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CRITICAL CARE AND TRAUMA

The Effect of Nitroglycerin on Microvascular Perfusion and Oxygenation During Gastric Tube Reconstruction

Marc P. Buise, MD^*, Can Ince, PhD, Hugo W. Tilanus, MD, PhD, Jan Klein, MD, PhD^*, Diederik Gommers, MD, PhD^*, and Jasper van Bommel, MD, PhD^*

Departments of *Anesthesiology and Surgery, Erasmus Medical Center, Rotterdam, and Department of Physiology, Amsterdam Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Address correspondence and reprint requests to M. P. Buise, Department of Anesthesiology, Erasmus Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Address e-mail to m.buise{at}erasmusmc.nl.

	Abstract

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Esophagectomy followed by gastric tube reconstruction is the surgical treatment of choice for patients with esophageal cancer. Complications of the cervical anastomosis are associated with impaired microvascular blood flow (MBF) and ischemia in the gastric fundus. The aim of the present study was to differentiate whether the decrease in MBF is a result of arterial insufficiency or of venous congestion. To do this we assessed MBF, microvascular hemoglobin oxygen saturation (µHbSo₂), and microvascular hemoglobin concentration (µHbcon) simultaneously during different stages of gastric tube reconstruction. In 14 patients, MBF was determined with laser Doppler flowmetry, and µHbSo₂ and µHbcon were determined with reflectance spectro- photometry. After completion of the anastomosis, nitroglycerin was applied at the fundus. Although MBF did not change significantly in the pylorus, MBF decreased progressively during surgery in the fundus from 210 ± 18 Arbitrary Units at baseline (normal stomach) to 52 ± 9 Arbitrary Units after completion of reconstruction (mean ± sem; P < 0.05). There was no change in µHbSo₂ and µHbcon during the reconstruction. After application of nitroglycerin, MBF doubled. We conclude that MBF decreases during gastric tube reconstruction but that µHbSo₂ and µHbcon do not. This decrease might be the result of venous congestion, which can partly be counteracted by application of nitroglycerin.

	Introduction

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Esophagectomy followed by gastric tube reconstruction is the surgical treatment of choice for patients with cancer of the esophagus (1). This operation is associated with frequent morbidity and mortality rates; complications associated with the gastroesophageal anastomosis are anastomotic leakage (5%–26%) and stenosis (12%–40%) (2). Although the cause of these complications is unknown, compromised microvascular blood flow (MBF) and hypoxia of the gastric tube are thought to be important factors. Perioperative evaluation of the tissue perfusion of the gastric tube is mainly based on clinical signs and is therefore subject to the judgement of the operating surgeon. Monitoring of systemic hemodynamic and oxygenation variables is not sufficient to ensure that the gastric tissue is provided with an adequate amount of oxygen. Therefore monitoring at the level of the tissue itself is necessary (3). To establish an objective measurement of both tissue blood flow and tissue oxygenation, accurate and clinically applicable techniques are required.

MBF in the cervical esophagogastrostomies has been studied with laser Doppler flowmetry (LDF), showing a decrease in MBF and an association between decreased MBF and impaired anastomotic healing (4–6). A perioperative decrease in tissue oxygen tension (Po₂) was observed using Clark-type tissue electrodes (7,8), suggesting that MBF and tissue Po₂ are related during gastric tube surgery. This is supported by the results from a pig model of gastric tube reconstruction in which a simultaneous decrease in MBF and tissue Po₂ was observed in the perioperative period, using LDF and Clark-type electrodes, respectively (9). These observations have been attributed to arterial insufficiency of the gastric tube resulting from the technique of gastric tube reconstruction. However, we think that venous congestion also plays a role in the decrease of MBF. Impaired arterial blood supply would lead to tissue with a pale appearance, whereas venous congestion produces tissue with a darker character. It is our observation that the fundus of the stomach has a blue color at the end of gastric tube reconstruction.

No clinical study combining the assessment of MBF and tissue oxygenation has been performed. The aim of the present study was to determine whether the decrease in MBF is a result of arterial insufficiency or of venous congestion. To do this we assessed MBF, microvascular hemoglobin oxygen saturation (µHbSo₂) and microvascular hemoglobin concentration (µHbcon) simultaneously at the gastric serosa during different stages of gastric tube reconstruction. We had three hypotheses: first, that a decrease in MBF, in combination with a decrease in µHbSo₂ and µHbcon, would be caused by arterial insufficiency; second, that a decrease in MBF with a simultaneous increase in µHbcon and preservation of µHbSo₂ would be the result of venous congestion; and third, that in the case of venous congestion the topical application of nitroglycerin (NTG) may restore MBF by vasodilatation but may not restore the MBF in case of impaired arterial blood supply resulting from ligation of the arteries during reconstruction.

	Methods

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With approval of the local institutional human investigations committee, and after obtaining written informed consent, microvascular measurements were performed in 14 patients. Twelve men and two women were scheduled for elective esophageal resection and reconstruction. All patients were ASA physical status I and II, and were aged between 42 and 78 yr.

General anesthesia was induced with propofol (1–2 mg/kg) or etomidate (0.15–0.3 mg/kg) and with sufentanil (0.2–0.4 µg/kg) or fentanyl (5–10 µg/kg) and a nondepolarizing muscle relaxant. Anesthesia was maintained by inhaled anesthesia with a combination of isoflurane (0.8–1.2 end-tidal percentage) and air in all patients. No patient received nitrous oxide. Before the induction of general anesthesia, a thoracic epidural catheter was placed to provide perioperative and postoperative analgesia. In all patients epidural blockade was started with a bolus of 12 mL, 1.5 mL per segment from T4 to T12, bupivacaine 0.175%, and sufentanil (2 µg/mL) before starting the operation. After 90 min bupivacaine 0.125% combined with fentanyl 2.5 µg/mL was started in a dosage of 10 mL/h.

All patients were ventilated with volume control, 8 mL/kg and a frequency to achieve an end-tidal CO₂ of 4.5–5.5 kPa. Fio₂ was 40% and positive end-expiratory pressure was set at 5 cm H₂O. Standard hemodynamic monitoring was used in all patients, and included radial arterial blood pressure and right atrial pressure (RAP) measurements through a central venous catheter placed in the left internal jugular vein. Fluid management was performed using hydroxyethyl starch (Voluven®, Fresenius, Hertogenbosch, the Netherlands) and lactated Ringer's solution to maintain mean arterial blood pressure (MAP) more than 60 mm Hg and RAP between 12 and 16 mm Hg (measured RAP – 1/3 of ventilation plateau pressure). Arterial oxygen and carbon dioxide partial pressures, hemoglobin concentration, and hemoglobin saturation were determined (ABL 707, Radiometer, Copenhagen, Denmark).

Two operation techniques were used: transhiatal (13 patients) and transthoracic esophagectomy (one patient). In both techniques, the gastric tube is constructed by means of ligation of the left gastric artery, the right gastric artery, the short gastric arteries, and the left gastroepiploic artery, and then fashioned along the greater curvature. The arterial supply of the gastric tube depends on the right gastroepiploic arterial arcade (10).

µHbSo₂ was measured using reflectance spectrophotometry (RS). The tissue was illuminated with visible white light (500–630 nm), which is back-scattered mainly by mitochondria and changed in color by hemoglobin according to the oxygen saturation status. This reflected spectrum is detected and analyzed by a spectrophotometer with a frequency of more than 100 times per second. The µHbSo₂ can be determined according to the equation Hbsat = Cox/Cox + Cdeox, in which Cox is the concentration of oxygenated hemoglobin and Cdeox is the concentration of deoxygenated hemoglobin expressed as a percentage. In addition, the relative µHbcon is calculated as a relative value: Hbcon = Hbox + Hbdeox, in Arbitrary Units (AU) (11,12). Previously, we have described the clinical usability of RS and its value for the assessment of microvascular oxygenation (3,13).

LDF is a well-established technique for the assessment of MBF (3,14) that has been used frequently during gastric tube reconstruction (2,4,15). MBF is determined by analysis of the power spectra of backscattered laser light (820 nm). All moving blood cells in the tissue generate Doppler frequencies that are displayed as power spectra. The power spectra show the complete distribution of Doppler shifts; hence a histogram of erythrocyte velocities is measured. The MBF value is defined mathematically as the first moment of the Doppler power spectra, so it relates to the velocity of the erythrocytes times the number of moving erythrocytes and is described in AU.

The microvascular variables MBF, µHbSo₂, and µHbcon were determined simultaneously using the O2C® (Lea Medizin Technik, Giessen, Germany). This device combines the two optical techniques, LDF and RS, in one optic fiber, allowing the measurements to be obtained at the same time and in the same place. There is no interference between the two techniques because they are operating in a different light wave range. We used a flat probe, which contains five optic fibers (Fig. 1). The measurement depth is determined by the distance between the illuminating and detecting fibers and by the absorption and reflection capacity of the tissue. The surface diameter of the probe was 14 mm and the distance between the fibers was 6 mm, corresponding with a measurement depth of 4–6 mm.

View larger version (82K): [in this window] [in a new window]   Figure 1. Photograph of the flat probe used with a normal match for size comparison. The outer diameter of the probe is 14 mm and the distance between the illuminating and detecting fibers is 6 mm (used with permission of Lea Medizin Technik, Giesen, Germany).

After opening the abdomen but before compromising the vascularization of the stomach, baseline values (T = 0) of MBF, µHbSo₂, and µHbcon were determined. An average of 4 measurements (with a time interval of 30 s) was obtained from 3 positions: the prepyloric antrum, the corpus at the greater curvature, and the fundus of the stomach, where the future anastomosis of the gastric tube was expected. The surgeon placed the probe, gently touching the surface of the serosal side of the stomach. Pressure artifacts were detected by an obvious decrease in signal in both LDF and RS curves and a change in configuration of the RS signal. After T = 0 the measurements were repeated 4 times: T = 1, after ligation of the left gastric artery, the gastric short vessels, and the left gastroepiploic artery; T = 2, after construction of the gastric tube; T = 3, after pulling the gastric tube up to the neck; and T = 4, after application of NTG. At T = 3, measurements at the corpus were not performed because of the intrathoracic position of the reconstruction. At T = 4, NTG was applied locally after the completion of the anastomosis. Nitroglycerin 25 mL 1.0 mg/mL (Nitro Pohl, Transmedico BV, Weesp, the Netherlands) was sprinkled over a 10 x 10 cm gauze. The gauze was then placed at the anastomotic site. After 2 min, the gauze was removed and the microvascular measurements were repeated. Parallel with the microvascular measurements, arterial blood samples were taken and systemic hemodynamics were recorded.

Values are reported as mean ± sem. Each variable was analyzed using analysis of variance for repeated measures. Measurements at the different sites were compared at each stage using one-way analysis of variance. When appropriate, post hoc analyses were performed with the Student-Newman-Keuls test. P values < 0.05 were considered significant. All analyses were performed with GraphPad Prism (version 3.0, GraphPad Software, San Diego, CA).

	Results

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MAP was 71 ± 5 mm Hg at T = 0 and did not change significantly during the procedure. In 3 patients vasopressors were administered at different stages of the procedure to maintain a MAP more than 60 mm Hg: once dopamine at T = 0 and twice phenylephrine, at T = 1 and T = 2. RAP was 15 ± 1 mm Hg at all measurements. Volume resuscitation was performed with mean volumes of 1500 ± 35 mL of colloid and 6430 ± 140 mL of crystalloid solutions. Mean arterial hemoglobin concentration was 9.6 ± 0.3 g/dL at T = 0 and decreased to 8.1 ± 0.2 g/dL at T = 4. Mean blood loss was 1392 ± 185 mL. Four patients received a blood transfusion, 2 patients received 1 U of packed cells, and 2 patients received 2 U of packed cells. At baseline, mean arterial hemoglobin saturation was 99% ± 0.2%; arterial Po₂ was 24 ± 3 kPa. Both variables did not change significantly during the operation. Systemic variables are shown in Table 1. All patients were kept normothermic throughout the procedure.

Baseline measurements of the gastric microcirculation showed a µHbSo₂ of 65% ± 4% at the pylorus, 66% ± 4% at the corpus, and 56% ± 5% at the top of the fundus. The µHbSo₂ values at the pylorus, the corpus, and the fundus were the same and did not change significantly during the operation (Fig. 2).

View larger version (28K): [in this window] [in a new window]   Figure 2. Microvascular blood flow (MBF), microvascular hemoglobin saturation (µHbSo2), and microvascular hemoglobin concentration (µHbconc) measured at the gastric pylorus and fundus during gastric tube reconstruction. Only the MBF at the fundus and pylorus decreased, whereas no significant change was observed in µHbSo2 and µHbconc. Data from the corpus are not shown but were identical to those from the pylorus. Values represent mean ± sem. *P < 0.05 versus baseline.

At baseline, MBF showed no significant difference at the 3 measurement sites: 200 ± 18 AU at the pylorus, 207 ± 8 AU at the corpus, and 210 ± 11 AU at the fundus. During the ensuing 3 stages of the operation, only the MBF at the top of the fundus decreased significantly, to 52 ± 9 AU. At the pylorus there was no change in MBF (Fig. 2). The µHbcon at baseline was 70 ± 4 AU at the pylorus, 66 ± 5 AU at the corpus, and 70 ± 2 AU at the fundus. These values were not statistically different and did not change significantly during the operation (Fig. 2). For reasons of clarity, only the data from the pyloric region and the fundus are shown because there was no difference between the values from the pyloric region and the corpus.

When the gastric tube reconstruction was finished, the topical application of NTG at the fundus (T = 4) doubled the MBF from 52 ± 9 AU to 100 ± 14 AU (P < 0.05). The increase in MBF was not accompanied by a statistically significant change in the other microvascular and systemic variables (Fig. 3).

View larger version (14K): [in this window] [in a new window]   Figure 3. Microvascular blood flow (MBF), microvascular hemoglobin saturation (µHbSo2), and microvascular hemoglobin concentration (µHbconc) measured near the cervical anastomosis after completion of the gastric tube reconstruction (T3) and after local application of nitroglycerin (NTG). Only MBF could be improved with administration of NTG. Values represent mean ± sem. *P < 0.05 versus T3.

	Discussion

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The main result of the present study is that during gastric tube reconstruction a decrease in MBF of almost 75% occurs at the fundus without significant changes in µHbSo₂ and µHbcon. A decrease in gastric MBF has been reported in previous clinical studies (4–6), but this was never related to a simultaneous measurement of µHbSo₂ and µHbcon.

According to our hypothesis, an increase in µHbcon and a gradual decrease in µHbSo₂ would be expected to occur in the presence of venous congestion. However, in this respect the short interval of measurement, which was restricted by the limited access to the gastric tissue during surgery, may be a limitation of our study: this effect may be more profound in the postoperative period. Based on these results, it can be concluded that venous congestion plays a role in the decrease of MBF during gastric tube reconstruction.

The importance of venous congestion has already been demonstrated by Murakami et al.(16), who showed a significant increase of MBF after performing a venous anastomosis between the short gastric vein and the internal and external jugular veins. Venous congestion has often been attributed to intrathoracic compression and twisting of the gastric tube (17). The results of the present study demonstrate that MBF is already compromised before closure of the thorax and can be improved without changing the pressure inside the thorax or repositioning of the gastric tube.

Our observation of a preserved µHbSo₂ seems to contradict previous studies showing that tissue Po₂ of the gastric tube decreases during the operation (7,8). The accuracy of our technique is confirmed by the comparison of our baseline measurements with the results of previous studies applying RS in gastric tissue (18). If both techniques (RS and tissue electrodes) are compared, a few remarks can be made that might explain the apparent differences. In the assessment of microvascular oxygenation it is difficult to determine which compartment is really being measured (3). The catchment depth of the oxygen electrode has been estimated to be approximately 15–20 µm, compared with a penetration depth of 4–6 mm with RS. Oxygen electrodes are limited by their sensitivity to oxygen. Vessels carrying high Po₂ blood in the catchment volume of the electrode can bias the electrode value despite the surrounding tissue being hypoxic; tissue electrodes are sensitive to changes in arterial Po₂. Presumably, the µHbSo₂ measured with RS originates from another compartment than the Po₂ measured with tissue electrodes (3).

The second observation made in our study is that MBF increases by 100% after local application of NTG. NTG has been shown to improve MBF during septic shock (19). The use of topical application of vasodilators to reverse disturbances in MBF in septic patients was described by DeBacker et al. (20). In addition, MBF in the gastric tube fundus has been observed to increase after systemic administration of prostaglandin E1 as well (21). These observations suggest that vasoconstriction in the gastric tube, leading to a decrease in MBF, can be counteracted by administration of a vasodilator (21). This is confirmed by our results and emphasizes the role of venous congestion in this process. In arterial insufficiency a local application of a vasodilator could not be expected to restore the effect of vascular ligation in another part of the gastric tube. Whether vasodilating substances such as NTG can influence the metabolism of the tissue itself, and thereby affect variables of microvascular oxygenation, remains to be determined.

Finally, we have demonstrated the clinical applicability of a device combining RS with LDF for the simultaneous measurement of µHbSo₂ and MBF during major surgery. No clinical study combining the assessment of tissue oxygenation and MBF has been performed.

In conclusion, MBF was decreased during gastric tube reconstruction but µHbSo₂ and µHbcon were not. Topical administration of the vasodilator NTG improved MBF, possibly as a result of general vasodilatation and decreased venous congestion. Further research will be required to provide more insight into the relationship between MBF and µHbSo₂ and µHbcon in gastric tissue and the effect of perioperative administration of systemic NTG on these variables and on patient outcome.

	Footnotes

 
A poster presenting the results of this study was awarded as the best presented poster at the annual meeting of the European Society of Intensive Care Medicine, Amsterdam, The Netherlands, 2003.

Accepted for publication September 27, 2004.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Buise, M. P. Articles by van Bommel, J. Search for Related Content PubMed PubMed Citation Articles by Buise, M. P. Articles by van Bommel, J. Related Collections Critical Care Monitoring (Non-cardiac)