Academiejaar 2015 – 2016

Comparison of three NIRS devices for the measurement of microvascular reactivity

Kevin Steenhaut

Promotor 1: Prof. dr. Anneliese Moerman Promotor 2: Prof. dr. Stefan De Hert

Masterproef voorgedragen in de master in de specialistische geneeskunde Anesthesie en reanimatie

Academiejaar 2015 – 2016

Comparison of three NIRS devices for the measurement of microvascular reactivity

Kevin Steenhaut

Promotor 1: Prof. dr. Anneliese Moerman Promotor 2: Prof. dr. Stefan De Hert

Masterproef voorgedragen in de master in de specialistische geneeskunde Anesthesie en reanimatie

Toelating tot bruikleen

“De auteur geeft de toelating deze masterproef voor consultatie beschikbaar te stellen en delen van de masterproef te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperkingen van het auteursrecht, in het bijzonder met betrekking tot de verplichting de

bron uitdrukkelijk te vermelden bij het aanhalen van resultaten uit deze masterproef.”

“The author gives permission to make this master thesis available for consultation and to copy parts of this master thesis for personal use. In the case of any other use, the limitations

of the copyright have to be respected, in particular with regard to the obligation to state expressly the source when quoting results from this master thesis.”

Gent, 27 april 2016

XKevin Steenhaut

Table of Content

List of abbreviations

Abstract

1. Introduction

1.1 Background

1.2 NIRS: principles of operation

1.3 Assumptions and limitations

1.4 Tissue oxygenation changes during vascular occlusion test

2. Aim

3. Materials and methods

3.1 Subject preparation

3.2 Different NIRS devices

3.3 Interventions

3.4 Missing values

3.5 Selected parameters of microvascular reactivity

3.6 Statistics

4. Results

4.1 Comparison of static parameters between the 3 devices

4.2 Comparison of dynamic parameters between the 3 devices

5. Discussion

5.1 Important findings

5.2 Comparison with previous studies

5.3 Clinical relevance

6. Conclusion

7. References

List of abbreviations

AUC= area under the curve

A/V ratio= arterial/venous ratio

BIS= bispectral index

BL/BSLN= baseline

CABG= coronary artery bypass grafting

CPB= cardiopulmonary bypass

Hb= hemoglobin, HHb= deoxygenated Hb, O2Hb= oxygenated Hb, THb= total Hb

ICU= intensive care unit

IQR= interquartile range

NIRS= near-infrared spectroscopy

PORH= post-occlusive reactive hyperemia

SD= standard deviation

SRS= Spatially Resolved Spectroscopy

StO2= peripheral tissue saturation

M1= first minute

TOI= tissue oxygenation index

VOT= vascular occlusion test

1

Abstract

Comparison of three NIRS devices for the measurement of microvascular reactivity

Kevin Steenhaut MD, Stefan De Hert MD, PhD, Anneliese Moerman MD, PhD

Ghent University Hospital, Dept of Anaesthesiology, Ghent, Belgium

Background and Goal

An increasing number of NIRS devices are used to provide measurements of microvascular

reactivity. The interchangeability of the different devices is however unclear. The aim of the

present study is to analyse tissue oxygenation measurements by three different NIRS devices

during a vascular occlusion test (VOT). The hypothesis is that measurements from the different

devices are similar.

Materials and Methods

Forty consenting adults scheduled for elective CABG surgery were recruited. Three disposable

NIRS sensors (INVOS 5100C; Foresight Elite and NIRO-200NX) were applied to the left

forearm over the brachioradial muscle. A standard blood pressure cuff at the upper arm was

inflated to a pressure of 50 mmHg above the individual systolic pressure. After 3 minutes of

ischaemia, cuff pressure was rapidly released. Tissue oxygenation (StO2) measurements

included baseline StO2 (BL), downsloping rate in first minute (DS-M1) and over 3 minutes

(DS), minimum value (Min), upsloping rate (US), rise time (Rt), maximum value (Max) and

settling time (St).

Comparisons between devices were performed with the Kruskal-Wallis test. Pairwise

differences among devices were examined by the Mann-Whitney U test.

Results and Discussion

There were no significant differences at baseline. Pairwise comparisons between devices

showed that INVOS has significantly higher downsloping rates, lower minimum values and

higher upsloping rates, while NIRO has lower maximum values and Foresight has longer rise

and settling times compared to the two other devices.

Table 1. Comparison of tissue oxygenation measurements during VOT

INVOS Foresight NIRO

BL (%) 66 [61-73] 70 [65-73] 69 [65-73]

DS-M1 (%/min) 17 [13-24]* 11 [6-15] 12 [7-16]

DS (%/min) 15 [11-21]* 11 [8-13] 12 [9-15]

Min (%) 36 [21-48]* 45 [40-51] 46 [36-51]

US (%/min) 311 [92-523]* 114 [65-199]* 202 [88-269]*

Rt (sec) 25 [23-35] 40 [28-50]* 27 [21-31]

Max (%) 82 [77-86] 81 [78-87] 79 [75-82]*

St (sec) 181 [146-223] 226 [181-266]* 187 [127-248]

* p<0.05 vs. the two other devices. Data are presented as median [IQR].

Conclusion

Although no significant differences were found at baseline, analysis of different parameters of

microvascular reactivity shows that different information is retrieved depending on the NIRS

device used. This phenomenon should be kept in mind when using NIRS as monitoring

technique for tissue oxygenation, especially during VOT.

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1. INTRODUCTION

1.1 Background

Alterations in microvascular perfusion are associated with impaired tissue oxygenation and

organ dysfunction.1 Therefore, assessment of microcirculation could provide the clinician

with information about the tissue oxygenation status, the severity of the disease and the

results of the applied therapies. Parameters derived from the functional evaluation of the

microcirculation by a vascular occlusion test (VOT) have been shown to predict outcome in

septic and trauma patients independently from the macrocirculation.2 A minimum tissue

oxygenation value precedes peak lactate levels by more than 90 min in patients with

hypovolemic shock, indicating that regional tissue perfusion might be an earlier indicator of

perfusion deficits.3 Whereas resting tissue oxygen saturation is largely insensitive to

hypoperfusion, dynamic parameters can provide information regarding tolerance to ischemia

and its recovery potential after ischemia.

Near-infrared spectroscopy (NIRS) is increasingly recognized as a method for non-invasive

assessment of microvascular reactivity. It enables to quantify endothelium-mediated changes

in vascular tone, elicited by creating post-occlusive reactive hyperemia (PORH).4 PORH

refers to the reproducible transient increase in blood flow after release of an arterial occlusion.

The velocity and degree of flow restoration depend on the capacity of the microvasculature to

recruit arterioles and capillaries, thereby reflecting the integrity of the microcirculation.4

An increasing number of NIRS devices are being used in research investigations to provide

measurements of vascular reactivity. However, comparability between the different devices is

unclear as there are several technical differences and every technology applies a different

computational algorithm to generate NIRS values.5 Currently, it is not known if and how well

measures from different devices are related.

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1.2 NIRS: Principles of operation

The physical and mathematical basis for NIRS is provided by the Beer-Lambert law, which

states that the quantity of light absorbed by a substance (A) is directly proportional to the

specific absorption coefficient of the substance at a particular wavelength (ɛ), the

concentration of the substance (c) and the path length of the light through the solution (l) (A =

ɛ . c . l).

The relative transparency of biological tissues to light in the near-infrared part of the spectrum

(700-1000 nm) enables light photons to pass through the tissues, where they are attenuated

due to a combination of absorption and scattering. Because of scattering by the tissue

components, the light does not travel in a straight line. Therefore, the Modified Beer-Lambert

law is applied: (A = ɛ . c . l . B + k), where B is the differential path length factor and k is an

additive geometry-dependent term, reflecting scatter loss. The geometrical path length l has to

be multiplied by B to find the true optical distance, because light that reaches the detector will

have been scattered multiple times and therefore has travelled a much greater distance than

the actual light emitter-detector distance. K corrects for the fact that not all emitted light

reaches the detector, because some of it is scattered away from the detector, giving scattering

losses. Scattering is a function of the tissue composition and the number of various tissue

interfaces. Because B and k are unknown factors, no absolute values can be measured with

the Modified Beer-Lambert law. NIRS technology is based on the assumption that the

quantity of scattering remains constant and that changes in attenuation result solely from

changes in absorption.

Several biological molecules, termed chromophores, absorb light in the near-infrared

spectrum. However, only hemoglobin and cytochrome oxidase are present in variable

concentrations, reflecting blood and intracellular oxygenation, respectively. Other

chromophores are assumed to be constant over the period of monitoring.

The wavelengths of near-infrared light used in commercial devices are selected to be sensitive

to hemoglobin. Cytochroom oxidase has a crucial role in mitochondrial oxidative energy

metabolism, and therefore provides a potential biomarker of the cellular oxygenation state,

with substantial physiological and clinical importance. However, it is present in much lower

concentrations in the tissue than oxygenated and deoxygenated hemoglobin and its absorption

spectrum overlaps that of these chromophores, and therefore, the validity of cytochroom

4

oxidase measurements is debated, and the signal is not incorporated into any clinical monitors

yet.

Oximetry relies in the fact that absorption of near-infrared light at specific wavelengths is

different in deoxygenated hemoglobin (HHb) when compared with oxygenated hemoglobin

(O₂Hb).

Commercial devices generally use wavelengths between 690 and 880 nm where the

absorption spectra of O₂Hb and HHb are maximally separated and there is minimal overlap

with that of water absorption (980 nm). Optical absorption at 1 wavelength for each

chromophore of interest must be known. NIRS devices use near-infrared light at two or more

specific wavelengths to differentiate between O2Hb and HHb. No attempt is made to measure

optical scattering. The scale of measured changes is dependent on the application of

assumptions of the scattering properties at different wavelengths, and is incorporated into the

algorithm of the respective devices. Algorithmic formulae are complex and their validity is

contingent on the assumptions made. The variability in algorithms between NIRS devices

implicates that there are differences in the chromophore concentrations derived, making

comparisons between oximeters produced by different manufacturers problematic.

NIRS uses reflected light rather than transmitted light to study the absorption of light in tissue

samples. Reflectance probes locate the light emitter and detector adjacent to one another. The

light takes a ‘banana-shaped’ pathway through the tissues, with the depth of photon

penetration proportional to the source-detector separation (principle of spatial resolution). In

order to compensate for superficial tissue, which is not the tissue of interest, differentially

spaced light detectors are used. Owing to the principle of spatial resolution, the closer receiver

will measure more superficial tissue while the distal optode measures both superficial and

deeper tissue. After subtraction of the interference from superficial tissues- the mathematical

details of which are not provided by the manufacturers- oxygenation in the deeper tissues is

derived.

1.3 Assumptions and limitations

First of all, NIRS does not quantify oxygen molecules but calculates the ratio of light

absorbencies at predefined wavelengths. External light sources may cause significant

artefacts. Secondly, the algorithms used to calculate oxygen saturation assume a fixed

distance for light to travel through the sampled area (the optical path length). However,

5

different tissue components produce very different amounts of photon scattering and

absorption. As a result, variations in probe positioning as well as inter-individual variations in

the composition of tissue may result in 10 to 15% variability of the true optical path length

measurement. The significant inter-individual biological variability in tissue composition

causes a wide variation in ‘normal’ baseline values of volunteers. Therefore, NIRS devices

are best used as trend monitors. Rather than to base therapeutic decisions on absolute

numbers, it is safer to rely on proportional changes of an individual’s baseline value as a basis

for clinical decision making. Thirdly, the physiological correlate to which tissue saturation

measurements obtained with NIRS relate, remains a matter of debate because the interrogated

tissue sample contains all the different vascular components and represents a mixture of

arterial, capillary and venous oxygen saturations.

1.4 Tissue oxygenation changes during vascular occlusion test

Fig 1. StO2 derived parameters during a vascular occlusion test. 1 ischemic downslope, 2 reperfusion

upslope, 3 hyperemic response.7

At resting state, a baseline value is given. After cuff-inflation, a rapid desaturation (=ischemic

downslope) is seen and after 3 minutes, when the cuff is released, the surge of blood flow

causes a rapid resaturation (=reperfusion upslope) and an endothelium-dependent

vasodilatation that creates a transient increase in blood flow to a level higher than at resting

state, this is called the hyperemic response or post-occlusive reactive hyperemia (PORH).

2. AIM

The aim of the present investigation is to determine the interrelationship among different

measurements of microvascular reactivity, obtained with 3 different NIRS devices. The

hypothesis is that measures of microvascular reactivity obtained with the different devices

would be significantly correlated to each other.

6

3. MATERIALS AND METHODS

This is a prospective, observational and descriptive study. The data were acquired as part of a

research project investigating the effects of the priming solution of the cardiopulmonary

bypass (CPB) on microvascular reactivity. After approval by the local research ethics

committee and after obtaining their written informed consent, 40 adult patients (33 males/7

females, mean age 66 +/- 9) scheduled for elective coronary artery bypass grafting surgery

were recruited. Exclusion criteria were an ejection fraction < 25%, diabetes, renal

insufficiency (creatinine > 2.0 mg/dl), significant hepatic disease (liver function tests > 3x

upper limit of normal), history of cerebrovascular disease, significant carotid artery stenosis

(> 60%), perioperative use of corticosteroids, and need for vasopressor or inotropic therapy

before surgery.

3.1 Subject preparation

All subjects needed to fasten at least 6 hours prior to anesthesia and were asked to refrain

from nicotine. On the morning of surgery, patients were allowed to take their routine

medication, except for angiotensin-converting enzyme inhibitors and angiotensin II

antagonists. Patients were premedicated with oral diazepam (5-10 mg). Standard monitoring

was used throughout the procedure, including elektrocardiogram, pulse oximetry and

bispectral index (BIS). Arterial blood pressure was recorded continuously via the right radial

artery catheter. Three disposable NIRS sensors (INVOS 5100C, Covidien, Mansfield, MA;

NIRO-200NX, Hamamatsu Photonics, Tokyo, Japan and Foresight Elite, CAS Medical

Systems, Branford, CT, USA) were applied to the left forearm in a circumferential orientation

(over the brachioradialis muscle, ~5 to 10 cm distal from the proximal head of the radius) for

measurement of microvascular reactivity.

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3.2 Different NIRS devices

INVOS 5100 Foresight Elite

Equanox 7600 NIRO 200-NX

Several NIRS devices for measuring tissue oxygen saturation are commercially available,

three of which are FDA-approved: INVOS 5100, Foresight and Equanox 7600 (Nonin

Medical Inc., Minneapolis, MN, USA). NIRO 200-NX is not FDA-approved. Despite the

identical basic technology using near-infrared wavelengths to detect changes in the

concentration of O2Hb and HHb, there are several technical differences. NIRO employs the

technique of Spatially Resolved Spectroscopy (SRS, multiple closely spaced detectors to

measure light attenuation as a function of source-detector separation) to measure the tissue

oxygenation index (TOI) and change in hemoglobin. Independently of the SRS method,

NIRO measures changes in concentration of O2Hb, HHb and THb using the modified Beer-

Lambert method. INVOS, Foresight and Equanox use the modified Beer-Lambert law to

measure tissue oxygen saturation, and eliminate the contribution of superficial tissue by using

the principle of Spatial Resolution (depth of photon penetration proportional to the source-

8

detector separation). INVOS 5100 features 2, NIRO 200-NX features 3 and Foresight Elite

features 5 wavelengths of near-infrared light. Theoretically speaking, more wavelengths

should lead to greater accuracy and enhanced tissue recognition.

3.3 Interventions

Sensitivity to changes in oxygenation was evaluated with a vascular occlusion test.

Measurements were performed on the awake patient before induction of anesthesia. A

sphygmomanometer cuff was wrapped around the arm over the left brachial artery. Arterial

occlusion was achieved by inflating a standard blood pressure cuff (EH50U, Siemens) at the

upper arm to a pressure of 50 mmHg above the individual systolic pressure of each subject.

The cuff was automatically inflated in less than 2 seconds to the pressure needed for the

arterial occlusion. After 3 minutes of ischemia, cuff pressure was rapidly released and StO2

response was recorded until it stabilized at the baseline value. Regarding the different values

given by NIRO 200-NX, only the TOI value was used in this study. This allows a comparison

between the tissue oxygen saturation values obtained by spatial resolution (INVOS and

Foresight) and tissue oxygen saturation values obtained by spatially resolved spectroscopy

(NIRO).

We chose to perform the measurements on the forearm because physiologically the forearm is

a predominant place for vasoconstriction in case of circulatory distress. So the vascular

response will be altered sooner and more intensely.8

In our study we used a VOT with a fixed time occlusion of 3 minutes. Several studies have

claimed it is better to occlude until a certain threshold is reached (mostly 40%), while others

claim a 3 min fixed time is better because then the induced stimulus is the same for

everybody. Still no consensus has been reached regarding this issue.

3.4 Missing values

Data of 7 people was missing for Foresight, of 2 people for INVOS and of 1 person for NIRO.

9

3.5 Selected parameters of microvascular reactivity (see Fig 2)

Several parameters of microvascular reactivity can be determined. Following parameters

where selected for this study:

(1) Baseline StO2 (%)

(2) Downslope (M1), desaturation rate (%/min) during first 60 seconds

(3) Downslope, desaturation rate (%/min) from baseline until nadir

(4) Minimum StO2 (%)

(5) Rise time (sec) = time from cuff release to maximum value

(6) Maximum StO2 (%)

(7) Upslope, resaturation rate (%/min) from minimum until maximum value

(8) Settling time (sec) = time from cuff release to second time baseline

Fig 2. Graphic presentation of parameters of microvascular reactivity

These 8 parameters give an insight in the microvascular reactivity of the peripheral tissues at

the time of the vascular occlusion test. The baseline, minimum and maximum values can be

considered as static parameters, the five other parameters as dynamic parameters because they

are time-related. The downslope in the ischemic phase has a biphasic pattern. The initial

desaturation rate is lineair, but after the tissue oxygen level decreases to about 50 %, the slope

often changes and becomes non-lineair. Measuring the first fraction of change of desaturation

10

rate reduces bias by the non-lineair part of the slope.9 For this reason the downslope during

the first minute was included in the analysis. The desaturation rate is a measure for the

oxygen consumption rate and local metabolic demand, while the upslope and rise time are

measures of the endothelial function (arteriolar and capillary recruitment) and the hyperemic

response is a measure for the vascular reserve.4 The hyperemic response is dependent of the

capillary integrity, the local blood volume, the local vasomotor tone, the perfusion pressure,

StO2 and total Hb. A comparison of the PORH parameters revealed that the time parameters

of reactive hyperemia most clearly distinguish between the group of patients with peripheral

vascular disease and the group of healthy volunteers and correlate best with the values of the

ankle-brachial index and transcutaneous tissue oxygenation.6,10 For this reason, and because

of the high intra-individual variability as shown in a study by Gomez et al11, the area under

the curve (AUC) was not included in the analysis.

3.7 Statistics

Statistical analysis was performed using the statistical software SPSS Statistics 22 (SPSS Inc.,

Chicago, IL). The raw data were tested for normality using the Shapiro-Wilk test and were

considered normally distributed if p > 0.05. The non-parametric data are presented as median

[IQR]. Comparisons between devices were performed with the Kruskal-Wallis test. Pairwise

differences among devices were examined for significance by using the Mann-Whitney U

test. The level of statistical significance was set at corrected 2-sided p-value <0.05.

4. RESULTS

4.1 Comparison of the static parameters between the 3 devices

Table 1. Results of comparison of the static parameters (values presented as median [IQR])

Foresight Elite INVOS 5100C NIRO 200-NX

Baseline StO2 (%) 70 [65-73] 66 [61-73] 69 [65-73]

Minimum StO2 (%) 45 [40-51] 36 [21-48]* 46 [36-51]

Maximum StO2 (%) 81 [78-87] 82 [77-86] 79 [75-82]*

* p<0.05 vs. the two other devices

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Figure 3. Results of comparison of the static parameters (values presented in %)

Values by Foresight are in blue, by INVOS in green and by NIRO in grey (presented in that order from left to

right). The boxes represent the interquartile ranges, the whiskers the range and the horizontal bar the median.

Outliers are marked by colored dots.

The Kruskal-Wallis test demonstrated no difference in the baseline StO2 values between the 3

devices. During the vascular occlusion test a significant difference was observed between

INVOS and NIRO for both minimum and maximum values (p=0.012 and p=0.034,

respectively), and between INVOS and Foresight for the minimum value (p=0.001). Foresight

and NIRO differed for the maximum value (p=0.022).

4.2 Comparison of dynamic parameters between the 3 devices

Table 2. Results of comparison of dynamic parameters (values presented as median [IQR])

Foresight Elite INVOS 5100C NIRO 200-NX

Downslope(M1) (%/min) 11 [6-15] 17 [13-24]* 12 [7-16]

Downslope (%/min) 11 [8-13] 15 [11-21]* 12 [9-15]

Rise time (sec) 40 [28-50]* 25 [23-35] 27 [21-31]

Upslope (%/min) 114 [65-199]* 311 [92-523]* 202 [88-269]*

Settling time (sec) 226 [181-266]* 181 [146-223] 187 [127-248]

* p<0.05 vs. the two other devices (results obtained with Kruskal-Wallis test)

12

Fig. 4 Results of comparison of the desaturation rates (values given in %/min)

Fig. 5 Results of comparison of the time parameters during reperfusion (values given in sec)

Values by Foresight are in blue, by INVOS in green and by NIRO in grey (presented in that order from left to

right). The boxes represent the interquartile ranges, the whiskers the range and the horizontal bar the median.

Outliers are marked by colored dots and *.

13

The results from pairwise comparisons among devices with the Mann-Whitney-U test are

shown in table 3:

Table 3. Pairwise comparison of the dynamic parameters (values given are p-values)

ISCHEMIA REPERFUSION

Downslope(M1) Downslope Rise time Upslope Settling time

Foresight vs

NIRO 0,361 0,208

0,001* 0,040* 0,020*

Foresight vs

INVOS 0,001* 0,001*

0,003* 0,001* 0,002*

INVOS vs

NIRO 0,002* 0,006*

0,513 0,024* 0,668

* p< 0,05

The Kruskal-Wallis test showed that there are significant differences in all 5 dynamic

parameters obtained by the 3 different NIRS devices. After pairwise comparison, it became

clear that INVOS had significantly higher desaturation rates in general and in the first minute

compared to Foresight and NIRO. Also the resaturation rate differed significantly between all

three devices, the fastest resaturation rate was seen with INVOS, the slowest with Foresight.

Foresight had significantly slower rise and settling times than NIRO and INVOS.

Interestingly, the upslope differed significantly between INVOS and NIRO, but the time-

related (rise time and settling time) parameters were similar.

Comparing Foresight with NIRO showed similar parameters during ischemia but significantly

different parameters during reperfusion. Foresight and INVOS differed significantly for all

five dynamic parameters.

No clear-cut difference between the values given by NIRO, using the SRS technique, and the

two other devices, using the spatial resolution technique, can be made. NIRO values differ

significantly from INVOS during ischemia, but not from Foresight, while vice versa is true

during reperfusion. Since no real reference value exists for StO2, it is not possible to state if

one technique is more valid than the other.

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5. DISCUSSION

5.1 Important findings

This study is the first study directly comparing these three NIRS devices for the measurement

of microvascular reactivity in peripheral tissues during a vascular occlusion test. When

comparing different NIRS devices, three parameters are of importance: the absolute StO2

values during the resting state, the changes in StO2 when oxygenation is altered and the

repeatability, i.e. the similarity of repeated measurements. In our study no significant

differences were found at baseline, but analysis of different parameters of microvascular

reactivity shows that different information is retrieved depending on the NIRS device used.

Repeatability was not tested in this study. So, measures of microvascular reactivity obtained

with different NIRS devices don’t seem to correlate significantly to each other.

As stated in the introduction, there are multiple possible reasons for this observation. The

NIRS devices differ significantly in applied computational algorithms to derive the oxygen

saturation values. Also, penetration depth differs depending on the wavelength and intensity

of the emitted light, the sensitivity of the light detector and the spacing between the light

emitter and light detectors. For example, the fact that INVOS has significantly lower

minimum values and significantly higher maximum values than NIRO, while both devices

have similar time parameters during reperfusion, is most likely a consequence of a difference

in sensitivity between both devices.12 The actual sources of device differences remain to be

elucidated and would probably require access to the raw optical data and exact algorithms and

calibrations which are now kept secret by the different companies. Indeed, every company

makes assumptions regarding the wavelength dependence of scattering that is necessary to

derive the spectral shape of absorption coefficient and thereby deduce StO2. These

assumptions in combination with assumptions about the water content and the different light

emitter and detector geometry probably account for the differences between devices.

5.2 Comparison with previous studies

Most previous studies have used NIRS devices for measuring cerebral tissue oxygenation,

while only a few have used them for measuring peripheral tissue oxygenation. Numerous

other studies have used NIRS devices for measurement of cerebral and peripheral tissue

oxygenation in neonates during the transition period.

15

It is uncertain how results from cerebral measurements can be applied for interpreting

peripheral measurements, because in cerebral oximetry a large variation in reading errors

between subjects is seen, with the mean bias possibly related to variations in the ratio of

arterial and venous blood in the sampling area of the brain. This ratio is probably not fixed, as

assumed by the manufacturers, but dynamically changes with hypoxia. In peripheral

measurements, the A/V ratio is more or less fixed.13-16

Another issue is the influence of extracranial contamination on the cerebral oxygenation

values measured, which has been the subject of multiple studies .8,13,14,17 This also made

possible interference of skin oxygenation on the measurement of peripheral tissue

oxygenation a paradigm on which a couple of studies have laid their focus.19,20 The results of

these studies remain conflicting. Most studies do seem to show that the SRS technique, used

by NIRO to derive the TOI value, more effectively rejects artifacts from superficial

hemodynamic changes in cutaneous microcirculation than the spatial resolution technique.19,21

The results from studies on neonates also cannot simply be extrapolated to be compared with

the results of peripheral tissue oxygenation measurements in adults because the use of

neonatal sensors and a different calibration algorithm influence the results.

Finally, the lack of standardization of the VOT leads to great difficulties when trying to

compare results from different studies.4 The length of occlusion time (fixed time or until

preset threshold), the place of vascular occlusion, the type of sensor used, the type of study

population (healthy volunteers vs patients with significant co-morbidities) and site of

measurements differ greatly among the different studies. It has been proven that

measurements depend strongly on the site, sensors and probes used. For example, a study by

Bezemer et al shows that the reperfusion upslope is greater when 25 mm probes are used vs

15 mm probes and is also greater when measured at the thenar muscle compared to the

forearm.10 INVOS values measured with pediatric or neonatal sensors are about 10% higher

than when adult sensors are used due to different calibration and different algorithm.22 The

results after a VOT also show a great intra-individual variability of the values in stable

conditions. The intra-subject variability can vary up to 14% points and responses to VOT

differ over time in the same patient.9 Needless to say, using a standardized VOT and using

agreed upon sensors is paramount for better comparability of future studies.

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As stated above, this study is the first study directly comparing these three devices for the

measurement of microvascular reactivity in peripheral tissues during a vascular occlusion test.

A few other studies have compared two of these three devices or have compared one of these

three devices to other devices.

A study by Hyttel et al compared INVOS, Foresight and Equanox in a similar fashion to our

study. His results regarding the comparison between INVOS and Foresight were dissimilar to

ours showing a significant difference in baseline values between the two devices, no

significant difference in desaturation downslope and a significant difference in post-cuff

release maximum values.23 A possible explanation for this discrepancy is that the

measurements were done on young healthy adults compared to adults scheduled for CABG in

our study. Or maybe, the difference is due to the difference between values given by

Foresight and the values given by Foresight Elite. His conclusion, on the other hand, was the

same as ours, values of peripheral tissue oxygenation on the forearm from the three different

devices cannot be used interchangeably.

Another study by Hyttel et al compared the mean values of regional tissue oxygenation, the

reproducibility and dynamic range of four NIRS-instruments (INVOS 5100, NIRO 200NX,

NIRO 300 and Oxyprem) on the human forearm.24 The baseline values between INVOS and

NIRO 200 NX were similar (like in our study), as were the reproducibility (not tested in our

study) and the dynamic range (mixed results in our study). The VOT though was combined

with exercise, so that differs from our study.

A study by Lee et al compared INVOS and Inspectra for the measurement of tissue

oxygenation during a VOT in healthy volunteers.22 The Inspectra model 325 is a NIRS device

specifically designed for peripheral measurements only. The study showed that both devices

give significantly different baseline values, deoxygenation rates, reoxygenation rates and

hyperemia values. Compared the our study, baseline values by INVOS were higher as were

the maximum values post-cuff release. The desaturation and resaturation rates on the other

hand were similar to our study.

A study by Fellahi et al. compared INVOS and Equanox for peripheral oximetry in healthy

volunteers and came to the conclusion that both devices are not comparable for measuring

both absolute and dynamic changes of peripheral StO2 and NIRS-derived parameters during

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VOT’s.25 The measurements by INVOS differed from our study showing higher baseline

values. Of course, an obvious explanation could be the study population: healthy volunteers

vs pre-CABG patients.

To date, no studies have compared Foresight and NIRO with regard to peripheral tissue

oxygenation measuring.

The observation that INVOS has significantly higher desaturation rates and significantly

lower values at lower tissue oxygenation levels than Foresight and NIRO has been reported

before.22 These results seem to imply that INVOS has the highest sensitivity for changes in

oxygenation of all 3 devices.

Although we did not check the repeatability of the measurements in this study, several other

studies have. They tend to show better repeatability for Foresight and NIRO compared to

INVOS.12,23 So the high sensitivity of INVOS seems to come at the expense of good

repeatability.

Either INVOS data show a greater variability due to less accurate measurement technology, or

alternatively, Foresight and NIRO data show less variability because of a more pronounced

signal attenuation technology, providing tissue oxygenation values that do not as readily

reflect true physiological changes. Clearly, more studies are needed to clarify this issue.

5.3 Clinical relevance

With NIRS technology, the standardization process still has to be initiated, and we are

currently confronted with a wide variety of devices measuring regional tissue oxygen

saturation by using (two to five) different wavelengths, and they come with multiple shaped

optodes or sensors intended to be used at different anatomic regions (forehead, thenar

eminence, somatic organs, muscle etc.). There are several clinical implications and

consequences when it comes to choosing a particular NIRS device: when NIRS oximetry is

intended to be used for trend monitoring, the repeatability of measurement is less important. If

the sensitivity of a NIRS device to changes in hemoglobin oxygen saturation is low, the risk

of undetected true hypoxia will be high. However, if NIRS is to be used as a spot

measurement (e.g. in the emergency room) or if the monitoring is started when the patient

status is uncertain (e.g. in the ICU in a deteriorating patient without having a baseline value),

18

a good repeatability of measurement or a close proximity to absolute (true) values becomes

more important. Since high sensitivity comes at the expense of good repeatability, a

pragmatic approach would be to care less about the closeness to the ‘true’ values, but to settle

for the device with the best combination of repeatability and sensitivity to changing

oxygenation.26

An important paradigm is that no monitoring device, however insightful its data, can improve

patient-centered outcomes, unless it is coupled to a treatment which itself improves

outcome.27 In this regard, a few studies have examined whether tissue oxygenation values can

be used as a target for goal-directed therapy in high-risk surgery. A pilot study by Van Beest

et al. is an example of one such studies and they hypothesized that intraoperative optimization

of StO2 by a perioperative treatment protocol can improve tissue perfusion and thus reduce

postoperative complications.28 The treatment protocol involved starting a dobutamine infusion

when the tissue saturation dropped below 80 %. The conclusion of the study was that no

statistically significant difference in outcome was realized through intraoperative optimization

of StO2 values. Further research is obligatory to define both the optimal StO2 threshold and

intervention to treat tissue hypoperfusion. And as has become clear from this study, each

NIRS device will need a customized treatment protocol.

6. CONCLUSION

Using NIRS for peripheral tissue oxygenation measurements leaves us with 4 main problems:

1) Since no real reference value exists for StO2, it is not possible to state if one monitor is

more valid than another.

2) The accuracy of quantitative data by NIRS is limited by inaccuracies in the estimation

of optical path length for light transmitted through tissue. Until real time path length

measurements are incorporated, relative changes will form the basis of NIRS.

3) There are significant differences in absolute values and dynamic measurements

between different devices (as shown in this and other studies)

4) There is a large intra- and inter-individual variability and a variable repeatability.

Further development of the technology to improve the precision and reproducibility, while

maintaining good sensitivity seems paramount. In the future, using a standardized VOT and

using agreed upon sensors is indicated. Further research is obligatory to define both the

optimal StO2 threshold and interventions to treat tissue hypoperfusion.

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Vergelijking tussen drie NIRS toestellen voor het meten van microvasculaire reactiviteit

Dr Kevin Steenhaut, Prof dr. Stefan De Hert, Prof. dr. Anneliese Moerman

Universiteit Gent, Afdeling anesthesie en reanimatie, Gent, België

Achtergrond en doelstelling

Nabije-infrarood spectroscopie (NIRS) wordt in toenemende mate erkent als een methode om

niet-invasief de microvasculaire reactiviteit in weefsels te bepalen. NIRS laat toe om

endotheel-gemedieerde veranderingen in vasculaire tonus, die optreden na een periode van

ischemie, te kwantificeren. Veranderingen in microvasculaire reactiviteit zijn geassocieerd

met gestoorde weefseloxygenatie en orgaandysfunctie. Bepaling van de microvasculaire

reactiviteit kan dus belangrijke informatie opleveren over de status van de weefseloxygenatie,

de ernst van de aandoening en de effecten van de toegepaste behandelingen. Het meten van de

weefseloxygenatie in rust laat niet toe hypoperfusie op te sporen, daarvoor is een vasculaire

occlusie test nodig.

Er komen steeds meer en meer NIRS toestellen op de markt en de mate waarin deze

verschillende toestellen gelijkaardige informatie opleveren, blijft onduidelijk. De doelstelling

van deze studie is om metingen van veranderingen in weefseloxygenatie tijdens een

vasculaire occlusie test door drie verschillende NIRS toestellen met elkaar te vergelijken.

Onze hypothese is dat deze metingen gelijkaardig zijn.

Methodiek

Veertig volwassenen die gepland waren om een electieve CABG te ondergaan, werden

geïncludeerd. Alle patiënten gaven hun toestemming tot deelname aan de studie door middel

van informed consent. Een sensor van elk NIRS toestel (INVOS 5100C; Foresight Elite en

NIRO-200NX) werd op de linker voorarm over de musculus brachioradialis aangebracht. Een

standaard bloeddrukmeter werd op de linker bovenarm aangebracht en werd opgeblazen tot

een druk van 50 mmHg boven de systolische bloeddruk van de patiënt. Na een ischemieduur

van 3 minuten werd de druk snel gelost. Volgende parameters van microvasculaire reactiviteit

werden bepaald voor verdere analyse: de waarde in rust, de snelheid van desaturatie in de

eerste minuut en over 3 minuten, de minimumwaarde, de snelheid van resaturatie, de bereikte

maximumwaarde, de tijd tussen lossen van de druk en bereiken van de maximum waarde en

de tijd tussen het lossen van de druk en het opnieuw stabiliseren rond de rustwaarde.

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De verschillende metingen werden met elkaar vergeleken door middel van de Kruskal-Wallis

test. Het bestaan van significante verschillen tussen twee van de drie toestellen werd

onderzocht met de Mann-Whitney U test.

Resultaten en discussie

Er waren geen significante verschillen in rust. Analyse van de veranderingen in

weefseloxygenatie tijdens de vasculaire occlusie test toonde aan dat er voor alle parameters

significante verschillen zijn tussen ten minste twee van de drie NIRS toestellen. Mogelijke

verklaringen hiervoor zijn het feit dat elk NIRS toestel een ander algoritme gebruikt voor zijn

metingen. Ook de sensoren van de verschillende NIRS toestellen hebben andere kenmerken.

Aangezien er op dit moment geen gouden standaard bestaat voor het bepalen van de

oxygenatie in weefsels, is het onmogelijk om te achterhalen welk NIRS toestel de meest

correcte metingen uitvoert.

Conclusie

Ondanks het feit dat er geen significante verschillen gevonden werden in rusttoestand, toont

de analyse aan dat er wel significante verschillen zijn tussen de drie NIRS toestellen wanneer

de weefseloxygenatie verandert. Bij het gebruik van NIRS toestellen moet hier steeds

rekening mee gehouden worden. Technische progressie in de NIRS technologie is nodig om

meer betrouwbare en meer correcte resultaten te bekomen.