting intravascular friction. Further coatings reducing or preventing intimal proliferation need to be validated. Besides that, in human application a preinterventional color Doppler ultrasound is necessary to measure the FA diameter and to exclude severe arterial sclerosis before implantation of the device in order to prevent a hemodynamically relevant stenosis. In the in vivo study, the readout measurements were done manually by holding the antenna above the telemetric unit during each measurement to ensure that all measures were recorded properly. In the future, the antenna can be constantly positioned at the body of the patient, e.g., integrated in a wearable textile, and measurements can be started automatically on a regular basis, triggered by the readout unit [13]. Moreover, an automated data transfer to an evaluation unit is conceivable. Limitations The goal of this pilot study was to demonstrate the feasibility of implantation as well as the technical functionality of a novel BP measurement device. However, the safety and stability of the system needs to be confirmed in additional large sample trials and ideally conducted with BPS
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systems that have been built up in a standardized smallscale series. Secondly, the ovine animal model used in this study was appropriate with regard to vascular size and accessibility of the FA. However, the anatomical site of the FA provided challenges with regard to the intense spontaneous hip joint movements of the animal. The antithrombogenic coating was effective, although an appropriate sterilization method has yet to be validated. Furthermore, we did not perform reference BP measurements during each trial except the one after implantation. Nevertheless, this should be investigated in future trials. Finally, we did not evaluate the removal of the BPS at the end of each trial, as we explanted the FA en bloc together with the sensor for histopathological analysis. This also needs to be investigated in subsequent trials.
Conclusions The experimental study in 12 sheep demonstrated the feasibility of implantation, the usability and long-term performance of a novel minimally invasive implantable, batteryless BPS system for long-term BP monitoring. Results revealed that the BPS system can be implanted easily in the FA. High-quality BP curves could be recorded over a period of 6 months. Moreover, the wireless communication system was easy to handle. The device has interesting potential as a new monitoring system for longterm BP monitoring of hypertension patients. Nevertheless, further research must be conducted to ensure full reliability, effectiveness, and safety of the BPS system. Acknowledgments The study was financially supported by the German Federal Ministry for Education and Research, Grant 16SV5000. The authors would like to thank the Osypka AG, Rheinfelden, Germany; the Fraunhofer Institute for Microelectronic Circuits and Systems, Duisburg, Germany; the Institute of Materials in Electrical Engineering - Chair 1, RWTH Aachen University, Germany and all coworkers for their support and cooperation. Conflict of interest Nina J. Cleven, Peter Isfort, Tobias Penzkofer, Anna Woitok, Benita Hermanns-Sachweh, Ulrich Steinseifer, and Thomas Schmitz-Rode declare that they have no conflict of interest.
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LABORATORY INVESTIGATION
Wireless Blood Pressure Monitoring with a Novel Implantable Device: Long-Term In Vivo Results Nina J. Cleven • Peter Isfort • Tobias Penzkofer Anna Woitok • Benita Hermanns-Sachweh • Ulrich Steinseifer • Thomas Schmitz-Rode
•
Received: 26 September 2013 / Accepted: 22 December 2013 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2014
Abstract Purpose Devices constantly tracking the blood pressure (BP) of hypertensive patients are highly desired to facilitate effective patient management and to reduce hospitalization. We report on experiences gathered in a pilot study that was designed to evaluate the prototype of a newly developed, minimally invasive implantable sensor system for long-term BP monitoring. Methods The device was implanted in the femoral artery (FA) of 12 sheep via standard FA catheterization under fluoroscopic control. Accuracy of the recorded blood pressure was determined by comparison with a reference catheter, which was positioned in the contralateral FA immediately after implantation. Regular follow-up included angiography, computed tomography (CT), and control of functionality and position of the BP sensor. Animals were euthanized after 6 months. FA segments with in situ
pressure sensor underwent macroscopic and histopathologic examinations. Results All implantations of the novel sensor device in the FA were successful and uneventful. High-quality BP recordings were documented. Bland–Altman plots indicate very good agreement. Comparison with measurements taken from the reference sensor revealed mean differences and standard deviations of -0.56 ± 0.85, 0.29 ± 1.44, and 0.85 ± 2.27 mmHg (diastolic, systolic, and pulse pressure, respectively) after exclusion of one outlier. CT uncovered deficiencies in cable stability that were addressed in a redesign. No thrombus formation, necrosis, or apoptosis were detected. Conclusions The pilot study proved the technical feasibility of wireless BP measurement in the FA via a novel miniature sensor device.
N. J. Cleven (&) U. Steinseifer T. Schmitz-Rode Department of Cardiovascular Engineering, Institute of Applied Medical Engineering, Helmholtz-Institute, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany e-mail: [email protected]
T. Penzkofer Surgical Planning Laboratory, Department of Radiology, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, USA e-mail: [email protected]
U. Steinseifer e-mail: [email protected] T. Schmitz-Rode e-mail: [email protected] P. Isfort T. Penzkofer Department of Diagnostic and Interventional Radiology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany e-mail: [email protected] T. Penzkofer e-mail: [email protected]
A. Woitok Institute for Laboratory Animal Science, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany e-mail: [email protected] B. Hermanns-Sachweh Institute of Pathology, RWTH Aachen University Hospital, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany e-mail: [email protected]
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N. J. Cleven et al.: Implantable Blood Pressure Sensor Fig. 1 Wireless blood pressure monitoring system. A Fullyimplantable, battery-less sensor system. B External readout unit for wireless communication (inner diameter of aerial coil: 6 cm)
Keywords Hypertension Intravascular blood pressure monitoring Implantable device Wireless measurement Pilot study Introduction Hypertension is a major risk factor for arteriosclerosis, cerebrovascular disease, heart disease, retinal damage, and kidney failure. According to latest statistics, 51 % of all cerebrovascular disease and 45 % of all ischemic heart disease deaths globally are contributed to high systolic blood pressure (BP) [1– 3]. Thus, being a major cause for cardiovascular disease with high hospitalization and mortality rates, a superior medical treatment of hypertension is mandatory to improve the general health situation and reduce future total health costs [1–6]. In cases where a lower BP cannot be achieved by lifestyle changes (diet, body weight, physical activity, etc.), a frequent surveillance combined with personalized drug treatment is the cornerstone of care. Recent studies confirm that long-term BP monitoring enables hypertensive patients to optimize therapy more effectively, improve symptoms, and reduce hospitalization time [7–10]. Implantable devices in particular could facilitate the long-term tracking of hemodynamic changes over time and improve hypertension treatment by reducing the need for patient compliance, recording accurate measures automatically and providing personalized feedback to the physician based on the recorded data [11, 12]. The purpose of this study was to evaluate the feasibility of implantation and long-term performance of a novel implantable and batteryless sensor system, which could serve as a wireless BP monitoring device for patients with hypertension [13]. We present our results and the lessons learned from this long-term in-vivo evaluation in the femoral artery (FA) of 12 sheep.
Methods BP Monitoring System The prototype of the BP monitoring system used consists of an implantable, miniature pressure sensor system (Fig. 1A)
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and an external communication unit (Fig. 1B) (company A, company B, company C, company D). The custom-developed blood pressure sensor (BPS) comprises two functional elements: the sensor tip—a capsule made of stainless steel embodying the capacitive pressure sensor—and the telemetric transducer, which communicates with the external readout unit. Both elements are connected via a data cable of 1 mm [3-French (F)] diameter. The full length of the BPS system amounts to 20 cm, including the 13 mm length of the sensor tip and the 18 mm length/diameter of the telemetric unit. Antithrombogenic coating (BaymedixTM CH 320 from Bayer Material Science, Pittsburgh, PA) was applied to the cable to prevent thrombus formation. The telemetric unit features three eyelets for subcutaneous fixation and enables wireless communication via inductive signal and energy coupling over a resonance circuit. It is batteryless and holds no data storage. The external readout unit communicates with the implant at a transmission frequency of 133 kHz and a sampling rate of 30 Hz while consuming up to 300 lW. It visualizes BP measurements online and automatically saves the recorded data, which can be easily transferred to an evaluation unit. The sensor measures the pressure with an accuracy of ±1.0 mmHg over the relative pressure range of 30–300 mmHg. For a detailed description of the BP monitoring system please refer to Cleven et al. [13]. Study Design The study was approved by the state committee on animal affairs. The BPS system is designed for minimally invasive implantation into the FA. To evaluate the system, an animal study with 12 female sheep was conducted. Percutaneous implantation was performed under angiographic guidance. After implantation, patency of the FA was assessed via conventional angiography and contrastenhanced computed tomography (ceCT). Invasive hemodynamic measurements were performed immediately after implantation. For direct comparison, reference measurements were obtained simultaneously in the contralateral FA. Follow-up hemodynamic assessments over a period of
N. J. Cleven et al.: Implantable Blood Pressure Sensor
6 months (daily in the first week after implantation, weekly from then on) as well as ceCT (directly after implantation, 1 week after implantation, two-monthly from then on) were performed to assess functionality and position of the BPS. Final ceCTs of all animals were performed before euthanization. For regular control measurements, sheep were gently held by a veterinary assistant while BP recordings were performed for up to 60 s. The antenna was therefore placed on the fur of the sheep right above the telemetric unit. Holding the antenna within a range with a mean of 10 cm was sufficient for data transmission. No sedation was necessary for the measurements. Animals A total of 12 adult female sheep (average body weight of 59 ± 9 kg) were included in this study. After intramuscular premedication with 100 mg of atropinsulfate 1 % (Atropinsulfat 1 %, Dr. Franz-Ko¨hler Chemie GmbH, Bensheim, Germany), 0.2–0.3 mg/kg xylazin 2 % (Xylazinhydochlorid, medistar, Ascheberg, Germany) anesthesia was induced by intravenous injection of diluted propofol 1 % (Propofol 1 %, Fresenius Kabi, Bad Homburg v.d.H., Germany). All animals were orotracheally intubated and mechanically ventilated with an oxygen-air mixture containing 1.5 vol% isoflurane (Isofluran Forene, Abbott, USA) at a respiratory rate of 14–18 breaths/min adjusted to the weight of the animal. For pain management, 2 ml/h of morphine (Fentanylcitrat, Rotexmedica GmbH, Trittau, Germany) was administered intravenously. A single-shot prophylactic antibiotic (Cefuroxime 1,500 mg, Fresenius Kabi, Bad Homburg v.d.H., Germany) was injected intravenously. Heparin, 1,000 I.E./10 ml, was administered (Heparin-Natrium-25000, Ratiopharm, Ulm, Germany) intra-arterially once during catheterization. At approximately 6 months (mean 6.5 months), postimplantation animals were euthanized by lethal barbiturate injection (Narcoren, Pentobarbital-Natrium, Merial, Hallbergmoos, Germany).
sensors were initially calibrated in the lab and adjusted for zero offset after sensor placement to rectify for errors induced by the implantation process, i.e., mechanical stress, and the intrinsic properties of blood, which could not be depicted during calibration in the laboratory setting. To validate the measurements of the implanted system, reference measurements were conducted with established invasive monitoring catheters (CPMS, Mammendorfer Institut fu¨r Physik und Medizin, Mammendorf, Germany) in the same segment of the contralateral FA immediately after implantation. Follow-up ceCT were performed with a dual-source CT scanner (Somatom Definition, Siemens, Forchheim, Germany). For contrast enhancement, 123 ml of iopromide (Ultravist 370, Bayer Medical, Berlin, Germany) followed by a 30 ml of saline bolus was injected via an ear vein at a flow rate of 3.3 ml/s. The image data were transferred to an external workstation equipped with a dedicated software tool (OsiriX PRO, aycan Digitalsysteme GmbH). Histopathology Animals were euthanized after a mean of 6.5 months. The implants were carefully excised en bloc together with the surrounding tissue including the FA and fixed in a 4 % buffered formalin solution. After macroscopic investigation, the specimens were divided into segments at defined spots. The cross-sections were embedded in paraffin and stained routinely in hematoxylin-eosin (H&E) and Elastica-van-Gieson (EvG) or were embedded in Technovit 7200 VLC in case of macroscopically conspicuous findings. Plastic embedded sections of 100 lm were obtained and stained with blue O-Tolouidin after dewatering for analysis with reflected-light microscopy. Histopathologic investigations for inflammation, foreign body reaction, connective tissue proliferation, fibrosis, intimal proliferation, luminal narrowing or occlusion, apoptosis, necrosis, or thrombus formation were performed. Statistical Analysis
Interventional Procedure All interventions were performed with a C-arm-based angiography system (Angiostar, Siemens, Forchheim, Germany). The animals were positioned supine on the angiography table. The right FA was percutaneously punctured with a standard 18-gauge (G) Terumo SURFOÒ catheter; thereafter a 4F peel-away sheath introducer set (PASIS) was inserted [12]. The sensor unit was then introduced via the sheath, and the telemetric unit was placed in a small subcutaneous pocket and fixed to the subcutaneous tissue using nonabsorbable sutures. All
BP measurements in form of BP waveforms were recorded for 1–2 min during each control measurement. Mean values of systolic and diastolic BP were calculated. Reference measurement with duration of 15 s was used to calculate the mean value of systolic, diastolic, and pulse pressure. Bland–Altman-plots, which allow the assessment of systematic bias, magnitude of deviation, as well as systematic trends and outliers, were used to compare BP readings of the novel implant and reference BP readings [14]. Data were analyzed using MedCalc 12.3.0 (MedCalc Software bvba, Mariakerke, Belgium).
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Fig. 2 Implanted blood pressure sensor (BPS). A 3D-reconstructed CT data of BPS in the right FA. B Selective angiography showing unimpaired FA blood flow
Results Preclinical Data The device was implanted successfully into the right FA of all 12 (100 %) animals. Delivery and introduction of the BPS via the PASIS was feasible. Fluoroscopy and selective angiography observation assured accurate implant position (Fig. 2). The average overall procedure time was 68 ± 17 min (range 30–93 min). Although no complications occurred during the implantation procedure, four devices had to be excluded from further evaluation (sensor performance and histopathology). One animal suffered from caseous lymphadenitis, which was not associated with the implantation of the sensor device. In another case, a wound infection and wound healing deficit made early euthanization necessary. The damage of the BPS, in one case during the implantation process and in the other through intense hind leg movements very early after implantation, led to the exclusion of two further devices. FA pressures could be obtained easily from the eight remaining implants. The communication distance was limited to 10 cm (distance between the internal telemetric unit and the external readout coil), which presents a comfortable reading distance above the implantation site. In the case of an unsuccessful connection buildup, the readout unit gave an acoustic warning and the measurement had to be restarted. Agreement between BP readings of the novel implant and reference BP readings is visualized in the Bland–Altman-plots in Fig. 3 comparing simultaneous diastolic, systolic, and pulse FA pressures from the implant and reference catheter directly after implantation [14]. Mean differences between implant and reference sensor
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recordings of -0.56, 0.29, and 0.85 mmHg (diastolic, systolic, and pulse pressures, respectively) indicate a low average error and, thus, a high accuracy. Standard deviations of 0.85, 1.44, and 2.27 mmHg (diastolic, systolic, and pulse pressures, respectively), in turn, result in low limits to agreement, indicating a small random error, equivalent to sufficient precision for a diagnostic conclusion. Moreover, the Bland–Altman-plot did not reveal any systematic trend based on the data. Because of its constant measurement failure from the very beginning, one sensor was excluded from Bland–Altman analysis. Table 1 gives an overview on the devices used in the in-vivo trials. Figure 4A shows a representative measurement series for over 3 months. Each measuring point displays the mean value, the minimum, and the maximum of the BP measurement, which was taken during the day. The series demonstrates good measurement stability of the BPS system with no systematic error and no drift over time. Moreover, the series reflects postural change and anesthesia captured by the BPS. Figure 5 shows BP curves of a measurement series over a time period of 197 days. This sensor measured equivalent BPs compared with the reference sensor after implantation but suffered from distinct offset drift over time. Control CTs revealed that the cable stiffness of the BPS was inadequate for the test environment, particularly the FA of an ovine animal. The intense leg movements caused the cable to dislocate gradually out of the artery and form loops in a subcutaneous position causing high mechanical stress on the system (Fig. 6). Subcutaneous tunneling of the cable before vessel entrance did not result in better local stability. For the last four trials, the stiffness of the cable was enhanced by insertion of a metal mesh into the outer cable sheathing. Dislocation did no longer occur from then on. In the histopathological examinations, no thrombus formation in the FA surrounding the intravascular part of the sensor cable was observed. Moderate to focally pronounced intimal proliferation occurred predominantly in central sections (Fig. 7A, B). Furthermore, connective tissue and intimal proliferation surrounding the sensor cable was observed close to the vascular entry point in some cases. The accumulated tissue growth amounted to approximately twice the thickness of the vascular wall of the FA (Fig. 7C). Accumulations of macrophages and lymphocytes appeared in the vascular wall and in the soft tissue surrounding the telemetric unit, indicating a normal foreign-body reaction to an intravascular implant. In three of the eight cases, great accumulations of granulocytes indicating an acute, fluoride inflammation reaction in the peri-implant tissue also was observed. No necrosis or apoptosis was detected.
N. J. Cleven et al.: Implantable Blood Pressure Sensor Fig. 3 Bland-Altman comparison of BP measurement with novel BPS and reference sensor (X-ray). Diastolic BP, systolic BP, and pulse pressure in FA
Table 1 Summary of all devices used in the in vivo trials No.
Sensor readout (days)
Test period (days)
Failures occurred
1
104
170
2
–
193
3 4
162 175
209 202
5
–
183
Caseous lymphadenitisa,b
6
–
187
Measurement failure from day 1c
7
–
187
Sensor damage during implantationb
8
–
100
Wound infectiona,b
9
175
225
10 11
197 71
226 196
12
264
280
Heavy cable dislocationb
a
Not device related
b
Excluded from Bland–Altman analysis and histopathology
c
Excluded from Bland–Altman analysis
Discussion Wireless home monitoring of vital signs has the potential to substantially improve the treatment, management, and
quality of life of patients with cardiovascular diseases. A major advantage of implantable devices is the ability to track measurements longitudinally and automatically, regardless of the patient’s compliance. Furthermore, they enable patients to manage their treatment more readily using customized alerts and instructions based on the sensor readings [18]. Implantable devices designed for long-term monitoring of hemodynamics therefore may help to reduce cardiovascular morbidity, hospitalization, and overall healthcare costs by reducing or preventing further aggravation of cardiovascular disease symptoms [6]. At the same time, numerous criteria need to be fulfilled by implantable sensor systems, such as small size, ease of implantation, biocompatibility, long-term functionality, user friendliness, and safety. The novel sensor system for long-term BP monitoring presented in this study has several advantages. Primarily, it was designed for minimally invasive implantation, an aspect that plays a vital role in obtaining acceptance. The cable diameter amounts to 3F and device implantation can be performed easily via a small surgical procedure very similar to a port-a-cath implantation. The intervention requires an 18-G needle arterial puncture and a small subcutaneous incision to implant the telemetric unit. This technique allows the implantation to be performed with local anesthesia on an outpatient basis. Moreover, energy as well as data transmission are supplied via wireless
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Fig. 4 a Intravascular BP measurement series with novel BPS. b Reference measurement directly after Implantation. * Measurement was done while sheep was narcotized (after implantation or CT). ** Measurement was done while sheep was turned on its backside
Fig. 5 Intravascular BP measurement with novel BPS over time. Parallel intravascular BP measurement with novel BPS (solid black line) and reference sensor (solid red line) directly after implantation while sheep was narcotized, intravascular BP measurement with
novel BPS 1 day after implantation (dashed black line), intravascular BP measurement with novel BPS 197 days after implantation (dotted black line)
magnetic telemetry. Hence, the patient is not affected by the monitoring system in everyday life, because no battery or transcutaneous cable feed-through is required.
Implantable hemodynamic monitoring systems which have been developed so far are mostly designated to assist chronic patient management for patients with congestive
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heart failure (ChronicleÒ IHM, Medtronic, Inc.; CardioMEMS HFI, CardioMEMS, Inc.; HeartPOD, SavacorÒ, Inc./St. Jude Medical; ImPressureTM, Remon Medical TechnologiesTM/Boston Scientific Corp.; ISSYS IHM, Integrated Sensing Systems, Inc.) [15–24]. These fully implantable systems also incorporate pressure sensors and use wireless technology for data transmission. They are placed in the pulmonary artery, the right heart, the right atrium across the septum, or the apex of the left ventricle,
Fig. 6 Bent sensor cable. Dislocation 13 days after implantation
and some of the devices rely on energy input via battery. Data transfer is either implemented via acoustic energy or radiofrequency telemetry. Several of the devices have already been tested in clinical studies or are still under evaluation but have not been FDA approved yet. In contrast to these devices, the system presented in this study is supposed to monitor hypertension patients. Therefore, the implantation site (peripheral arterial system) as well as the measurement range (30-300 mmHg) involving the recording of systemic BP pulsatility differ considerably. The goal of our pilot in vivo study was to evaluate the proposed device regarding measurement accuracy, longterm functionality, communication performance with the readout device, as well as histopathological alterations using an ovine animal model. Moreover, the evaluation of the FA as a vascular access point for minimally invasive implantation of the BPS was an aim of this study. The BPS communicated with the external readout station without any problems for a period of 6 months. Reference measurements and follow-up hemodynamic assessments revealed high accordance between BPS and reference sensor but also varying degrees of drift amongst all tested systems. Figure 4A, for example, shows a measurement series of a likely drift-free sensor. The measured values are constant in a typical range. Figure 5 shows that
Fig. 7 Histopathological sections of the FA. A Area were sensor tip was positioned (sensor tip removed). B FA directly behind the sensor tip (cable removed). C FA, 2 cm before vessel entering (cable removed). IP intimal proliferation, FBR foreign body reaction, M macrophages
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not every sensor we tested was drift-free. Due to the pilot nature of this study, the manual way in which the BPS was built may have contributed to the drift observed. In the future, an automated production process needs to ensure high reproducibility. Further on, invasion of humidity into the system or mechanical damage by cable fracture might have contributed to errors. The incident of sensor damage suggests that, although vessel sizes in human and sheep are in a fairly similar dimension, an ovine animal model may not be optimal for testing the wireless BPS. The absence of fat tissue on the upper leg of a sheep necessitated the fixation of the telemetric unit on a thin tissue layer close to the fasciae. The sensor system was hence directly exposed to leg and hip joint movement. Although the movements of sheep and patients with severe hypertension may differ significantly it is undeniable that the danger of cable withdrawal and damage also exists for the use of the device in humans. A further miniaturization of the system is supposed to counteract these shortcomings and, further on, allows implantation of the BPS at other sites than the FA, such as brachial or radial artery. Histopathological analysis indicated that the antithrombogenic coating prevented thrombus formation on the intravascular part of the cable and sensor. However, inflammation and foreign body reactions in the periimplant tissue as well as vascular luminal narrowing caused by connective tissue and intimal proliferation were observed. The biomechanics of the sheep may have contributed to these results by benefitting intravascular friction. Further coatings reducing or preventing intimal proliferation need to be validated. Besides that, in human application a preinterventional color Doppler ultrasound is necessary to measure the FA diameter and to exclude severe arterial sclerosis before implantation of the device in order to prevent a hemodynamically relevant stenosis. In the in vivo study, the readout measurements were done manually by holding the antenna above the telemetric unit during each measurement to ensure that all measures were recorded properly. In the future, the antenna can be constantly positioned at the body of the patient, e.g., integrated in a wearable textile, and measurements can be started automatically on a regular basis, triggered by the readout unit [13]. Moreover, an automated data transfer to an evaluation unit is conceivable. Limitations The goal of this pilot study was to demonstrate the feasibility of implantation as well as the technical functionality of a novel BP measurement device. However, the safety and stability of the system needs to be confirmed in additional large sample trials and ideally conducted with BPS
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systems that have been built up in a standardized smallscale series. Secondly, the ovine animal model used in this study was appropriate with regard to vascular size and accessibility of the FA. However, the anatomical site of the FA provided challenges with regard to the intense spontaneous hip joint movements of the animal. The antithrombogenic coating was effective, although an appropriate sterilization method has yet to be validated. Furthermore, we did not perform reference BP measurements during each trial except the one after implantation. Nevertheless, this should be investigated in future trials. Finally, we did not evaluate the removal of the BPS at the end of each trial, as we explanted the FA en bloc together with the sensor for histopathological analysis. This also needs to be investigated in subsequent trials.
Conclusions The experimental study in 12 sheep demonstrated the feasibility of implantation, the usability and long-term performance of a novel minimally invasive implantable, batteryless BPS system for long-term BP monitoring. Results revealed that the BPS system can be implanted easily in the FA. High-quality BP curves could be recorded over a period of 6 months. Moreover, the wireless communication system was easy to handle. The device has interesting potential as a new monitoring system for longterm BP monitoring of hypertension patients. Nevertheless, further research must be conducted to ensure full reliability, effectiveness, and safety of the BPS system. Acknowledgments The study was financially supported by the German Federal Ministry for Education and Research, Grant 16SV5000. The authors would like to thank the Osypka AG, Rheinfelden, Germany; the Fraunhofer Institute for Microelectronic Circuits and Systems, Duisburg, Germany; the Institute of Materials in Electrical Engineering - Chair 1, RWTH Aachen University, Germany and all coworkers for their support and cooperation. Conflict of interest Nina J. Cleven, Peter Isfort, Tobias Penzkofer, Anna Woitok, Benita Hermanns-Sachweh, Ulrich Steinseifer, and Thomas Schmitz-Rode declare that they have no conflict of interest.
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