Real-time assessment of tissue oxygen saturation during
endovascular therapy for chronic limb threatening
ischemia using a novel oximeter
Naoki Unno, MD, PhD,a,b,c Kazunori Inuzuka, MD, PhD,a,b Masaki Sano, MD, PhD,a,b
Masatsugu Niwayama, PhD,d Ena Naruse, CVT,a,b and Hiroya Takeuchi, MD, PhD,b Hamamatsu, JapanABSTRACT
In the present study, we have introduced a novel real-time, near-infrared spectroscopy oximeter, the TOE-20 (Astem, Co,Ltd, Kawasaki, Japan), which can simultaneously measure the regional tissue oxygen saturation (rSO2) in the skin andsubcutaneous tissue at three angiosomes of the foot. Seven patients with chronic limb threatening ischemia who had
undergone successful revascularization of the superﬁcial femoral artery were included. The analysis revealed a signiﬁcantcorrelation between the rSO2 and skin perfusion pressure. After revascularization, the rSO2 and skin perfusion pressure
had both increased at the three regions, although the increase at the plantar foot was insigniﬁcant. These results indicatethat the TOE-20 can be successfully used to monitor the rSO2 during endovascular treatment. (J Vasc Surg Cases Innov
Tech 2022;8:158-61.)
Keywords: Chronic limb-threatening ischemia; Endovascular treatment; Foot ulcer; Near-infrared spectroscopic
oximeter; Regional oxygen saturation monitoring

Owing to the increasing incidence of diabetes andrenal insufﬁciency, the number of patients with chronic
limb threatening ischemia (CLTI) has increased to >6
million globally.1 Endovascular therapy (EVT) is a major
treatment of CLTI, especially for patients with a high surgical risk.2 Previously, we introduced the use of a ﬁngermounted tissue oximeter that relies on near-infrared
spectroscopy (NIRS) techniques (Toccare; Astem Co,Ltd, Kawasaki, Japan) to assess ischemia severity in patients with peripheral artery disease.3 Subsequently, theteam developed an NIRS device to simultaneously
facilitate intra-EVT monitoring of tissue oxygenation atmultiple sites. In the present report, we have described
this novel device and presented our preliminary results

From the Division of Vascular Surgery,a and Second Department of Surgery,bHamamatsu University School of Medicine; the Division of Vascular Surgery,
Hamamatsu Medical Centerc; and the Department of Electrical and Electronic Engineering, Shizuoka University.d
The present study was supported in full by the Development of Medical Devices and Systems for Advanced Medical Services Project of the Division ofMedical Device Research (grant 20he1602005h0004) in the Japan Agency
for Medical Research and Development (to N.U.).
Author conﬂict of interest: N.U. and M.N. have patents associated with the TOE20 oximeter (PCT/JP2020/039614; WO 2007/139192). K.I., M.S., E.N., and H.T.
have no conﬂicts of interest.
Correspondence: Naoki Unno, MD, PhD, Division of Vascular Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 4313192, Japan (e-mail: unno@hmedc.or.jp).
The editors and reviewers of this article have no relevant ﬁnancial relationships todisclose per the Journal policy that requires reviewers to decline review of any
manuscript for which they may have a conﬂict of interest.
2468-4287! 2021 The Author(s). Published by Elsevier Inc. on behalf of Society for VascularSurgery. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://doi.org/10.1016/j.jvscit.2021.07.001

158

for the real-time monitoring of regional tissue oxygen
saturation (rSO2) in the skin and subcutaneous tissue atthree angiosomes of the foot during EVT.

METHODS
Study approval. The ethical committee of Hamamatsu
University School of Medicine approved the present
study (approval no. 16-057). The study protocol wasregistered at the UMIN (university hospital medical information network) clinical trials registry (identiﬁcation no.
UMIN000025021) and Japan registry of clinical trials(identiﬁcation no. CRB4180008). All the participants
provided written informed consent.
Tissue oximeter. The new NIRS oximeter (TOE-20;Astem, Co, Ltd) enables real-time monitoring of therSO2 (Supplementary Fig 1, A). The device’s name, TOE, isan abbreviation for “target region oxygenation-based
endovascular treatment,” which was previously proposed as a new strategy for EVT.4 The oximeter comprises three components: a small, box-shaped body(70 ! 72 ! 25 mm; weight, 120 g) that includes a multiplexer, microcomputer, blue-tooth module, and two AAbatteries; three sensor probes with 40-cm long cables;and a tablet personal computer that displays the measurement results (Supplementary Fig 1, B). Each probe
has near-infrared light-emitting diodes (770 nm and830 nm) and detectors (photodiodes; SupplementaryFig 1, C). The path length distribution obtained from thesimulation results is shown in Supplementary Fig 1, D.
The path length distribution superimposed on a typicalmagnetic resonance image of the foot is shown in
Supplementary Fig 1, E and F. The equations used to
calculate the concentrations of oxyhemoglobin anddeoxyhemoglobin are shown in Supplementary Fig 1, G.

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Table. Demographic and clinical characteristics
EVT
Successful

FailedPatients

Characteristic

75Age, years

76 (62-85)

74 (57-85)

Male sex

4 (57)

3 (60)

Hypertension

5 (71)

6 (60)

Dyslipidemia

3 (43)

6 (60)

Diabetes mellitus

5 (71)

6 (60)

History of smoking

5 (71)

8 (80)

End-stage renal disease

4 (57)

6 (60)

Coronary artery disease

2 (29)

6 (60)

75Toe

74Plantar foot01Outer ankle

000.63 6 0.130.58 6 0.25

Limbs treatedUlcer location

Ankle brachial index

EVT, Endovascular treatment.
Data presented as number, median (interquartile range), number (%),
or mean 6 standard deviation.

Application to patients. Three sensor probes can beplaced at the operator’s discretion to monitor tissueperfusion. The placement of probes according to theangiosome model is shown in Supplementary Fig 2:
one on the dorsal aspect of the foot, one on the outerankle (Supplementary Fig 2, A) and one on the plantar
aspect of the foot (Supplementary Fig 2, B). The actual
monitoring setup for measuring rSO2 during EVT isshown in Supplementary Fig 2 C.
Participants. The present prospective study included
seven patients with CLTI who had undergone successful
revascularization of the superﬁcial femoral artery (SFA)
without intervention in the tibial arteries and ﬁvepatients with CLTI who had undergone failed EVT (fourwith failed tibial artery intervention and one with failed
SFA intervention; Table). All the patients were categorized as having Rutherford classiﬁcation 5 with intractable toe ulcers. Successful revascularization of the SFA
was deﬁned as <30% residual stenosis of the target
lesion on the completion angiogram without peripheral
emboli. The rSO2 values were measured within 0.5 second per point. Although the rSO2 was monitoredcontinuously, we waited for 5 minutes to observe theeffect of revascularization after each procedure because
the values required a few minutes to stabilize (Fig, A). The
skin perfusion pressure (SPP) was also measured at thesame regions in the ambulatory clinic before and after
treatment using an SPP system (SensiLase PAD 3000;
Vasamed, Eden Prairie, Minn).

Statistical analysis. The correlations between the rSO2and SPP values were analyzed using the nonparametric
Spearman rank correlation tests. The results are presented as the mean 6 standard deviation. Paired t tests
were used to compare the rSO2 and SPP values frombefore and after revascularization at the same sites.
One-way analysis of variance and nonparametric Friedman tests with the post hoc Tukey test were used toexamine differences in the time course of the rSO2 values
in the dorsal foot among the seven patients. The level ofstatistical signiﬁcance was set at P < .05 (SPSS, version
25.0 software; IBM Corp, Armonk, NY).

RESULTSSFA revascularization was successfully performed via
endovascular intervention with balloon angioplasty inﬁve patients, a Viabahn stent-graft (W.L. Gore & Associates, Flagstaff, Ariz) in one patient, and stent placement
in one patient. In the outﬂow arteries below the knee,completion angiography revealed two run-off vessels infour patients and one run-off vessel in three patients.
Therefore, all seven patients had at least one straightline ﬂow found on the below-the-knee angiogram. Afterrevascularization, the sensor probes gradually responded
to the increased blood ﬂow to increase the rSO2 to astable value. A signiﬁcant correlation was found between
the SPP and rSO2 values (P < .01; Fig, B). After revascularization, the rSO2 and SPP had both increased at the dorsal foot and outer ankle (Fig, C and D). The time course ofthe rSO2 values in the seven patients on the day of hospitalization, before EVT, after EVT, and on postoperative
day 1 are shown in Fig. E. By 3 months after EVT, all theulcers had healed in all seven patients. In contrast, nosigniﬁcant increase was found in the rSO2 at any region
in the patients with failed EVT (Fig, F).

DISCUSSION
The present results have demonstrated the utility of theTOE-20 for simultaneous monitoring of the rSO2 in theskin and subcutaneous tissue in three angiosomes ofthe foot during EVT. Previous NIRS oximeters focusedon measuring oxygen levels in the brain or muscles at a
depth of 10 to 20 mm below the skin surface.5 However,these devices might not be able to measure theoxygen levels in the skin and subcutaneous tissue ofthe toe because bones or tendons are present atdepths <10 mm from the skin surface. In contrast, theTOE-20 is speciﬁcally designed to measure the rSO2 inthe skin and subcutaneous tissue. The superimposedmagnetic resonance image of the foot revealed that
the TOE-20 reﬂects the rSO2 levels to #5 mm under
the skin surface and can measure the rSO2 of the skinand subcutaneous tissue without the inﬂuence of bone.
This characteristic is quite unique compared with theother NIRS devices, which mainly measure the cerebral
oxygen levels using an algorithm that diminishes the160

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Fig. Regional tissue oxygen saturation (rSO2). A, The rSO2 curve for one patient during the endovascular procedure. The rSO2 values had stabilized after a few minutes. B, Scatter plot showing the relationship between therSO2 and skin perfusion pressure (SPP) at the surface of the foot (P < .01; r ¼ 0.653). The values reﬂect the datafrom all seven patients who had undergone successful superﬁcial femoral artery (SFA) revascularization via
endovascular treatment (EVT). C, Comparison of rSO2 values at the dorsal foot, plantar foot, and outer ankle
before and after EVT in seven patients. *P < .01 compared with before EVT. D, Comparison of SPP values at thedorsal foot, plantar foot, and outer ankle before and after EVT in seven patients. *P < .01 compared with before
EVT. E, Changes in rSO2 values at the dorsal foot in seven patients who had undergone successful SFA EVT on
the day of hospitalization and before EVT, after EVT, and on postoperative day 1. *P < .05 compared with before
EVT. F, Comparison of rSO2 values at the dorsal foot, plantar foot, and outer ankle before and after EVT in ﬁvepatients who had undergone failed EVT. n.s., Not signiﬁcant.

contribution of the skin and scalp.6 One of the greatest
advantages of the TOE-20 is the speed with which therSO2 can be measured. Continuous monitoring allows
one to obtain the values almost instantly (withinw0.5 second), reducing the inﬂuence of the patient’s

bodily movements on the measurements. High andlow rSO2 areas were observed even within the sameangiosome, because peripheral tissue perfusion in thefoot of patients with CLTI (especially those with diabetes)is determined by the peripheral microvascular blood

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ﬂow in the skin and subcutaneous tissue.7 After revascularization, the increases in the rSO2 and SPP at theplantar foot were not signiﬁcant. The lack of a patentpedal arch in some of the patients might explain why
the plantar rSO2 did not increase signiﬁcantly after EVT.
Because all seven patients had toe ulcers, we had
assumed that the rSO2 in the dorsal foot most likely reﬂected the oxygenation in the toe ulcers.
We previously investigated the use of a ﬁnger-mounted
oximeter that relies on the same algorithm as the TOE20 in 34 patients with CLTI without infection who had
undergone EVT. All patients with an rSO2 of $50% in thedorsal foot on postoperative day 1 exhibited improved ulcer healing, indicating that an rSO2 of $50% might be acutoff value for wound healing.8 Further studies withlonger observation periods are required to verify the cutoff
value of rSO2 for wound healing.

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Utility of a ﬁnger-mounted tissue oximeter with near-infrared spectroscopy to evaluate limb ischemia in patients with peripheral arterial
disease. Ann Vasc Dis 2019;12:36-43.
4. Unno N, Inuzuka K, Sano M, Kayama T, Naruse E, Takeuchi H. Target
region oxygenation-based endovascular treatment in a chronic limbthreatening ischemia patient with multifocal arterial diseases. J VascSurg Cases Innov Tech 2020;6:228-32.
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6. Hyttel-Sorensen S, Sorensen LC, Riera J, Greisen G. Tissue oximetry: acomparison of mean values of regional tissue saturation, reproducibility and dynamic range of four NIRS-instruments on the humanforearm. Biomed Opt Express 2011;2:3047-57.
7. Kagaya Y, Ohura N, Suga H, Eto H, Takushima A, Harii K. “Real angiosome” assessment from peripheral tissue perfusion using tissue
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8. Kayama T, Sano M, Yata T, Inuzuka K, Katahashi K, Yata T, et al. A pilot
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Submitted Mar 3, 2021; accepted Jul 2, 2021.

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Supplementary Fig 1. Novel tissue oximeter TOE-20 (“target region oxygenation-based endovascular treatment”; Astem, Co, Ltd, Kawasaki, Japan). A, Photograph of the TOE-20 oximeter. B, Engineering schematic for
the TOE-20. C, Sensor probe of the TOE-20. D, Model for the Monte Carlo analysis and sensitivity distribution
obtained via simulation. E, Path length distribution superimposed on a typical magnetic resonance image ofthe foot. F, Magniﬁed image of the area surrounded by the red-colored square in E. The depth of the bone fromthe skin surface was 6.7 mm at the dorsum of the foot. G, The equations used to calculate the concentrations ofoxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb).

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Supplementary Fig 2. TOE-20 (“Target region Oxygenationbased Endovascular treatment”; Astem, Co, Ltd, Kawasaki,Japan) application to patients. A, Two sensor probes of theTOE-20 are attached to the dorsum of the foot and outerankle of the angiosome model. B, Two sensor probes of theTOE-20 are attached to the plantar foot and outer ankle of
the angiosome model. C, Simultaneous measurement ofregional tissue oxygen saturation (rSO2) at the three angiosome sites of the foot using the TOE-20 in a patient withchronic limb threatening ischemia (CLTI).

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