Effect of ephedrine on gastric conduit perfusion measured by laser speckle contrast imaging after esophagectomy: a prospective in vivo cohort study

Effect of ephedrine on gastric conduit perfusion measured by laser speckle contrast imaging after... SUMMARY Compromised perfusion due to ligation of arteries and veins in esophagectomy with gastric tube reconstruction often (5–20%) results in necrosis and anastomotic leakage, which relate to high morbidity and mortality (3–4%). Ephedrine is used widely in anesthesia to treat intraoperative hypotension and may improve perfusion by the increase of cardiac output and mean arterial pressure (MAP). This study tests the effect of ephedrine on perfusion of the future anastomotic site of the gastric conduit, measured by laser speckle contrast imaging (LSCI). This prospective, observational, in vivo pilot study includes 26 patients undergoing esophagectomy with gastric tube reconstruction from October 2015 to June 2016 in the Academic Medical Center (Amsterdam). Perfusion of the gastric conduit was measured with LSCI directly after reconstruction and after an increase of MAP by ephedrine 5 mg. Perfusion was quantified in flux (laser speckle perfusion units, LSPU) in four perfusion locations, from good perfusion (base of the gastric tube) toward decreased perfusion (fundus). Intrapatient differences before and after ephedrine in terms flux were statistically tested for significance with a paired t-test. LSCI was feasible to image gastric microcirculation in all patients. Flux (LSPU) was significantly higher in the base of the gastric tube (791 ± 442) compared to the fundus (328 ± 187) (P < 0.001). After administration of ephedrine, flux increased significantly in the fundus (P < 0.05) measured intrapatients. Three patients developed anastomotic leakage. In these patients, the difference between measured flux in the fundus compared to the base of the gastric tube was high. This study presents the effect of ephedrine on perfusion of the gastric tissue measured with LSCI in terms of flux (LSPU) after esophagectomy with gastric tube reconstruction. We show a small but significant difference between flux measured before and after administration of ephedrine in the future anastomotic tissue (313 ± 178 vs. 397 ± 290). We also show a significant decrease of flux toward the fundus. INTRODUCTION Ephedrine, a mixed acting agent with positive inotropic and chronotropic effects,1 is routinely used in anesthesia to increase cardiac output (CO) and mean arterial pressure (MAP) in case of intraoperative hypotension.2 The effect of ephedrine on localized perfusion is widely described in the brain and heart tissue.3,4 The sympathetic nervous system is positively influenced and therefore MAP and CO increases. Despite the inhibition of the parasympathetic system, resulting in vasoconstriction of the gastrointestinal arteries and a decreased splanchnic perfusion,2,3 we hypothesize that it can potentially lead to improved perfusion in the gastric conduit, in patients undergoing esophagectomy with gastric tube reconstruction. During surgery the left and short gastric arteries as well as the left gastroepiploic artery are ligated, which means that gastric tissue perfusion is mainly depending on the right gastroepiploic artery.5 The ligations additionally may result in vasoconstriction and capillary and venous congestion. This decreased gastric tissue perfusion, resulting in a lack of oxygen and nutrients and accumulation of metabolic waste, is seen as a major contributing factor for the development of anastomotic leakage.6 Anastomotic leakage leads to high rates of morbidity (leakage, stricture, 20%) and mortality (3–4%),6,7 and monitoring perfusion, in combination with, if needed, an intervention to increase perfusion, could therefore improve surgery outcomes. Laser speckle contrast imaging (LSCI) uses near-infrared laser light to image tissue perfusion in a wide field overview (15 × 20 cm2).8 Perfusion imaging with LSCI was validated in a phantom model.9 The photons that are backscattered from different tissue components will have path length differences, thereby inducing the characteristic interference (speckle) pattern on the camera. Movement of the tissue components, such as blood, will induce fluctuations in the speckle pattern. These fluctuations, which are related to the speed and the amount of the flowing blood, can be characterized either in time or spatially. In the former approach, the time variation is directly measured by the camera. In the latter approach, the speckle pattern will be blurred due to the movement of the blood during the integration time of the camera. The primary aim of this study is to test the feasibility of LSCI to image and measure perfusion during gastric tube reconstruction after esophagectomy. The so-called measured flux by LSCI is then quantified in laser speckle perfusion units (LSPU). The secondary aim of this study is to test the effect of ephedrine on the measured perfusion (flux) in the gastric conduit. Thereto, we will measure and compare perfusion in four different areas and we statistically test the difference of perfusion before and after ephedrine. MATERIALS AND METHODS The methodology of this prospective in vivo cohort study was based on the STROBE guideline10 and the STARD statement.11 During surgery, directly after reconstruction of the gastric tube, perfusion was imaged with LSCI and flux was determined at four perfusion areas, from the base of the gastric tube toward the fundus (from good to decreased perfusion) in LSPU. After imaging, 5 mg ephedrine was administered and perfusion was measured again. During data analysis, flux was measured in four different perfusion areas of the gastric conduit, from good to decreased perfusion. Flux before and after ephedrine was measured in all the four areas. Patients This study prospectively enrolled 26 consecutive patients with esophageal cancer who underwent an esophagectomy with gastric tube reconstruction in the Academic Medical Center (Amsterdam, The Netherlands) between October 2015 and June 2016. Surgery was executed by two expert upper gastrointestinal surgeons (M.I.B., S.S.G.). This study was approved by the Medical Ethics Committee (NL52377.018.15) of the Academic Medical Center of the University of Amsterdam, and submitted to the clinicaltrials.gov database (NCT02902549). Informed consent was obtained from all patients. Follow-up time was 3 months to assess adverse events and complication development. Surgical procedure Surgery was performed following the three-stage thoracolaparoscopic esophageal cardia resection and gastric tube reconstruction protocol (Ivor Lewis and McKeown approach). After mobilization of the esophagus and following intrathoracic and abdominal lymphadenectomy, ligation of the left gastric artery, part of the right gastric artery, the left epiploic artery, and the short gastric vessels are executed. After reconstruction, the perfusion of the gastric tube is depending on inflow from the right gastroepiploic artery and partly from the right gastric artery. The anesthesia procedure was standard in all patients. Induction was done with propofol, sufentanil, and rocuronium. Maintenance was done with sevoflurane and sufentanil. An epidural was standardly placed before induction. Standard hemodynamic management in our practice is to use goal-directed fluid management in these patients. During the operation, stroke volume was optimized, titrating with fluid boluses of 200 mL (colloids). Vasopressors were given if MAP < 65 mmHg. Noradrenalin was used as a standard for continuous infusion. Ephedrine 5 mg or phenylephrine 100 mcg was used as bolus medication. Related hemodynamic parameters in terms of MAP, cardiac index (CI), CO, stroke volume (SV), and peripheral capillary oxygen saturation, minute volume, fraction of inspired oxygen, tidal volume, and respiratory rate, and vasoactive medication at timing of monitoring were recorded in a clinical report form (CRF). Intraoperative perfusion imaging with LSCI Perfusion of the gastric tube was assessed directly after the reconstruction with the MoorFLPI-1 LSCI system (Moor Instruments, Devon, UK). A near-infrared laser light source of 785 nm illuminated the tissue from a distance of 40 cm (optimal work distance 26–40 cm) to image the gastric tube perfusion in a wide field (15 × 20 cm2) (Fig. 1). The speckle pattern of this light source will change by changes in the amount and motion of predominantly red blood cells within the field of view. Consequently, by measuring the speckle contrast, a measure of the perfusion of the images tissue can be determined. MoorFLPI-1 software (MoorFLPI-1 Measurement V3.0, Moor Instruments, Devon, UK) was used to create high-resolution images of this perfusion obtained for an integration time of 8.3 milliseconds. The system was calibrated before measurements were taken, as prescribed by the manufacturer. In short, a calibration block was used consisting of a container of motility standard which provides a flux reference and a static reflector which provides a zero reference. Measurements were taken 25 cm above the calibration block. Fig. 1 View largeDownload slide LSCI system (A), schematic figure (B) of gastric tube with field of view (15 × 20 cm2) of LSCI and color-coded LSCI-image with 4.2 milliseconds integration time with low perfusion units in blue at the fundus side, and high perfusion units in red at the base of the gastric tube (C). Fig. 1 View largeDownload slide LSCI system (A), schematic figure (B) of gastric tube with field of view (15 × 20 cm2) of LSCI and color-coded LSCI-image with 4.2 milliseconds integration time with low perfusion units in blue at the fundus side, and high perfusion units in red at the base of the gastric tube (C). A laser distance meter (Leica Geosystems D110, Germany) was used to position the MoorFLPI-1 LSCI system perpendicular at an exact distance of 40 cm above the gastric tube. Optimal focus, zoom, and polarization settings were adjusted, as described by the manufacturer, before imaging. A metric ruler was placed in the field of view next to the gastric tube, in order to correct resolution and distance calibration after imaging. Also, a sterile gauze was used to point out the area of the watershed (between the right and left gastroepiploic arteries) as a landmark for the perfusion measurements. During measurements, all OR light was switched off to decrease back reflections. Perfusion was imaged for 50 seconds generating a total of 5 images (10 seconds/frame). After this imaging, blood pressure and cardiac output were increased by administering a bolus of ephedrine 5 mg. Ephedrine was chosen for its fast working and short acting ability, enabling to test a change in MAP without interfering in the hemodynamics of the patient too much. For safety reasons and to avoid hypertension, a standard dose (5 mg) was used as a first step to increase the MAP. After increase of the MAP with a mean of 18 ± 9 mm/Hg, which lasted for 5–10 minutes, 10 extra images were obtained per patient. Data were used to check if ephedrine 5 mg would increase perfusion, and if this increase was visible with LSCI. In total 20 images were obtained per patient, 10 pre- and 10 postephedrine administration. Time needed to obtain LSCI data and anesthetic parameters were recorded in the CRF. Data acquisition Obtained data were analyzed by two independent researchers (S.M.J., D.M.B.), blinded for patient outcome, using MoorFLPI analysis software (MoorFLPI Review V4.0, Moor Instruments, Devon, UK). After adjustment of threshold settings, flux was measured in a field of view (FOV) of 1 × 1 cm2 (using the metric ruler as calibration) in a standard method to generate reproducible data. Regions of interest were placed at four perfusion areas: 3 cm under the watershed, exactly on the watershed, 3 cm above the watershed, and at the fundus site. We anticipated that the perfusion in these regions would range from good (near the supplying artery) to decreased (at distance from the supplying artery) perfusion (Fig. 2). Flux, based on the amount and movement of particles, was obtained at these four areas in all images. Differences between the four perfusion areas were compared statistically. To measure the noise influence on flux, a fifth static site was selected for flux measurements: on the metric ruler. Our hypothesis is that flux is zero in this ROI. Fig. 2 View largeDownload slide Laser speckle image of the gastric tube in color-code (A) and in corresponding gray scale (B) with region of interest at 1: 3 cm below watershed; 2: watershed; 3: 3 cm above watershed; and 4: fundus. To determine noise we measured at 5: metric ruler as a reference point. The color bar indicates the correlation of color to the flux given in LSPU. The bar indicates greyscale values. The metric ruler is used for calibration and sterile gauze to point to the watershed in region 2. Fig. 2 View largeDownload slide Laser speckle image of the gastric tube in color-code (A) and in corresponding gray scale (B) with region of interest at 1: 3 cm below watershed; 2: watershed; 3: 3 cm above watershed; and 4: fundus. To determine noise we measured at 5: metric ruler as a reference point. The color bar indicates the correlation of color to the flux given in LSPU. The bar indicates greyscale values. The metric ruler is used for calibration and sterile gauze to point to the watershed in region 2. Because surgeons are interested in the decrease of perfusion in the future anastomotic side: location 4, the fundus, pre- and postephedrine measurements of flux in this side were compared and tested for statistical significance, assuming that ephedrine will have a positive effect on perfusion in this area. Statistical analysis Data analysis was performed using Prism (GraphPad Prism 5.01, La Jolla, USA). The study size was based on the detection of hemodynamic changes in images between good versus sparse blood flow, using Hedges’ g.12 A sample size of 20 patients will have 80% power to detect an effect size of different values between the base and the fundus of the gastric tube of 0.66, using a paired t-test with a 0.05 two-sided significance level. Taking 10% missing/unevaluable measurements into account, we included 22 evaluable patients. To test data sets for normality a D’Agostino–Pearson test was used. To compare data between four perfusion areas a repeated ANOVA was performed. To compare data before and after ephedrine administration in location 4 a paired t-test was used. Differences with a P < 0.05 were considered as statistically significant. Data will be presented as boxplots with mean, interquartile ranges, and maximum and minimum. The correlation between flux (LSPU) and MAP, heart beat (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), CO, SV, and stroke volume variation (SVV) was measured using a linear regression model. RESULTS Participants In total four patients were excluded based on unrelated delay in operation time, which made imaging logistically impossible, so measurements were not carried out. A total of 22 patients were included for data analysis, 19 male and 3 female with a mean age of 60.5 and a mean body mass index of 25.8 kg/m2. A complete summary of baseline characteristics is presented in Table 1 and followed the normal criteria. Table 1. Patient characteristics Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  View Large Table 1. Patient characteristics Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  View Large Systemic hemodynamic parameters, in terms of MAP, HR, SBP, DBP, temperature, cardiac output (CO), SV, SVV, and CI, before and after a bolus of ephedrine 5 mg are presented in Table 2. MAP was significantly increased (P < 0.001). Table 2. Hemodynamic parameters before and after administration of 5 mg ephedrine (mean and standard deviation) Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  View Large Table 2. Hemodynamic parameters before and after administration of 5 mg ephedrine (mean and standard deviation) Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  View Large Feasibility of LSCI imaging and effect of ephedrine LSCI of the microvascular perfusion was successful in 20 patients. The first two patients were excluded for data analysis based on different settings of integration time of the LSCI modality. With LSCI in combination with the laser distance meter we were able to create reproducible images of the total gastric tube in a wide field of view. An example of a typical LSCI image with a FOV of 15 × 20 cm2, with the four regions of interest, and good perfusion, depicted in red, in the base of the gastric tube and less perfusion, depicted in blue, in the fundus is shown in Figure 2. Noise, measured in the fifth ROI, was small in all patients (0–30 LSPU), thus correction for noise was not needed. A summary of the flux measured in all patients before and after ephedrine and the increase of the MAP are shown in Table 3. Data of patients 1 and 2 were obtained in a different integration time and therefore excluded from the analysis. Flux data of patients 1, 2, and 7 are pointed out with an ‘*’ because they developed anastomotic leakage. Table 3. Data of flux (LSPU) in 4 locations in all patients before and after ephedrine Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  *Patients who developed anastomotic leakage in italic, *patient who developed anastomotic leakage and died in bold. View Large Table 3. Data of flux (LSPU) in 4 locations in all patients before and after ephedrine Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  *Patients who developed anastomotic leakage in italic, *patient who developed anastomotic leakage and died in bold. View Large The MAP was increased in all patients after the bolus of ephedrine, except for patient 9. In Figure 2 the effect of ephedrine on the measured perfusion in location 4 is depicted. The flux after ephedrine was significant higher compared to the flux in location 4 before ephedrine (P < 0.05) (Fig. 3). The flux in five patients responded really well to the administered ephedrine. This group of ‘responders’ had a mean age of 55.6 years (vs. 62 years), a body mass index (BMI) of 23.8 (vs. 26.4), developed no leakage (vs. 3), and had, except for one patient with Chronic Obstructive Pulmonary Disease (COPD), no comorbidities (vs. 7 comorbidities in the ‘nonresponding’ group). Interestingly, the MAP, SV, and CO were similar as in the ‘nonresponding’ group of patients (before ephedrine MAP 71 vs. 70 and after ephedrine MAP 88 vs. 88, SV 74 vs. 76, and CO 7.5 vs. 6.8). Fig. 3 View largeDownload slide Measurements of flux with LSCI in location 4 which is the fundus and thus the future anastomotic side before (preephedrine) and after (postephedrine) administration of a bolus of 5 mg ephedrine. Fig. 3 View largeDownload slide Measurements of flux with LSCI in location 4 which is the fundus and thus the future anastomotic side before (preephedrine) and after (postephedrine) administration of a bolus of 5 mg ephedrine. Perfusion diagnostics with LSCI We were able to analyze the flux within the region of interest (1 × 1 cm2) in the four perfusion zones of 18 patients (Fig. 4). Flux was significantly different between locations, most notably decreased in location 4 (328 ± 187 LSPU) compared to location 1 (791 ± 442 LSPU) (P < 0.001). After administration of 5 mg ephedrine the flux increased at location 4 in 11 patients. The flux at that position was again lower (380 ± 287 LSPU) compared to location 1 (894 ± 467 LSPU) of the gastric tube (P < 0.001). Fig. 4 View largeDownload slide Flux of gastric microcirculation measured in all locations (1: 3 cm under watershed; 2: watershed; 3: 3 cm above watershed; 4: fundus) before (A) and after 5 mg ephedrine (B) with a significant decrease of flux towards the fundus (P < 0.001). Fig. 4 View largeDownload slide Flux of gastric microcirculation measured in all locations (1: 3 cm under watershed; 2: watershed; 3: 3 cm above watershed; 4: fundus) before (A) and after 5 mg ephedrine (B) with a significant decrease of flux towards the fundus (P < 0.001). There was no significant correlation between flux and MAP, CI, CO, HR, or SV, measured with a linear regression. In three patients anastomotic leakage developed. We do see that flux measured in location 4 of two of these three leakage patients is lower compared to the mean flux measured in the other patients, both before (77 and 170 vs. 200) and after (−12 and −23 vs. 45) administration of ephedrine. However, the study population was too small to draw any conclusions to this. Time to obtain LSCI images was between 3 and 5 minutes. No change was observed in imaging time during the study (R2 = 0.04). DISCUSSION This study shows the feasibility of laser speckle contrast imaging to measure perfusion of the gastric conduit during gastric tube reconstructions. Moreover, we demonstrated the effect of ephedrine 5 mg on perfusion, quantitatively analyzed as flux depicted in LSPU, in the future anastomotic site of the gastric tube. LSCI was feasible to create a wide field overview of gastric microvascular perfusion intraoperative in a color-coded image. We demonstrated a small but significant effect of ephedrine 5 mg on the perfusion in the fundus of the gastric conduit (increase of 27%, P < 0.05) and we show a significant difference between the fundus (reduced perfusion) and watershed (good perfusion) of the gastric tube microcirculation (P < 0.001). Intervention with ephedrine increased the MAP with 18 ± 9 mmHg. Ephedrine also resulted in an increased flux measured in the gastric tube microcirculation of the fundus (P < 0.05). Interestingly, this increase of flux after administration of ephedrine was prominent in five patients. These ‘responders’ were younger compared to the ‘nonresponders’, had a lower BMI, less comorbidities, and developed no anastomotic leakage. This suggests a place for the administration of inotropes to improve perfusion for a selected patient group. Furthermore, these results show the feasibility of LSCI to quantitatively measure perfusion changes in the gastric conduit. Also, it indicates a role for ephedrine in optimizing perfusion during gastric tube reconstruction. Ephedrine is a vasopressor that has positive inotropic and chronotropic effects on the heart. It stimulates the sympathetic nervous system and therefore MAP and CO increase, but also inhibits the parasympathetic system, resulting in vasoconstriction of the gastrointestinal arteries and a decreased splanchnic perfusion.2,3 Our hypothesis was that ephedrine would create a fast change in MAP, CO, and flow enabling us to image change of localized perfusion with LSCI intraoperative. Previous studies show that ephedrine increases localized flow in contrast to other inotropes like noradrenaline.13 However, the effect of ephedrine is only 10–15 minutes. Future studies should investigate inotropes with a longer half-life time like dobutamine, which increases flow but decreases systemic blood pressure. What is the effect of ephedrine on flux? Jansen et al. showed in a phantom study that flux measured with LSCI is related to velocity of erythrocytes and the amount of moving particles.9 We therefore expect that the use of ephedrine results in higher flow, thus higher flux, although a smaller amount of particles will be imaged due to vasoconstriction. We observed an increase of localized perfusion on the fundus of the gastric tube, although the effect was smaller than expected. This limited effect can be explained by the vasoconstriction and by the fact that this perfusion site is on the boundary between the areas that are regulated by the sympathetic and parasympathetic nervous systems. In a recent study of the gastric tube perfusion with sidestream darkfield microscopy (Jansen et al. submitted, Annals of Surgery), venous congestion was clearly visible in locations 4. Venous congestions result in a decrease of gastric tube perfusion by the restriction of outflow. This restricted outflow could also explain the small effect of ephedrine on the flux in this location. Venous congestion in gastric tube surgery was described before by Murakami et al. who showed the improvement of blood flow after the reconstruction of a venous anastomosis at the future anastomotic side of the gastric tube.14 Buise et al. observed an increase of gastric tube perfusion after the administration of nitroglycerine, reducing venous congestions by vasodilatation.15 We demonstrate that LSCI enables us to quantitatively measure the influence of interventions on perfusion in the gastric tube during surgery. Perfusion diagnostics of the gastric tube with LSCI was previously described by Klijn et al. in an animal study.16 LSCI was used to evaluate the effect of an increase of mean arterial pressure on gastric tube perfusion, an effect that was not visible in that study. Milstein et al. showed the feasibility and the reliability of blood flow measurements intraoperatively in 11 patients undergoing gastric tube reconstructions. They also found a progressive decrease of flux toward the fundus. In that study they also demonstrated the capability of LSCI to measure changes in the perfusion, by changing the position of the patient during surgery. Flux significantly decreased across all locations during reverse Trendelenburg (P < 0.05).17 Although LSCI is capable of measuring difference in the perfusion, still several limitations exist. The first limitation of this study is the missing data on baseline perfusion, which could not be obtained during laparoscopic surgery. The gastric tube was reconstructed intrathoracic and therefore LSCI measurements of the intact gastric microcirculation could not be carried out as a baseline measurement. Second, it is important to note that the parameter flux given by LSCI in LSPU is not an absolute quantitative measure. By definition, flux is the flow rate per unit area depicted in, e.g. mL/(min area), however the correlation of the flux quantified in LSPU of the MoorFLPI system with the flow rate per unit area is lacking. The precise relation between the measured speckle contrast and the number of LSPU is not given either. Nadort et al. suggested a method to translate perfusion measurements by LSCI to a quantitative parameter (blood flow velocity), showing many steps (e.g. multiexposure images, convert raw speckle image to speckle contrast image, apply nonlinear curve fit to find, correct for offset decorrelation, estimate vessel diameter, and scattering events, in order to correct for multiple scattering)18 before LSPU can be translated to absolute flow or perfusion values. Although we can conclude that LSCI measurements do not give absolute perfusion or flux values, using the exact same settings (e.g. integration time, distance between camera and tissue, perpendicular imaging in relation to the tissue under study) relative intrapatient differences in perfusion can be determined and used in clinical settings. A third limitation of LSCI is the wide variation in flux values between patients as depicted in Figure 4. Therefore, interpatient evaluation is difficult. Prediction of the development of anastomotic leakage intraoperative based on these absolute flux values will be unlikely. We anticipate that in the future it is more likely that a relative parameter will predict the development of leakage. This parameter would then allow the surgeon to decide whether to react or not. In this regard it is interesting to note that in the patients that developed anastomotic leakage, a large difference in measured flux between the watershed and the fundus existed. Therefore, relative measurements as the decrease of flux in the gastric tube might be more indicative for leakage prediction than their values. However, this study population was too small to draw conclusions to this. Further studies that relate potential parameters with leakage development are needed. Within these studies, the potential of other techniques to measure perfusion intraoperatively and quantitatively can be considered, such as laser Doppler flowmetry,19–21 thermography,22 fluorescence imaging.23–28 These techniques differ from LSCI in terms of resolution, field of view, and image content. LSCI and thermography have the advantage that it creates color-coded wide field images. Due to the spatial heterogeneity of the microcirculation, wide field imaging is preferable above point measurements (as is used in laser Doppler flowmetry). Also in the case of thermography the quantitative measured parameters (change in temperature) has to be converted into perfusion or flux. Therefore, the organ has to be precooled and rewarmed in order to create good perfusion measurements. The disadvantage of fluorescence imaging is that the administration of a dye is needed, in contrast with LSCI. Conclusion We show the feasibility of LSCI to quantitative image the effect of ephedrine on microcirculation in the gastric tube perfusion in all patients. We depict a small but significant increase of perfusion after ephedrine 5 mg together with an increase of MAP. Moreover, we found a decrease of perfusion measured in the gastric tube toward the fundus. This amount of decrease could potentially be a more relevant parameter than their absolute values for future prediction of anastomotic leakage, enabling risk stratification in gastric tube reconstruction after esophagectomy. The authors would like to thank Martin van Gemert for his contribution to this manuscript. Moreover, they would like to thank ZonMw for their financial support and Institute Quantivision for their support in trial conception. Specific author contributions: SMJ made substantial contributions to conception and design, acquisition of data and data analysis and interpretation of data. Drafting the article and revising it critically, final approval of the submitted version; DMB, MIB and SSG made substantial contributions to conception and design, acquisition of data and interpretation of data. Revising the article critically, final approval of the submitted version; PRB made substantial contributions to conception and design, acquisition of data. Revising the article critically, final approval of the submitted version; SDS made substantial contributions to conception and design and the interpretation of data. Revising the article critically, final approval of the submitted version; DPV and TGL made substantial contributions to conception and design, interpretation of data. Revising the article critically, final approval of the submitted version. REFERENCES 1. Dyer R A, Reed A R, Dyk D Van, James M F. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology  2009; 111: 753– 65. Google Scholar CrossRef Search ADS PubMed  2. Nygren A, Ricksten S. Vasopressors and intestinal mucosal perfusion after cardiac surgery: Norepinephrine vs. phenylephrine. Crit Care  2006; 34: 722– 9. Google Scholar CrossRef Search ADS   3. Meng L, Cannesson M, Alexander B S et al.   Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients. Br J Anaesth  2011; 107: 209– 17. Google Scholar CrossRef Search ADS PubMed  4. El-Tahan M R. Preoperative ephedrine counters hypotension with propofol anesthesia during valve surgery: a dose dependent study. Ann Card Anaesth  2011; 14: 30– 40. Google Scholar PubMed  5. Lewis I. The surgical treatment of carcinoma of the oesophagus with special reference to a new operation for growths of the middle third. Br J Surg  1946; 34: 18– 31. Google Scholar CrossRef Search ADS PubMed  6. Briel JW, Tamhankar AP, Hagen JA et al.   Prevalence and risk factors for ischemia, leak, and stricture of esophageal anastomosis: gastric pull-up versus colon interposition. J Am Coll Surg  2004; 198: 536– 41. Google Scholar CrossRef Search ADS PubMed  7. van Hagen P, Hulshof M C C M C, van Lanschot J J B J et al.   Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med  2012; 366: 2074– 84. Google Scholar CrossRef Search ADS PubMed  8. Briers D, Duncan D D, Hirst E et al.   Laser speckle contrast imaging: theoretical and practical limitations. J Biomed Opt  2013; 18: 66018-9. Google Scholar CrossRef Search ADS   9. Jansen S M, de Bruin D M, Faber D J et al.   Applicability of quantitative optical imaging techniques for intraoperative perfusion diagnostics: a comparison of laser speckle contrast imaging, sidestream dark-field microscopy, and optical coherence tomography. J Biomed Opt  2017; 22: 9. Google Scholar CrossRef Search ADS   10. Vandenbroucke J P, von Elm E, Altman D G et al.   Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Int J Surg  2014; 12: 1500– 24. Google Scholar CrossRef Search ADS PubMed  11. Bossuyt P M. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem  2003; 49: 7– 18. Google Scholar CrossRef Search ADS PubMed  12. Borenstein M, Hedges L V, Higgins J P T, Rothstein H R. Introduction to Meta-Analysis . John Wiley Sons, 2009; 21– 32. Google Scholar CrossRef Search ADS   13. Buise M, Gommers D, De Jonge J, Van Genderen M, Bakker J, Van Bommel J. Effects of intravenous nitroglycerin and noradrenaline on gastric microvascular perfusion in an experimental model of gastric tube reconstruction. Crit Care  2009; 13: S72. Google Scholar CrossRef Search ADS   14. Murakami M, Sugiyama A, Ikegami T et al.   Revascularization using the short gastric vessels of the gastric tube after subtotal esophagectomy for intrathoracic esophageal carcinoma. J Am Coll Surg  2000; 190: 71– 77. Google Scholar CrossRef Search ADS PubMed  15. Buise M, van Bommel J, Jahn A, Tran K, Tilanus H, Gommers D. Intravenous nitroglycerin does not preserve gastric microcirculation during gastric tube reconstruction: a randomized controlled trial. Crit Care  2006; 10: R131. Google Scholar CrossRef Search ADS PubMed  16. Klijn E, Niehof S, de Jonge J et al.   The effect of perfusion pressure on gastric tissue blood flow in an experimental gastric tube model. Anesth Analg  2010; 110: 541– 6. Google Scholar CrossRef Search ADS PubMed  17. Milstein D M J, Ince C, Gisbertz S S et al.   Laser speckle contrast imaging identifies ischemic areas on gastric tube reconstructions following esophagectomy. Medicine (Baltimore)  2016; 95: e3875. Google Scholar CrossRef Search ADS PubMed  18. Nadort A, Kalkman K, van Leeuwen T G, Faber D J. Quantitative blood flow velocity imaging using laser speckle flowmetry. Sci Rep  2016; 6: 25258. Google Scholar CrossRef Search ADS PubMed  19. Boyle N, Pearce A, Owen WJ, Mason RC. Validation of scanning laser Doppler flowmetry against single point laser Doppler flowmetry in the measurement of human gastric serosal/muscularis perfusion. Int J Surg Investig  2000; 2: 203– 11. Google Scholar PubMed  20. Schilling M K, Redaelli C, Maurer C et al.   Gastric microcirculatory changes during gastric tube formation: assessment with laser Doppler flowmetry. J Surg Res  1996; 62: 125– 9. Google Scholar CrossRef Search ADS PubMed  21. Svensson H, Bergqvist D, Takolander R. Laser Doppler blood flow monitoring in reconstructive vascular surgery: case studies. Vasc Surg  1987; 21: 58– 65. Google Scholar CrossRef Search ADS   22. Pauling J D, Shipley J A, Raper S et al.   Comparison of infrared thermography and laser speckle contrast imaging for the dynamic assessment of digital microvascular function. Microvasc Res  2012; 83: 162– 7. Google Scholar CrossRef Search ADS PubMed  23. Rino Y, Yukawa N, Sato T et al.   Visualization of blood supply route to the reconstructed stomach by indocyanine green fluorescence imaging during esophagectomy. BMC Med Imaging  2014; 14: 14– 18. Google Scholar CrossRef Search ADS PubMed  24. Shimada Y, Okumura T, Nagata T et al.   Usefulness of blood supply visualization by indocyanine green fluorescence for reconstruction during esophagectomy. Esophagus  2011; 8: 259– 66. Google Scholar CrossRef Search ADS PubMed  25. Kubota K, Yoshida M, Kuroda J et al.   Application of the HyperEye Medical System for esophageal cancer surgery: a preliminary report. Surg Today  2013; 43: 215– 20. Google Scholar CrossRef Search ADS PubMed  26. Kumagai Y, Ishiguro T, Haga N et al.   Hemodynamics of the reconstructed gastric tube during esophagectomy: Assessment of outcomes with indocyanine green fluorescence. World J Surg [Internet]  2014; 38: 138– 43. Google Scholar CrossRef Search ADS   27. Yukaya T, Saeki H, Kasagi Y et al.   Indocyanine green fluorescence angiography for quantitative evaluation of gastric tube perfusion in patients undergoing esophagectomy. J Am Coll Surg  2015; 221: e37– 42. Google Scholar CrossRef Search ADS PubMed  28. Zehetner J, DeMeester S R, Alicuben E T et al.   Intraoperative assessment of perfusion of the gastric graft and correlation with anastomotic leaks after esophagectomy. Ann Surg  2015; 262: 74– 78. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Effect of ephedrine on gastric conduit perfusion measured by laser speckle contrast imaging after esophagectomy: a prospective in vivo cohort study

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Abstract

SUMMARY Compromised perfusion due to ligation of arteries and veins in esophagectomy with gastric tube reconstruction often (5–20%) results in necrosis and anastomotic leakage, which relate to high morbidity and mortality (3–4%). Ephedrine is used widely in anesthesia to treat intraoperative hypotension and may improve perfusion by the increase of cardiac output and mean arterial pressure (MAP). This study tests the effect of ephedrine on perfusion of the future anastomotic site of the gastric conduit, measured by laser speckle contrast imaging (LSCI). This prospective, observational, in vivo pilot study includes 26 patients undergoing esophagectomy with gastric tube reconstruction from October 2015 to June 2016 in the Academic Medical Center (Amsterdam). Perfusion of the gastric conduit was measured with LSCI directly after reconstruction and after an increase of MAP by ephedrine 5 mg. Perfusion was quantified in flux (laser speckle perfusion units, LSPU) in four perfusion locations, from good perfusion (base of the gastric tube) toward decreased perfusion (fundus). Intrapatient differences before and after ephedrine in terms flux were statistically tested for significance with a paired t-test. LSCI was feasible to image gastric microcirculation in all patients. Flux (LSPU) was significantly higher in the base of the gastric tube (791 ± 442) compared to the fundus (328 ± 187) (P < 0.001). After administration of ephedrine, flux increased significantly in the fundus (P < 0.05) measured intrapatients. Three patients developed anastomotic leakage. In these patients, the difference between measured flux in the fundus compared to the base of the gastric tube was high. This study presents the effect of ephedrine on perfusion of the gastric tissue measured with LSCI in terms of flux (LSPU) after esophagectomy with gastric tube reconstruction. We show a small but significant difference between flux measured before and after administration of ephedrine in the future anastomotic tissue (313 ± 178 vs. 397 ± 290). We also show a significant decrease of flux toward the fundus. INTRODUCTION Ephedrine, a mixed acting agent with positive inotropic and chronotropic effects,1 is routinely used in anesthesia to increase cardiac output (CO) and mean arterial pressure (MAP) in case of intraoperative hypotension.2 The effect of ephedrine on localized perfusion is widely described in the brain and heart tissue.3,4 The sympathetic nervous system is positively influenced and therefore MAP and CO increases. Despite the inhibition of the parasympathetic system, resulting in vasoconstriction of the gastrointestinal arteries and a decreased splanchnic perfusion,2,3 we hypothesize that it can potentially lead to improved perfusion in the gastric conduit, in patients undergoing esophagectomy with gastric tube reconstruction. During surgery the left and short gastric arteries as well as the left gastroepiploic artery are ligated, which means that gastric tissue perfusion is mainly depending on the right gastroepiploic artery.5 The ligations additionally may result in vasoconstriction and capillary and venous congestion. This decreased gastric tissue perfusion, resulting in a lack of oxygen and nutrients and accumulation of metabolic waste, is seen as a major contributing factor for the development of anastomotic leakage.6 Anastomotic leakage leads to high rates of morbidity (leakage, stricture, 20%) and mortality (3–4%),6,7 and monitoring perfusion, in combination with, if needed, an intervention to increase perfusion, could therefore improve surgery outcomes. Laser speckle contrast imaging (LSCI) uses near-infrared laser light to image tissue perfusion in a wide field overview (15 × 20 cm2).8 Perfusion imaging with LSCI was validated in a phantom model.9 The photons that are backscattered from different tissue components will have path length differences, thereby inducing the characteristic interference (speckle) pattern on the camera. Movement of the tissue components, such as blood, will induce fluctuations in the speckle pattern. These fluctuations, which are related to the speed and the amount of the flowing blood, can be characterized either in time or spatially. In the former approach, the time variation is directly measured by the camera. In the latter approach, the speckle pattern will be blurred due to the movement of the blood during the integration time of the camera. The primary aim of this study is to test the feasibility of LSCI to image and measure perfusion during gastric tube reconstruction after esophagectomy. The so-called measured flux by LSCI is then quantified in laser speckle perfusion units (LSPU). The secondary aim of this study is to test the effect of ephedrine on the measured perfusion (flux) in the gastric conduit. Thereto, we will measure and compare perfusion in four different areas and we statistically test the difference of perfusion before and after ephedrine. MATERIALS AND METHODS The methodology of this prospective in vivo cohort study was based on the STROBE guideline10 and the STARD statement.11 During surgery, directly after reconstruction of the gastric tube, perfusion was imaged with LSCI and flux was determined at four perfusion areas, from the base of the gastric tube toward the fundus (from good to decreased perfusion) in LSPU. After imaging, 5 mg ephedrine was administered and perfusion was measured again. During data analysis, flux was measured in four different perfusion areas of the gastric conduit, from good to decreased perfusion. Flux before and after ephedrine was measured in all the four areas. Patients This study prospectively enrolled 26 consecutive patients with esophageal cancer who underwent an esophagectomy with gastric tube reconstruction in the Academic Medical Center (Amsterdam, The Netherlands) between October 2015 and June 2016. Surgery was executed by two expert upper gastrointestinal surgeons (M.I.B., S.S.G.). This study was approved by the Medical Ethics Committee (NL52377.018.15) of the Academic Medical Center of the University of Amsterdam, and submitted to the clinicaltrials.gov database (NCT02902549). Informed consent was obtained from all patients. Follow-up time was 3 months to assess adverse events and complication development. Surgical procedure Surgery was performed following the three-stage thoracolaparoscopic esophageal cardia resection and gastric tube reconstruction protocol (Ivor Lewis and McKeown approach). After mobilization of the esophagus and following intrathoracic and abdominal lymphadenectomy, ligation of the left gastric artery, part of the right gastric artery, the left epiploic artery, and the short gastric vessels are executed. After reconstruction, the perfusion of the gastric tube is depending on inflow from the right gastroepiploic artery and partly from the right gastric artery. The anesthesia procedure was standard in all patients. Induction was done with propofol, sufentanil, and rocuronium. Maintenance was done with sevoflurane and sufentanil. An epidural was standardly placed before induction. Standard hemodynamic management in our practice is to use goal-directed fluid management in these patients. During the operation, stroke volume was optimized, titrating with fluid boluses of 200 mL (colloids). Vasopressors were given if MAP < 65 mmHg. Noradrenalin was used as a standard for continuous infusion. Ephedrine 5 mg or phenylephrine 100 mcg was used as bolus medication. Related hemodynamic parameters in terms of MAP, cardiac index (CI), CO, stroke volume (SV), and peripheral capillary oxygen saturation, minute volume, fraction of inspired oxygen, tidal volume, and respiratory rate, and vasoactive medication at timing of monitoring were recorded in a clinical report form (CRF). Intraoperative perfusion imaging with LSCI Perfusion of the gastric tube was assessed directly after the reconstruction with the MoorFLPI-1 LSCI system (Moor Instruments, Devon, UK). A near-infrared laser light source of 785 nm illuminated the tissue from a distance of 40 cm (optimal work distance 26–40 cm) to image the gastric tube perfusion in a wide field (15 × 20 cm2) (Fig. 1). The speckle pattern of this light source will change by changes in the amount and motion of predominantly red blood cells within the field of view. Consequently, by measuring the speckle contrast, a measure of the perfusion of the images tissue can be determined. MoorFLPI-1 software (MoorFLPI-1 Measurement V3.0, Moor Instruments, Devon, UK) was used to create high-resolution images of this perfusion obtained for an integration time of 8.3 milliseconds. The system was calibrated before measurements were taken, as prescribed by the manufacturer. In short, a calibration block was used consisting of a container of motility standard which provides a flux reference and a static reflector which provides a zero reference. Measurements were taken 25 cm above the calibration block. Fig. 1 View largeDownload slide LSCI system (A), schematic figure (B) of gastric tube with field of view (15 × 20 cm2) of LSCI and color-coded LSCI-image with 4.2 milliseconds integration time with low perfusion units in blue at the fundus side, and high perfusion units in red at the base of the gastric tube (C). Fig. 1 View largeDownload slide LSCI system (A), schematic figure (B) of gastric tube with field of view (15 × 20 cm2) of LSCI and color-coded LSCI-image with 4.2 milliseconds integration time with low perfusion units in blue at the fundus side, and high perfusion units in red at the base of the gastric tube (C). A laser distance meter (Leica Geosystems D110, Germany) was used to position the MoorFLPI-1 LSCI system perpendicular at an exact distance of 40 cm above the gastric tube. Optimal focus, zoom, and polarization settings were adjusted, as described by the manufacturer, before imaging. A metric ruler was placed in the field of view next to the gastric tube, in order to correct resolution and distance calibration after imaging. Also, a sterile gauze was used to point out the area of the watershed (between the right and left gastroepiploic arteries) as a landmark for the perfusion measurements. During measurements, all OR light was switched off to decrease back reflections. Perfusion was imaged for 50 seconds generating a total of 5 images (10 seconds/frame). After this imaging, blood pressure and cardiac output were increased by administering a bolus of ephedrine 5 mg. Ephedrine was chosen for its fast working and short acting ability, enabling to test a change in MAP without interfering in the hemodynamics of the patient too much. For safety reasons and to avoid hypertension, a standard dose (5 mg) was used as a first step to increase the MAP. After increase of the MAP with a mean of 18 ± 9 mm/Hg, which lasted for 5–10 minutes, 10 extra images were obtained per patient. Data were used to check if ephedrine 5 mg would increase perfusion, and if this increase was visible with LSCI. In total 20 images were obtained per patient, 10 pre- and 10 postephedrine administration. Time needed to obtain LSCI data and anesthetic parameters were recorded in the CRF. Data acquisition Obtained data were analyzed by two independent researchers (S.M.J., D.M.B.), blinded for patient outcome, using MoorFLPI analysis software (MoorFLPI Review V4.0, Moor Instruments, Devon, UK). After adjustment of threshold settings, flux was measured in a field of view (FOV) of 1 × 1 cm2 (using the metric ruler as calibration) in a standard method to generate reproducible data. Regions of interest were placed at four perfusion areas: 3 cm under the watershed, exactly on the watershed, 3 cm above the watershed, and at the fundus site. We anticipated that the perfusion in these regions would range from good (near the supplying artery) to decreased (at distance from the supplying artery) perfusion (Fig. 2). Flux, based on the amount and movement of particles, was obtained at these four areas in all images. Differences between the four perfusion areas were compared statistically. To measure the noise influence on flux, a fifth static site was selected for flux measurements: on the metric ruler. Our hypothesis is that flux is zero in this ROI. Fig. 2 View largeDownload slide Laser speckle image of the gastric tube in color-code (A) and in corresponding gray scale (B) with region of interest at 1: 3 cm below watershed; 2: watershed; 3: 3 cm above watershed; and 4: fundus. To determine noise we measured at 5: metric ruler as a reference point. The color bar indicates the correlation of color to the flux given in LSPU. The bar indicates greyscale values. The metric ruler is used for calibration and sterile gauze to point to the watershed in region 2. Fig. 2 View largeDownload slide Laser speckle image of the gastric tube in color-code (A) and in corresponding gray scale (B) with region of interest at 1: 3 cm below watershed; 2: watershed; 3: 3 cm above watershed; and 4: fundus. To determine noise we measured at 5: metric ruler as a reference point. The color bar indicates the correlation of color to the flux given in LSPU. The bar indicates greyscale values. The metric ruler is used for calibration and sterile gauze to point to the watershed in region 2. Because surgeons are interested in the decrease of perfusion in the future anastomotic side: location 4, the fundus, pre- and postephedrine measurements of flux in this side were compared and tested for statistical significance, assuming that ephedrine will have a positive effect on perfusion in this area. Statistical analysis Data analysis was performed using Prism (GraphPad Prism 5.01, La Jolla, USA). The study size was based on the detection of hemodynamic changes in images between good versus sparse blood flow, using Hedges’ g.12 A sample size of 20 patients will have 80% power to detect an effect size of different values between the base and the fundus of the gastric tube of 0.66, using a paired t-test with a 0.05 two-sided significance level. Taking 10% missing/unevaluable measurements into account, we included 22 evaluable patients. To test data sets for normality a D’Agostino–Pearson test was used. To compare data between four perfusion areas a repeated ANOVA was performed. To compare data before and after ephedrine administration in location 4 a paired t-test was used. Differences with a P < 0.05 were considered as statistically significant. Data will be presented as boxplots with mean, interquartile ranges, and maximum and minimum. The correlation between flux (LSPU) and MAP, heart beat (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), CO, SV, and stroke volume variation (SVV) was measured using a linear regression model. RESULTS Participants In total four patients were excluded based on unrelated delay in operation time, which made imaging logistically impossible, so measurements were not carried out. A total of 22 patients were included for data analysis, 19 male and 3 female with a mean age of 60.5 and a mean body mass index of 25.8 kg/m2. A complete summary of baseline characteristics is presented in Table 1 and followed the normal criteria. Table 1. Patient characteristics Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  View Large Table 1. Patient characteristics Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  Patient characteristics  Age (year)   Median  62   Range  37–79  Body mass index (kg/m2)   Median  25.9   Range  17–34.2  Gender—male, female (n)  19, 3  Procedures—no. (%)   Ivor Lewis  20 (91)   McKeown  2 (9)  Cardiovascular disease—no. (%)  5 (23)  Diabetes Mellitus 1—no. (%)  0 (0)  Diabetes Mellitus 2—no. (%)  2 (9)  COPD—no. (%)  2 (9)  View Large Systemic hemodynamic parameters, in terms of MAP, HR, SBP, DBP, temperature, cardiac output (CO), SV, SVV, and CI, before and after a bolus of ephedrine 5 mg are presented in Table 2. MAP was significantly increased (P < 0.001). Table 2. Hemodynamic parameters before and after administration of 5 mg ephedrine (mean and standard deviation) Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  View Large Table 2. Hemodynamic parameters before and after administration of 5 mg ephedrine (mean and standard deviation) Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  Hemodynamic parameters  Before ephedrine 5 mg  After ephedrine 5 mg  MAP (mmHg)  70 ± 9  88 ± 9  HR (beats min)  85 ± 13  90 ± 13  SBP (mmHg)  106 ± 16  122 ± 19  DBP (mmHg)  62 ± 17  68 ± 12  Temperature nasopharyx (°C)  36.2 ± 0.6  36.2 ± 0.5  CO (L/min)  6.9 ± 2.3  7.4 ± 1.9  SV (mL)  75.4 ± 18.5  81 ± 13  SVV (%)  7.8 ± 2.6  8 ± 4.1  CI (L/min m2)  3.1 ± 0.9  3.4 ± 0.8  View Large Feasibility of LSCI imaging and effect of ephedrine LSCI of the microvascular perfusion was successful in 20 patients. The first two patients were excluded for data analysis based on different settings of integration time of the LSCI modality. With LSCI in combination with the laser distance meter we were able to create reproducible images of the total gastric tube in a wide field of view. An example of a typical LSCI image with a FOV of 15 × 20 cm2, with the four regions of interest, and good perfusion, depicted in red, in the base of the gastric tube and less perfusion, depicted in blue, in the fundus is shown in Figure 2. Noise, measured in the fifth ROI, was small in all patients (0–30 LSPU), thus correction for noise was not needed. A summary of the flux measured in all patients before and after ephedrine and the increase of the MAP are shown in Table 3. Data of patients 1 and 2 were obtained in a different integration time and therefore excluded from the analysis. Flux data of patients 1, 2, and 7 are pointed out with an ‘*’ because they developed anastomotic leakage. Table 3. Data of flux (LSPU) in 4 locations in all patients before and after ephedrine Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  *Patients who developed anastomotic leakage in italic, *patient who developed anastomotic leakage and died in bold. View Large Table 3. Data of flux (LSPU) in 4 locations in all patients before and after ephedrine Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  Summarized data of flux (LSPU) in 4 locations in all patients    Flux (LSPU) before ephedrine  ΔFlux (LSPU) after ephedrine          Location  Location  Location  Location  Location  Location  Location  Location  MAP  ΔMAP  Patients  1  2  3  4  1  2  3  4  pre epi  post epi  1  646*  817*  781*  367*          54*    2    414*  319*  77*    −43*  −30*  −23*      3  1548  892  487  443  −193  −203  −130  −52  66  15  4  1285  1152  686  688  282  −44  −8  361  66  25  5  806  462  417  319  232  73  −18  −21  72  31  6  247  148  131  64  188  156  216  92  66  30  7  1393*  821*  238*  170*  −298*  −32*  −3*  −12*  66*  22*  8  984  748  465  448  −243  −155  145  −76  73  6  9  555  487  222  619  −555  −487  −222  −619  100  −13  10  1176  1037  1054  341  −38  −340  −331  542  83  25  11  465  272  195  191  −45  −25  50  31  75  10  12  570  517  575  693  52  6  256  248  63  12  13  258  198  197  190  −18  7  −67  −29  69  28  14  868  412  297  430  −136  −36  4  −89  70  25  15  217  1549  567  285  −23  −185  −64  312  71  22  16  187  576  342  176  1203  −90  −66  99  72  18  17  890  559  428  203  62  −42  −40  38  76  15  18  1626  553  397  232  −26  −20  25  18  58  22  19  660  551  357  482  −68  −25  −7  172  73  2  20  752  415  375  235  11  72  0  −98  70  13  21  913  873  369  271  764  57  −45  71  65  13  22  438  231  116  83  −24  −15  5  −17  65  27  *Patients who developed anastomotic leakage in italic, *patient who developed anastomotic leakage and died in bold. View Large The MAP was increased in all patients after the bolus of ephedrine, except for patient 9. In Figure 2 the effect of ephedrine on the measured perfusion in location 4 is depicted. The flux after ephedrine was significant higher compared to the flux in location 4 before ephedrine (P < 0.05) (Fig. 3). The flux in five patients responded really well to the administered ephedrine. This group of ‘responders’ had a mean age of 55.6 years (vs. 62 years), a body mass index (BMI) of 23.8 (vs. 26.4), developed no leakage (vs. 3), and had, except for one patient with Chronic Obstructive Pulmonary Disease (COPD), no comorbidities (vs. 7 comorbidities in the ‘nonresponding’ group). Interestingly, the MAP, SV, and CO were similar as in the ‘nonresponding’ group of patients (before ephedrine MAP 71 vs. 70 and after ephedrine MAP 88 vs. 88, SV 74 vs. 76, and CO 7.5 vs. 6.8). Fig. 3 View largeDownload slide Measurements of flux with LSCI in location 4 which is the fundus and thus the future anastomotic side before (preephedrine) and after (postephedrine) administration of a bolus of 5 mg ephedrine. Fig. 3 View largeDownload slide Measurements of flux with LSCI in location 4 which is the fundus and thus the future anastomotic side before (preephedrine) and after (postephedrine) administration of a bolus of 5 mg ephedrine. Perfusion diagnostics with LSCI We were able to analyze the flux within the region of interest (1 × 1 cm2) in the four perfusion zones of 18 patients (Fig. 4). Flux was significantly different between locations, most notably decreased in location 4 (328 ± 187 LSPU) compared to location 1 (791 ± 442 LSPU) (P < 0.001). After administration of 5 mg ephedrine the flux increased at location 4 in 11 patients. The flux at that position was again lower (380 ± 287 LSPU) compared to location 1 (894 ± 467 LSPU) of the gastric tube (P < 0.001). Fig. 4 View largeDownload slide Flux of gastric microcirculation measured in all locations (1: 3 cm under watershed; 2: watershed; 3: 3 cm above watershed; 4: fundus) before (A) and after 5 mg ephedrine (B) with a significant decrease of flux towards the fundus (P < 0.001). Fig. 4 View largeDownload slide Flux of gastric microcirculation measured in all locations (1: 3 cm under watershed; 2: watershed; 3: 3 cm above watershed; 4: fundus) before (A) and after 5 mg ephedrine (B) with a significant decrease of flux towards the fundus (P < 0.001). There was no significant correlation between flux and MAP, CI, CO, HR, or SV, measured with a linear regression. In three patients anastomotic leakage developed. We do see that flux measured in location 4 of two of these three leakage patients is lower compared to the mean flux measured in the other patients, both before (77 and 170 vs. 200) and after (−12 and −23 vs. 45) administration of ephedrine. However, the study population was too small to draw any conclusions to this. Time to obtain LSCI images was between 3 and 5 minutes. No change was observed in imaging time during the study (R2 = 0.04). DISCUSSION This study shows the feasibility of laser speckle contrast imaging to measure perfusion of the gastric conduit during gastric tube reconstructions. Moreover, we demonstrated the effect of ephedrine 5 mg on perfusion, quantitatively analyzed as flux depicted in LSPU, in the future anastomotic site of the gastric tube. LSCI was feasible to create a wide field overview of gastric microvascular perfusion intraoperative in a color-coded image. We demonstrated a small but significant effect of ephedrine 5 mg on the perfusion in the fundus of the gastric conduit (increase of 27%, P < 0.05) and we show a significant difference between the fundus (reduced perfusion) and watershed (good perfusion) of the gastric tube microcirculation (P < 0.001). Intervention with ephedrine increased the MAP with 18 ± 9 mmHg. Ephedrine also resulted in an increased flux measured in the gastric tube microcirculation of the fundus (P < 0.05). Interestingly, this increase of flux after administration of ephedrine was prominent in five patients. These ‘responders’ were younger compared to the ‘nonresponders’, had a lower BMI, less comorbidities, and developed no anastomotic leakage. This suggests a place for the administration of inotropes to improve perfusion for a selected patient group. Furthermore, these results show the feasibility of LSCI to quantitatively measure perfusion changes in the gastric conduit. Also, it indicates a role for ephedrine in optimizing perfusion during gastric tube reconstruction. Ephedrine is a vasopressor that has positive inotropic and chronotropic effects on the heart. It stimulates the sympathetic nervous system and therefore MAP and CO increase, but also inhibits the parasympathetic system, resulting in vasoconstriction of the gastrointestinal arteries and a decreased splanchnic perfusion.2,3 Our hypothesis was that ephedrine would create a fast change in MAP, CO, and flow enabling us to image change of localized perfusion with LSCI intraoperative. Previous studies show that ephedrine increases localized flow in contrast to other inotropes like noradrenaline.13 However, the effect of ephedrine is only 10–15 minutes. Future studies should investigate inotropes with a longer half-life time like dobutamine, which increases flow but decreases systemic blood pressure. What is the effect of ephedrine on flux? Jansen et al. showed in a phantom study that flux measured with LSCI is related to velocity of erythrocytes and the amount of moving particles.9 We therefore expect that the use of ephedrine results in higher flow, thus higher flux, although a smaller amount of particles will be imaged due to vasoconstriction. We observed an increase of localized perfusion on the fundus of the gastric tube, although the effect was smaller than expected. This limited effect can be explained by the vasoconstriction and by the fact that this perfusion site is on the boundary between the areas that are regulated by the sympathetic and parasympathetic nervous systems. In a recent study of the gastric tube perfusion with sidestream darkfield microscopy (Jansen et al. submitted, Annals of Surgery), venous congestion was clearly visible in locations 4. Venous congestions result in a decrease of gastric tube perfusion by the restriction of outflow. This restricted outflow could also explain the small effect of ephedrine on the flux in this location. Venous congestion in gastric tube surgery was described before by Murakami et al. who showed the improvement of blood flow after the reconstruction of a venous anastomosis at the future anastomotic side of the gastric tube.14 Buise et al. observed an increase of gastric tube perfusion after the administration of nitroglycerine, reducing venous congestions by vasodilatation.15 We demonstrate that LSCI enables us to quantitatively measure the influence of interventions on perfusion in the gastric tube during surgery. Perfusion diagnostics of the gastric tube with LSCI was previously described by Klijn et al. in an animal study.16 LSCI was used to evaluate the effect of an increase of mean arterial pressure on gastric tube perfusion, an effect that was not visible in that study. Milstein et al. showed the feasibility and the reliability of blood flow measurements intraoperatively in 11 patients undergoing gastric tube reconstructions. They also found a progressive decrease of flux toward the fundus. In that study they also demonstrated the capability of LSCI to measure changes in the perfusion, by changing the position of the patient during surgery. Flux significantly decreased across all locations during reverse Trendelenburg (P < 0.05).17 Although LSCI is capable of measuring difference in the perfusion, still several limitations exist. The first limitation of this study is the missing data on baseline perfusion, which could not be obtained during laparoscopic surgery. The gastric tube was reconstructed intrathoracic and therefore LSCI measurements of the intact gastric microcirculation could not be carried out as a baseline measurement. Second, it is important to note that the parameter flux given by LSCI in LSPU is not an absolute quantitative measure. By definition, flux is the flow rate per unit area depicted in, e.g. mL/(min area), however the correlation of the flux quantified in LSPU of the MoorFLPI system with the flow rate per unit area is lacking. The precise relation between the measured speckle contrast and the number of LSPU is not given either. Nadort et al. suggested a method to translate perfusion measurements by LSCI to a quantitative parameter (blood flow velocity), showing many steps (e.g. multiexposure images, convert raw speckle image to speckle contrast image, apply nonlinear curve fit to find, correct for offset decorrelation, estimate vessel diameter, and scattering events, in order to correct for multiple scattering)18 before LSPU can be translated to absolute flow or perfusion values. Although we can conclude that LSCI measurements do not give absolute perfusion or flux values, using the exact same settings (e.g. integration time, distance between camera and tissue, perpendicular imaging in relation to the tissue under study) relative intrapatient differences in perfusion can be determined and used in clinical settings. A third limitation of LSCI is the wide variation in flux values between patients as depicted in Figure 4. Therefore, interpatient evaluation is difficult. Prediction of the development of anastomotic leakage intraoperative based on these absolute flux values will be unlikely. We anticipate that in the future it is more likely that a relative parameter will predict the development of leakage. This parameter would then allow the surgeon to decide whether to react or not. In this regard it is interesting to note that in the patients that developed anastomotic leakage, a large difference in measured flux between the watershed and the fundus existed. Therefore, relative measurements as the decrease of flux in the gastric tube might be more indicative for leakage prediction than their values. However, this study population was too small to draw conclusions to this. Further studies that relate potential parameters with leakage development are needed. Within these studies, the potential of other techniques to measure perfusion intraoperatively and quantitatively can be considered, such as laser Doppler flowmetry,19–21 thermography,22 fluorescence imaging.23–28 These techniques differ from LSCI in terms of resolution, field of view, and image content. LSCI and thermography have the advantage that it creates color-coded wide field images. Due to the spatial heterogeneity of the microcirculation, wide field imaging is preferable above point measurements (as is used in laser Doppler flowmetry). Also in the case of thermography the quantitative measured parameters (change in temperature) has to be converted into perfusion or flux. Therefore, the organ has to be precooled and rewarmed in order to create good perfusion measurements. The disadvantage of fluorescence imaging is that the administration of a dye is needed, in contrast with LSCI. Conclusion We show the feasibility of LSCI to quantitative image the effect of ephedrine on microcirculation in the gastric tube perfusion in all patients. We depict a small but significant increase of perfusion after ephedrine 5 mg together with an increase of MAP. Moreover, we found a decrease of perfusion measured in the gastric tube toward the fundus. This amount of decrease could potentially be a more relevant parameter than their absolute values for future prediction of anastomotic leakage, enabling risk stratification in gastric tube reconstruction after esophagectomy. The authors would like to thank Martin van Gemert for his contribution to this manuscript. Moreover, they would like to thank ZonMw for their financial support and Institute Quantivision for their support in trial conception. Specific author contributions: SMJ made substantial contributions to conception and design, acquisition of data and data analysis and interpretation of data. Drafting the article and revising it critically, final approval of the submitted version; DMB, MIB and SSG made substantial contributions to conception and design, acquisition of data and interpretation of data. Revising the article critically, final approval of the submitted version; PRB made substantial contributions to conception and design, acquisition of data. Revising the article critically, final approval of the submitted version; SDS made substantial contributions to conception and design and the interpretation of data. Revising the article critically, final approval of the submitted version; DPV and TGL made substantial contributions to conception and design, interpretation of data. Revising the article critically, final approval of the submitted version. REFERENCES 1. Dyer R A, Reed A R, Dyk D Van, James M F. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology  2009; 111: 753– 65. Google Scholar CrossRef Search ADS PubMed  2. Nygren A, Ricksten S. Vasopressors and intestinal mucosal perfusion after cardiac surgery: Norepinephrine vs. phenylephrine. Crit Care  2006; 34: 722– 9. Google Scholar CrossRef Search ADS   3. Meng L, Cannesson M, Alexander B S et al.   Effect of phenylephrine and ephedrine bolus treatment on cerebral oxygenation in anaesthetized patients. Br J Anaesth  2011; 107: 209– 17. Google Scholar CrossRef Search ADS PubMed  4. El-Tahan M R. Preoperative ephedrine counters hypotension with propofol anesthesia during valve surgery: a dose dependent study. Ann Card Anaesth  2011; 14: 30– 40. Google Scholar PubMed  5. Lewis I. The surgical treatment of carcinoma of the oesophagus with special reference to a new operation for growths of the middle third. Br J Surg  1946; 34: 18– 31. Google Scholar CrossRef Search ADS PubMed  6. Briel JW, Tamhankar AP, Hagen JA et al.   Prevalence and risk factors for ischemia, leak, and stricture of esophageal anastomosis: gastric pull-up versus colon interposition. J Am Coll Surg  2004; 198: 536– 41. Google Scholar CrossRef Search ADS PubMed  7. van Hagen P, Hulshof M C C M C, van Lanschot J J B J et al.   Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med  2012; 366: 2074– 84. Google Scholar CrossRef Search ADS PubMed  8. Briers D, Duncan D D, Hirst E et al.   Laser speckle contrast imaging: theoretical and practical limitations. J Biomed Opt  2013; 18: 66018-9. Google Scholar CrossRef Search ADS   9. Jansen S M, de Bruin D M, Faber D J et al.   Applicability of quantitative optical imaging techniques for intraoperative perfusion diagnostics: a comparison of laser speckle contrast imaging, sidestream dark-field microscopy, and optical coherence tomography. J Biomed Opt  2017; 22: 9. Google Scholar CrossRef Search ADS   10. Vandenbroucke J P, von Elm E, Altman D G et al.   Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Int J Surg  2014; 12: 1500– 24. Google Scholar CrossRef Search ADS PubMed  11. Bossuyt P M. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem  2003; 49: 7– 18. Google Scholar CrossRef Search ADS PubMed  12. Borenstein M, Hedges L V, Higgins J P T, Rothstein H R. Introduction to Meta-Analysis . John Wiley Sons, 2009; 21– 32. Google Scholar CrossRef Search ADS   13. Buise M, Gommers D, De Jonge J, Van Genderen M, Bakker J, Van Bommel J. Effects of intravenous nitroglycerin and noradrenaline on gastric microvascular perfusion in an experimental model of gastric tube reconstruction. Crit Care  2009; 13: S72. Google Scholar CrossRef Search ADS   14. Murakami M, Sugiyama A, Ikegami T et al.   Revascularization using the short gastric vessels of the gastric tube after subtotal esophagectomy for intrathoracic esophageal carcinoma. J Am Coll Surg  2000; 190: 71– 77. Google Scholar CrossRef Search ADS PubMed  15. Buise M, van Bommel J, Jahn A, Tran K, Tilanus H, Gommers D. Intravenous nitroglycerin does not preserve gastric microcirculation during gastric tube reconstruction: a randomized controlled trial. Crit Care  2006; 10: R131. Google Scholar CrossRef Search ADS PubMed  16. Klijn E, Niehof S, de Jonge J et al.   The effect of perfusion pressure on gastric tissue blood flow in an experimental gastric tube model. Anesth Analg  2010; 110: 541– 6. Google Scholar CrossRef Search ADS PubMed  17. Milstein D M J, Ince C, Gisbertz S S et al.   Laser speckle contrast imaging identifies ischemic areas on gastric tube reconstructions following esophagectomy. Medicine (Baltimore)  2016; 95: e3875. Google Scholar CrossRef Search ADS PubMed  18. Nadort A, Kalkman K, van Leeuwen T G, Faber D J. Quantitative blood flow velocity imaging using laser speckle flowmetry. Sci Rep  2016; 6: 25258. Google Scholar CrossRef Search ADS PubMed  19. Boyle N, Pearce A, Owen WJ, Mason RC. Validation of scanning laser Doppler flowmetry against single point laser Doppler flowmetry in the measurement of human gastric serosal/muscularis perfusion. Int J Surg Investig  2000; 2: 203– 11. Google Scholar PubMed  20. Schilling M K, Redaelli C, Maurer C et al.   Gastric microcirculatory changes during gastric tube formation: assessment with laser Doppler flowmetry. J Surg Res  1996; 62: 125– 9. Google Scholar CrossRef Search ADS PubMed  21. Svensson H, Bergqvist D, Takolander R. Laser Doppler blood flow monitoring in reconstructive vascular surgery: case studies. Vasc Surg  1987; 21: 58– 65. Google Scholar CrossRef Search ADS   22. Pauling J D, Shipley J A, Raper S et al.   Comparison of infrared thermography and laser speckle contrast imaging for the dynamic assessment of digital microvascular function. Microvasc Res  2012; 83: 162– 7. Google Scholar CrossRef Search ADS PubMed  23. Rino Y, Yukawa N, Sato T et al.   Visualization of blood supply route to the reconstructed stomach by indocyanine green fluorescence imaging during esophagectomy. BMC Med Imaging  2014; 14: 14– 18. Google Scholar CrossRef Search ADS PubMed  24. Shimada Y, Okumura T, Nagata T et al.   Usefulness of blood supply visualization by indocyanine green fluorescence for reconstruction during esophagectomy. Esophagus  2011; 8: 259– 66. Google Scholar CrossRef Search ADS PubMed  25. Kubota K, Yoshida M, Kuroda J et al.   Application of the HyperEye Medical System for esophageal cancer surgery: a preliminary report. Surg Today  2013; 43: 215– 20. Google Scholar CrossRef Search ADS PubMed  26. Kumagai Y, Ishiguro T, Haga N et al.   Hemodynamics of the reconstructed gastric tube during esophagectomy: Assessment of outcomes with indocyanine green fluorescence. World J Surg [Internet]  2014; 38: 138– 43. Google Scholar CrossRef Search ADS   27. Yukaya T, Saeki H, Kasagi Y et al.   Indocyanine green fluorescence angiography for quantitative evaluation of gastric tube perfusion in patients undergoing esophagectomy. J Am Coll Surg  2015; 221: e37– 42. Google Scholar CrossRef Search ADS PubMed  28. Zehetner J, DeMeester S R, Alicuben E T et al.   Intraoperative assessment of perfusion of the gastric graft and correlation with anastomotic leaks after esophagectomy. Ann Surg  2015; 262: 74– 78. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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Diseases of the EsophagusOxford University Press

Published: Apr 13, 2018

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