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1.IntroductionA spectroscopic method1 of assessing the oxygenation status of tissue was adapted using a simple two-optical-fiber probe suitable for use via laparoscopy. In contrast to pulse oximetry,2, 3, 4, 5 which measures arterial blood oxygenation, and Doppler flowmetry,6, 7, 8 which measures a combination of blood volume and blood flow velocity, this steady-state measurement separately measures the blood volume fraction (B) and hemoglobin oxygenation (S) in the mixed arteriovenous microvasculature, and B and S together characterize the oxygen content in the tissue. The near-infrared wavelength has been used9, 10 for sampling with deep probing (>1 cm), but in this work, we tested shallow (<5 mm) monitoring of tissue oxygenation during human esophagectomy,11 which is the surgical procedure of removal of a cancerous esophagus and restoration of gastrointestinal continuity with part of the stomach that is remodeled to serve as a gastric conduit tube. To mobilize the stomach tissue that will become the conduit, the tethering short gastric and left gastric arteries must be surgically ligated. The right gastroepiploic artery is the sole remaining vessel supplying the gastric conduit, and consequently the blood supply is decreased to the very tissue that must be anastamosed to the remaining esophagus in the patient's neck. Ischemia is known to impact the occurrence rates of the two types of complications that can result in this surgery: 1. stricture, which can be treated postsurgically, and 2. anastomotic failure/leak, which leads to sepsis, a far more dangerous complication. Anastomotic failure requires surgical intervention to fix leakage at the anastomosis connecting the gastric conduit to the pharynx. Postmortem examination of gastric conduits in postesophagectomy patients showed that the blood supply of the proximal 20% of the gastric conduit was through a microscopic network of capillaries and arterioles.12 Ischemia of the gastric conduit due to altered arterial inflow and venous drainage has been implicated in high anastomotic leak rates.12, 13, 14, 15, 16, 17 Karl 18 reported that the incidence of anastomotic leak ranges between 3.5 and 19%. Similar results19 report 4.2% for anastomosis in the thoracic region and 15.5% for the cervical region. Many factors influence the outcome, but adequate oxygenation at the anastamosis is critical to success. Anastamosis strength has been correlated with oxygen by Karliczek, 20 who showed that partially ischemic anastomoses had diminished breaking strength. There is currently no commercial means to monitor oxygenation of the anastomosis. Anastomotic leaks present too late for effective preventative intervention. Anastomotic leak contributes substantially to the 5% mortality11 rate associated with esophagectomy, therefore any method of early detection for the scheduling of prefailure intervention would improve patient outcome. Detection of a significant decrease in normal tissue oxygenation at the anastomosis could alert the surgeon that the conduit or anastamosis may be at risk for ischemic injury, and further diagnostic and therapeutic intervention must be scheduled. This probe system contributes to the movement of steady-state optical spectroscopy21, 22, 23, 24, 25, 26 into clinical practice.9, 10 , 27, 28, 29 Fiber optic spectroscopy can be implemented with a small footprint (two 1-mm-diam optical fibers placed 3 mm apart) and can avoid the dangers of placing electrical components in the patient. The probe measures a strong steady-state light signal, as opposed to a pulse oximetry unit3 that must lock onto a weak pulsatile signal to extract information. The oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) molecules exhibit distinct absorption properties in the visible spectral range. The spectroscopic analysis utilizes the absorption spectra of oxy- and deoxyhemoglobin and optical diffusion theory, incorporating the tissue scattering properties and blood absorption to estimate the blood volume fraction (B) and the oxygen saturation of hemoglobin [S = HbO2/(Hb+HbO2)] in the mixed arteriovenous microvasculature. 2.Materials and MethodsFiberoptic probes were prepared for sterile, one-time use on patients using standard machining and fiber polishing tools. The clear, 8-mm-diam cylindrical probe tip had 1-mm-diam holes drilled parallel to its axis at a separation distance of about 3 mm. Plastic fibers (NT02–534, Edmund Optics, Barrington,New Jersey) were used for flexibility and safety. The delivery fiber and a second identical fiber for light collection were polished along with the probe tip face to achieve one clear planar surface. Because the probes were hand-made, the separation distance varied from r = 2.5 to 3.5 mm, and for each probe this fiber separation was measured and cataloged for use in subsequent spectral analysis. In the operating room, two sterile 4-m-long fibers delivered and collected light between the surgeons and the “scrubbed in” engineer outside of the surgical sterile zone. A white light source (HL-2000-LL, Ocean Optics, Dunedin, Florida) was coupled to the plastic fiber with a standard SMA connector (11040A, Thor Labs, Newton, New Jersey). A thin glass fiber of 100-μm core diameter (BFL22–200, Thor Labs, Newton, New Jersey) was coupled between the collection fiber and the spectrometer (QE 65000 using the OOI Base32 Spectrometer Software, Ocean Optics, Dunedin, Florida), which improved the resolution of the spectrometer. The spectrometer was controlled by a laptop computer (Dell Computer, Round Rock, Texas) running the Windows XP Professional operating system. The wavelength response of the probe depended on the wavelength dependence of the light source S(λ) [W], and of the detector D(λ) [counts/W]. Measured spectra of tissue were normalized by a measured spectrum of a white standard while holding the fiber a 3 cm from the standard, yielding the measurement M in Eq. 1: Eq. 1[TeX:] \documentclass[12pt]{minimal}\begin{document}\begin{eqnarray} M &=& \frac{{S(\lambda)T_{\rm tissue} A_{\det} \eta _{\rm tissue} D(\lambda)}}{{S(\lambda)R_{\rm std} \eta _{\rm std} D(\lambda)}} \nonumber\\ &=& T_{\rm tissue} \frac{{A_{\det} \eta _{\rm tissue}}}{{R_{\rm std} \eta _{\rm std}}} = R_{\rm tissue} {\rm CALIB}, \end{eqnarray}\end{document} M=S(λ)TtissueAdetηtissueD(λ)S(λ)RstdηstdD(λ)=TtissueAdetηtissueRstdηstd=RtissueCALIB,M=S(λ)TtissueAdetηtissueD(λ)S(λ)RstdηstdD(λ)=TtissueAdetηtissueRstdηstd=RtissueCALIB,The probe was introduced percutaneously into the abdominal cavity through a 10-mm-diam trocar, and placed on the gastroesophageal anastamosis by the surgeons using surgical forceps via a second trocar. Visualization was by endoscopy through a third trocar. The endoscope light was turned off for spectral measurements. Spectra were collected at five time points during the surgery: 1. a baseline value, 2. after division of the short gastric arteries, 3. after division of the left gastric artery, 4. after creation of the gastric conduit, and 5. after completion of the anastamosis. At each time point, five measurements were taken in rapid succession at each of three locations (n = 15, although sometimes the surgeon measured fewer sites) within 2 cm of a marking stitch that identified the measurement location on the caudal side of the anastamosis site during creation of the gastric conduit. The integration time for each measurement was about 200 ms, but was adjusted for each measurement to obtain adequate signal without saturation of the spectrometer. Each spectrum was recorded with its integration time, and subsequent data analysis used the counts per spectral bin divided by the integration time [counts/bin/s]. The placement of the probe by the surgeon was important for a reliable spectral mesurement, and since the surgeon had only visual feedback on whether a successful placement had occurred, often several of the placements at one site were not reliable. Therefore, following spectral analysis (see next), the median of B and S values deduced from spectra were used for evaluation of tissue status, which rejected outliers and found the center of the cluster of measurements at a particular surgical step. The spectra were analyzed in the range 500 to 650 nm by least squares fitting using fminsearch() in Matlab (Mathworks, Natick, Massachusetts), which is a multidimensional unconstrained nonlinear minimization (Nelder-Mead). The measurement M in Eq. 1 was simulated as M theory by the expression: Eq. 2[TeX:] \documentclass[12pt]{minimal}\begin{document}\begin{equation} M_{{\rm theory}} = {\rm CALIB\ get}\ Rr(\mu _{a}, \mu _{s} ^\prime, r,n). \end{equation}\end{document} Mtheory=CALIBgetRr(μa,μ′s,r,n).The least-squares fitting minimized the error parameter ERROR = sum{log[M(λ)] – log[M theory(λ)]}2. The function getRr() in Eq. 2 was based on the diffusion theory expression of Farrell, Patterson, and Wilson22 for flux escaping at a distance r from a source fiber when placed topically on a tissue. The fiber separation was r ≈ 0.3 cm (adjusted to the actual r of each constructed probe), and the refractive index mismatch between plastic and tissue was assumed to be n = 1.10. Equation 2 required the absorption coefficient μa [cm–1] and the reduced scattering coefficient μ's [cm–1], discussed later. The use of this analytical expression was valid, since the 3-mm source-detector separation was large compared to the transport mean free path [1/(μa + μ's) = 1.26 mm at 630 nm], and the reduced scattering dominated over the absorption. The absorption coefficient of the tissue was specified: Eq. 3[TeX:] \documentclass[12pt]{minimal}\begin{document}\begin{equation} \mu _a = B(S\mu _{a,{\rm oxy}} + (1 - S)\mu _{a,{\rm deoxy}}) + W\mu _{a,{\rm water}}, \end{equation}\end{document} μa=B(Sμa,oxy+(1−S)μa,deoxy)+Wμa,water,Eq. 4[TeX:] \documentclass[12pt]{minimal}\begin{document}\begin{equation} \mu _s ^\prime = \mu _{s\ {\rm 630}_{\rm nm}} ^\prime \left({\frac{\lambda}{{630\ {\rm nm}}}} \right)^{- b}, \vspace*{10pt} \end{equation}\end{document} μ′s=μ′s630nm(λ630nm)−b,Table 1Median of ∼15 measurements per subject of blood volume fraction (B) and hemoglobin oxygen saturation (S) at the anastamotic site after each surgical step (1 = baseline, 2 = short gastric arterial ligation, 3 = left gastric artery ligation, 4 = completion of the conduit, 5 = completion of anastamosis) The 16 patients with no post-surgery complications, and the seven patients with postsurgical complications are listed. (NA = measurement not available.)
A total of 1439 spectra were acquired, and 1063 spectra were accepted as good on the basis of the least-squares fitting convergence, and the parameter ERROR was below a threshold value appropriate for excluding obvious outliers. The means and standard deviations for the fitted parameters for all the accepted spectra were B = 0.0151±0.0067 and S = 0.453±0.162, for n = 100 median values on sites from 23 subjects and five surgical steps. 3.ResultsTable 1 shows the statistics for accepted data for each time point during the surgery. There was a progressive drop in S and rise in B, until the anastamosis was completed. Figure 1 shows a sample spectrum from each surgical step where the saturation followed the typical trend. In general, after the first step (division of short gastric arteries), S dropped slightly, but B remained constant. The subsequent steps (division of left gastric artery, creation of conduit) caused a further and larger drop in S and rise in B. After completion of the anastamosis, S recovered partially but B remained high. Compared to patients without anastomotic complications, those who manifested anastomotic complications had greater intraoperative changes in S and B. Table 2 shows the statistically significant p values of less than 0.05 for such complications that exhibited low blood volume fractions at step 2, and poor oxygen saturation as well as low blood volume fractions at step 4. Fig. 1DownloadTable 2Mean Values ± standard deviations for the grouped median measurements at the surgical steps shown in Table 1. Statistical significance is denoted by bold p values, as determined with a 1-tailed student T-test assuming unequal variance. The top section (A) expresses the raw data, in while the lower section (B) expresses the data as a fraction of the baseline value for only the patients with baseline measurments.
There were complications, either leakage or strictures, in 7 of the 23 subjects. A threshold value S th was chosen for the minimum value of oxygen saturation (S) at either the completion of the conduit (surgical step 4) or the completion of the anastamosis (surgical step 5). If the mean value of S for either surgical step dropped below S th, a complication was predicted. Figure 2 is a receiver-operator curve (ROC) that shows the sensitivity (S e) and specificity (S p) for predicting complications using different values of S th. The S e = S p = 0.71 when S th = 0.230. Figure 2 shows a similar ROC using a threshold blood content B th as the discriminator, yielding S e = S p = 0.57 when S th = 0.0127. Fig. 2Download4.DiscussionWhile the number of patients tested and complications arising are still low, the preliminary data suggest that tissue oxygen saturation (S) may identify when the anastamoses is at risk for complications. Blood content (B) is less predictive, but can also contribute to assessing risk. Flagging patients at risk for extra attention in postoperative care should prove useful in patient management. AcknowledgmentsThis work was supported in part by the Oregon Clinical and Translational Research Institute (OCTRI) and in part by the National Institutes of Health, USA (NIH RO1-HL084013). Dan Gareau is supported by an NIH National Research Service Award (NIH 5-T32-CA106195, PI: Molly Kulesz-Martin). ReferencesD. A. Benaron,
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