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Clinical Hemorheology and Microcirculation 38 (2008) 31–44 31 

IOS Press 

Contrast harmonic ultrasound and 

indocyanine-green fluorescence video 

angiography for evaluation of dermal and 

subdermal microcirculation in free 

parascapular flaps 

L. Prantl a,∗ , St. Schmitt a ,S.Gais a ,T.Y.Tsui a ,P.Lamby a , P. Babilas a , M. Nerlich a , 

R. Kubale c ,N.Zorger b ,T.Herold b , S. Feuerbach b and E.M. Jung b 

a Institute of Trauma, Plastic and Reconstructive Surgery, University Hospital Regensburg, Germany 

b Institute of Diagnostic Radiology, University Hospital Regensburg, Germany 

c Institute of Radiology, Nuclear Medicine and Sonography, Hospital Pirmasens, Germany 

Abstract. Purpose: Contrast harmonic ultrasound (CHI) with a linear transducer is a new diagnostic approach that allows dynamic 

and quantitative flow detection of tissue perfusion in microsurgery. The aim of the study was the evaluation of perfusion of 

the dermal and subdermal layers of microvascular tissue transplants with CHI in comparison to ICG-fluorescence angiography. 

Material and method: In a prospective clinical study indocyanine-green fluorescence video angiography and contrast enhanced 

high resolution ultrasound (5–10 MHz; linear transducer; Logiq 9; GE) were used for evaluation of the microcirculation in 10 

transplanted free parascapular flaps. Two regions were analysed, the centre of the flap and the region of the anastomosis. The 

perfusion patterns of both methods were compared. Results: The perfusion indexes measured by ICG-fluorescence angiography 

correlated very precisely in all patients with the quantitative perfusion curves of contrast-enhanced US with CHI. Two flaps 

with slow filling and low dye intensity showed low contrast enhancement in CHI with modified perfusion curves with slow 

increase. In two cases a reduced perfusion and filling were found. There were no statistical differences between the two diagnostic 

methods (p >0.01). Conclusion: CHI improves US detections of dermal and subdermal microcirculation in comparison 

to ICG fluorescence angiography. CHI is a new diagnostic method for postoperative monitoring of free flaps. 

1. Introduction 

With the development of high-resolution digital ultrasound technology with contrast-enhanced harmonic 

imaging (CHI) the evaluation of tissue perfusion improves [1,2]. Especially with low MI technique 

with pulse inversion harmonic imaging a dynamic evaluation of tumor vascularisation and perfusion 

of liver tumors is possible [3,4]. Thus tumorcharacterisation has become much more precise. With 

increasing availability of ultrasound contrast-enhanced harmonic imaging (CHI) application and comparison 

amplifies. Therefore the importance of tissue perfusion for evaluation of other organ and soft 

* Corresponding author: Dr. Lukas Prantl, MD, Department of Plastic Surgery, Regensburg University, Franz-Josef-Strauss- 

Allee 11, 93053 Regensburg, Germany. Tel.: +49 941 944 6947; Fax: +49 941 944 6806; E-mail: lukas.prantl@klinik.uniregensburg.de. 

1386-0291/08/$17.00 © 2008 – IOS Press and the authors. All rights reserved

32 L. Prantl et al. / Video angiography for evaluation of dermal and subdermal microcirculation 

tissue tumors and control of therapy increases [5,6]. Application includes also the evaluation of tissue 

perfusion through the skull. 

The evaluation of microcirculation of soft tissue, especially of the cutaneous and subcutaneous layers 

bears the challenge for high resolution dynamic speckle reduction imaging (SRI) [7–9]. 

A combination of contrast-enhanced harmonic imaging with the possibility of differentiated tissue 

imaging in B scan modus and the evaluation of perfusion by microbubbles in low MI technique imaging 

is needed. A parallel imaging of dynamic B scan modus and contrast-enhanced speckle reduction 

imaging (SRI) is of special importance. These techniques can than be used for comparison of soft tissue 

perfusion with ICG-fluorescence angiography [4,10–19]. 

An early detection of insufficiently perfused skin that will undergo necrosis is highly desirable since 

it may lead to surgical decisions such as immediate flap revision to restore the blood flow or early 

resection of the necrosis. It is proved, that a reliable method to quantify perfusion and predict flap 

necrosis improves quality of treatment, shows lower morbidity and reduces costs and hospital length of 

stay [17]. Clinical tests of flap temperature, turgor and color, capillary refill, bleeding time are frequently 

used [20]. However, these clinical tests are not reliable for monitoring buried, nonvisible flaps and muscle 

flaps. Furthermore judgement depends on experience of the investigator. Mostly these signs appear to 

late, so revision of the free flap can be already too late at that time. 

Other monitoring techniques include Doppler ultrasound, electrical impedance plethysmography, 

99 mTc sestamibiscintigraphy, fluorescein angiography, laser Doppler, photoplethysmography, pulse 

oximetry, temperature monitoring, tissue pH, transcutaneous oxygen monitoring, implantable Doppler 

monitoring and muscle contractility tests. None of these techniques have become generally accepted as 

standard method for monitoring free flaps [1,20–27]. 

The aim of this study was to evaluate dynamic contrast-enhanced ultrasound imaging of true agent 

detection, a new method of pulse inversion harmonic imaging (PIHI) to detect perfusion of dermal and 

subdermal layers of microvascular grafts. The results were compared to perfusion patterns of laserinduced 

indocyanine-green fluorescence video angiography (ICG-FA). 

2. Patients and methods 

2.1. Methods 

Ten patients (male : female = 8 : 2, mean age of 43 ± 17 years, average BMI of 26 ± 3) with free 

parascapular flaps to cover tissue defects of the lower limb were examined after tissue transfer. Pregnant 

women, patients with liver failure and patients with history of allergic reactions to ICG or iodide were 

excluded from the study. All free tissue transfers were performed by one experienced attending surgeon. 

The size of the soft-tissue defects before flap coverage ranged from 7 × 3cmto30× 12 cm (mean: 

17.8 ± 6.6 cm × 7.3 ± 2.5 cm) and flap size ranged from 8 × 4cmto30× 13 cm (20.4 ± 6.6 cm × 

8.9 ± 2.6 cm). The microvascular anastomoses were performed using high-power magnifying glasses. 

Flaps were connected to the posterior tibial artery by end-to-end anastomosis in seven patients and 

by end-to-side anastomosis in one patient. Two flaps were connected to the dorsalis pedis artery by 

end-to-end anastomosis. Two veins were anastomosed in all patients. 

The perfusion of the flap was examined by dynamic contrast-enhanced ultrasound imaging and by 

laser-induced indocyanine green (ICG)-fluorescence angiography. Sensitivity and prognostic value of

L. Prantl et al. / Video angiography for evaluation of dermal and subdermal microcirculation 33 

dynamic contrast-enhanced ultrasound imaging was compared with laser-induced fluorescence angiography 

with indocyanine-green (ICG-FA) and with clinical parameters (turgor, temperature, reperfusion 

time). The approval of the Medical Ethics Committee was obtained prior to the study. 

Indocyanine green is a water-soluble tricarbocyanine dye (775 g/mol) that was first approved for clinical 

use in humans in 1956 [28,29]. After intravenous injection ICG, is bound to plasma proteins and in 

80% to globulins, mainly α-lipoproteins (MW 200 kDa). Thus, it is confined to the intravascular space 

with minimal leakage from abnormal or fenestrated vessels. Under physiological conditions ICG is eliminated 

from the blood exclusively via the liver and excreted chemically unchanged into the bile. Half life 

is approximately 3 min and there is no entero-hepatic circulation. Due to its fast pharmacokinetics, ICG 

allows administration and light irradiation in one session. Owing these characteristics, ICG is clinically 

approved for determination of liver function [30], plasma volume [31] and cardiac output [32]. 

In human plasma, the absorption spectrum exhibits a strong band between 600 and 900 nm which 

is far beyond the absorption maximum of hemoglobin and melanin and which is coincident with the 

emission wavelength of a near infrared laser (780 nm) providing a maximal penetration of light into 

tissue (approx. 3 mm). Thus ICG localized in the microvasculature can be used as parameter for the 

microcirculation [17–19]. 

ICG (Pulsion Medical Systems AG, Munich, Germany) was dissolved in an aqueous solvent (pH 

7.4) at a concentration of 0.75 mg/ml and immediately applied intravenously as bolus (0.5 mg kg −1 

b.w.). Immediately after administration the chromophore was activated using a near-infrared-laser device 

(λem = 780 nm, fluence dose: 0.16 W) that is part of the IC-View ® -System (Pulsion Medical Systems, 

Munich, Germany). The fluorescence was detected in real time with the aid of a camcorder and the 

appropriate filter set (IC-View ® -System, Pulsion Medical Systems, Munich, Germany). Measurements 

were made at a distance of 30–100 cm from the tissue of interest. This form of laser exposure does not 

damage local tissue, since the energy absorbed is far below damage threshold of the skin. 

A fluorescence standard was added in each measurement. The experiments were performed in darkness. 

The analysis of the data was performed with the aid of the IC-Calc ® -Software. For each patient 

different regions of interest were defined: the area of the anastomosis (ROI1) and the center of the flap 

(ROI2). Both were compared to normally perfused surrounding tissue (ROI3) as reference and adjusted 

to a constant. The maximum fluorescence intensity as well as the relative perfusion index was calculated. 

The increase (or decrease) of intensity was plotted as a graph. The slope of the graph can be correlated 

with the perfusion index and is therefore a parameter for the arterial perfusion. 

The evaluation of hemodynamic flow parameters of transanastomotic blood circulation of microvascular 

flap grafts was made with color coded Doppler sonography (CCDS) in comparison to the blood 

circulation of the communal femoral artery, the superficial femoral artery, the polpiteal artery and the 

tibial artery, which was used for the anastomosis, the posterior tibial artery in 8 cases, the anterior tibial 

artery in 2 cases. 

Patients where examined in resting position after a minimum of 20 min of recovery under control of 

temperature. All ultrasound investigations were performed by an examiner experienced in ultrasound 

diagnostics with a multi-frequency linear transducer (5–10 MHz, Logiq 9, GE). Flow evaluation was 

angle-optimized using digital image technology in the DICOM format with the CCDS and automatic 

spectral analysis with measurement of the maximum systolic and diastolic flow velocities, the resistance 

index (RI), the pulsatility index (PI), as well as the vessel diameter (D) and blood flow volume. 

Measured data were averaged over at least 3 flow-spectra. In view of the smaller distal vessel diameter, 

hemodynamic flow detection was performed depending of reduced flow velocity with adapted low pulse 

repetition velocity (PRF) and wall filter (WF) and increased color and Doppler gain.


To determine perfusion, a contrast-enhanced investigation with Contrast Harmonic Imaging (CHI) was 

performed in pulse inversion mode (PIHI). Written patient consent and the permission of the ethic commission 

of the hospital had been given. Allergic diathesis, incompatibility reactions to contrast medium, 

a severe hart disease and the restriction of kidney function were considered as exclusion criteria for a 

maximum bolus injection of 5 ml ultrasound contrast agent (Sonovue ® , Bracco). Through a peripheral 

cubital cannula, a first bolus injection was made of 2.5 ml Sonovue ® with subsequent injection of 10 ml 

NaCl to evaluate the perfusion near the anastomosis and the microcirculation in a strictly defined skin 

area, which was situated over temperature sensors. With a further bolus injection of 2.5 ml Sonovue ® , 

the perfusion and microcirculation were evaluated in a defined area in the flap center. The perfusion was 

recorded in each case in dynamic digital image sequences over 30 s in each case. Grey scale parameters, 

penetration depth and focus zones remained unchanged. 

In a special double image investigation mode, the fundamental B scan morphology of the microvascular 

flap could be appraised at the same time and the most intense dynamic flap perfusion was 

established in the subtraction mode of the PIHI (true agent detection mode, Logiq 9, GE). Based on 

these digital dynamic graphic data, the perfusion curves were then evaluated retrospectively. It was 

possible to determine maximum contrast enhancement, inflow time, time of the maximum signal rise 

and the area of the entire perfusion curve (area under the curve) using automatic analysis tools. Three 

defined circular measurement zones were positioned in the free flap up to 1 cm starting from the cutis. 

The perfusion over real time detected by means of low MI technology, with a mechanical index (MI) of 

0.15 with representation in curve form due to the averaged individual measurements was then recorded 

automatically via the integrated workstation (Logiq Works, Logic 9, GE). 

All statistical tests were performed using SPSS (Statistical Package for the Social Sciences, Chicago, 

IL, USA). Analysis of correlation between the different hemodynamic flow parameters was performed 

using the McNemar Test. In this process digital raw data comprehend Grey scale parameters up to 500 

single data, consisting of detection of three defined perfusion areal. 

3. Results 

Hemodynamic flow parameters of the thigh, the micro-vascular flap applied to the lower leg artery 

and the location of the anastomosis were determined successfully by CCDS in all 10/10 cases. Clear 

effects on blood circulation in the region of anastomosis of maximum systolic and end-diastolic flow 

velocity of the common femoral artery and the popliteal artery, as well as in particular the flow velocities 

of the appropriate lower leg arteries were visible. The volumetric flow rate of the anastomosis was 

affected by circulation parameters and vessel diameter. Under reduced flow with a maximum systolic 

velocity < 30 cm/s and end-diastolic velocity < 10 cm/s of the lower leg arteries, there was a reduction 

of the volumetric flow rate in the anastomosis of up to 8.9 ml/min. 

After obtaining written consent and considering possible contraindications, contrast-enhanced US diagnostics 

for measuring perfusion could be evaluated in 10 cases. A successful dynamic evaluation of 

flap perfusion was possible with a bolus injection of 2.5 ml ultrasound contrast agent (Sonovue ® ). No 

side effects attributable to a contrast medium allergy where found. 

Pulse Inversion Imaging (PIHI) with the special modality of True Agent Detection Imaging showed 

the dynamic flap perfusion from the superficial dermal and subdermal layer in all 10/10 cases examined 

with the high solution linear scan without advanced distance. The dynamic double image representation 

of B scan images and the subtracted contrast-enhanced PIHI (true agent detection modality) sequences


facilitated dynamic analysis of the microcirculation in all 10/10 cases. With quantitative computerized 

perfusion analysis it was possible to represent the deep-dependent tissue perfusion as a curve. In addition 

it was possible to plot the microcirculation as curve by using the perfusion data resulting from the noted 

digital image sequences. 

Immediately after the bolus injection of ultrasound contrast medium, a clear perfusion could already 

be recognized in the dermal, subdermal and subcutaneous layers of all 10 cases examined. A reduced 

maximum velocity (2/10 cases) or clearly reduced volume flow in the area of the anastomosis (2/10 

cases) corresponded to a reduced tissue perfusion in accord with diminished rise in the curve of the 

dermal and subdermal perfusion. Comparable tissue perfusions were seen both within the area of the 

anastomosis and within the area of the marking of the center of the flap. 

Analysis of Grey scale digital raw data showed alteration after bolus injection of ultrasound contrast 

medium between 4 dB up to 10 dB, with an average of 3.5 dB over the first 30 s. Under clearly reduced 

flow there was a clearly prolongated rise of the perfusion curve of the digital raw data in all of the three 

continuous measured data, who showed signal changes of a maximum of 1.5 dB, in average 0.75 dB. 

In case of reduced tissue perfusion an early plateau in curve analysis with signal changes up to 2.5 dB 

with an average of 1.25 dB occurred. Additional analysis of tissue perfusion with corresponding curve 

analysis showed in 4 cases with reduced or clearly reduced tissue perfusion corresponding to the raw 

data a tissue perfusion after only 30–60 s, with an average of 45 sec. A strong perfusion of the dermal 

and subdermal layers showed signal changes after bolus injection which continued up to 2 min, with an 

average of 170 s. 

Based on digital dynamic graphic data of PIHI in all of 10 cases, it was possible to show dynamic flap 

perfusion and microcirculation of the flap with capillary perfusion. Using basic ultrasound procedures, 

this was not possible without contrast harmonic enhancement. 

Eight of the flaps showed clinically normal parameters (turgor, temperature, reperfusion time). The 

evaluation of the ICG-fluorescence angiography showed a mean perfusion index of 90 ± 7% in the two 

ROIs compared to reference skin. The perfusion index represents the speed of dye accumulation and is 

a measure of the quality of the arterial blood supply in that region. The average fluorescence maximum 

amounted to 92 ± 8% (Fig. 1). 

In our experiments the perfusion index correlated in eight patients almost precisely with the curve 

courses ascertained from the ultrasound data in the two well-chosen ROIs, in the centre of the flap 

and over the anastomosis. The quantitative evaluation of two patients showed slow filling and low dye 

intensity (Fig. 2). 

Table 1 shows the results of flap perfusion of the dermal and subdermal flap by CHI and ICGfluorescence 

angiography in comparison. No significant differences (p >0.01) were found between 

the two diagnostic methods in all 10/10 cases for characterization the perfusion of the anastomotic and 

central region of the free flaps (Figs 3–7). 

4. Discussion 

An early detection of flap failure caused by blood flow abnormalities (vascular thrombosis, compression, 

twisting) and an immediate reoperation to restore blood flow may prevent free flap failure. Recent 

advances in technology and improvements in surgical technique have led to reported success rates for 

flap salvage through early intervention in 33–57% of cases [1,17,18,20,22]. An ideal monitoring method 

should appraise the patency of microvascular anastomoses as well as the perfusion and microcirculation 

of flap tissue.


Fig. 1. Evaluation of the perfusion of the ICG-fluorescence angiography: (a) the free flap with the two ROIs (red: center of 

the flap, green: area of the anastomotic region); (b) perfusion in false-colours (red and yellow: high perfusion, green: medium, 

blue: low perfusion); (c) representation of the perfusion for the time: quick increase of the fluorescence and high fluorescence 

intensity. 

Fig. 2. Evaluation of the perfusion in a critical perfused free flap: (a) the free flaps with the two ROI’s (red: center of the 

flap, green: area of the anastomotic region); (b) perfusion in false-colours (green: medium perfusion, blue: low perfusion); 

(c) representation of the perfusion for the time: slow increase of the fluorescence and low fluorescence intensity.


Table 1 

Analysis of contrast enhanced perfusion with harmonic ultrasound imaging (CHI) and fluoroscopie (Flu) in 10 cases of free 

scapular flaps. A: anastomotic region, M: middle of the flap; (+) less enhancement and low perfusion; (++) good visualization 

of perfusion; (+++) early and high enhancement in dynamic sequences 

Anastomotic region of the flap Middle of the flap Diagnostic modalities 

Patient 1 +++ +++ CHI 

[KI] +++ +++ Flu 


[CI] +++ +++ Flu 


[DÖ] ++ ++ Flu 


[0T] ++ ++ Flu 

Patient 5 ++ ++ CHI 

[Schn] ++ ++ Flu 

Patient 6 + + CHI 

[Schm] + + Flu 

Patient 7 + + CHI 

[Ge] + + Flu 

Patient 8 ++ ++ CHI 

[Schu] ++ ++ Flu 


[De] +++ +++ Flu 


[Ta] +++ +++ Flu 

Since ultrasound with CCDS has good general availability, it has become very important for evaluation 

of blood circulation in the lower leg and to measure the hemodynamic flow parameters of the anastomosis 

of a transplanted free flap. Using angle-optimized flow detection the evaluation of maximum systolic 

and diastolic flow velocities, the resistance index (PI), as well as the vessel diameter (D) and blood 

flow volume is possible. Angle-dependent flow representation with CCDS and examiner dependence is 

particular disadvantageous. 

Digital dynamic imaging technologies in combination with special subtraction techniques with contrast 

harmonic imaging (CHI) enables an evaluation of capillary perfusion. With the technology of pulse 

inversion harmonic imaging (PIHI) a maximum reinforcement of the harmonic imaging with microbubbles 

is attained after intravenous injection from ultrasonic contrast medium. Only the residual harmonic 

frequencies after subtraction of the echoes by pulses with inverse polarity are used. The evaluation of 

the flap perfusion is already possible with a bolus injection of 2.5 ml Sonovue ® . The new technology 

of true detection harmonic imaging visualizes the blood circulation within the epidermal, subcutaneous 

and epifascial layer. With simultaneous imaging of the dynamic gray scale images it is possible to assess 

the tissue architecture at any time. Evaluation of the flap margins and more precisely anastomosis is 

facilitated. 

The maximum contrast-enhancement, the steepness of slope and the area under the curve can enable 

an evaluation of the perfusion at different locations of a flap transplant. 

The ICG has been investigated in several studies and represents a sensitive diagnostic tool for detecting 

compromised tissue perfusion [17–19,30–33]. According to the study of Giunta et al. [17] the perfusion


Fig. 3. Perfusion of the flap with contrast enhancement detected by CHI after bolus injection of 2.5 ml Sonovue ® .InTIC 

analysis and by gray scale analysis changes of the echo signal were detected with a peak of the perfusion curve after 10–15 s.


Fig. 4. Perfusion of the flap with contrast enhancement detected by CHI after bolus injection of 2.5 ml Sonovue ® .TheTIC 

analysis and gray scale analysis show a early and strongly enhancement of the free flap in the anastomatic part.


Fig. 5. TIC-analysis: wash-in-curve. B: Baseline parameter. It should represent the data value at the time-of-arrival. A: The 

amplitude scale factor, it describes the peak at time t = infinity for wash in (that is were exp(−kt). If the curve is still rising 

at the end of the fit, the A value will be higher than the peak at the last frame. If the data has flattened out, the data amplitude 

at the user selected last frame will be approximately the same as the data amplitude at t = infinity, so the A value in the fit 

will accurate reflect the peak seen in the data. k: The exponential decay factor; k just tells it how fast that will happen. So a 

wash in curve uses 1 − exp(−kt), this expression starts at 0, and ends at 1 (times the scale factor A). MSE: The mean standard 

error, how much the real data at each time t is different from the value of the fit, F (t), at the same time t. MSE is equal to the 

standard deviation of the data set relative to the fit data values divided by the square root of the number of data points. 

index represents the most important parameter for flap viability. An index of less than 25% results in 

flap necrosis. According to the data of their study an index of 25% is both 100% sensitive and specific 

and is a reliable cut-off value. Indexes below should recommend surgical decision to either improve flap 

perfusion or resect the critical parts of the flap. The high accordance of the ICW data with the ultrasonic 

data in our study confirms the high value of this method for the evaluation of tissue perfusion. 

In order to prevent early destruction of the microbubbles, imaging with Sonovue ® takes place with a 

mechanical index from 0.1–0.15. Harmonic imaging based on the analysis of nonlinear tissue acoustic 

signals can also be implemented in the higher-frequency range. Detection of microvascular perfusion in 

high local resolution by means of contrast-enhanced ultrasound in nonlinear low MI technology becomes 

possible [28–30]. 

Special importance should be given the monitoring of arterial perfusion after bolus injection directly 

post-surgery. The development of new high resolution perfusion ultrasound-techniques enables to reduce 

the amount of contrast agent and therefore also a more effective and less expensive evaluation


Fig. 6. Reduced perfusion of the flap with slow enhancement detected by CHI after bolus injection of 2.5 ml Sonovue ® .InTIC 

analysis and by gray scale analysis less changes of the echo signal were detected with a slow peak of the perfusion curve.


Fig. 7. Perfusion of the free flap with contrast enhancement detected by CHI after bolus injection of 2.5 ml Sonovue ® .TIC 

analysis and gray scale analysis show a continuous signal rise during the first 25 s. 

method with the new technique of contrast harmonic imaging (CHI). Continuous collection of data over 

a minimum of 2 minutes needs a corresponding amount of memory, as well as perfusion analysis needs 

postprocessing of digital raw data. The essential limitation of ultrasound perfusion analysis is the shortness 

of operational availability at the moment. However presented results can be compared to other 

studies with perfusion analysis by other technologies. 

The are limitations of the study. Contrast harmonic imaging with a linear transducer is a new ultrasound 

technology and not available in all US departments and depends on the experience of the examiner.


For both methods injection of contrast agents with known risks are necessary. The ICG-fluorescence angiography 

is not established for free flap monitoring. No standard diagnostic reference method is defined. 

However in our study we could show a good correlation between the two methods. 

For evaluation of further flap areas a renewed injection of Sonovue ® is necessary, as there is a temporally 

restricted echo signal reinforcement after a bolus injection of 2.5 ml Sonovue ® . Besides the 

contraindications in relation to ultrasonic contrast agent, the need for repeated bolus injection is a limitation 

of the ultrasound contrast technology. However, in an early evaluation of a reduced perfusion of 

a free-flap transplant CHI improves detection of dermal and subdermal microcirculation in comparison 

with ICG-fluorescence angiography and detection of the capillary perfusion in relation to the MRA or 

intra-arterial DSA results. 

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