http://informahealthcare.com/jmt ISSN: 0309-1902 (print), 1464-522X (electronic) J Med Eng Technol, 2015; 39(3): 191–197 ! 2015 Informa UK Ltd. DOI: 10.3109/03091902.2015.1019650

INNOVATION

Use of a functionalized introducer sheath and bioimpedance spectroscopy for real-time detection of vascular access complications C. Alexander Arevalos1, Joanna Nathan1, and Mehdi Razavi*2 1

Department of Bioengineering, Rice University, Houston, TX, USA and 2Department of Cardiology, Texas Heart Institute, 6624 Fannin, Suite 2480, Houston, TX 77030, USA Abstract

Keywords

Internal bleeding complications (IBCs) occurring at vascular access sites are associated with worsening patient outcomes and increased costs. This study assessed the IBC detection capabilities of a bioimpedance spectroscopy (BS) monitoring system that uses a novel functionalized introducer sheath. The device was tested in three large animal models of a clinical IBC. A 120-mL perivascular saline injection after sheath insertion, a slow continuous perivascular saline injection of 2.6 mL min1 of saline and a vessel-puncture model were tested. In each case, a significant change in normalized impedance was detected compared to the controls. This study provides evidence that a functionalized vascular access sheath using BS can detect an intraprocedural vascular access IBC. Clinical use of the device could help guide patient care by directly detecting vascular access complications early, thereby preventing unnecessary diagnostic scans to rule out the presence of IBCs.

Catheterization, catheters, complications, haemorrhage

1. Introduction Vascular access is necessary for any medical procedure that requires stable communication with a blood vessel. In 2010, more than 17.7 million vascular access procedures were conducted in the US [1,2]. One per cent of these procedures were associated with a bleeding complication at the access site severe enough to warrant blood transfusion. These complications are difficult to detect; in most cases, extensive bleeding has occurred by the time signs or symptoms become evident [3,4]. Vascular access bleeding complications lead to adverse consequences, including increased mortality [5], longer hospitalization [6] and higher cost to the provider [7]. Vascular access is an ubiquitous practice in a variety of medical procedures. It is most commonly achieved by using a hollow-bore needle to puncture the vessel, then introducing a hollow sheath into the vessel via the Seldinger [8] technique. Often, during the initial vessel puncture, the physician may accidentally penetrate the back wall of the vessel, initiating a bleeding complication [3,4,9]. Bleeding is further aggravated by the fact that many patients undergoing these procedures are receiving high-dose anticoagulant therapy [9,10]. Aggressive anticoagulation is often an independent risk factor for bleeding, leading to this complication even when needle punctures are ‘clean’ [9,10]. In most cases, signs or symptoms of bleeding will not occur until well after its actual onset. *Corresponding author. Email: [email protected]

History Received 5 September 2014 Revised 10 February 2015 Accepted 10 February 2015

Unfortunately, no method exists to diagnose the presence of these IBCs during interventional procedures or to predict their occurrence post-sheath removal. Accurate real time monitoring of these IBCs may improve patient outcomes by allowing operators to intervene early to mitigate blood loss and to prevent the need for costly diagnostic scans to rule out IBCs when their symptoms present. Bioimpedance spectroscopy (BS) has been demonstrated to be able to accurately detect changes in fluid volume in a variety of biological models and systems [11,12]. This study hypothesized that a standard vascular access sheath functionalized with four electrodes could act as a conduit for a BS system to detect a model IBC in a live large animal model.

2. Methods 2.1. Animals This study used four sheep and one pig, all of which were commercially available domestic Suffolk crosses and/or other domestic crosses, aged 6–12 months and weighing 34–54 kg. Institutional Animal Care and Use Committee (IACUC) approval was obtained for all studies. 2.1.1. Construction of functionalized vascular access sheaths Commercially available 10 French vascular access sheaths (Terumo Medical Corporation, Elkton, MD) were functionalized with four copper electrode bands, as shown in

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Figure 1. (a) The 4-pole electrode array vascular introducer sheath. In this configuration, the current waves are driven from the last and first electrodes and voltage measurements are taken at the medial electrodes. (b) Ultrasound of implanted functionalized vascular access sheath.

Figure 1(a). Each electrode added 0.5 French to the diameter of the sheath. To create an uninhibited passageway for instruments through the sheath, the 10 French sheaths were placed over 7 French sheaths to create a dual-lumen design so that the internal conduit could be used as a normal vascular access sheath. Each electrode was electrically isolated and all internal circuitry was isolated from the animal’s body. Addition of the electrodes did not impede the implantation of the sheath into the vessel. After the sheath was placed into the femoral artery or vein, each electrode was connected to its corresponding source through a Molex connector. Ultrasound was used to confirm that each sheath was placed into the proper blood vessel, as shown in Figure 1(b). 2.2. Bioimpedance spectroscopy system design The BS system was designed similar to previously described systems [13,14]. A flow diagram of the device is shown in Figure 2. In brief, multiple voltage sine waves are generated at 5, 10, 50, 100 and 500 kHz using a function generator (NI PXI - 5406, National Instruments, Austin, TX). These sine waves are converted to a sinusoidal current wave form using a Howland bridge circuit described previously [15]. The resultant current sine wave was relayed to the functionalized vascular access introducer sheath, as depicted in Figure 1(a). The two medial electrodes on the sheath are relayed to two analogue-to-digital converters (NI PXI - 5114, National Instruments) as depicted in Figure 1(a). On-board software (Labview, National Instruments) utilizes a fast Fourier transform to track changes in the result voltage waveforms at the specific input frequencies. Five data points were averaged per frequency at a sampling rate of 250 MS s1 per time point measured. The raw data were then post-processed in MATLAB (The MathWorks, Inc., Natick, MA) as the absolute value of the ratio of the impedance for each time point to the impedance at the beginning of each trial in order to normalize the data. The average and standard deviation of the absolute change in normalized impedance across the five measured frequencies was then calculated. In order to simulate how such a device would operate in a clinical setting, the controlling software was ported over to an

embedded processor with a field programmable gate array (NI sbRIO-9636, National Instruments), which allowed for real time monitoring and alerting for the presence of bleeding complications. 2.3. Study design Five in vivo animal studies (four ovine, one porcine) were performed. Once the animals were anaesthetized with inhalant isoflurane 0.5–4.0% delivered in oxygen, the functionalized sheaths were placed bilaterally in the femoral arteries and veins using the Seldinger technique. Ultrasonographic imaging was performed to confirm that no IBC was created due to implantation of the sheaths. The sheaths remained in place until after the animal was euthanized. An IBC was modelled by injecting saline at specific time points in each animal in the perivascular space. Impedance measurements were taken continuously throughout each animal trial in order to correlate the measured change in impedance with the size of the complication. Once the sheaths were placed in the animal, a negative control baseline measurement was taken for 5 min. The operator of the dataacquisition-system was blinded as to when each injection was given until after post-processing. Thirty millilitres of saline was injected 4-times each at a location 6 cm posteromedial to the distal tip of the sheath. Injections were 5 min apart. The cross-frequency normalized impedance measured was averaged across each 5-min time interval. Therefore, the discrete injection data results represent the mean cross-frequency time averaged normalized impedance ± the SE from nine different sheaths used in three different animals. A one-way analysis of variance (ANOVA) with a Tukey’s post-hoc analysis was used to detect for differences between the groups using the statistical package JMP. To assess the specificity of the system towards a slow IBC compared to an uninjured patient, a slow continuous saline injection was started 5 min before the insertion of the sheaths at the same location as the discrete IBC model. The saline was injected at a rate of 2.6 ml min1 for 45 min in this model. Next, the normalized cross-frequency impedance was measured throughout the completion of the injection. The

DOI: 10.3109/03091902.2015.1019650

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when a statistically significant change from the baseline was measured.

3. Results A total of 38 measurements of changes in impedance were observed in this study using a total of 11 prototype functionalized vascular access sheaths from five separate animals. Figure 3(a) shows a representative output for one trial from the discrete injection model. The first vertical black line represents the start of the calibration period and each subsequent line represents a 30 mL injection of saline into the perivascular space. Ultrasonography was performed at the site of injection for the continuous injection model. The saline accumulated proximal and inferior to the regions of perivascular space where the sheaths were placed, as shown by Figure 3(b). Figure 3(c) shows the quantified relative changes in the average cross-frequency normalized impedance from the calibration period to the post-injection period after a total saline injection of 30 mL (1.08

± 0.02), 60 mL (1.19





± 0.05), 90 mL (1.33 ± 0.08) and 120 mL (1.48 ± 0.11). The difference between these interval impedance values was significant (1-way ANOVA; n ¼ 9; p50.0001). After performing Tukey’s post-hoc analysis, the interval impedance value associated with the 90 mL injection was the first to be significantly different from the starting point. Using this data set, an equation was derived to predict the size and speed of an IBC from the changes in the normalized impedance value by using linear regression analysis. This equation was (mL of

CrossFrequency Impedance Tracking

Figure 2. Overall test apparatus design. Multiple sine waves are generated at an array of frequencies. These voltage waveforms are converted to a sinusoidal current waveform, and they are relayed to the sheath. Two voltage measurements are read by two oscilloscopes and a fast Fourier transform is used to only track changes in the specific frequencies that were originally sent. The impedance is then calculated and tracked in real time. Post-processing algorithms then quantify when the impedance has changed significantly and alert the operator to the presence of the worsening IBC.

continuous injection data results represent the change in the average normalized impedance for each of the five measured frequencies ± the SE between the frequencies tested. A t-test and an ANOVA was used to test for statistical difference between the changes in the average and variance between the impedance measured from one sheath in the slow IBC model and one in a control animal where no saline was injected using the statistical package JMP. In order to assess how the device would function in a true clinical setting, a bleeding complication was started in a heparinized ovine model by puncturing the artery with a functionalized sheath in it using an 18-gauge needle. The operator of the device was blinded to when the vessel was injured. The device was programmed to alert the operator

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(normalized Impedance) ± 0.9745 with IBC) ¼ 0.0041 mLl mLl 2 an R value of 0.986. Figure 4 shows the results from the continuous injection model. Figure 4(a) shows the resultant spectral changes in the normalized impedance values between the array of frequencies used in the continuous injection model. The location and size of extravasations caused by the saline injection was imaged using ultrasound, as shown by Figure 4(c). As noted in Figure 4(b), the sham injection showed no spectral changes at all ranges of measured frequencies. The absence of bleeding in the control scenario was confirmed by ultrasound and later by necropsy. The cross-frequency average (1-tailed t-test; p50.05) and variance (ANOVA; p50.05) were significantly higher than the respective control values after only 30 mL of saline had been injected. The resultant crossfrequency average and variance after the 45-min trials in the IBC model and in the sham treatment are shown in Table 1. The final bleeding model tested in this study was aimed at blindly detecting a true internal bleeding complication. The results from this study are shown in Figure 5. In this study, a flat impedance value was measured in the animal until the vessel was punctured, as indicated in Figure 5. As the blood accumulated, the normalized impedance values changed from the baseline value. A t-test was used to compare each time point from the average baseline measurements and a p value score was calculated for each time point. Three minutes after the initial puncture, the device measured a significant change in normalized impedance (p50.05), as indicated in Figure 5 and continued to measure an increasingly significant change as the complication grew with time.

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Figure 3. (a) Representative chart showing changes of impedance due to four saline injections into the perivascular space. Each colour represents a different frequency in Hz. (b) Ultrasonogram of the perivascular space after the 120 mL saline injection. (c) Quantification of the average change in cross-frequency normalized impedance for each saline-injection amount. Groups not connected by the same letter are significantly different from one another.

4. Discussion Our feasibility study suggests that the modified sheath, via use of real-time bioimpedance spectroscopy, can accurately detect the onset and progression of perivascular bleeding during vascular access procedures. Furthermore, our data suggests that the sheath can detect onset and progression of bleeding at a rate and in a manner seen commonly in clinical situations by a blinded operator. In a recent review, Vavalle and Rao [9] summarized key studies and registry data concerning bleeding complications in patients undergoing percutaneous coronary intervention (PCI). In the 3-hospital registry (n ¼ 10 974) described by Kinnaird et al. [10], 5.4% of the patients had major bleeding (Thrombolysis in Myocardial Infarction [TIMI] classification) and received transfusions. In the NHLBI registry (n ¼ 6656), 1.8% of the patients had access site haematomas that necessitated transfusion [5]. In the GRACE registry (n ¼ 24 045), there was a 3.9% incidence of major bleeding; almost a fourth of these haemorrhages (23.8%) occurred at the vascular access site [10]. Detection of bleeding while the sheath is in place may lead to better overall identification and management of patients at high risk for post-procedural vascular access-site bleeding

[16,17]. Many access site bleeding complications are noted only after sheath removal. However, their trigger is thought to occur at the time of needle puncture and small leaks are believed to occur immediately before and during sheath placement [10,18]. Early awareness of internal bleeding could potentially allow physicians to directly and immediately address this complication and increase post-procedural vigilance regarding these high risk-patients. Thus, early detection of these complications intra-procedurally may improve patient outcomes. Unfortunately, no commercial technology currently exists that can alert clinicians to an ongoing IBC in its early stages. While existing imaging modalities such as ultrasound and CT scans can sometimes be used to identify these bleeding complications, it would be unrealistic and prohibitively expensive to include them as part of the clinical workflow for every procedure involving vascular access. To address this unmet need, a device was constructed that uses a vascular access sheath functionalized with a series of electrodes to detect bleeding in real time at the site of vascular entry. The current standard of care and future envisioned clinical application of such a device are compared in Figure 6.

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Figure 4. Representative resultant spectral changes in the normalized impedance values between the array of frequencies used in the (a) continuous injection and (b) sham injection model. (c) Composite ultrasonogram of the perivascular region at the end of the 120 mL saline injection which predated the insertion of the functionalized sheath. This model recreates the pathology of a retroperitoneal haematoma as seen clinically.

Table 1. Changes in cross-frequency average and variance. Treatment

Average

Variance

Continuous injection Sham treatment p Value

1.936 795 0.685 679 0.009 (t-test)

1.112 945 0.003 218 0.029 (ANOVA)

ANOVA, analysis of variance.

The preliminary data from this study suggest that the device could potentially help guide patient care three different ways. The data suggests that the device is able to detect not only accumulations of fluid at known injection intervals, as demonstrated by our discrete injections, but also continuous bleeding that has begun before the device is even implemented. This information could be used by clinicians to help diagnose the presence of an IBC when it is early in the procedure or if there is a sudden rupture so they could take the necessary steps to treat the problem. The control data from the two models suggest that, in the setting of symptoms such as groin pain or hypotension, the absence of bioimpedance

Figure 5. Bleeding before sheath removal correlates with bleeding after sheath removal. In a clinical study the extent of fluid accumulation before sheath removal correlates with the total fluid accumulated on the following day after sheath removal. This correlation suggests that the functionalized vascular access sheath may identify patients at high risk for bleeding after sheath removal.

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Figure 6. Comparison between the current standard of care and the future envisioned clinical application of a bioimpedance sensing vascular access sheath. (a) Current standard of care, where an accidental backside needle stick together with heavy anticoagulation leads to a serious internal bleeding complication with no outward signs until there is a systemic emergency. (b) Envisioned use of a functionalized bioimpedance sensing vascular access sheath. Early detection allows for early intervention of the complication mediating blood loss and any potential systemic complications that come from an internal bleeding complication.

changes may prevent the need for routine CT scans currently used to rule out significant internal bleeding. By providing this data immediately to clinicians at the point of care, the clinical use of such a device could potentially improve overall outcomes of patients undergoing vascular access procedures. Due to the design of the device, it could offer this clinical benefit without interrupting normal procedural work flow, since the sheath is used the same as current vascular access sheaths. Although the prototype utilizes extensive hardware, the system was designed to be scalable to become an affordable bedside option, allowing for its widespread use. The current study has a number of limitations. Saline was tested in the IBC model instead of blood for the initial experiments. Subsequent data presented, however, used a needle to create a small bleed. A blinded operator was able to detect the onset of bleeding within 3 min. Also, no human studies were performed with the BS system. More studies, including human studies, will further strengthen the conclusions derived from the current project. The data obtained, however, speak powerfully towards the validity of the concept.

Declaration of interest The authors report no financial relationships or conflicts of interest regarding the content herein. The work described in this manuscript was funded through internal research funding through the Texas Heart Institute, which is currently a minority owner of Saranas, Inc.

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Use of a functionalized introducer sheath and bioimpedance spectroscopy for real-time detection of vascular access complications.

Internal bleeding complications (IBCs) occurring at vascular access sites are associated with worsening patient outcomes and increased costs. This stu...
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