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Jimenez, Ramon E.; Warshaw, Andrew L.; Rattner, David W.; Willett, Christopher G.; McGrath, Deborah; Fernandez-del Castillo, Carlos
doi: 10.1001/archsurg.135.4.409pmid: 10768705
HypothesisStaging laparoscopy in patients with pancreatic cancer identifies unsuspected metastases, allows treatment selection, and helps predict survival.DesignInception cohort.SettingTertiary referral center.PatientsA total of 125 consecutive patients with radiographic stage II to III pancreatic ductal adenocarcinoma who underwent staging laparoscopy with peritoneal cytologic examination between July 1994 and November 1998. Seventy-eight proximal tumors and 47 distal tumors were localized.InterventionsBased on the findings of spiral computed tomography (CT) and laparoscopy, patients were stratified into 3 groups. Group 1 patients had unsuspected metastases found at laparoscopy and were palliated without further operation. Group 2 patients had no demonstrable metastases, but CT indicated unresectability due to vessel invasion. This group underwent external beam radiation with fluorouracil chemotherapy followed in selected cases by intraoperative radiation. Patients in group 3 had no metastases or definitive vessel invasion and were resection candidates.Main Outcome MeasureSurvival.ResultsStaging laparoscopy revealed unsuspected metastases in 39 patients (31.2%), with 9 having positive cytologic test results as the only evidence of metastatic disease (group 1). Fifty-five patients (44.0%) had localized but unresectable carcinoma (group 2), of whom 2 (3.6%) did not tolerate treatment, 20 (36.4%) developed metastatic disease during treatment, and 21 (38.2%) received intraoperative radiation. Of 31 patients with potentially resectable tumors (group 3), resection for cure was performed in 23 (resectability rate, 74.2%). Median survival was 7.5 months for patients with metastatic disease, 10.5 months for those receiving chemoradiation, and 14.5 months for those who underwent tumor resection (P=.01 for group 2 vs group 1; P<.001 for group 3 vs group 1).ConclusionsStaging laparoscopy, combined with spiral CT, allowed stratification of patients into 3 treatment groups that correlated with treatment opportunity and subsequent survival. Among the 125 patients, laparoscopy obviated 39 unnecessary operations and irradiation in patients with metastatic disease not detectable by CT. Laparoscopic staging can help focus aggressive treatment on patients with pancreatic cancer who might benefit.THE MAIN GOAL of staging protocols for pancreatic cancer is to categorize patients into groups to optimize strategic decisions and response to treatment. Three groups are frequently recognized. The first group includes individuals who present with metastatic disease. Surgery is best avoided in these patients in view of their short survival time, and chemotherapy is their principal treatment modality.The second group comprises patients with advanced local disease (ie, major vascular invasion) but without metastases. These patients can benefit from external beam radiotherapy (EBRT) combined with chemotherapy and, according to their response, are candidates for intraoperative radiation (IORT).A third and last subpopulation is patients with resectable tumors. These individuals may benefit from transfer to a tertiary referral center where pancreatic resection can be performed with low mortality rates.They may also be candidates for protocols that combine surgery and IORT or local hepatic chemotherapy and aim to improve current surgical results.The most powerful noninvasive diagnostic test for evaluation of suspected pancreatic cancer is high-resolution, contrast-enhanced spiral computed tomography (CT).Computed tomography is more than 95% accurate in predicting unresectability by identifying tumor extension into adjacent viscera, hepatic and/or peritoneal metastases, and vascular invasion (particularly of the celiac axis, superior mesenteric vessels, or portal vein). However, multiple studieshave shown that up to 40% of tumors predicted to be resectable by CT are not resectable during surgical exploration. In most cases, lesions missed are beyond the resolution of current radiologic imaging and include both small implants on the peritoneal surfaces of the liver, abdominal wall, stomach, intestines, or omentum and micrometastases indicated by cytologic examination of peritoneal washings. Successful detection of such tumor dissemination depends on access to the peritoneal cavity and visual inspection, which at present can only be achieved by laparoscopy or laparotomy. Therefore, precise preoperative staging of pancreatic malignant neoplasms requires a diagnostic laparoscopy.In this study, we reviewed our experience with laparoscopic staging of patients with pancreatic cancer during the past 4 years. Our goals were 2-fold. First, we evaluated the contribution of staging laparoscopy in identifying patients with metastatic, locally advanced, and resectable disease. Second, we analyzed if this stratification of patients correlates with disease survival, which is the ultimate goal of any staging protocol.PATIENTS AND METHODSA total of 125 consecutive patients with radiographic stage II to IIIpancreatic ductal adenocarcinoma underwent staging laparoscopy at our institution between July 1994 and November 1998. Histologic confirmation of diagnosis was ultimately obtained in all cases. Patients with radiologic stage I pancreatic cancer (tumors <2 cm) are not included, since we do not perform laparoscopy in these cases given the low yield of unsuspected metastases. Patients with bile duct, ampullary, duodenal, and pancreatic endocrine or acinar tumors were excluded from the study population, as were patients with cystadenocarcinoma or intraductal papillary mucinous tumors. In addition, patients with gastric outlet obstruction were excluded, because laparotomy was indicated regardless of the findings at laparoscopy. All patients underwent thin-section, contrast-enhanced spiral CT preoperatively to evaluate the primary tumor and adjacent structures, rule out metastatic disease, and evaluate large vessel invasion (portal vein, superior mesenteric vessels, and celiac axis). Angiography was used in a small minority of patients (n=21) in whom CT findings were questionable. All patients without metastatic disease, irrespective of vessel invasion, were considered candidates for laparoscopy.Based on the combined findings of CT and laparoscopy, patients were divided into 3 groups according to the management algorithm illustrated in Figure 1. Patients in group 1 were found to have unsuspected metastases at laparoscopy and were offered chemotherapy, some opting for no treatment. Group 2 patients, who had no metastases detected at laparoscopy but had obvious vessel encasement apparent on CT, underwent EBRT with fluorouracil chemotherapy. Selected patients who completed this regimen without interval development of metastatic disease received a booster dose of IORT. Finally, patients in group 3 had no metastatic disease at laparoscopy and only vessel encroachment but not encasement apparent on CT. These patients were considered candidates for resection.Figure 1.Management algorithm for patients with locally advanced pancreatic cancer at Massachusetts General Hospital, Boston. CT indicates computed tomography; EBRT, external beam radiotherapy; and IORT, intraoperative radiation.Patient survival from the date of staging laparoscopy was assessed during February and March 1999 and this information was available for 95% of patients. Survival data were obtained through telephone interviews with patients or family members, physicians' and surgeons' office notes, or the hospital cancer registry. Data obtained are presented as Kaplan-Meier survival curves.Statistical analysis involved the Fisher exact test and Wilcoxon rank sum test (for Kaplan-Meier plots). P<.05 was accepted as significant.The main purpose of laparoscopy is to identify metastatic dissemination not detectable by CT. Patients undergo examination under general anesthesia as outpatients or with a 23-hour observation stay. Following establishment of pneumoperitoneum, a 10-mm trocar is inserted through a small infraumbilical incision. The telescope is introduced through this trocar, and examination begins by inspection of the lower abdomen and pelvis. The lower abdomen is a frequent site of peritoneal metastasis in pancreatic cancer, and laparoscopic visualization of this area is often superior to laparotomy. Free fluid is aspirated and saved for cytologic examination. The laparoscope is then rotated for examination of the upper quadrants. Inspection begins by assessment of the omentum and the subdiaphragmatic spaces. Meticulous examination of the liver surface is essential. Insertion of a second 5-mm trocar in the right upper quadrant is necessary for adequate evaluation of the undersurface of the liver. A rod inserted through this second trocar site is used to elevate the liver, allowing inspection of the gallbladder fossa and liver hilum. We do not perform extensive dissection of the retrogastric space or use laparoscopic ultrasound.Peritoneal washings are performed before further dissection or biopsy to prevent sample contamination. Subsequently, biopsies are performed on all suspicious peritoneal or omental nodules using forceps inserted through the second trocar site. Access to lesions in the pelvic peritoneum may require insertion of a third 5-mm trocar in the lower midline. Biopsies on implants in the liver are most easily performed using the Tru-Cut needle (Travenol Laboratories, Deerfield, Ill) inserted directly through the abdominal wall or by biopsy forceps through the second trocar site. The entire procedure takes 20 to 30 minutes.RESULTSPATIENT POPULATIONCharacteristics of the patient population are summarized in Table 1. Sixty-two percent of patients had tumors localized to the head of the pancreas, of whom 65% presented with jaundice. Average tumor size was greater than 3 cm, consistent with locally advanced disease (stage II-III). Neoplasms in the distal pancreas were larger on average than those in the head of the gland. Vascular encasement by CT criteria was noted in 66% of patients.Table 1. Patient CharacteristicsNo. of patients125Age, mean ± SD, y63.3 ± 9.5Male/female66/59Tumor location, No. (%)Head of pancreas78 (62)Body or tail of pancreas47 (38)Jaundice, No. (%)51 (41)Tumor size, mean ± SD, cm*Head of pancreas3.11 ± 1.28Body or tail of pancreas4.0 ± 1.4Vascular encasement, No. (%)*83 (66)*As determined by computed tomography.STAGING LAPAROSCOPYTable 2illustrates the frequency of unsuspected metastatic disease found during staging laparoscopy. Thirty-one percent of patients had unsuspected metastatic disease not detected by CT, and in 23% of these patients (9 patients, 7.2% of total group) metastases were evident only by peritoneal cytologic examination. Gross metastases and positive cytologic test results were more frequent in tumors of the body or tail of the pancreas, consistent with the more advanced growth of these tumors. Micrometastases, indicated by positive peritoneal cytologic test results, were detected frequently (52.2%) in tumors that demonstrated gross intraperitoneal spread, but micrometastases without visible macrometastatic accompaniment occurred in 42.9%.Table 2. Laparoscopic Staging of Pancreatic CancerUnsuspected metastases*39 (31)Gross metastases detected30 (24)Proximal mass13/78 (17)§Distal mass17/47 (36)§Positive cytologic test result21/117 (18)Without gross metastasis†9/94 (9.6)∥With gross metastasis†12/23 (52)∥Proximal mass7/78 (9)∥Distal mass14/39 (36)∥Sensitivity‡97%*Missed by computed tomography and detected by laparoscopy with peritoneal cytologic testing.†Detected by laparoscopy.‡Based on 31 patients explored after laparoscopy.§P=.02.∥P<.001.Only one postoperative complication occurred in 125 staging laparoscopies (complication rate, 0.8%). This was an umbilical trocar site abscess that required surgical drainage. The sensitivity of the staging procedure was calculated by evaluating the laparotomy findings in 31 patients explored shortly after laparoscopy (group 3). A single patient had a liver metastasis missed at laparoscopy, yielding a sensitivity of 97%. The specificity of the test was judged to be 100%, since all patients with positive results had cancer demonstrated on biopsy samples.TREATMENT GROUPSThirty-nine patients (31.2%) were found to have metastatic disease at laparoscopy (group 1). Patients without metastases at laparoscopy included 55 (44.0%) with definite vessel encasement apparent on CT (group 2) and 31 (24.8%) without vessel invasion apparent on CT (group 3).Of the 55 patients in group 2, two (3.6%) did not tolerate EBRT with fluorouracil chemotherapy because of severe adverse effects, and 20 (36.4%) developed metastatic disease during this treatment, eliminating their candidacy for IORT. Twenty-seven patients (49.1%) fulfilled criteria for IORT, and 21 (38.2%) consented and received such treatment.All patients in group 3 underwent exploratory laparotomy shortly after staging laparoscopy. The tumors of 23 patients were resected for cure, yielding a resectability rate of 74.2% for the 31 patients explored with intention to resect their tumors. Operations performed included 19 pancreaticoduodenectomies, 3 distal pancreatectomies with splenectomy, and 1 total pancreatectomy. As mentioned previously, 1 patient was found to have an unsuspected liver metastasis at laparotomy. The remaining 7 patients, whose tumors were found to be unresectable because of vessel encasement that was underappreciated by CT assessment, underwent palliative biliary and duodenal bypass procedures.SURVIVALSurvival data were obtained for all patients (Figure 2). Median survival was 7.5 months for patients in group 1, 9 months for patients in group 2, and 13 months for those in group 3 (P=.14 for group 1 vs group 2; P<.001 for group 1 or 2 vs group 3). Patients with localized unresectable disease (group 2) were further subdivided into those who developed metastatic disease during EBRT and fluorouracil chemotherapy (n=20) and those who completed treatment without interval development of metastases and received IORT (n=21). Survival for these 2 subgroups is illustrated in Figure 3, which shows that survival for patients stratified to group 2 who developed metastatic disease during treatment was identical to that in group 1.Figure 2.Survival of patients with pancreatic cancer staged by laparoscopy. Survival time of patients with resectable tumors (group 3) was significantly longer than that of patients with localized unresectable (group 2) or metastatic disease (group 1) (P<.001).Figure 3.Survival of patients with localized unresectable cancer (group 2). Patients who developed metastatic disease during treatment with external beam radiation and fluorouracil had shorter survival times than those who completed treatment without disease progression. IORT indicates intraoperative radiation.Figure 4illustrates survival of patients who underwent curative resection or chemoradiation and IORT compared with patients with metastatic disease who received chemotherapy or no treatment. Median survival was 10.5 months for patients receiving IORT and 14.5 months for patients undergoing curative resection (P=.01 for group 1 vs group 2; P<.001 for group 1 vs group 3). Two patients of the 21 who were treated with IORT remain alive at 26 and 49 months. Four patients are alive after curative resection at 30, 30, 44, and 54 months, 3 of whom have had no evidence of disease recurrence.Figure 4.Survival of patients with pancreatic cancer according to treatment received. Patients who underwent curative resection lived significantly longer than those who received chemotherapy or no treatment (P<.001). Significant improvements in survival times were also noted for patients who received chemoradiation plus intraoperative radiation (IORT) when compared with patients who received chemotherapy or no treatment (P=.01).COMMENTAppropriate treatment of patients with pancreatic cancer depends on accurate staging of their disease. Although complete resection offers the only chance for cure, surgical exploration of most of these patients is no longer necessary to establish unresectability. Patients with metastatic disease can benefit from minimally invasive percutaneous and endoscopic techniques, which allow tissue sampling and treatment of malignant biliary obstructionwithout the potential morbidity and convalescence time characteristic of surgical approaches.Ninety-seven percent of patients treated with only minimally invasive techniques never require a laparotomy.Our results demonstrate that 31% of patients with negative CT examination results were found to have occult metastatic disease at laparoscopy. Therefore, staging laparoscopy prevented 39 unnecessary surgical explorations, and more than 95% of these patients have not required further surgery. Staging laparoscopy was efficient in the detection of metastases, showing a sensitivity of 97%. These findings mirror those of a previous cohort from our institution.Metastatic implants or positive peritoneal cytologic test results were more frequent in tumors of the distal pancreas than those in the proximal gland, which is consistent with their usual lack of significant symptoms and more advanced stage at presentation.We use peritoneal cytologic testing to detect very early, invisible metastatic disease. The combination of peritoneal cytologic testing and simple laparoscopy has increased our detection of occult metastases from 24% to 31%, with 9 patients having positive cytologic test results as their only evidence of metastases. Several studieshave evaluated the significance of positive peritoneal cytologic test results (micrometastases) in the absence of gross metastases in patients with pancreatic cancer. Most studies confirm that positive cytologic test results are an indicator of unresectable, aggressive disease characterized by early metastasis and short survival times. In fact, no difference in survival times exists between patients with gross metastasis detected at laparoscopy and those with positive cytologic test results but no visible metastatic disease.We have advocated classification of patients with positive peritoneal cytologic test results as M1 in the TNM system,as is the case for gastric,ovarian,and endometrialcancers. These patients do not derive further benefit from surgical resection or radiation therapy.The main goal of staging laparoscopy in patients with pancreatic cancer is the identification of unresectability due to metastasis or portal vein invasion (if laparoscopic ultrasound is added). Many centers have evaluated the success of their staging protocols by the resectability rates following diagnostic laparoscopy,but the focus should properly be on identifying those who have cancer beyond reasonable bound of removal."Resectability" depends in part on the surgeon's willingness to resect and reconstruct major vascular structuresor leave tumor behind ("palliative resection")and may not reflect the accuracy of the staging protocol.We use staging laparoscopy not only to select patients with resectable disease but also to evaluate those with localized unresectable disease due to major vessel encasement who can benefit from local radiation therapy. Current trends for aggressive multimodality treatment of locally advanced carcinomas (combinations of radiotherapy and chemotherapy) underscore the importance of excluding metastatic disease.The morbidity, cost, and time commitment required by these new treatment modalities are not negligible, and patient selection is as important as for surgical resection. Other centers that offer similar neoadjuvant therapies also include laparoscopy in their staging protocols.Our study demonstrates that staging laparoscopy and abdominal CT allow stratification of patients into 3 treatment groups based on the presence or absence of occult metastases and vascular invasion. Previously, our staging algorithm required angiography to evaluate the status of vascular structures adjacent to the primary tumor mass.During the past 4 years, improvements in the CT resolution of vascular structures have rendered angiography obsolete in most cases.A comparison between a previous series from our institutionwith the present series reveals almost identical resectability rates (75% and 74%, respectively) despite our current disuse of routine angiography.One of the main goals of this study was to investigate if subdivision of patients by our staging protocol correlated with prognosis. The data confirm shortest and longest survival for patients with metastatic and resectable neoplasms, respectively, with intermediate survivals occurring in those with localized but unresectable disease. It appears that patients in group 2 may be further subdivided into those who progress rapidly to demonstrable metastatic disease vs those who remain localized during EBRT, having shorter and longer survivals, respectively. Differentiation between these 2 patient subgroups remains a challenge that may only be met with new genetic markers or behavioral indices for cancer. Other differences in survival among our groups and subgroups may reflect timing of disease detection (early vs late), individual tumor biology, treatment efficacy, or a combination of factors.Recent published serieshave demonstrated that laparoscopic ultrasound or extended laparoscopic dissection can further enhance the accuracy of the staging procedure. These studies have demonstrated resectability rates close to 90% and have used this information to support extensive and exhaustive staging procedures. However, in our experience the added value of laparoscopic ultrasound to the vascular staging provided by a good spiral CT with vascular enhancement is minimal, and laparoscopic dissection of the portal-mesenteric vein is time-consuming, potentially dangerous, and beyond the skills of the nonexpert. In our view, staging laparoscopy should be a tool both for the high-volume pancreatic surgeon and for the general surgeon to identify patients who can be well palliated in the community setting and those who may benefit from transfer to specialized centers for aggressive therapy.ALWarshawCFernandez-del CastilloPancreatic carcinoma.N Engl J Med.1992;326:455-465.SFSenerAFremgenHRMenckDPWinchesterPancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database.J Am Coll Surg.1999;189:1-7.CGMoertelSFrytakRGHahnTherapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: the Gastrointestinal Tumor Study Group.Cancer.1981;48:1705-1710.CGWillettALWarshawIntraoperatic electron beam irradiation in pancreatic cancer.Front Biosci.1998;3:E207-E213.TAGordonHMBowmanEBBassComplex gastrointestinal surgery: impact of provider experience on clinical and economic outcomes.J Am Coll Surg.1999;189:46-56.CFernandez-del CastilloDWRattnerALWarshawStandards for pancreatic resection in the 1990s.Arch Surg.1995;130:295-299.PCFreenyLWTraversoJARyanDiagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography.Am J Surg.1993;165:600-606.GMFuhrmanCCharnsangavejJLAbbruzzeseThin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms.Am J Surg.1994;167:104-111.DJGulliverMEBakerCAChengWCMeyersTNPappasMalignant biliary obstruction: efficacy of thin-section dynamic CT in determining resectability.AJR Am J Roentgenol.1992;159:503-507.WCDooleyJLCameronHAPittKDLillemoeNCYueACVenbruxIs preoperative angiography useful in patients with periampullary tumors?Ann Surg.1990;211:649-654.WABemelmanLTde WitOMvan DeldenDiagnostic laparoscopy combined with laparoscopic ultrasonography in staging of cancer of the pancreatic head region.Br J Surg.1995;82:820-824.KCConlonEDoughertyDSKlimstraDGCoitADMTurnbullMFBrennanThe value of minimal access surgery in the staging of patients with potentially resectable peripancreatic malignancy.Ann Surg.1996;223:134-140.CFernandez-del CastilloDWRattnerALWarshawFurther experience with laparoscopy and peritoneal cytology in the staging of pancreatic cancer.Br J Surg.1995;82:1127-1129.TGJohnJDGreigDCCarterOJGardenCarcinoma of the pancreatic head and periampullary region: tumor staging with laparoscopy and laparoscopic ultrasonography.Ann Surg.1995;221:156-164.DBEvansJLAbbruzzeseTARichCancer of the pancreas.In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Philadelphia, Pa: Lippincott-Raven; 1997:1054-1087.DBRobinsRLKatzDBEvansENAtkinsonLGreenFine needle aspiration of the pancreas: in quest of accuracy.Acta Cytol.1995;39:1-10.RPvan den BoschGPvan der SchellingJHKlinkenbijlPGMulderMvan BlankensteinJJeekelGuidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas.Ann Surg.1994;219:18-24.TASohnKDLillemoeJLCameronJJHuangHAPittCJYeoSurgical palliation of unresectable periampullary adenocarcinoma in the 1990s.J Am Coll Surg.1999;188:658-666.NJEspatMFBrennanKCConlonPatients with laparoscopically staged unresectable pancreatic adenocarcinoma do not require subsequent surgical biliary or gastric bypass.J Am Coll Surg.1999;188:649-655.ALWarshawInvited commentary.J Am Coll Surg.1999;188:667-668.SDLeachJARoseAMLowySignificance of peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreatic head.Surgery.1995;118:472-478.MAMakaryALWarshawBACentenoCGWilletDWRattnerCFernandez-del CastilloImplications of peritoneal cytology for pancreatic cancer management.Arch Surg.1998;133:361-365.JKJMartinJRGoellnerAbdominal fluid cytology in patients with gastrointestinal malignant lesions.Mayo Clin Proc.1986;61:467-471.NBMerchantKCConlonPSaigoEDoughertyMFBrennanPositive peritoneal cytology predicts unresectability of pancreatic adenocarcinoma.J Am Coll Surg.1999;188:421-426.ALWarshawImplications of peritoneal cytology for staging of early pancreatic cancer.Am J Surg.1991;161:26-29.JJBonenkampISongunJHermansCJvan de VeldePrognostic value of positive cytology findings from abdominal washings in patients with gastric cancer.Br J Surg.1996;83:672-674.SCRubinEDDulaneyMMarkmanWJHoskinsPESaigoJLJLewisPeritoneal cytology as an indicator of disease in patients with residual ovarian carcinoma.Obstet Gynecol.1988;71:851-853.RNGrimshawWCTupperRCFraserMGTompkinsJFJeffreyPrognostic value of peritoneal cytology in endometrial carcinoma.Gynecol Oncol.1990;36:97-100.ELuque-de LeonGGTsiotosBBalsigerJBarnwellLJBurgartMGSarrStaging laparoscopy for pancreatic cancer should be used to select the best means of palliation and not only to maximize the resectability rate.J Gastrointest Surg.1999;3:111-118.SDLeachJELeeCCharnsangavejSurvival following pancreaticoduodenectomy with resection of the superior mesenteric-portal vein confluence for adenocarcinoma of the pancreatic head.Br J Surg.1998;85:611-617.KDLillemoeJLCameronCJYeoPancreaticoduodenectomy: does it have a role in the palliation of pancreatic cancer?Ann Surg.1996;223:718-725.TMBreslinNAJanjanJELeeNeoadjuvant chemoradiation for adenocarcinoma of the pancreas.Front Biosci.1998;3:E193-E203.William Meyers, MD, Worcester, Mass:This is the latest in a long list of studies from a great surgical group that has consistently blessed the surgical literature. The studies represent an accumulation of an immense amount of data, which lead us into future directions with respect to care of patients with pancreatic cancer. The modern era of laparoscopy has had profound impact on what we surgeons do today. Laparoscopic staging prior to definitive pancreatic or hepatic resection has emerged as a meaningful technique. It is important to pause and reflect on what the present study is telling us and what it is not telling us today. I share with the authors certain biases. Laparoscopy prevents bigger incisions. We should strive to stage patients into groups and be aggressive, particularly with locally unresectable disease. We have made tremendous progress with resection of selected cancers, and neoadjuvant and adjuvant therapy will ultimately have great roles. Laparoscopy helps identify patients with miliary disease who might not benefit from aggressive therapy. I agree with the authors also that one should not be aggressive after laparoscopy, CT, or cytologic demonstration of widespread disease. Also resection does improve the quality of life of selected patients with known incurable disease.Several of the conclusions of the paper, however, are not quite correct. This study stratifies retrospectively 3 patient groups based on a combination of tests. It makes strong implications both about staging and effective treatment. There are too many variables to make both types of conclusions. The validity of this staging scheme presumes that we are talking about the natural course of the disease and that the treatment regimens were basically similar. These presumptions are easy to support, since one is dealing with such a dismal disease, particularly after the patients with the best prognoses are excluded. It is a mistake for this study to also imply that the authors can select out patients who might benefit from certain therapy. There are just too many variables. Therefore, any implication that survival might be related to a specific therapy in this study or, for example, intraoperative radiation or even resection, is not justified from these data. These are biases and not conclusions.There are certain other parts of the paper that are also a bit misleading, for example, that laparoscopic ultrasound is not useful. The data presented do not address ultrasound, and therefore this conclusion is not appropriate. Many people have different biases plus data about ultrasound, such as Garden and Callery. Likewise, the importance of peritoneal washings and staging seems minimally useful unless this information is obtainable at surgery.I do have one practical question that comes up all the time in our practices. When one performs laparoscopy at the same sitting as potential resection, and then one does open the patient and resects, it is very difficult to get the most expensive part of the case, the laparoscopy, paid by the insurance companies. They, the insurance companies, call the operation a "conversion" rather than a staging laparoscopy, and most companies deny payment for the professional or hospital charges related to the laparoscopy and the "conversion." When one calculates the cost of the lack of payment, this very beneficial technique becomes a financial burden for the hospital and clinical system. How do you address this practical question at your institution? Despite these criticisms, your experience illustrates some tremendous strides forward in the care of patients with pancreatic cancer. It represents a great experience: the utility of laparoscopy even without ultrasonography, the ability to stage patients, and the importance of staying current with new techniques.John C. Russell, MD, New Britain, Conn:Two questions. First, you stated that 9 of 91 patients had positive cytology only, which is about 10%. But did you compare pancreatic head lesions with lesions of the body and tail? You found that laparoscopy had a higher yield of grossly metastatic disease (CT scan negative) for body and tail lesions than for tumor of the pancreatic head, but was there a similar difference in cytology-only positive tumors between body and tail tumors vs pancreatic head tumors? If the yield of cytology-positive only pancreatic lesions is below 10%, the added expense of staged preoperative laparoscopy (rather than immediate preoperative laparoscopy) for pancreatic head lesions would not seem justified.Second, did you study whether any noninvasive modalities, such as serum CA19-9 [cancer antigen 19-9] levels, would predict whether patients who were negative by CT scan would be positive on laparoscopy for either grossly metastatic disease or positive cytology?Dr Jimenez:I would like to start with Dr Meyers' questions. The patient survival data presented in our study are dependent on a variety of factors, including tumor biology, timing of the disease detection, treatment administered, and individual response to treatment. Patient survivals are presented as a simple observation, and at no point do we suggest that these survivals are a result of treatments administered. The purpose of presenting the survival data was to illustrate that laparoscopic staging of pancreatic cancer patients correlates with disease survival. We demonstrate that an apparently homogeneous cohort of patients can be subdivided into 3 different groups and that this subdivision helps in allocating treatment and determining prognosis. Ideally, we would have liked to present the natural history of our 3 groups of patients by showing their survivals without treatment interventions. However, because the study was a retrospective review, this information was not available.As Dr Meyers has mentioned, some centers include laparoscopic ultrasonography in their staging procedures. In particular, there is a recent series(Minnard et al. Laparoscopic ultrasound enhances standard laparoscopy in the staging of pancreatic cancer. Ann Surg.1998;228:182-187) from Memorial Sloan-Kettering where laparoscopic ultrasound was used to evaluate the liver parenchyma for metastases and to evaluate vessel invasion. These surgeons also perform extensive laparoscopic dissection to examine the porta hepatis, lesser sac, and celiac axis. Their excellent results show that the combination of laparoscopic dissection and ultrasound allows correct determination of resectability in greater than 95% of patients. We have used laparoscopic ultrasound sparingly and do not use it routinely in our staging laparoscopies. We believe that laparoscopic dissection and ultrasound can significantly lengthen the staging procedure, and we do not recommend laparoscopic dissection near large vessels because of potential bleeding complications. We propose that staging laparoscopy should be a very simple procedure, involving only peritoneal cytology and biopsy of suspicious lesions. Our procedures are usually completed in 20 to 30 minutes.I am not well qualified to answer questions on procedure reimbursement but can discuss related issues. Our staging laparoscopies are always scheduled as single procedures, and most patients are discharged home on the same day. Patients who require exploration for resection have this done after several days, and therefore none of our laparoscopies qualify as "converted" procedures. The delay between laparoscopy and open exploration allows time to obtain the results of the peritoneal cytology samples.The second discussant inquired about the results of peritoneal cytology in patients with proximal vs distal tumors of the pancreas. I have shown that tumors of the distal pancreas showed gross metastatic disease almost twice as often as tumors of the head of the gland. Likewise, we found that 36% of distal tumors had positive peritoneal cytology, but only 9% of proximal tumors had positive cytology. These findings are consistent with the more advanced stage of tumors of the tail of the pancreas, resulting from their lack of significant symptomatology.In terms of other tumor markers, such as carcinoembryonic antigen and CA19-9, we frequently use these tests in our preoperative patient evaluations. However, we have not collected these data as part of this study.Finally, Dr Dibbins asked about the role of staging laparoscopy in patients with demonstrable vessel invasion on CT. Clearly, these patients are not candidates for resection. The reason they undergo staging laparoscopy is to determine their candidacy for radiotherapy. Radiotherapy is only of benefit to patients with localized disease, and patients with metastatic disease detected by laparoscopy are not offered such treatment.This study was supported by the Marshall K. Bartlett, MD, Resident Research Fellowship, Harvard Medical School, Boston, Mass (Dr Jimenez).Presented at the 80th Annual Meeting of the New England Surgical Society, Newport, RI, September 24, 1999.Reprints: Carlos Fernandez-del Castillo, MD, Department of Surgery, Massachusetts General Hospital, 15 Parkman St, WACC 336, Boston, MA 02114 (e-mail: [email protected]).
doi: 10.1001/archsurg.135.4.415pmid: N/A
The ARCHIVES is pleased to announce the appointment of the following distinguished surgeon to its International Advisory Board. (Figure 1) View LargeDownload Bernard F. Ribeiro, MBBS, LRCP, MRCS, FRCS(Lond), consultant surgeon at the Basildon and Thurrock General Hospitals in Essex, England, is currently president of the Association of Surgeons of Great Britain and Ireland.
Jarrar, Doraid; Wang, Ping; Cioffi, William G.; Bland, Kirby I.; Chaudry, Irshad H.
doi: 10.1001/archsurg.135.4.416pmid: 10768706
BackgroundDehydroepiandrosterone (DHEA) is the most abundant adrenal hormone in man and has been shown to improve immune functions after trauma-hemorrhage. However, it remains unknown whether this agent has any salutary effects on the depressed organ functions under such conditions.HypothesisAdministration of DHEA after trauma-hemorrhage attenuates depressed cardiac and hepatocellular functions, and beneficial effects are mediated via the estrogen receptors.Design, Interventions, and Main Outcome MeasuresMale rats underwent laparotomy and were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer lactate (RL) solution. The animals were then resuscitated with 4 times the maximum bleed-out volume with RL for 60 minutes. Subcutaneous administration of DHEA (30 mg/kg of body weight) or vehicle occurred after resuscitation. At 24 hours after resuscitation, cardiac output was measured by a dye-dilution technique. Hepatocellular function, ie, the maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the active transport (Km), was determined using an in vivo hemoreflectometer. Plasma levels of DHEA, sex hormone binding globulin, 17β-estradiol, and testosterone were also determined. Moreover, additional groups of animals received a high-affinity estrogen receptor antagonist (ICI 182,780) with or without DHEA treatment.ResultsCardiac output decreased by 12.9% at 24 hours after trauma-hemorrhage; however, it was similar to shams in DHEA-treated animals. Moreover, hepatocellular function was significantly depressed after hemorrhage (Vmax, −74.4%; Km, −62.3%), whereas DHEA treatment restored those values to sham levels. Plasma levels of 17β-estradiol and testosterone were not significantly altered in animals receiving DHEA. The hemorrhage group treated with DHEA and ICI 182,780 showed markedly depressed cardiac and hepatocellular functions.ConclusionsSince DHEA treatment after trauma-hemorrhage restored the depressed cardiac and hepatocellular functions, it appears that DHEA is a safe and inexpensive adjunct to fluid resuscitation for restoring the depressed cardiac and hepatocellular responses after severe hemorrhagic shock in male subjects. Furthermore, since ICI 182,780 administration with DHEA abolished the salutary effects of DHEA, it appears that these effects on cardiac and hepatocellular functions after trauma-hemorrhage are mediated via the estrogen receptors.RECENT STUDIES have indicated that circulating male sex steroids may account for depressed organ functions after trauma-hemorrhage.Furthermore, a number of investigators have shown that sexual dimorphism exists during circulatory stress, and that androgens and estrogens play a pivotal role in regulating the stress responses.In this regard, studies by Wichmann et aland Zellweger et alhave shown that female mice have enhanced immune responses as opposed to decreased responses in male mice after trauma-hemorrhage. Moreover, castration of male animals 14 days before hemorrhagic shock prevented the depression in myocardial functions and immune responses usually observed under those conditions.Furthermore, administration of the testosterone receptor antagonist flutamide improved the depressed immune responses and cardiac and hepatic functions in male animals after trauma and severe hemorrhage.Thus, male sex hormones appear to play a deleterious role in the development of cell and organ dysfunction after trauma and hemorrhage.Dehydroepiandrosterone (DHEA) is the most abundant adrenal hormone in men and has been shown to improve immune functions in mice after burn injury, sepsis, and trauma-hemorrhage.Depending on the prevailing hormonal milieu, DHEA has been shown to have androgenic and estrogenic effects.Evidence of the dual role of DHEA came from studies using orchiectomized and ovariectomized rats. Under both conditions, administration of DHEA restored seminal vesicle and uterine weight to values similar to those of intact animals.Moreover, studies by Nephew et alsuggested that DHEA is an estrogen receptor agonist. In light of the above information, our aim was to determine whether administration of DHEA after trauma-hemorrhage and resuscitation has any salutary effects on the depressed cardiac and hepatocellular functions and, if so, whether this is mediated by an estrogen receptor–dependent process.MATERIALS AND METHODSEXPERIMENTAL PROCEDURESWe used our previously described nonheparinized model of trauma-hemorrhage in the rat,with minor modifications. Briefly, food was withheld overnight from male Sprague-Dawley rats (275-325 g; Charles River Laboratories, Wilmington, Mass) before the experiment, but water was allowed ad libitum. The rats were anesthetized using methoxyflurane (Mallinckrodt Veterinary Inc, Mundelein, Ill) inhalation before the induction of trauma (ie, 5-cm midline laparotomy). The abdomen was then closed in layers, and catheters were placed in both femoral arteries and the right femoral vein (polyethylene [PE-50] tubing; Becton Dickinson and Co, Sparks, Md). The wounds were bathed with 1% lidocaine hydrochloride (Elkins-Sinn Inc, Cherry Hill, NJ) throughout the surgical procedure to reduce postoperative pain. The rats were then allowed to awaken, and bled to and maintained at a mean arterial pressure of 40 mm Hg. This level of hypotension was continued until the animals could not maintain a mean arterial pressure of 40 mm Hg unless given extra fluid in the form of Ringer lactate. This time was defined as maximum bleed out, and the amount of withdrawn blood was noted. After this, the rats were maintained at mean arterial pressure of 40 mm Hg until 40% of the maximum bleed-out volume was returned in the form of Ringer lactate. The animals were then resuscitated with 4 times the volume of the withdrawn blood for 60 minutes (approximately 45 mL/rat) with Ringer lactate. The shed blood was not used for resuscitation. At the end of the resuscitation period, the rats received DHEA, 30 mg/kg of body weight (Sigma-Aldrich Corp, St Louis, Mo) subcutaneously or an equal volume (approximately 0.5 mL) of the vehicle consisting of ethanol and propylene glycol. In additional groups of animals, the high-affinity estrogen receptor antagonist ICI 182,780 (3 mg/kg of body weight, dissolved in a combination of ethanol and dimethyl sulfoxide [DMSO]; Tocris Cookson Ltd, Ballwin, Mo) was given intraperitoneally with and without simultaneous subcutaneous injection of DHEA.The catheters were then removed, the vessels were ligated, and the skin incisions were closed with sutures. Sham group animals underwent the same groin dissection, which included the ligation of the femoral artery and vein; however, neither hemorrhage nor resuscitation was performed.After returning the rats to their cages, they were allowed food and water ad libitum. At 24 hours after the completion of fluid resuscitation or sham operation, the animals were anesthetized with methoxyflurane and then catheterized via the right jugular vein. Under continued general anesthesia with pentobarbital sodium (25-30 mg/kg of body weight), cardiac output and hepatocellular function were measured in each animal.All animal experiments were performed according to the guidelines of the Animal Welfare Act and the Guide for Care and Use of Laboratory Animalsfrom the National Institutes of Health, Bethesda, Md. This project was approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital, Providence.MEASUREMENT OF CARDIAC OUTPUTA 2.4F fiberoptic catheter was placed into the right carotid artery, which was connected to an in vivo hemoreflectometer (Hospex Fiberoptics, Chestnut Hill, Mass) as described previously.Indocyanine green (ICG) (Cardio Green; Becton Dickinson) solution was injected via the catheter in the jugular vein (1 mg/mL aqueous solution as a 50-µL bolus). Twenty ICG concentrations per second were recorded for approximately 30 seconds with the aid of a data acquisition program (Asystant+; Asyst Software, Rochester, NY). The area under the ICG dilution curve was determined according to a previous publication from our laboratoryto calculate cardiac output. Cardiac output was then divided by the body weight to determine cardiac index.MEASUREMENT OF HEPATOCELLULAR FUNCTIONHepatocellular function was measured by the in vivo ICG clearance technique.Indocyanine green was administered by bolus injection (50 µL) of 1-, 2-, and 5-mg/mL ICG in aqueous solvent. The arterial concentration of ICG was recorded each second for 5 minutes. After this, the initial velocity of ICG clearance for each dose was calculated after performing a nonlinear regression of the ICG clearance curves according to an e-raised second-order polynomial function.The initial velocities of ICG clearance were then plotted against the ICG doses according to the method described by Hauptman et al.This results in a straight line, allowing the determination of a maximum of ICG clearance (Vmax) and the Michaelis-Menten constant (Km). In this active hepatocellular membrane transport system, Vmaxrepresents the functional hepatocyte ICG receptors, whereas Kmrepresents the efficiency of the active transport process.DETERMINATION OF PLASMA SEX STEROIDSAt the end of all measurements (ie, 25 hours after the end of trauma-hemorrhage and resuscitation), unheparinized and heparinized whole blood was obtained and placed in microcentrifuge tubes. The tubes were then centrifuged at 16 000gfor 15 minutes at 4°C. Plasma and serum were separated, placed in pyrogen-free microcentrifuge tubes, immediately frozen, and stored (−70°C) until assayed.Plasma levels of DHEA and sex hormone binding globulin (SHBG) were determined using an enzyme immunoassay and a radioimmunoassay (RIA) kit, respectively, according to the manufacturer's instructions (Diagnostic Systems Lab, Webster, Tex). Total plasma 17β-estradiol and testosterone concentrations were determined using a commercially available RIA kit specifically designed for rats and mice (ICN Biomedicals, Costa Mesa, Calif). The cross-reactivity of the RIA for 17β-estradiol was found to be 100% (estrone, 20%; estriol, 1.51%; 17α-estradiol, 0.68%; and all other tested steroids, <0.01%). The cross-reactivity of the RIA for testosterone was found to be 100% (5α-dihydrotestosterone, 3.4%; all other tested steroids, <0.01%). Plasma levels of protein were measured according to the method of Lowry et al.STATISTICAL ANALYSISResults are presented as mean ± SEM. One-way analysis of variance and Tukey test were used, and the differences were considered significant at P≤.05.RESULTSEFFECTS OF DHEA ON CARDIAC INDEXThe results in Figure 1indicate that cardiac index was 40.1 ± 0.3 and 40.4 ± 0.5 mL/min per 100 g in the sham groups receiving vehicle and DHEA, respectively. Cardiac index decreased by 12.9% (P<.05) in the vehicle-treated hemorrhage group 24 hours after the completion of fluid resuscitation. Administration of DHEA after hemorrhage, however, restored the depressed cardiac index to sham levels.Figure 1.Effects of dehydroepiandrosterone (DHEA) on cardiac index in rats 24 hours after sham operation or trauma-hemorrhage and resuscitation. The figure compares sham groups treated with vehicle (Sham-Vehicle) or DHEA (Sham-DHEA) with hemorrhage groups treated with vehicle (Hemorrhage-Vehicle) or DHEA (Hemorrhage-DHEA). There were 5 to 7 animals in each group. Data are presented as mean ± SEM, and compared using 1-way analysis of variance and Tukey test. Asterisk indicates P<.05 compared with the respective sham group; dagger, P<.05 compared with Hemorrhage-Vehicle group.EFFECTS OF DHEA ON HEPATOCELLULAR FUNCTIONThe values of Vmaxof ICG clearance were 1.3 ± 0.3 and 1.0 ± 0.3 mg/kg per minute in the sham groups receiving vehicle or DHEA, respectively (Figure 2, top). In the vehicle-treated hemorrhage group, Vmaxdecreased by 74.4% (P<.05) at 24 hours after trauma-hemorrhage. In contrast, the DHEA-treated hemorrhage group had Vmaxvalues similar to those of the respective sham group. As indicated in Figure 2(bottom), Kmwas 2.6 ± 0.4 and 3.2 ± 0.7 mg/kg in the sham groups receiving vehicle or DHEA, respectively, and it decreased by 62.3% (P<.05) after trauma-hemorrhage and resuscitation in vehicle-treated rats. Treatment with DHEA significantly improved Kmat 24 hours after the completion of resuscitation compared with the vehicle-treated group, and the values were similar to those of the sham groups.Figure 2.Effects of dehydroepiandrosterone (DHEA) administration on the active hepatocellular function at 24 hours after sham operation or trauma-hemorrhage and resuscitation as measured by the indocyanine green (ICG) clearance technique. Vmaxindicates the maximal velocity of ICG clearance (top); Km, the overall efficiency of the ICG transport (bottom). There were 5 to 7 animals in each group. Data are presented as mean ± SEM, and compared using 1-way analysis of variance and Tukey test. Groups are described in the legend to Figure 1. Asterisk indicatesP<.05 compared with the respective sham group; dagger,P<.05 compared with Hemorrhage-Vehicle group.ALTERATIONS IN CIRCULATING LEVELS OF DHEA AND SHBG AFTER TRAUMA-HEMORRHAGECirculating levels of DHEA were found to be 7.0 ± 0.9 nmol/L in the vehicle-treated sham group and increased by 1971% after the administration of DHEA (Figure 3, top). In the vehicle-treated hemorrhaged group, DHEA levels increased by 170% at 24 hours after the end of resuscitation (P<.05), whereas the levels increased by 1767% in the DHEA-treated hemorrhaged group (P<.05). Serum levels of SHBG were 21.7 ± 0.2 and 21.3 ± 0.4 nmol/L in the sham groups treated with vehicle or DHEA, respectively (Figure 3, bottom). After trauma-hemorrhage and resuscitation, SHBG levels remained unchanged in both hemorrhaged groups.Figure 3.Alterations in circulating levels of sex hormone binding globulin (SHBG) (top) and dehydroepiandrosterone (DHEA) (bottom) 24 hours after sham operation or completion of fluid resuscitation. There were 5 to 7 animals in each group. Data are presented as mean ± SEM, and compared using 1-way analysis of variance and Tukey test. Groups are described in the legend to Figure 1. Asterisk indicates P<.05 compared with the respective sham group; dagger, P<.05 compared with Hemorrhage-Vehicle group.ALTERATIONS IN CIRCULATING LEVELS OF 17β-ESTRADIOL AND TESTOSTERONE AFTER TRAUMA-HEMORRHAGECirculating levels of 17β-estradiol were found to be 115 ± 13 pmol/L (31.3 ± 3.5 pg/mL) in the vehicle-treated sham group, and were not significantly altered after DHEA administration or trauma-hemorrhage and resuscitation (Figure 4, top). Plasma levels of testosterone were 11.0 ± 2.0 and 8.8 ± 2.2 nmol/L (317 ± 58 and 254 ± 58 ng/dL) in the sham groups receiving vehicle or DHEA, respectively (Figure 4, bottom). At 24 hours after trauma-hemorrhage and resuscitation, circulating levels of testosterone decreased by 87.7% and 74.6% in vehicle- and DHEA-treated animals, respectively (Figure 4, bottom).Figure 4.Alterations in circulating levels of total 17β-estradiol (top) and testosterone (bottom) 24 hours after sham operation or completion of fluid resuscitation. There were 5 to 7 animals in each group. Data are presented as mean ± SEM, and compared using 1-way analysis of variance and Tukey test. Groups are described in the legend to Figure 1. Asterisk indicates P<.05 compared with the respective sham group.EFFECTS OF ICI 182,780 AND DHEA ON CARDIAC INDEXCardiac index was 36.0 ± 0.3 and 37.7 ± 1.0 mL/min per 100 g in the sham group receiving DHEA combined with ICI 182,780 or ICI 182,780 alone, respectively, and decreased by 15.0% and 26.6% in the hemorrhage group receiving DHEA combined with ICI 182,780 or ICI 182,780 alone, respectively (Figure 5).Figure 5.Effects of dehydroepiandrosterone (DHEA) and the estrogen receptor antagonist ICI 182,780 on cardiac index in rats 24 hours after sham operation or trauma-hemorrhage and resuscitation. The figure shows the comparison of sham groups treated with DHEA combined with ICI 182,780 (Sham–DHEA-ICI) or ICI 182,780 only (Sham-ICI) and hemorrhage groups treated with DHEA combined with ICI 182,780 (Hemorrhage–DHEA-ICI) or ICI 182,780 only (Hemorrhage-ICI). There were 3 to 5 animals in each group. Data are presented as mean ± SEM, and compared using 1-way analysis of variance and Tukey test. Asterisk indicates P<.05 compared with the respective sham group.EFFECTS OF DHEA AND ICI 182,780 ON HEPATOCELLULAR FUNCTIONSThe values of the Vmaxof ICG clearance were 0.8 ± 0.1 and 0.9 ± 0.2 mg/kg per minute in the sham groups receiving DHEA combined with ICI 182,780 or ICI 182,780 only, respectively (Figure 6, top), and decreased by 76.2% and 58.5% in the hemorrhage groups receiving DHEA combined with ICI 182,780 or ICI 182,780 only, respectively. As indicated in Figure 6(bottom), Kmwas 2.5 ± 0.6 and 3.1 ± 0.6 mg/kg in the sham groups receiving DHEA combined with ICI 182,780 or ICI 182,780 only, respectively, and decreased by 65.9% and 59.6% (P<.05) in the hemorrhage groups receiving DHEA combined with ICI 182,780 or ICI 182,780 alone, respectively.Figure 6.Effects of dehydroepiandrosterone (DHEA) and the estrogen receptor antagonist ICI 182,780 on active hepatocellular function 24 hours after sham operation or trauma-hemorrhage and resuscitation as measured by the indocyanine green (ICG) clearance technique. Vmaxindicates the maximal velocity of ICG clearance (top); Km, the overall efficiency of the ICG transport (bottom). There were 3 to 5 animals in each group. Data are presented as mean ± SEM, and compared using 1-way analysis of variance and Tukey test. Groups are described in the legend to Figure 5. Asterisk indicates P<.05 compared with the respective sham group.COMMENTRecent studies using male animals have indicated that organ functions such as cardiac output, heart performance, adrenal responsiveness to exogenous corticotropin, and hepatocellular clearance of ICG are markedly depressed after trauma-hemorrhage and resuscitation.In contrast, female rats in the proestrus state, in which plasma estradiol levels were found to be the highest, showed normal organ functions at 24 hours after severe hemorrhagic shock.Alternatively, administration of the testosterone receptor antagonist flutamide in male animals significantly improved cardiac and hepatic functions after trauma-hemorrhage.Taken together, these studies suggest that male and female sex steroids, such as testosterone and estradiol, play an opposite role in the development of cell and organ dysfunctions after injury.Dehydroepiandrosterone is the most abundant steroid secreted by the adrenal gland, and has been shown to have androgenic and estrogenic effects. In male patients who typically have low estrogen and high androgen levels, DHEA appears to have estrogenic properties, whereas in premenopausal women with high estrogen and low androgen levels, androgenic effects have been reported with DHEA.Studies by Catania et aldemonstrated that DHEA administration after trauma-hemorrhage is immunoprotective in male mice. Moreover, they reported that the immunoenhancing effects of DHEA on splenocyte proliferation were ablated by the addition of the estrogen antagonist tamoxifen citrate, but not by the testosterone receptor antagonist flutamide.Furthermore, Angele et alshowed that DHEA not only improved immune functions, but also decreased the susceptibility to sepsis after trauma-hemorrhage. In light of these findings, we hypothesized that administration of DHEA after trauma-hemorrhage would improve the depressed cardiac and hepatocellular functions. Moreover, we hypothesized that the salutary properties of DHEA would be inhibited by the simultaneous administration of an estrogen receptor antagonist.The results indicate that cardiac output and hepatocellular functions were significantly compromised at 24 hours after trauma-hemorrhage and crystalloid resuscitation. Subcutaneous injection of DHEA, however, significantly improved the depressed heart and liver functions. Moreover, the significantly increased circulating levels of DHEA in the DHEA-treated animals were not associated with changes in plasma level of 17β-estradiol or testosterone when compared with the respective vehicle-treated group. Simultaneous administration of the highly specific estrogen receptor antagonist ICI 182,780 prevented the salutary effects of DHEA, and such animals displayed significantly compromised organ functions comparable to those of untreated hemorrhage-group animals. Administration of ICI 182,780 with and without DHEA had no effect on heart and liver function in the sham group. Moreover, to avoid excessive numbers of groups, we have not included a comparison between vehicle-treated and untreated animals. However, recent studies in our laboratory have indicated that the vehicle ethanol combined with dimethyl sulfoxide administered intraperitoneally did not have any adverse or beneficial effects on cardiac and hepatocellular functions.Circulating levels of testosterone were significantly decreased at 24 hours after completion of fluid resuscitation when compared with the respective sham group. However, preliminary data indicated that at 4 hours after resuscitation, plasma levels of testosterone were not yet decreased. Thus, it could be argued that the high baseline levels of testosterone compared with female rodents are the culprit for producing organ dysfunction in male animals, despite a decrease at a later time. Plasma levels of SHBG were comparable in all 4 groups after sham operation or trauma-hemorrhage. Sex hormone binding globulin is a glycoprotein that binds sex hormones with high specificity, and is synthesized primarily in the liver. Although stress and estrogens have been shown to induce SHBG production, the exact role of SHBG after trauma-hemorrhage and resuscitation with concomitantly decreased total testosterone concentration remains to be determined. Because the measured plasma levels of 17β-estradiol and testosterone represent total (ie, bound and unbound) portions of the sex steroids, it remains unknown whether the ratios of bound and free 17β-estradiol and testosterone are altered after trauma-hemorrhage.Although several studies have shown beneficial effects of DHEA treatment on immune functions after injury such as burn, sepsis, and hemorrhagic shock,the precise mechanism for the salutary effects of DHEA remains unknown. Studies of Okabe et alsuggested the existence of a high-affinity binding site for DHEA; however, a specific receptor has not been characterized yet. Furthermore, Nephew et alsuggested that DHEA interacts with the estrogen receptor and modulates estrogen-signaling mechanisms. Using orchiectomized and ovariectomized rats, Labrie et alshowed that administration of DHEA increased prostate and uterine weight to levels of intact animals, respectively. Thus, DHEA can exert androgenic and estrogenic activity depending on the hormonal milieu and target tissue. Our data indicate that administration of DHEA had salutary effects on organ functions in male animals after trauma-hemorrhage, and that this might be mediated via an estrogen receptor–dependent process.Although we have not generated a detailed dose-response curve for DHEA, previous studies by Labrie et alhave shown that a dose of 30 mg/kg is optimal to produce stimulatory effects on sex-steroid sensitive variables such as uterine and dorsal prostate weight in ovariectomized and orchiectomized rats, respectively. However, it remains to be determined whether lower or higher doses than the one used in this study would also have salutary effects on the depressed cardiac and hepatocellular functions after trauma-hemorrhage and resuscitation. Nevertheless, it appears that the 170% increase in endogenous levels of DHEA after trauma-hemorrhage, compared with the vehicle-treated sham group, is insufficient to protect cardiac and hepatic functions under such conditions.Although the precise mechanism responsible for the beneficial effects of DHEA on organ function is unknown, several possibilities should be considered. These include the following. First, DHEA has direct effects on tissues such as the liver and the cardiovascular system.Although binding sites for DHEA have been characterized in T cells, this has not been described for hepatic or myocardial tissues, to our knowledge. Nevertheless, it could be speculated that direct effects of DHEA protect hepatocytes and/or myocytes from damage after low-flow conditions. Second, DHEA activates the estrogen receptors and therefore modulates estrogen-signaling pathways. Several studies have shown that estrogens have protective effects on the cardiovascular system, including rapid nongenomic and long-term genomic mechanisms.These results are in line with our observations, since simultaneous administration of a specific estrogen receptor antagonist ablated the salutary effects of DHEA on organ functions. Moreover, the significance of estrogens in maintaining organ functions after adverse circulatory conditions has been further established using proestrus,ie, high levels of 17β-estradiol, and in ovariectomized females with and without 17β-estradiol replacement therapy. Third, DHEA might be converted in target tissues to estradiol derivatives via dehydrogenase and aromatase enzyme activity. This might occur without leakage of DHEA-derived estrogens into the circulation. Since circulating levels of 17β-estradiol were not altered at 24 hours after subcutaneous injection of DHEA, it is possible that tissue-specific conversion of DHEA to estrogenic derivatives might account for the observed beneficial effects. This suggestion is in line with the results of Labrie et al,who showed that physiological changes in DHEA are not reflected by alterations in serum levels of active androgens and estrogens, but of their metabolites.In contrast to our observations of the salutary effects of DHEA after trauma-hemorrhage, Schurr et alfound no beneficial effects of DHEA in a 2-hit pig model of hemorrhage and subsequent lipopolysaccharide (LPS) infusion. This discrepancy might be explained by the difference of the models used, ie, hemorrhage and subsequent LPS challenge compared with our model of laparotomy and hemorrhage alone. Nevertheless, additional studies are required to determine the precise mechanism leading to improved cardiac and hepatocellular functions after trauma-hemorrhage and DHEA administration.Our data indicate that administration of DHEA after trauma-hemorrhage and crystalloid resuscitation significantly improved cardiac output and hepatocellular functions. Moreover, it appears that the salutary effects of DHEA treatment are mediated via an estrogen receptor–dependent process. We therefore conclude that DHEA administration appears to be a useful adjunct for improving cardiac and hepatocellular responses after trauma and hemorrhagic shock in male subjects.Statement of Clinical RelevanceDespite advances in the management of severely injured patients, a large number of trauma victims subsequently succumb to sepsis and ensuing multiple organ failure. Recent studies have indicated that male sex hormones appear to play a deleterious role in the development of cell and organ dysfunction after trauma-hemorrhage, whereas female sex steroids may have protective effects. The inexpensive steroid hormone dehydroepiandrosterone (DHEA) has been shown to exert androgenic and estrogenic effects, depending on the hormonal milieu. Moreover, DHEA has been used clinically to restore age-associated decline in bone density without any adverse effects. Our data indicate that DHEA administration after trauma-hemorrhage restored the depressed cardiac and hepatocellular functions usually observed in males under those conditions. 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high-affinity dehydroepiandrosterone binding activity by dehydroepiandrosterone in activated human T lymphocytes.J Clin Endocrinol Metab.1995;80:2993-2996.MAragnoETamagnoVGattoDehydroepiandrosterone protects tissues of streptozotocin-treated rats against oxidative stress.Free Radic Biol Med.1999;26:1467-1474.KTKhawDehydroepiandrosterone, dehydroepiandrosterone sulphate and cardiovascular disease.J Endocrinol.1996;150(suppl):S149-S153.DMHerringtonNNanjeeSCAchuffDECameronBDobbsKLBaughmanDehydroepiandrosterone and cardiac allograft vasculopathy.J Heart Lung Transplant.1996;15:88-93.MEMendelsohnRHKarasThe protective effects of estrogen on the cardiovascular system.N Engl J Med.1999;340:1801-1811.ZChenISYuhannaZGalcheva-GargovaRHKarasMEMendelsohnPWShaulEstrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen.J Clin Invest.1999;103:401-406.RHKarasMEMendelsohnRapid vasomotor effects of estrogen: men are part of the club.Chest.1998;114:1508-1509.FLabrieABelangerLCusanBCandasPhysiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology.J Clin Endocrinol Metab.1997;82:2403-2409.MJSchurrTCFabianMACroceLEVarnavasKGProctorDehydroepiandrosterone, an endogenous immune modulator, after traumatic shock.Shock.1997;7:55-59.Kenneth Burchard, MD, Lebanon, NH:Intriguing information has been emerging for several years linking the male gender with evidence of more severe organ dysfunction following trauma and hemorrhage, and this study along with the next study to be presented at this meeting are consistent with these findings. I have several questions.I presume the authors would contend that the 255% increase in endogenous DHEA blood levels is insufficient to protect cardiac and hepatic tissue and that clearly a pharmacologic dose of DHEA is needed for cellular protection. Why is the endogenous response insufficient? Has there been a dose-response curve generated for DHEA that demonstrates that more than 10 times the endogenous blood level is needed to cause organ improvement? Also, why did the blood level of DHEA given after trauma-hemorrhage increase more than after the administration of DHEA alone?Second, if DHEA can be metabolized to testosterone as well as estradiol, why did the DHEA-treated animals exhibit a decrease in testosterone similar to the trauma-hemorrhage animals without DHEA? Has DHEA been given to female animals to determine if protection can be achieved beyond that of the female gender alone?And finally, are there any clinical data that support the concept that male gender is a disadvantage following inflammation and hypoperfusion? I performed a short review of burn mortality statistics to look for a model I thought would exhibit consistent injury across genders, and the data I found related to burn injuries suggest that females are at greater risk than males.Richard J. Shemin, MD, Boston, Mass:I'd like to ask the authors a methodological question in that cardiac index is one of the crudest measurements of cardiac performance and whether or not any other technique, such as maybe echocardiography, would give more information about cardiac filling and myocardial contraction, which would be much more germane to the cellular function of the heart.Erwin F. Hirsch, MD, Boston:Going back to the issue of burns, Basil Pruitt once said that the burn patient is the universal model of trauma, and along those lines, he once studied patients that were resuscitated with Ringer's lactate, and another group of burn patients that were resuscitated with early use of albumin. The net result of that study was that the albumin[-treated group] regained a hyperdynamic state much sooner than the Ringer's lactate group of patients, but ultimate survival was not different. My question to the authors is what is the carrot and what is the stick? If they would have elevated the cardiac index of these animals by means other than Ringer's lactate, like a colloid solution, would they have seen the same changes in liver function? Is this an issue or just better perfusion, or is this just a separate issue altogether?Dr Jarrar:With regard to Dr Burchard's first question as of why the 255% increase in endogenous DHEA following trauma-hemorrhage is not sufficient to protect organ functions, we speculate that this is part of the adrenal stress response. We have observed increased levels of corticosterone and aldosterone in this model of H1injury. In addition, we presented a paper last year at this meeting, showing that there was a 30% decrease in hepatic enzyme 11β-hydroxysteroid dehydrogenase, which is primarily responsible for the degradation of steroids. It could be argued that the elevated levels of DHEA following trauma-hemorrhage may also be due to the increased production of this agent. Although this may be the case, it is most likely that the elevated levels of DHEA are due to both increased production and depressed clearance following trauma-hemorrhage.To address your second question, we have not carried out detailed dose-response studies, and we have chosen the present dose based on data by other investigators using a rat model.Your third question dealt with whether DHEA can be metabolized to estradiol or testosterone and why their plasma levels were not altered. It has been shown that DHEA administration might not be reflected by changes in plasma levels of estradiol or testosterone in laboratory as well as clinical studies. However, DHEA may be metabolized to estradiol or testosterone in target tissues and exert its beneficial effects locally.With regard to your fourth question, it has been shown that estrogen receptors are expressed in the male cardiovascular system. One would expect that this is in even much greater abundance in females, so that administration of DHEA in females should also exert salutary effects on cell and organ functions following trauma-hemorrhage.In regard to the burn data and mortality studies, Drs Herndon and Barrow published a paper in 1990 reporting 185 burn patients with injury greater than 30% of the total body surface area. They indeed observed a higher mortality in the males than in females. Moreover, the late Roger Bone actually analyzed several sepsis studies and reported that males were at greater risks for developing infections, multiple organ failure, and subsequently dying following severe injury. Thus, the above clinical data support our current observation.With regard to cardiac index measurement, we have also performed measurements of heart performance, but data are [not] presented here. In this regard, measurements of tissue perfusion and oxygen delivery and consumption will also provide further insight of the beneficial effects of DHEA following trauma and hemorrhage. It should be noted that different organ systems relate to each other. The improvement of cardiac output will most likely result in better tissue perfusion and an improvement in hepatic function.With regard to the resuscitation regimen, recent studies have indicated that autologous blood does not necessarily improve organ dysfunction, despite an increase in mean arterial pressure in comparison to the Ringer's lactate group. In this regard, recent studies published in the American Journal of Physiology(Kerger et al; 1999;276[Heart Circ Physiol]:G2035-H2043) this year have shown that microcirculatory disturbance in perfusion still exists despite the use of blood products. This would suggest that simply elevating the blood pressure is not enough to affect distal organ function.This investigation was supported by award R37 GM 39519 from the National Institutes of Health, Bethesda, Md (Dr Chaudry). Dr Wang is the recipient of Independent Scientist Award KO2 AI 01461, National Institutes of Health.Presented at the 80th Annual Meeting of the New England Surgical Society, Newport, RI, September 24, 1999.We thank Zheng F. Ba and Joachim Kübler, MD, for their superb assistance during the experiments.Reprints: Irshad H. Chaudry, PhD, Center for Surgical Research, Rhode Island Hospital, Middle House II, 593 Eddy St, Providence, RI 02903 (e-mail: [email protected]).
Knöferl, Markus W.; Diodato, Michael D.; Angele, Martin K.; Ayala, Alfred; Cioffi, William G.; Bland, Kirby I.; Chaudry, Irshad H.
doi: 10.1001/archsurg.135.4.425pmid: 10768707
HypothesisAdministration of female sex steroids in males after trauma-hemorrhage has salutary effects on the depressed immune responses.DesignRandomized laboratory experiment.InterventionsMale C3H/HeN mice were subjected to midline laparotomy and hemorrhagic shock (35 ± 5 mm Hg for 90 minutes, then resuscitation) or sham operation and received subcutaneous 17β-estradiol (40 µg/kg body weight) or corn oil vehicle at the beginning of resuscitation.Main Outcome MeasuresAt 24 hours after hemorrhage, the animals were killed and plasma 17β-estradiol and IL-6, splenocyte interleukin (IL) 2, IL-3, and IL-10 production as well as splenic and peritoneal macrophage IL-1β, IL-10, and IL-6 release were measured.ResultsSplenocyte IL-2 and IL-3 release were significantly depressed after hemorrhage in vehicle-treated mice (P<.05, analysis of variance). Treatment with 17β-estradiol after hemorrhage led to the restoration of splenocyte IL-2 and IL-3 release. The depressed proinflammatory cytokine (IL-1 and IL-6) release seen in splenic and peritoneal macrophages was restored in the 17β-estradiol–treated hemorrhage group. In contrast, the sustained release of the anti-inflammatory cytokine IL-10 by splenocytes and splenic and peritoneal macrophages in vehicle-treated mice after hemorrhage was decreased in 17β-estradiol–treated mice. The increase in circulating IL-6 levels after hemorrhage was significantly attenuated in 17β-estradiol–treated mice. Although administration of 17β-estradiol increased plasma 17β-estradiol levels by approximately 100% in sham as well as hemorrhage groups, improved immune responses were seen only in posthemorrhage 17β-estradiol–treated mice. There was no adverse effect of 17β-estradiol treatment in the sham or posthemorrhage groups.ConclusionSince administration of a single dose of 17β-estradiol in males after trauma-hemorrhage restores the immune functions and decreases circulating levels of IL-6, hormones with estrogenic properties should be considered as safe and novel therapeutic agents for restoring the immune responsiveness in male trauma victims.SEVERAL STUDIES indicate that immune functions are markedly depressed in male subjects after trauma-hemorrhage and that these changes persist for as long as 10 days after resuscitation.Furthermore, testosterone has been shown to play a significant role in producing immunodepression after trauma-hemorrhage. Support for this notion comes from studies that indicate that depletion of testosterone by castration of male mice before the insult prevents the depression of splenocyte immune functions.Furthermore, administration of a testosterone receptor antagonist, ie, flutamide, in healthy male animals after trauma-hemorrhage restored the depressed immune responses and increased the survival rate of animals subjected to subsequent sepsis.In contrast to male mice, female mice in the proestrus state of the estrus cycle demonstrate enhanced immune responses after trauma-hemorrhage.Thus, it appears that elevated levels of female sex hormones, ie, prolactin and estrogen, in the proestrus state contribute to the sexual dimorphism in the immune response after trauma-hemorrhage.Support for the notion that the female sex steroid 17β-estradiol might have protective effects on immune responses after trauma-hemorrhage comes from recent studies performed in castrated male mice.Although supplementation of testosterone for 2 weeks before the insult in the castrated male mice led to a depression of immune functions after trauma-hemorrhage comparable to that of healthy male mice, immune functions were restored when the animals received 17β-estradiol in combination with testosterone.Although studies have shown that administration of 17β-estradiol in male mice before trauma-hemorrhage produces immunoenhancing effects,it remains unknown whether postinsult treatment with 17β-estradiol has any beneficial or deleterious effects on the depressed cell-mediated immune responses after trauma-hemorrhage. The aim of our study, therefore, was to determine whether administration of 17β-estradiol during resuscitation has any salutary effects on the depressed splenocyte as well as splenic and peritoneal macrophage functions in male subjects after trauma-hemorrhage.MATERIALS AND METHODSANIMALSInbred male C3H/HeN mice (Charles River Laboratories, Wilmington, Mass), 7 weeks of age (weight, 24-27 g) were used. All procedures were performed in accordance with the guidelines set forth in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health, Bethesda, Md. This project was approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital and Brown University, Providence.EXPERIMENTAL GROUPSMale mice were randomized into 4 groups (8-9 mice per group). The mice in groups 3 and 4 were subjected to trauma-hemorrhage, whereas the mice in groups 1 and 2 underwent the sham procedure. Groups 1 and 3 received a subcutaneous injection of 200 µL corn oil vehicle at the beginning of resuscitation, whereas groups 2 and 4 received a subcutaneous injection of 1 µg or 100 µg 17β-estradiol per mouse (40 or 4000 µg/kg body weight, respectively). In preliminary studies, administration of this dose of 17β-estradiol in male mice was found to increase plasma 17β-estradiol concentrations comparable to levels seen in female mice in the proestrus state (data not shown). In addition to these groups, sham and trauma-hemorrhage groups were treated with 100 µg 17β-estradiol per mouse to determine whether there are any deleterious or additional beneficial effects of a high dose of 17β-estradiol on immune responses.TRAUMA-HEMORRHAGE PROCEDUREMice in the trauma-hemorrhage groups were lightly anesthetized with methoxyflurane (Metofane; Pitman Moore, Mundelein, Ill) and restrained in a supine position, and a 2.5-cm midline laparotomy (ie, soft tissue trauma–induced) was performed, which was then closed aseptically in 2 layers using 6-0 sutures (Ethilon; Ethicon, Inc, Somerville, NJ). Both femoral arteries then were aseptically cannulated with polyethylene-10 tubing (Clay-Adams, Parsippany, NJ) using a minimal dissection technique, and the animals were allowed to awaken. Blood pressure was monitored constantly by attaching one of the catheters to a blood pressure analyzer (Micro-Med, Inc, Louisville, Ky). Lidocaine hydrochloride was applied to the incision sites to provide analgesia during the study period. On awakening, the animals were bled rapidly through the other catheter to a mean (± SEM) arterial blood pressure of 35 ± 5 mm Hg (prehemorrhage mean [± SEM] arterial blood pressure, 95 ± 5 mm Hg), which was maintained for 90 minutes. At the end of that period, the animals were resuscitated with 4 times the shed blood volume in the form of lactated Ringer solution. The catheters were then removed, the vessels were ligated, and the groin incisions were closed. Sham groups underwent the same surgical procedure, which included ligation of both femoral arteries, but neither hemorrhage nor fluid resuscitation. There was no mortality observed in this model of trauma-hemorrhage.BLOOD, TISSUE, AND CELL HARVESTING PROCEDUREThe animals were killed by methoxyflurane overdose 24 hours after the completion of the experiment to obtain the spleen, peritoneal macrophages, and whole blood samples. The mice were killed at the same time of day to avoid fluctuations due to circadian rhythm.PLASMA COLLECTION AND STORAGEWhole blood was obtained using cardiac puncture and placed in microcentrifuge tubes (Microtainer; Becton Dickinson and Co, Rutherford, NJ). The tubes then were centrifuged at 16 000gfor 15 minutes at 4°C. Plasma was separated, placed in pyrogen-free microcentrifuge tubes, immediately frozen, and stored (−80°C) until assayed.DETERMINATION OF PLASMA 17β-ESTRADIOL CONCENTRATIONConcentration of 17β-estradiol was determined using a commercially available radioimmunoassay (RIA) (ICN Biomedical, Costa Mesa, Calif) as described by the manufacturer.PREPARATION OF SPLENOCYTE CULTURETwenty-four hours after trauma-hemorrhage, the spleens were removed aseptically and placed in separate Petri dishes containing ice-cold phosphate-buffered saline (PBS) solution. Splenocytes were isolated as previously described,and the ability of the splenocyte cultures to produce lymphokines in response to a mitogenic challenge was assessed by incubation for 48 hours (at 37°C, 5% carbon dioxide [CO2], and 90% humidity) in the presence of 2.5 µg/mL concanavalin A (Con A; Pharmacia/LKB Biotech Inc, Piscataway, NJ). After incubation, the cell suspension was centrifuged at 300gfor 15 minutes, and the supernatants were harvested and stored at −80°C until assayed for interleukin (IL) 2, IL-3, IL-10, and interferon γ (IFN-γ).CELL-LINE MAINTENANCEThe IL-2–dependent CTLL-2 cells and the IFN-γ–dependent RAW 264.7 cells were obtained from the American Type Culture Collection and maintained according to their directions. The IL-3–dependent FDC-P1 cells were maintained as previously described.The IL-6–sensitive murine B-cell hybridoma (7TD1) was maintained as previously described.ASSESSMENT OF LYMPHOKINE RELEASEThe capacity of the mixed splenocyte culture to produce IL-2 or IL-3 was assessed by determining the amount of IL-2 or IL-3 in the collected culture supernatant. Serial dilutions of the supernatants were added to CTLL-2 cells (1 × 105cells/mL) or to FDC-P1 cells (2.5 × 105cells/mL) and incubated for 48 or 24 hours, respectively, at 37°C and 5% CO2. At the end of this period, 0.037 MBq of tritiated thymidine (specific activity, 24.79 × 1010Bq/mmol; New England Nuclear, Wilmington, Del) was added to each well, and the cultures were incubated for an additional 16 hours. The cells were then harvested onto glass-fiber mats, and the beta decay was detected using liquid scintillation radiography as previously described.PREPARATION OF PERITONEAL AND SPLENIC MACROPHAGE CULTUREResident peritoneal macrophages were obtained from mice, and monolayers were established as previously described.The spleens were removed aseptically and placed in separate Petri dishes containing cold (4°C) PBS solution. The spleens were dissociated by grinding and then suspended and used to establish a macrophage culture as previously described.The macrophage monolayers were stimulated with lipopolysaccaride (LPS), 10 µg/mL Click medium containing 10% fetal calf serum for 48 hours (at 37°C, 5% CO2, and 90% humidity) to assess the cells' ability to release IL-1β, IL-6, and IL-10. At the end of the incubation period, the culture supernatants were removed, divided into aliquots, and stored at −80°C until assayed.ASSESSMENT OF IL-1β AND IL-10 RELEASELevels of IL-1β and IL-10 in the macrophage supernatants were determined using Sandwich enzyme-linked immunosorbent assay described by Mosmann et al.In brief, 96-well plates were coated overnight with 2 µg monoclonal hamster anti–mouse IL-1β capture antibody (Genzyme Diagnostics, Cambridge, Mass) per milliliter of 0.1-mol/L carbonate (pH, 9.5) or 4 µg rat anti–mouse IL-10 capture antibody (clone JES-5; Pharmingen, San Diego, Calif) per milliliter of 0.1-mol/L sodium bicarbonate (pH, 8.2). The plates were washed 3 times with PBS solution containing 0.05% polyoxyethylenesorbitan 20 (Tween 20; Sigma-Aldrich Corporation, St Louis, Mo) and blocked with PBS solution containing 20% fetal calf serum for 2 hours. After the plates were washed, 100 µL of the samples and standard (1000 pg/mL murine IL-1β [Genzyme Diagnostics] or 1000 pg/mL murine IL-10 [Pharmingen]) were added to the plates in duplicate, and they were incubated overnight (4°C). After repeated washings, the plates were incubated for 1 hour with 100 µL of biotinylated polyclonal rabbit anti–mouse IL-1β (Genzyme Diagnostics) at a concentration of 0.8 µg/mL at 37°C or biotinylated monoclonal rat anti–mouse IL-10 (clone SXC-1; Pharmingen) at a concentration of 2 µg/mL at room temperature. For IL-1β detection, the washed plates were incubated with horseradish peroxidase-conjugated streptavidin (Genzyme Diagnostics) for 15 minutes at 37°C. After multiple washings, 100 µL of 3,3‘,5,5‘-tetramethylbenzidine (TMB; Sigma-Aldrich Corporation) was added for 10 minutes at room temperature. After the addition of 100 µL of stop solution (0.5 mol/L sulfuric acid), the optical density of each well was determined at 450 nm on a plate reader (EL-311; Bio-Tek Instruments Inc, Winooski, Vt). For detection of IL-10, the plates were washed and incubated at room temperature for 30 minutes with avidin-peroxidase (diluted 1:400; Sigma-Aldrich Corporation). After washing, 100 µL of 2,2‘-azinobis(3-ethylbenzthiazolinesulfonic acid)–hydrogen peroxide substrate buffer was added to each well to initiate color development. The optical density at 405 nm for each well was then determined on a microplate reader. The concentration of IL-1β and IL-10 present in the samples was determined by interpolation using a standard curve produced with murine IL-1β and IL-10, respectively.ASSESSMENT OF IL-6 RELEASEActivity of IL-6 in culture supernatant was determined by the degree of proliferation of the murine B-cell hybridoma cell line 7TD1, which only grows in the presence of IL-6. Serial dilutions of macrophage supernatants were added to 4 × 1047TD1 cells/mL, and the cells were incubated for 72 hours at 37°C in 5% CO2. For the last 4 hours of incubation, 20 µL of a 3-(4,5-dimethylthiazol-2-L)-2,5-diphenyltetrazolium-bromide solution (5 µg/mL in RPMI-1640 [Sigma-Aldrich Corporation]) was added to each well (only viable cells incorporate the solution). The assay was stopped by aspiration of 150 µL of supernatant from each well, with subsequent replacement by 100 µL of 10% sodium dodecyl sulfate solution in PBS (lauryl sulfate; Sigma-Aldrich Corporation) to dissolve the dark blue formazan crystals. Using an automated microplate reader (EL-311), the light absorbance was measured at 570 nm.STATISTICAL ANALYSISResults are presented as mean ± SEM. One-way analysis of variance followed by the Newman-Keuls test as a post hoc test for multiple comparisons was used to determine the significance of the differences between experimental means. A Pvalue of less than .05 was considered statistically significant.RESULTSEFFECT OF 17β-ESTRADIOL ADMINISTRATION ON PLASMA 17β-ESTRADIOL CONCENTRATIONLevels of 17β-estradiol were 69.4 ± 8.8 pmol/L (18.9 ± 2.4 pg/mL) in the vehicle-treated sham group and 58.4 ± 11.4 pmol/L (15.9 ± 3.1 pg/mL) in the vehicle-treated group undergoing trauma-hemorrhage. At 24 hours after administration of a single dose of 1 µg 17β-estradiol per mouse, plasma 17β-estradiol levels increased significantly (Figure 1, top) compared with vehicle-treated animals (145.0 ± 7.3 pmol/L [39.5 ± 2.0 pg/mL] in the sham group and 115.6 ± 10.3 pmol/L [31.5 ± 2.8 pg/mL] in the hemorrhage group receiving 17β-estradiol). Animals treated with the high dose of 17β-estradiol (ie, 100 µg per mouse) had significantly higher plasma estradiol levels than the vehicle-treated animals (sham group, 11 377.0 ± 1950.2 pmol/L [3100.2 ± 531.4 pg/mL]; trauma-hemorrhage group, 16 492.6 ± 1744.0 pmol/L [4493.9 ± 475.2 pg/mL]).Figure 1.Male C3H/HeN mice underwent sham operation or trauma-hemorrhage and resuscitation and were treated with corn oil vehicle or 1 µg 17β-estradiol at the beginning of resuscitation. At 24 hours thereafter, plasma 17β-estradiol levels were determined using specific radioimmunoassay (top). Plasma interleukin (IL) 6 levels were determined using a specific bioassay (7TD1) (bottom). Values are given as mean ± SEM of 7 to 8 animals in each group; comparisons were made using analysis of variance. Asterisk indicates P<.05 vs vehicle-treated sham group; dagger, P<.05 vs vehicle-treated trauma-hemorrhage group.EFFECT OF 17β-ESTRADIOL ADMINISTRATION ON PLASMA IL-6 LEVELSThere was no significant difference in circulating levels of IL-6 between the vehicle-treated sham group (0.03 ± 0.00 U/mL) and the sham group treated with 17β-estradiol (0.03 ± 0.02 U/mL) (Figure 1, bottom). Plasma IL-6 levels significantly increased in vehicle-treated animals that underwent the trauma-hemorrhage procedure (0.38 ± 0.16 U/mL). Treatment with 17β-estradiol after trauma-hemorrhage significantly attenuated the increased circulating levels of IL-6 (0.10 ± 0.06 U/mL).EFFECT OF 17β-ESTRADIOL ADMINISTRATION ON SPLENOCYTE FUNCTION AFTER TRAUMA-HEMORRHAGEThere was no significant difference in IL-2 release capacity by splenocytes from the sham group receiving vehicle or 1 µg 17β-estradiol (Figure 2, top). Trauma-hemorrhage produced a significant depression of splenocyte IL-2 release in vehicle-treated animals (−46% compared with the vehicle-treated sham group). Administration of 17β-estradiol after trauma-hemorrhage significantly increased the release of IL-2 to levels comparable to those of the sham groups (97.8% compared with the vehicle-treated trauma-hemorrhage group). Comparable to IL-2, IL-3 release capacity was significantly depressed in animals receiving vehicle after trauma-hemorrhage (−56.6% compared with the vehicle-treated sham group) (Figure 2, bottom). Treatment with 17β-estradiol after trauma-hemorrhage led to a restoration of splenocyte IL-3 release (173.9% compared with the vehicle-treated trauma-hemorrhage group). In addition, the release of IFN-γ was significantly depressed in animals subjected to trauma-hemorrhage and treated with vehicle (−28.9% compared with the vehicle-treated sham group) (Figure 3, top). In contrast, no depression of IFN-γ release capacity was observed in animals that received 1 µg of 17β-estradiol at the beginning of resuscitation. The release of the anti-inflammatory cytokine IL-10 was maintained in vehicle-treated mice subjected to trauma-hemorrhage (Figure 3, bottom). In contrast, the release of IL-10 decreased in mice treated with 17β-estradiol compared with the corresponding sham group (−52.4%). However, these changes did not reach statistical significance.Figure 2.Splenocytes were harvested at 24 hours after trauma-hemorrhage or sham operation from male C3H/HeN mice treated with corn oil vehicle or 1 µg of 17β-estradiol. The release of interleukin (IL) 2 by splenocytes stimulated with 2.5 µg/mL concanavalin A for 48 hours was determined using a specific bioassay (CTLL-2) (top); IL-3 release was measured using a bioassay specific for IL-3 (bottom). Values are given as mean ± SEM of 7 to 8 animals in each group; comparisons were made using analysis of variance. Asterisk indicates P<.05 vs vehicle-treated sham group; dagger, P<.05 vs vehicle-treated trauma-hemorrhage group.Figure 3.Splenocytes were harvested at 24 hours after trauma-hemorrhage or sham operation from male C3H/HeN mice treated with corn oil vehicle or 1 µg of 17β-estradiol. The release of interferon (IFN) γ by splenocytes stimulated with 2.5 µg/mL concanavalin A for 48 hours was determined using a specific bioassay (RAW 264.7) (top); interleukin-10 (IL-10) release was measured using enzyme-linked immunosorbent assay (bottom). Values are given as mean ± SEM of 7 to 8 animals in each group; comparisons were made using analysis of variance. Asterisk indicates P<.05 vs vehicle-treated sham group; dagger, P<.05 vs vehicle-treated trauma-hemorrhage group.EFFECT OF 17β-ESTRADIOL ADMINISTRATION ON MONOKINE RELEASE BY SPLENIC AND PERITONEAL MACROPHAGESNo significant difference in peritoneal macrophage IL-1β release was evident between the sham groups receiving vehicle or 1 µg of 17β-estradiol (Figure 4, top). However, the trauma-hemorrhage group receiving vehicle had significantly decreased IL-1β release (−35.9% compared with the vehicle-treated sham group). In contrast, peritoneal macrophage IL-1β release was restored in mice that received 1 µg of 17β-estradiol after trauma-hemorrhage (61.2% compared with the vehicle-treated trauma-hemorrhage group). Peritoneal macrophage IL-6 release capacity was comparable in both sham groups. Vehicle-treated mice subjected to trauma-hemorrhage had significantly decreased peritoneal macrophage IL-6 release (−57.6% compared with the vehicle-treated sham group). Administration of 17β-estradiol increased but did not restore the depressed IL-6 release after trauma-hemorrhage (56.8% compared with the vehicle-treated trauma-hemorrhage group). At 24 hours after trauma-hemorrhage, peritoneal macrophage IL-10 release was maintained in vehicle-treated animals (Figure 5). However, the release of the anti-inflammatory cytokine IL-10 significantly decreased in animals that received 1 µg of 17β-estradiol after trauma-hemorrhage (−45.6% compared with the estradiol-treated sham group).Figure 4.Peritoneal macrophages were harvested at 24 hours after trauma-hemorrhage or sham operation from male C3H/HeN mice treated with corn oil vehicle or 1 µg of 17β-estradiol and cultured in the presence of 10 µg/mL lipopolysaccharide for 48 hours. Peritoneal macrophage interleukin (IL) 1β release was measured using enzyme-linked immunosorbent assay (top); IL-6 release was determined using a specific bioassay (7TD1) (bottom). Values are given as mean ± SEM of 7 to 8 animals in each group; comparisons were made using analysis of variance. Asterisk indicates P<.05 vs vehicle-treated sham group.Figure 5.Peritoneal macrophages were harvested at 24 hours after trauma-hemorrhage or sham operation from male C3H/HeN mice treated with corn oil vehicle or 1 µg of 17β-estradiol and cultured in the presence of 10 µg/mL lipopolysaccharide for 48 hours. Peritoneal macrophage interleukin (IL) 10 release was measured using enzyme-linked immunosorbent assay. Values are given as mean ± SEM of 7 to 8 animals in each group; comparisons were made using analysis of variance. Asterisk indicates P<.05 vs estradiol-treated sham group.Splenic macrophage IL-1β release (Figure 6, top) was comparable in both sham groups. Animals subjected to trauma-hemorrhage and vehicle had significantly depressed splenic macrophage IL-1β release (−42.6% compared with the vehicle-treated sham group). Splenic macrophage IL-1β release in the trauma-hemorrhage group treated with 17β-estradiol, however, showed IL-1β release that was comparable to IL-1β release by macrophages from the sham groups (60.8% compared with the vehicle-treated trauma-hemorrhage group). Comparable findings were obtained for splenic macrophage IL-6 release (Figure 6, bottom). After trauma-hemorrhage, IL-6 release was significantly depressed in vehicle-treated animals compared with the vehichle-treated sham group (−64.4%). Animals treated with 1 µg of 17β-estradiol at the beginning of resuscitation had restored IL-6 release capacity (143.2% compared with the vehicle-treated trauma-hemorrhage group). Similarly, IL-12 release was significantly depressed in the vehicle-treated group after trauma-hemorrhage (−44.0% compared with the vehicle-treated sham group), whereas no depression was evident in animals that received 17β-estradiol treatment (Figure 7, bottom). After trauma-hemorrhage, the release of IL-10 increased in the vehicle-treated group (57.4% compared with the vehicle-treated sham group) (Figure 7, top). This increase, however, was not statistically significant. In animals treated with 17β-estradiol after trauma-hemorrhage, no increase in IL-10 release was observed.Figure 6.Splenic macrophages were harvested at 24 hours after trauma-hemorrhage or sham operation from male C3H/HeN mice treated with corn oil vehicle or 1 µg of 17β-estradiol and cultured in the presence of 10 µg/mL lipopolysaccharide for 48 hours. Splenic macrophage interleukin (IL) 1β release was measured using enzyme-linked immunosorbent assay (top); IL-6 release, by a specific bioassay (7TD1) (bottom). Values are given as mean ± SEM of 7 to 8 animals in each group; comparisons were made using analysis of variance. Asterisk indicates P<.05 vs vehicle-treated sham group.Figure 7.Splenic macrophages were harvested at 24 hours after trauma-hemorrhage or sham operation from male C3H/HeN mice treated with corn oil vehicle or 1 µg of 17β-estradiol and cultured in the presence of 10 µg/mL lipopolysaccharide for 48 hours. Splenic macrophage interleukin (IL) 10 (top) and IL-12 release (bottom) were measured using enzyme-linked immunosorbent assay. Values are given as mean ± SEM of 7 to 8 animals in each group; comparisons were made using analysis of variance. Asterisk indicates P<.05 vs vehicle-treated sham group.EFFECT OF HIGH-DOSE 17β-ESTRADIOL ADMINISTRATION ON IMMUNE FUNCTIONSAs shown in Table 1, treatment of male mice with the high dose of 17β-estradiol (ie, 100 µg per mouse) after trauma-hemorrhage normalized splenocyte and splenic and peritoneal macrophage immune functions comparable to the pattern observed after treatment with the low dose of 17β-estradiol (ie, 1 µg per mouse). In addition, the increased plasma IL-6 levels after trauma-hemorrhage were significantly attenuated in animals receiving the high dose of 17β-estradiol compared with vehicle-treated animals (Table 1).Effects of High-Dose 17β-Estradiol Administration on Plasma 17β-Estradiol Levels and Immune Functions 24 Hours After Sham Operation or Trauma-Hemorrhage*Sham-VehicleSham–17β-EstradiolHemorrhage-VehicleHemorrhage–17β-EstradiolPlasma 17β-estradiol, pmol/L (pg/mL)69.4 ± 8.8 (18.9 ± 2.4)11,377.0 ± 1950.2 (3100.2 ± 531.4)†58.4 ± 11.4 (15.9 ± 3.1)16,492.6 ± 1744.0 (4493.9 ± 475.2)‡Plasma-IL-6, U/mL0.027 ± 0.0110.018 ± 0.0080.375 ± 0.162†0.087 ± 0.027‡Splenocyte IL-2, U/mL1.78 ± 0.071.74 ± 0.100.96 ± 0.22†1.46 ± 0.21Splenocyte IL-3, U/mL714.1 ± 59.9797.9 ± 83.6310.1 ± 64.8†995.6 ± 90.5‡Splenocyte IFN-γ, U/mL15,177 ± 61914,531 ± 74810,789 ± 475†13,270 ± 798‡Peritoneal macrophage IL-6, U/mL2377 ± 2482286 ± 4681009 ± 112†1480 ± 232Peritoneal macrophage IL-10, pg/mL373.9 ± 54.2464.1 ± 43.5303.9 ± 60.9250.0 ± 24.4§Splenic macrophage IL-1β, pg/mL28.6 ± 3.719.5 ± 2.516.4 ± 2.2†26.9 ± 2.9‡Splenic macrophage IL-6, U/mL16.3 ± 3.69.2 ± 1.35.8 ± 1.5†11.4 ± 1.6Splenic macrophage IL-10, pg/mL71.8 ± 15.071.7 ± 17.7113.1 ± 25.249.3 ± 11.2*Data are given as mean ± SEM. Sham-Vehicle indicates vehicle-treated sham group; Sham–17β-Estradiol, 17β-estradiol–treated sham group; Hemorrhage-Vehicle, vehicle-treated trauma-hemorrhage group; Hemorrhage–17β-Estradiol, 17β-estradiol–treated trauma-hemorrhage group; IL, interleukin; IFN, interferon; and ANOVA, analysis of variance. Groups are described in the "Experimental Groups" subsection of the "Materials and Methods" section.†P<.05 vs Sham-Vehicle (ANOVA).‡P<.05 vs Hemorrhage-Vehicle (ANOVA).§P<.05 vs Sham–17β-Estradiol (ANOVA).COMMENTSeveral studies have shown that cell-mediated immunity is markedly depressed in male subjects after trauma-hemorrhage despite adequate fluid resuscitation.This depression in immune responses persists for up to 10 days after resuscitation and is associated with increased susceptibility to sepsis.Studies also have suggested that male sex steroids play a critical role in initiating the depression of immune responses.This suggestion is supported by the observation that depletion of testosterone in male mice by castration 2 weeks before trauma-hemorrhage prevented the depression of immune responses.Moreover, administration of a testosterone receptor antagonist, eg, flutamide, in healthy male animals after trauma-hemorrhage restored the depressed immune responses after trauma-hemorrhage and improved survival rates after subsequent sepsis.In contrast to male mice, female mice in the proestrus state of the estrus cycle have enhanced immune functions after trauma-hemorrhage.Since the proestrus state of the cycle is characterized by increased plasma levels of female sex hormones such as estrogen and prolactin,it could be postulated that these hormones are responsible for producing immunoenhancing effects after trauma-hemorrhage. Indeed, administration of prolactin in males after trauma-hemorrhage has been shown to restore the depressed splenocyte and macrophage immune responses and to decrease mortality rates due to subsequent sepsis.However, little information is available concerning the effects of the female sex steroid 17β-estradiol on the immune responses after trauma-hemorrhage. Our aim, therefore, was to determine whether the female steroid hormone 17β-estradiol has any beneficial or deleterious effects on the depressed immune function after trauma-hemorrhage in males. Our results indicate that administration of 17β-estradiol at the beginning of resuscitation restores the depressed splenocyte as well as splenic and peritoneal macrophage function after trauma-hemorrhage. In this study, 17β-estradiol was administered subcutaneously at a dose of 1 µg per mouse, because preliminary studies from our laboratory have shown that this dose increased plasma 17β-estradiol concentrations in males comparable to levels observed in female mice in the proestrus state.In addition to this low dose of 17β-estradiol (ie, 1 µg per animal), we also investigated whether high-dose estradiol treatment (100 µg of 17β-estradiol per mouse) has any deleterious or additional salutary effects on immune responses. The results indicate that immune functions in animals treated with the high dose of 17β-estradiol were comparable to the findings observed after administration of the low dose. Thus, there appear to be no deleterious effects of administration of high doses of 17β-estradiol. Although administration of 17β-estradiol at a dose of 1 µg per animal after trauma-hemorrhage restored the immune responses, doses of 17β-estradiol even lower than 1 µg per animal may have salutary effects on the immune responses. This, however, remains to be determined.Previous studies have demonstrated that normalization of the depressed macrophage and splenocyte functions in male mice treated with the immunomodulatory hormone prolactin after hemorrhagic shock was associated with decreased lethality owing to subsequent sepsis.Thus, it is possible that the restoration of immune responsiveness seen in 17β-estradiol–treated animals after trauma-hemorrhage might decrease the lethality rates due to a subsequent lethal septic challenge. However, as the animals in our study were not subjected to a subsequent septic challenge, further studies are necessary to address this issue.Additional support for the findings that 17β-estradiol has immunoenhancing properties comes from the studies of Chao et al.These investigators demonstrated that 17β-estradiol at concentrations within the physiological range increases male rat peritoneal macrophage tumor necrosis factor-α release capacity in vitro.Further support for direct effects of 17β-estradiol on immune cells comes from studies by Fox et al,who demonstrated that 17β-estradiol markedly increased the activity of the IFN-γ promoter in lymphoid cells that express the appropriate hormone receptor. Support for the notion that the female sex steroid 17β-estradiol also has protective effects on immune responses after trauma-hemorrhage comes from recent studies from our laboratory.The results of those studies indicate that supplementation of testosterone in castrated male mice for 14 days before the insult led to depressed immune functions after trauma-hemorrhage comparable to the depression observed in healthy male mice under such conditions. However, when castrated mice received 17β-estradiol in addition to testosterone, immune functions after trauma-hemorrhage were restored to sham levels.In addition to restoration of splenic and peritoneal macrophage functional capacity, 17β-estradiol treatment significantly reduced circulating levels of IL-6 after trauma-hemorrhage. These findings are in line with the results of studies by Zuckerman et al,who demonstrated significantly decreased levels of plasma IL-6 in mice pretreated with 17α-ethynyl estradiol and subjected to endotoxemia. These findings suggest that under adverse conditions, estrogens might exert systemic effects by influencing the profile of circulating cytokines. In this regard, Kupffer cells have previously been shown to be the major source of circulating IL-6.Although the increasing IL-6 levels in circulation seem at first discordant with our observed restoration of macrophage IL-6 release capacity, a previous study from our laboratory has shown that the increased blood IL-6 concentrations are a product of Kupffer cell activation and not from the splenic or peritoneal macrophages.Kupffer cell IL-6 release was not measured in our study. Therefore, the finding that plasma IL-6 levels after trauma-hemorrhage are significantly lower in 17β-estradiol– treated mice than in mice receiving vehicle suggests that 17β-estradiol attenuates proinflammatory cytokine production by this macrophage population.Our results indicate that in contrast to proinflammatory cytokine release, IL-10 production by cells obtained from the trauma-hemorrhage groups was enhanced in splenic macrophages or unchanged in peritoneal macrophage or splenocytes. In this regard, it has been suggested that the increased IL-10 release in splenocytes from male mice after simple hemorrhage might contribute to the depression of immune functions.Thus, we suggest that the maintenance of anti-inflammatory IL-10 production in the face of diminishing cell-mediated proinflammatory cytokine productive capacity supports the role of IL-10 as one of several potential immunosuppressive agents present after trauma-hemorrhage. This is also supported by our observation that the release of IL-10 by splenic and peritoneal macrophages was decreased in 17β-estradiol–treated male mice after trauma-hemorrhage. Therefore, it could be speculated that the reduction of IL-10 production, or possibly concomitant suppression of other anti-inflammatory agents not assessed herein (eg, transforming growth factor-β, IL-4) in 17β-estradiol–treated animals subjected to trauma-hemorrhage might contribute to the maintenance of macrophage functions.The underlying mechanisms by which 17β-estradiol mediates its beneficial effects on different immune cell populations after trauma-hemorrhage in males remain unclear. Our results showing that administration of 17β-estradiol did not enhance the immune responses in the sham groups suggest that 17β-estradiol is immunostimulatory only in an immunologically compromised host. Since 17β-estradiol plasma levels did not change significantly after trauma-hemorrhage, our findings further suggest that the number of 17β-estradiol receptors or the receptor affinity might be altered under such conditions. Therefore, provision of additional agonist, ie, 17β-estradiol, for the receptors might contribute to the improvement of the depressed immune responses after trauma-hemorrhage. The fact that estradiol receptors have been demonstrated on macrophages suggests that these cells may be susceptible to functional modulation by the additional estrogens administered after trauma-hemorrhage.Additional studies, however, are needed to determine whether the salutary effects of 17β-estradiol on immune responsiveness after trauma-hemorrhage are receptor mediated and which immune cell populations are primarily affected by this treatment. Alternatively, salutary effects of 17β-estradiol on immune functions after trauma-hemorrhage might be the indirect result of effects on other organ systems. For example, recent findings in cardiovascular disease provide evidence that estradiol acts via rapid, "nongenomic" as well as long-term, "genomic" mechanisms.In this regard, it is possible that the nongenomic effects of pharmacological doses of 17β-estradiol, such as vasodilation, are due to changes in ion-channel functionas well as increased endothelial nitric oxide production.Such effects might contribute to the beneficial effects on immune functions by improving microcirculation after trauma-hemorrhage. However, the contribution of such a mechanism has not been assessed yet in our experimental setting.In summary, our study indicates that posttreatment with 17β-estradiol not only restores splenic and macrophage cytokine productive capacity but suppresses the release of a potential immunosuppressant, IL-10, and attenuates the increase in plasma IL-6 levels seen after trauma-hemorrhage. Although the exact mechanism for the immunomodulatory properties of 17β-estradiol remains unknown, these findings suggest salutary effects of this steroid hormone after adverse circulatory conditions. Therefore, administration of 17β-estradiol should be considered a novel and useful approach for the treatment of immune dysfunction in male trauma victims.Statement of Clinical RelevanceA number of studies have shown that various immune functions are markedly depressed in males after trauma-hemorrhage and that this dysfunction is associated with an increased susceptibility to subsequent sepsis. It also has become evident that sex steroids are involved in the regulation of immune responses under normal and pathophysiological conditions. Although the immunosuppressive role of testosterone has been well characterized and testosterone receptor blockade has been shown to be beneficial after trauma-hemorrhage, it remained unclear whether female sex steroids have any salutary or deleterious effects under such conditions. Our study indicates that administration of a single dose of the female sex steroid 17β-estradiol after trauma and hemorrhagic shock normalizes the depressed immune functions in male mice. In view of this, hormones with estrogenic properties should be considered novel therapeutic agents for the treatment of immune dysfunction encountered in male trauma victims.IHChaudryAAyalaImmunological Aspects of Hemorrhage.Austin, Tex: Medical Intelligence Unit, RG Landes Co; 1992.YXXuAAyalaIHChaudryProlonged immunodepression after trauma and hemorrhagic shock.J Trauma.1998;44:335-341.MWWichmannAAyalaIChaudryMale sex steroids are responsible for depressing macrophage immune function after trauma-hemorrhage.Am J Physiol.1997;273:C1335-C1340.MKAngeleMWKnöferlMGSchwachaSex steroids regulate pro- and anti-inflammatory cytokine release by macrophages after trauma-hemorrhage.Am J Physiol.1999;277:C35-C42.MKAngeleMWWichmannAAyalaWGCioffiIHChaudryTestosterone receptor blockade after hemorrhage in males: restoration of the depressed immune functions and improved survival following subsequent sepsis.Arch Surg.1997;132:1207-1214.MWWichmannMKAngeleAAyalaWGCioffiIChaudryFlutamide: a novel agent for restoring the depressed cell-mediated immunity following soft-tissue trauma and hemorrhagic shock.Shock.1997;8:1-7.MWWichmannRZellwegerCMDeMasoAAyalaIHChaudryEnhanced immune responses in females as opposed to decreased responses in males following hemorrhagic shock.Cytokine.1996;8:853-863.TFOgleJIKitayOvarian and adrenal steroids during pregnancy and the oestrous cycle in the rat.J Endocrinol.1977;74:89-98.RZellwegerAAyalaCMDeMasoIHChaudryTrauma-hemorrhage causes prolonged depression in cellular immunity.Shock.1995;4:149-153.JNIhleJKellerJSGreenbergerLHendersonRAYetterHCMorsePhenotypic characteristics of cell lines requiring IL-3 for growth.J Immunol.1982;129:1377-1383.MKAngeleAAyalaBAMonfilsWGCioffiKIBlandIHChaudryTestosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage.J Trauma.1998;44:78-85.TRMosmannJHSchumacherDFFiorentinoJLeverahKWMooreMWBondIsolation of monoclonal antibodies specific for IL-4, IL-5, IL-6 and a new Th2-specific cytokine (IL-10), cytokine synthesis inhibitory factor, by using a solid phase radioimmunoadsorbent assay.J Immunol.1990;145:2938-2945.RZellwegerX-HZhuMWWichmannAAyalaCMDeMasoIHChaudryProlactin administration following hemorrhagic shock improves macrophage cytokine release capacity and decreases mortality from subsequent sepsis.J Immunol.1996;157:5748-5754.RZellwegerMWWichmannAAyalaCMDeMasoIHChaudryProlactin: a novel and safe immunomodulating hormone for the treatment of immunodepression following severe hemorrhage.J Surg Res.1996;63:53-58.TCChaoAPVanJAGreagerRJWalterSteroid sex hormones regulate the release of tumor necrosis factor by macrophages.Cell Immunol.1995;160:43-49.HSFoxBLBondTGParslowEstrogen regulates the IFN-γ promoter.J Immunol.1991;146:4362-4367.SHZuckermanNBryan-PooleGFEvansLShortALGlasebrookIn vivo modulation of murine serum tumour necrosis factor and interleukin-6 levels during endotoxemia by oestrogen agonists and antagonists.Immunology.1995;86:18-24.PJO'NeillAAyalaPWangRole of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation.Shock.1994;1:43-47.AAyalaDLLehmanCDHerdonIHChaudryMechanism of enhanced susceptibility to sepsis following hemorrhage: interleukin-10 suppression of T-cell response is mediated by eicosanoid-induced interleukin-4 release.Arch Surg.1994;129:1172-1178.SGulshanABMcCrudenWHStimsonOestrogen receptors in macrophages.Scand J Immunol.1990;31:691-697.MEMendelsohnRHKarasThe protective effects of estrogen on the cardiovascular system.N Engl J Med.1999;340:1801-1811.ADFreaySWCurtisKSKorachGMRubanyiMechanism of vascular smooth muscle relaxation by estrogen in depolarized rat and mouse aorta: role of nuclear estrogen receptor and Ca2+ uptake.Circ Res.1997;81:242-248.TKitazawaEHamadaKKitazawaAKGaznabiNon-genomic mechanism of 17 β-estradiol–induced inhibition of contraction in mammalian vascular smooth muscle.J Physiol (Lond).1997;499:497-511.TCaulin-GlaserGGarcia-CardenaPSarrelWCSessaJRBender17 β-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization.Circ Res.1997;81:885-892.RLLantin-HermosoCRRosenfeldISYuhannaZGermanZChenPWShaulEstrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium.Am J Physiol.1997;273:L119-L126.Herbert B. Hechtman, MD, Boston, Mass:Dr Knöferl has continued the focus train of Dr Chaudry's research regarding the ability of female steroid hormones to modulate immune function. These data are in concert with prior reports from his laboratory as well as the reports of several other groups regarding the ability of estrogen and other female steroids to alter production of a variety of cytokines. The net effect favors an anti-inflammatory action. The story is complex. Not only are there multitudes of pro- and anti-inflammatory cytokines released as a result of stress, but there are a variety of lymphoid and phagocytic cells of origin which may respond quite differently to similar stimuli. Thus an article by you of more than 10 years ago indicated that LPS will stimulate peritoneal macrophage production of IL-1, and this is in contrast to the effects of trauma and hemorrhage that are now reported to limit production of IL-1.Indeed, one of the problems in interpretation is that the authors utilize a number of study stimuli. First is the application of laparotomy as a form of trauma. Second, there is hemorrhage and resuscitation. And third, there is in vitro stimulation of splenocytes with concanavalin A, but stimulation of peritoneal and splenic macrophages with LPS. The difficulty in simple interpretation is the multiplicity and lack of definition of stimuli. Thus, what are the independent roles of laparotomy, hemorrhage, and LPS of bacterial sepsis?Another problem in interpretation is the report of depressed in vitro IL-6 production by splenic macrophages but elevated in situ plasma IL-6 concentrations after trauma. The conclusion that Kupffer cell synthesis of IL-6 is stimulated by trauma and depressed by estradiol is based on previous studies using gadolinium, which suggests the importance of Kupffer cell synthesis of IL-6. This remarkable heterogeneity, however, of macrophage function requires more proof of the role of each class of cells, such as changes in cytokine messenger RNA.These comments should not detract from the novel results that demonstrate the clinical ability of female steroids to modulate immune function. How important this will prove to be remains open to question.John A. Mannick, MD, Boston:I too enjoyed the paper and I have only 1 question, being a devotee of the motto in vivo veritas.Do you have any evidence that estradiol therapy in your model of trauma-hemorrhage with later challenge with cecal ligation and puncture will actually increase survival after an infectious challenge?Dr Knöferl:In previous studies from our laboratory, the independent roles of trauma in the form of a midline laparotomy, as well as simple hemorrhagic shock alone, have been studied. In the present study, we used a model of combined trauma and hemorrhagic shock in order to have a severe model which is clinically relevant. Dr Hechtman mentioned the fact that splenocyte IL-6 production is decreased in response to LPS stimulation, whereas plasma IL-6 levels are increased. As you mentioned, in previous studies from our laboratory, it has been shown that the Kupffer cell population in the liver is a major cellular source for production of IL-6. Therefore, it appears that administration of 17β-estradiol indeed has influence on Kupffer cell proinflammatory cytokine production. This, however, was not studied in the present work.He mentioned whether we have any clinical indication for the trend differences we observed in our animal models of trauma and hemorrhagic shock. Indeed, there is a wealth of information from epidemiological studies that indicate a predominance of the male gender for infection. In addition, a study recently published by a group in Denver indicated that in the surgical ICU male gender is a major risk factor for infection. Another study published from Germany indicates that even mortality from sepsis is increased in the male gender.Dr Mannick asked whether we subjected our animals in the present study to cecal ligation and puncture in order to see the clinical relevance of our cytokine changes. This was not performed; however, the result that estradiol administration restores peritoneal and splenic macrophage cytokine release capacity as well as splenocyte cytokine release suggests that those animals would have a survival benefit, since the restoration of those immune functions in previous studies was associated with increased survival rates following a septic challenge.This investigation was supported by grant R01 GM 37127 from the National Institutes of Health, Bethesda, Md.Presented at the 80th Annual Meeting of the New England Surgical Society, Newport, RI, September 24, 1999.The IL-3–dependent FDC-P1 cells were a gift from Charles Janeway, MD, Yale University, New Haven, Conn; the IL-6–sensitive murine B-cell hybridoma was a gift from Jacques Van Snick, PhD, The Ludwig Institute for Cancer Research, Brussels, Belgium.Reprints: Irshad H. Chaudry, PhD, Center for Surgical Research, Rhode Island Hospital, Middle House II, 593 Eddy St, Providence, RI 02903 (e-mail: [email protected]).
Tamim, Wael Z.; Ghellai, Ali; Counihan, Timothy C.; Swanson, Richard S.; Colby, Jay M.; Sweeney, W. Brian
doi: 10.1001/archsurg.135.4.434pmid: 10768708
HypothesisTo assess the applicability and efficacy of endoluminal colonic wall stents (ECWSs) in the management of large bowel obstruction (LBO).DesignInception cohort study.SettingUniversity-based tertiary medical center.PatientsEleven consecutive patients with LBO in the absence of peritonitis.InterventionPlacement of ECWS under endoscopic and fluoroscopic guidance.Main Outcome MeasuresThe success rate in ECWS placement, the efficacy in decompressing the obstruction, and the patency rate of the ECWS.ResultsSuccessful placement of ECWSs was obtainable in 10 of 11 patients. Once placed, all 10 patients achieved immediate decompression of their LBO. Eight patients had malignant obstructions associated with distant spread of disease; 3 patients had diverticular disease. Among those with malignant obstruction, 6 patients had successful and lasting palliation without colostomy, 1 patient underwent 1-stage resection 1 month later with no evidence of obstruction, and 1 patient could not be stented so diversion was done. None of the patients with diverticular disease required diversion: 2 had complete bowel preparation followed by resection with primary anastomosis, whereas the third declined surgery. Four of the 10 patients required overlapping ECWSs to bridge the stricture. One patient required a second ECWS secondary to recurrence of obstruction after stent migration and has continued palliation of his stage 4 rectal cancer for the last 11 months. No other complications were encountered.ConclusionsUrgent surgery with colostomy for LBO was avoided in 10 of 11 patients because of successful placement of ECWSs. We believe that endoscopic colonic stenting is safe, effective, and lasting, and should be considered as initial nonoperative management in all patients seen with LBO in the absence of peritonitis.LARGE BOWEL obstruction (LBO) is a common surgical problem caused by colorectal carcinoma, diverticular disease, and metastatic genitourinary tumors.Traditionally, treatment options include emergency decompressing colostomy or resection with or without anastomosis. Urgent surgery performed on acutely ill, obstructed patients carries a high price. The mortality and morbidity rates of performing decompressive colostomy are 5% and 16%, respectively.Similar high mortality and complication rates occur in patients fit enough for resection.In addition to the risks associated with their formation, diverting colostomies are associated with long-term problems such as hernia, prolapse, and dehydration, and cause considerable psychological distress. Because of many factors, these colostomies end up being permanent in up to 40% of patients.Recently several alternative treatments for LBO have been reported, including cryotherapy,photodynamic therapy,electrocoagulation,laser coagulation,and balloon dilatation.Expandable endoluminal stents, which are widely used in treating biliaryand esophageal strictures,have been used successfully to treat LBO in patients with malignant strictures with low morbidity rates.These early results prompted us to try this new treatment approach for all patients initially seen with LBO. Our goal in treating these patients was to avoid emergent surgery and colostomy formation. In patients with end-stage malignant neoplasms, stent placement was used as long-term palliation. In patients with diverticular stricture, or resectable colonic malignancy, the stent allowed bowel preparation and 1-stage resection.PATIENTS AND METHODSAll patients hospitalized with acute LBO referred to 1 of 3 surgeons (T.C.C., R.S.S., or W.B.S.) at a university medical center were offered endoluminal colonic wall stents (ECWSs). All 3 surgeons were experienced in complex colonoscopy prior to attempting stent placement. Patients who had signs of peritonitis were taken to the operating room and were not considered for this procedure. Over 2½ years, 11 consecutive patients were enrolled in this study and 10 underwent ECWS under colonoscopic and fluoroscopic guidance; 10 patients had successful placement and they are the subject of our study. Patients were considered to have an LBO by the clinical history of not passing stool or gas via the rectum and having signs of complete obstruction on plain radiography, computed tomographic scan, or contrast-enhanced enema. No patient refused attempted ECWS placement. One patient underwent endoscopy, but complete obstruction prohibited passing a guidewire. Stenting was performed urgently, usually within 24 hours of admission to the hospital.The procedure for endoluminal stenting involved conscious sedation with midazolam hydrochloride and fentanyl citrate and colonoscopy to the point of obstruction. A guide wire was negotiated through the stricture into the proximal dilated bowel under colonoscopic and fluoroscopic guidance. A catheter was placed over the guide wire, and a small amount of water-soluble contrast was injected to accurately define the proximal aspect of the obstruction. The catheter was then withdrawn while the guide wire was kept in place. With the colonoscope in place, a 22 × 90-mm or 22 × 60-mm wall stent enteral endoprosthesis (Boston Scientific, Boston, Mass) was introduced over the guide wire beyond the proximal end of the stricture. Under fluoroscopy, the ECWS was slowly deployed. If the stricture was longer than 8 cm, an additional stent (90 × 22 mm or 60 × 22 mm) was deployed with a generous overlap with the first stent. Endoscopic evaluation during ECWS deployment ensured a good relation between the distal aspect of the obstruction and the ECWS, and documented relief of the obstruction. Endoscopic photographs show placement of the ECWS and decompression (Figure 1). Plain abdominal radiography was performed after the procedure to exclude perforation and document baseline ECWS position. Figure 2shows plain radiographs before and immediately after ECWS placement.Figure 1.Endoscopic view shows placement of endoluminal colonic wall stent (A and C) and resultant decompression (B and D).Figure 2.Plain radiograph before (A) and immediately after (B) endoluminal colonic wall stent placement.RESULTSOver 2½ years, 14 ECWSs were placed in 10 patients initially seen with acute LBO using a combined endoscopic and fluoroscopic technique. In 4 patients (40%), 2 overlapping stents were used to bridge the stricture. In 1 patient with LBO the guide wire could not be passed through the blockage; and therefore, no ECWS was placed. There were 5 male and 5 female patients, whose mean age was 64 years (age range, 37-80 years). Seven patients had malignant disease: 3 patients with sigmoid adenocarcinoma, 1 patient with rectal adenocarcinoma, 1 patient with splenic flexure adenocarcinoma, 1 patient with recurrent rectal adenocarcinoma, and 1 patient with small cell carcinoma with pelvic wall metastasis. Five patients had liver metastasis and 1 patient had lung metastasis. The other 3 patients had diverticular strictures of the sigmoid colon. All patients had immediate decompression after ECWS deployment and had marked radiographic and clinical improvement of their condition. One stent migrated proximally, and obstruction recurred 5 days after the initial ECWS placement. This was treated with a second ECWS placement. The procedure was palliative in 6 patients, 5 of whom died of their disease with no evidence of obstruction 2, 60, 113, 133, and 315 days after the surgical procedure. One patient is still alive with the ECWS in place for more than 11 months. The procedure served as a bridge to surgical resection in 3 patients, 2 patients with diverticular disease and 1 patient with adenocarcinoma. The presence of the ECWS did not complicate resection in any of the 3 patients. The patients with diverticular disease were operated on 7 days and 6 weeks after ECWS placement. The patient with adenocarcinoma was operated on 22 days following stent placement. One patient with diverticular disease refused surgical resection after decompression.COMMENTEmergent decompressive colostomy or colonic resection has been associated with high mortality and morbidity rates for various reasons.Placement of ECWSs avoids urgent surgery in this high-risk group of patients. Other authorshave had good results with this technique (Table 1). Endoluminal colonic wall stenting is associated with a lower complication rate than emergent surgery, but there are several concerns specific to this technique. The first is failure to relieve obstruction due to the inability to get a guide wire through the mass. This occurs up to 36% of the time in 1 series,but with more experience, this may be less of a problem. The second technical issue is perforation. This endoscopic technique is clearly a high-risk procedure given the presence of tumor or inflammation. Although 1 series had 2 perforations for a rate of 15.4%,the overall rate seems to be less then 5%. With early diagnosis of perforation, patients are treated essentially the same as if stenting were unavailable. Finally, the complication of tenesmus, which occurs when the stent is in contact with the sphincter complex, is a completely avoidable problem. Our tendency if faced by a very low rectal tumor would be to use an alternative method of decompression such as dilatation or laser therapy.Review of Experience With Endoluminal Colonic StentingSource, yDeans et al,41994Canon et al,151997Tejero et al,161997Turegano et al,171997Mainar et al,181999Current StudyNo. of patients/No. of stents10/1013/1638/3811/1771/7210/14No. of patients with malignant neoplasms/benign neoplasms9/113/038/011/071/07/3Success rate, %100100100649091No. of palliative stents/No. of stents used as bridges to surgery4/69/413/226/10/646/4Failure of stent to decompress, %107.75.304.70No. of patients with perforation, %015.4004.70No. of patients with tenesmus, %. . .*15.4. . .. . .6.30No. of recurrent obstruction, %030.82.60. . .10Longest follow-up time, mo6. . .197. . .14*Ellipses indicate not applicable.Five series,other than our own, are listed in Table 1. From these 5 series, 142 colon stents were placed for malignancy and only 1 stent was placed for benign disease. In our series 3 patients with benign disease had ECWS placement without complications. From our experience, we believe any patient who is initially seen with LBO should be offered a colon stent as initial therapy; there is no need to document a malignant stricture prior to placing a stent. This approach simplifies the management of a patient who initially was seen emergently with LBO. After stent placement, the patient's condition can be evaluated further. If appropriate, resection of the affected colon can be performed as a 1-stage procedure.The long-term complications of recurrent obstruction and stent migration may be limiting factors in the use of this technique for long-term palliation of malignant disease. In one study,up to 30.8% of patients developed recurrent obstruction. This problem will be dependent on the disease process and length of follow-up time. Many patients will die before recurrent obstruction becomes an issue. Stent migration can occur in diverticular disease as inflammation resolves, but this implies a colonic lumen that can support normal bowel function without a stent. Similarly, stents may migrate in the presence of malignant disease that is treated with palliative chemotherapy or radiotherapy after stent placement.In our series, we placed a total of 14 ECWSs in 10 patients with acute LBO. The ECWS allowed us to adequately decompress the obstructing lesion. The patients could then undergo further resuscitation, begin nutritional therapy, and have proper evaluation of the extent of their disease. One-stage surgical resection then could be considered for appropriate candidates. Six of our patients underwent ECWS placement as their definitive treatment because of either disseminated tumor spread or prohibitive medical risk. One of these patients tolerating a regular diet died 2 days after ECWS placement of an unrelated cause. Another patient from our group had recurrence of obstructive symptoms 5 days after ECWS placement, despite initial decompression. On endoscopy, the ECWS appeared shorter than the obstructive lesion and had migrated proximally. Two overlapping stents were placed, the initial ECWS was retrieved and the patient is doing well 5 months after the surgical procedure.Four patients compose a second group, 2 of them had obstruction secondary to diverticular stricture, and 2 had potentially resectable adenocarcinoma. Three of these patients in this group underwent decompressive ECWS placement followed by bowel cleansing and 1-stage surgical resection. One patient with diverticular disease refused surgery and remains symptom free. In this group 2-stage surgical treatment was avoided, with ECWS serving as a bridge to safe elective 1-stage resection.Except for migration of 1 stent leading to recurrent obstruction in that patient, there were no complications. Tenesmus, as seen by other authors,is a potential complication in patients with low rectal tumors where the edge of a bridging stent may irritate the anal sphincter. The patency rate and durability of ECWS is encouraging. In our series, 6 patients received palliative ECWSs, all of whom either died with functioning ECWSs in place or are alive without recurrent obstruction. One patient has had an ECWS for longer than 14 months with no complications. In addition to the short-term benefits, ECWS may also be cost-effective. One recent study showed an overall cost savings of 20% in patients treated for palliation and 29% in patients who ultimately undergo resection.Endoluminal colonic wall stents avoid at least 1 and sometimes 2 major operations, potentially lowering hospital charges and overall cost. The physical, economical, and psychological stress of colostomy to the patient is also avoided by using an ECWS.In conclusion, 10 patients avoided emergent surgery with colostomy because of successful placement of ECWSs. We believe that endoscopic colonic wall stenting is safe and effective, and thus, should be considered as initial treatment in all patients with benign or malignant disease seen with LBO in the absence of peritonitis.AGDiethelmRJStanleyThe acute abdomen.In: Sabiston DC Jr, ed. Textbook of Surgery. Philadelphia, Pa: WB Saunders Co; 1991:736-755.IJKodnerRDFryJWFleshmanEHBirnbaumColon, rectum and anus.In: Schwartz SI, Shires GT, Spencer FC, Husser WC, eds. Principles of Surgery. New York, NY: McGraw Hill Co; 1994:1191-1306.GLTelfordDiverticular disease.In: Greenfield LJ, Mulholland MW, Oldham KT, Zelenock GB, eds. Surgery: Scientific Principles and Practice. Philadelphia, Pa: JB Lippincott; 1993:1035-1041.GTDeansZHKrukowskiSTIrwinMalignant obstruction of the left colon.Br J Surg.1994;81:1270-1276.RSGriffithPreoperative evaluation: medical obstacles to surgery.Cancer.1992;70:1333-1341.BMlasowskyWDubenDJungCryosurgery for palliation of rectal tumors.J Exp Clin Cancer Res.1985;4:81-84.HBarrSGBrownNKrasnerPBBoulosPhotodynamic therapy for colorectal disease.Int J Colorectal Dis.1989;4:15-19.HJHoekstraRCJVerschuerenJOldhoffEVan Der PloegPalliative and curative electrocoagulation for rectal cancer: experience and results.Cancer.1985;55:210-213.PSpinelliMDal FanteEMeroniEndoscopic laser therapy of colorectal tumors.Acta Endosc.1987;17:15-168.MCOzKAFordeEndoscopic alternatives in management of colonic strictures.Surgery.1990;108:513-519.WCwikielHStridbeckK-GTranbergMalignant esophageal strictures: treatment with self-expanding nitinol stent.Radiology.1993;187:661-665.HGCoonsSelf-expanding stainless steel biliary stents.Radiology.1989;170:979-983.MDohmotoMHunerbeinPMSchlagApplication of rectal stents for palliation of obstructing rectosigmoid cancer.Surg Endosc.1997;11:758-761.YSaidaYSumiyamaJNanaoMTakaseStent endoprosthesis for obstructing colorectal cancers.Dis Colon Rectum.1996;39:552-555.CLCanonBHToddMEDesireePADeanREKoehlerTreatment of colonic obstruction with expandable metal stents: radiologic features.AJR Am J Roentgenol.1997;168:199-205.ETejeroRFernandez-LobatoAMainarInitial results of a new procedure for treatment of malignant obstruction of the left colon.Dis Colon Rectum.1997;40:432-436.FTuregano-FuentesAEchenagusia-BeldaGSimo-MuerzaTransanal self-expanding metal stents as an alternative to palliative colostomy in selected patients with malignant obstruction of the left colon.Br J Surg.1998;85:232-235.AMainarMAGArizaETejeroAcute colorectal obstruction: treatment with self-expandable metallic stents before scheduled surgery: results of a multicenter study.Radiology.1999;210:65-69.CABinkertHLedermannRJostMDecurtinsCZollinkoferAcute colonic obstruction: clinical aspects and cost-effectiveness of preoperative and palliative treatment with self-expanding metallic stents, a preliminary report.Radiology.1998;206:199-204.Paul C. Shellito, MD, Boston, Mass:For patients with obstructing left-sided colon tumors, there is much to recommend the maneuver described in this article. Emergency surgery can be avoided for those with resectable cancer, and surgery can probably be avoided entirely for patients with widespread malignant neoplasms. Elective surgery, of course, is associated with a much more favorable morbidity and mortality rate and is easier on the surgeon. Furthermore, in an elective situation, and in the absence of bowel dilatation, probably a technically better cancer operation can be accomplished. Most important, the patient can have a single operation, instead of multiple-staged laparotomies including a colostomy (and many "temporary" colostomies are never closed). A major cost savings is likely. After acute obstruction is relieved with a stent, the patient's condition can then be more thoroughly evaluated. Colonoscopy can be performed to rule out synchronous neoplasms. A CT scan might show locally advanced rectal cancer, which would be appropriate for neoadjuvant chemoradiation. It might also unexpectedly show multiple liver metastases, in which case the stent could be left in place indefinitely for palliation as was done in some patients described in this article. The major disadvantage of this approach is the necessity of having readily available experienced endoscopists, interventional radiologists, and ancillary personnel for these emergencies.It is a fairly small study population, as had been the 10 or so previous similar reports in the literature. The rates of 91% success, 9% stent migration, 0% perforation, and 0% tenesmus compare very favorably with others. Before wire mesh stents were available, tumor recanalization was accomplished in some medical centers by endoscopic laser vaporization. This was an inferior approach I believe, however, because of the greater risk of serious bleeding and perforation and fistula, and the need for repeated treatments to maintain a lumen. It was also technically very unsatisfactory doing a difficult endoscopy amid stool, smoke, blood, and charred necrotic tissue.These skilled interventionalists have admirably managed a difficult problem nonoperatively. They have confirmed that ECWS for large bowel obstruction are feasible, effective, and safe. In a larger sense, it is another illustration of how patients with complex problems can benefit from the collaboration of endoscopists, radiologists, and surgeons. The challenge now will be to make it more widely available and to select patients appropriately. Some similarly treated patients for "obstruction" in previous reports actually have had only obstructive symptoms, but not a complete obstruction, and probably could have been managed simply by semiurgent single-stage surgery (eg, sometimes in previous reports, the colonoscope could be passed completely through the tumor). Patients with LBO might have concomitant cecal perforation, small bowel obstruction, or a synchronous stenosing cancer, which would contraindicate nonoperative treatment. Finally, in patients treated for palliation with stents, although obstruction can be nicely overcome, palliation of other symptoms such as pain, tenesmus, incontinence, discharge, and cachexia is unlikely to last more than about 6 months, due to extraluminal tumor growth.I have 2 questions for the authors. First, how did you define LBO and how urgently after referral or diagnosis did you carry out the procedure? Second, in some medical centers this procedure has been carried out by interventional radiologists alone, which simplifies matters somewhat. How necessary is the colonoscopy component?Frederick Bagley, MD, Rutland, Vt:How far proximal in the colon would you attempt this procedure?Dr Tamim:First in terms of definition of LBO, the way we defined it was based on KUB [kidney, ureter, and bladder] and single–contrast-enhanced enema which showed the obstruction. In addition, the patient had obstructive symptoms. So it was a clinical and radiographic diagnosis.In terms of peritonitis, we made sure that the patient does not have generalized peritonitis as mentioned and the patient does not have high fevers or a very elevated white blood cell count.In terms of the question on timing of the procedure, most of the time it took us around probably 24 to 48 hours after being called. This period gives us time (1) for diagnosis and to undergo the diagnostic procedure, tests and (2) to allow for some hydration at times if you need antibiotics to decrease the risk of translocation. So most of the time we did the procedure around 48 hours after we were consulted, unless we needed to do it earlier.Now on the question on the need for colonoscopy. Actually this is a very sensitive issue. You are right, in the literature the reports from Spain came from interventional radiologists. Even here from the University of Alabama, Birmingham, it was done by gastroenterologists and interventional radiologists. Actually we believe the contrary. We believe that a surgeon or an experienced gastroenterologist should be involved. The reason for it is that you want to have somebody who is technically skilled to do the procedure, take care of the complications that happen which is perforation, and at the same time we believe that you really need the scope in there to be able to do the procedure safely. Doing it with fluoroscopic guidance, in our minds, is not safe enough. You really need to see the scope so that you know where your guide wire is going and you are really not causing any injuries to the bowel which is very friable and inflamed in these patients. And actually going to the complications that were reported in the literature, we see that the perforations were reported mostly by the reports that came from the radiologists.For the second question about the proximal distance of the tumor, in our population which is small, most of the lesions were in the rectosigmoid area so they were distal. However, in the literature there have been attempts at stenting lesions in the proximal descending colon as well as in the transverse colon and, I think, as this technology improves, and the expertise improves, there is a role to stent any lesion in any part of the colon.Presented at the 80th Annual Meeting of the New England Surgical Society, Newport, RI, September 24, 1999.Corresponding author: Timothy C. Counihan, MD, Department of Surgery, University of Massachusetts Memorial Health Care, Memorial Campus, 119 Belmont St, Memorial 3, Worcester, MA 01605.
Stewart, Robert D.; Doyle, Jennifer; Lollis, S. Scott; Stone, Michael D.
doi: 10.1001/archsurg.135.4.439pmid: 10768709
HypothesisThis study sought to determine the attitudes of general surgery residents in New England toward research and the factors that affect their research participation and productivity.DesignSurvey.SettingEighteen of the 20 general surgery residency programs in New England.ParticipantsFour hundred fifty-nine surgical residents taking the American Board of Surgery In-Training Examination in 1999.Main Outcome MeasuresRationale for and amount of time spent in research and the number of publications.ResultsA majority of residents (61%) participated in research. Rationales for research participation included initiating an academic career (82%) and enhancing fellowship application prospects (83%). Personal debt was substantial, but had little influence on decisions regarding research. Gender was not a factor in the decision to participate in research, although women were more likely to cite a break from residency as a positive influence in their decision for doing research. Residents from larger programs (>25 residents) were more likely to participate in research, spend more time in research, and to publish an article than those from programs with fewer than 25 residents.ConclusionsMost surgical residents in New England plan to or participate in research and publish their work. Significant differences in the type, duration, and productivity of research exist between larger and smaller programs, and may reflect differing priorities among residents, or differences in the variety of research opportunities available.RESEARCH PERFORMED by surgical residents during residency is considered to be an initial step on the road to a career as an academic surgeon. The benefits of time engaged in research are myriad. During this time, residents learn and gain experience in the generation of research ideas, the development of hypotheses, and the use of scientific methods, as well as honing verbal and written communication skills—all requisite skills for a successful career. At the same time, they develop critical thinking skills and enhance their ability to evaluate the scientific literature, as well as learning the difficulties of carrying out a successful research project. They also develop a broader perspective on clinical questions. In our experience, residents return to surgical training after a research period with notably greater maturity as surgeons. Evidence of research during residency is often considered a prerequisite for acceptance into surgical subspecialty fellowship programs. The research period may allow residents who are uncertain of their desire for an academic career to make informed decisions in this regard.Many surgical residents participate in original investigation during their residency period. To date, however, only a few studies have looked at the attitudes and outcomes of surgical research during residency. Souba et alfound that surgical residents, more so than their chairs, felt that basic science research was essential for an academic career; however, their motivation for entering the laboratory was a genuine interest in research. Lessin and Kleinexamined the academic credentials of pediatric surgeons and compared their record of laboratory research during general surgery training with their academic pursuits and productivity after specialty training, and found no correlation. Dunn et alshowed a positive correlation between length of research time during training and academic careers of graduates in a single program. These select groups, however, do not necessarily reflect the attitudes, experience, or productivity of general surgical residents in research.Stress levels in training programs and among residents are higher than ever before. Changes in the health care system, including reduced hospital and departmental revenues, increased personal debt on the part of residents, and a greater desire for a controllable lifestyle among medical school graduates, have all occurred over the last 10 to 15 years. In today's milieu of decreased funding for graduate medical education, the cost of providing or covering residents' research periods are straining the already constrained budgets of academic medical centers. At the same time, with unprecedented debt levels, residents may feel increased pressure to complete their clinical training in shorter time. For female residents, this pressure may be compounded by family planning concerns.Given these pressures, answers to the questions of why residents choose to pursue or to opt out of research during their clinical training programs are increasingly important.We hypothesized that changes in program funding, resident indebtedness, and stress may have a negative impact on residents' interest and ability to engage in research during residency, and sought to compare attitudes of those who select research with those who do not.SUBJECTS AND METHODSAs part of a multistage assessment of research during surgical residency, we surveyed residents in New England programs to assess current attitudes toward and performance of research. An initial survey was piloted with a sample of residents in our program. Revised surveys were distributed to all 20 general surgery residency programs in New England. Residents were asked by their program directors to complete the questionnaire after administration of the American Board of Surgery In-Training Examination (ABSITE) in January 1999. Instructions asked for voluntary and anonymous participation of residents sitting for the examination. A return envelope was included, but no identification of individual programs was made.The survey asked residents for demographic information (age, sex, postgraduate year (PGY) level, other advanced degrees held, marital status, number of children, and indebtedness level) and their involvement in research. Those who were doing or planned to do research were asked about the nature of the research (basic vs clinical), the timing, and the outcome in terms of the number of publications, and were asked to rate, on a 3-point scale (1, no; 2, some; and 3, significant influence), 6 factors that may have influenced their decision to do research. Those who had decided against a research elective were asked to rate, again on the same 3-point scale, 7 factors that may have influenced that decision.Data from returned questionnaires was entered into a Microsoft Access database (Microsoft Inc, Redmond, Wash). A numeric code was assigned to all questionnaires from a single program, based on order of receipt. As a surrogate for university-based, academic programs, programs with more than 25 residents were categorized as "large." Conversely, programs with fewer than 25 residents were categorized as "small."Responses were analyzed by item across all programs, as well as by size of the program. Responses were also analyzed by resident sex, parenthood status, and level of indebtedness. For purposes of analysis, productivity was defined as the publication of at least 1 article per year of research; those individuals with less than 1 year of research experience were excluded. We used the χ2and Fisher exact tests to determine, as appropriate, association for all responses. Significance was determined at a 2-sided level of .05.RESULTSEighteen (90%) of the 20 residency programs participated. Overall, 459 (79%) of the 584 surgical residents taking the ABSITE in New England responded: 332 (73%) of 456 respondents were male; 124 (27%) were female; and 3 did not indicate sex. Sixty-nine (15%) of the respondents possessed an advanced degree in addition to their medical degree. Respondents ranged in age from 24 to 46 years, with a mean ± SD age of 30.1 ± 3.4 years (Table 1).Table 1. Respondent Demographics (N=459)No. (%) of RespondentsSexMale332 (72)Female124 (27)Unknown3 (1)PGY level1135 (30)293 (20)392 (20)465 (14)572 (16)Not indicated2 (. . .)Advanced degreesYes69 (15)No390 (85)Marital statusSingle220 (48)Married229 (50)Divorced9 (2)Not indicated1 (. . .)ParenthoodYes370 (80)No185 (19)Not indicated4 (1)Level of indebtedness, $0124 (27)<10,00015 (3)10,000-25,00032 (7)>25,000-50,00051 (11)>50,000-100,000101 (22)>100,000130 (29)Unknown6 (1)Of the respondents, 279 residents (61%) either have done or are planning to do research (34% plan or are currently engaged in research and 27% have completed research). The majority (56%) of those who elect to do research do so for 2 years or more, and 84% of those who engage in research schedule their electives somewhere between the PGY-2 and PGY-4 years in training: 46% schedule them between the PGY-2 and PGY-3 years and 38% between PGY-3 and PGY-4. Of those who have completed their electives, most (69%) have published at least 1 article; 18% published 3 or more (Table 2).Table 2. Research Patterns of Residents in Large (>25) and Small (<25) Programs*ItemAll Responses, No. (%) (N=459)Large Programs, No. (%) (n=357)Small Programs, No. (%) (n=102)PPlan to or have participated in research279 (61)232 (65)47 (46).001Type of research planned or doneClinical162 (59)150 (66)11 (24)Basic science81 (30)49 (22)32 (70)<.001Both31 (11)28 (12)3 (7)Time spent in research≤6 mo54 (19)27 (12)27 (59)1 y69 (25)52 (23)15 (33)<.0012 y123 (45)121 (52)2 (4)>2 y30 (,11)28 (12)2 (4)Timing of researchBetween PGY-2 and PGY-3127 (46)106 (46)21 (45)Between PGY-3 and PGY-4105 (38)97 (42)8 (17).001After graduation6 (2)4 (2)2 (4)Other41 (15)25 (10)16 (34)Publications, No.†036 (31)24 (26)12 (50)127 (23)24 (26)3 (13)219 (16)14 (15)5 (21).12‡315 (13)14 (15)1 (4)>321 (17)18 (19)3 (12)*PGY indicates postgraduate year. Numbers do not add up to total, as some questions were not completed by all residents.†Includes only residents who have completed their research period: for large programs, n=94; for small programs, n=24.‡Comparison of 0 publications vs ≥1 publication (P=.03).Among residents completing or planning research electives, the factor credited with the most significant influence in the decision was "to initiate an academic career" (51%); an additional 31% of residents in research cited this as a factor of some influence. A research period's perceived ability to help the resident obtain a desirable fellowship followed closely in influence, with 46% of those in or planning research citing this as a significant influence, and another 37% citing it as a factor of some influence. Finding out whether they liked research was a significant influence for 19%; an additional 42% said it had some influence on their decision to engage in research. Sixty-one percent of residents said the desire to take a break from residency exerted some influence on their decision to do research, with 20% of residents in research citing this as a significant influence and 41% citing it as a factor of some influence. Of less influence in residents' decision-making process was the fact that research was mandatory in respondents' programs: 18% cited this as a significant influence and 28% as of some influence. The opportunity to earn money moonlighting was also less influential: only 7% cited this as a significant influence and 20% cited it as a factor of some influence (Table 3).Table 3. Resident Rationale for Planning or Participating in Research*Factor/ReasonDegree of InfluenceAll Responses, No. (%) (N=279)Large Programs, No. (%) (n=232)Small Programs, No. (%) (n=47)PInitiate an academic careerNone50 (18)23 (10)25 (53)Some86 (31)77 (33)12 (25).001Significant142 (51)132 (57)10 (22)Help obtain fellowshipNone47 (17)35 (15)14 (30)Some103 (37)84 (36)20 (43).02Significant128 (46)116 (50)13 (27)Take break from residencyNone109 (39)74 (32)37 (78)Some114 (41)107 (46)9 (18).001Significant56 (20)107 (46)9 (18)Earn money moonlightingNone201 (72)155 (67)46 (98)Some56 (20)56 (24)1 (2).001Significant20 (7)21 (9)0 (0)Mandatory in programNone151 (54)132 (57)19 (40)Some78 (28)63 (27)14 (30). . .Significant50 (18)37 (16)14 (30)Find out if I liked researchNone109 (39)91 (39)18 (38)Some117 (42)95 (41)23 (48). . .Significant53 (19)46 (20)7 (15)*Ellipses indicate value was not significant. Only included residents who answered affirmatively to research participation question. Numbers do not add up to total, as some questions were not answered by all residents.Among residents who neither had done nor plan to do research, lack of interest seems to be the most influential factor, with 64% of nonresearch residents saying it was of significant (25%) or some (39%) influence. Having done research before residency was cited by 54% of nonresearch residents as exerting either significant (25%) or some (29%) influence on the decision not to pursue research during residency. Forty-five percent cited their plan to do research during fellowship as influencing their decision not do research during residency: 22% said it had a significant influence and 23% said it had some. Lack of time for research was a significant influence for 19% of these residents, and had some influence on another 25%. "Family conflict" was cited by 37% of residents as a factor weighing in on their decision not to do research during residency: 9% said it was a significant influence, and another 28% said it had some influence. Nearly a quarter (23%) of these residents said that lack of opportunity in their program was a factor influencing their decision: 6% said it had significant influence and 17% said it had some. Those with advanced degrees were no more or less likely to engage in research (P=.40) (Table 4).Table 4. Resident Rationale Against Participation in Research*ReasonDegree of InfluenceAll Responses, No. (%) (N=279)Large Programs, No. (%) (n=232)Small Programs, No. (%) (n=47)PNot available in my programNone215 (77)195 (84)29 (62)Some47 (17)39 (14)11 (23).001Significant17 (6)6 (2)7 (15)Lack of interestNone100 (36)84 (36)17 (37)Some109 (39)100 (36)17 (37). . .Significant70 (25)51 (22)15 (31)Did research before residencyNone126 (45)84 (36)24 (50)Some81 (29)65 (28)15 (31). . .Significant70 (25)65 (28)9 (19)Plan research during fellowshipNone154 (55)116 (50)31 (65)Some64 (23)67 (29)5 (10).02Significant61 (22)46 (20)12 (25)Lack of timeNone154 (55)130 (56)26 (55)Some73 (26)67 (29)11 (24). . .Significant53 (19)35 (15)10 (21)Family conflictNone176 (63)169 (73)27 (58)Some78 (28)58 (25)14 (29).05Significant25 (9)5 (2)6 (13)*Ellipses indicate value was not significant. Only included residents who answered affirmatively to research participation question. Numbers do not add up to total, as some questions were not answered by all residents.Although the majority of residents (51%) in the study had $50 000 or more in personal debt, indebtedness seems to have no influence in either prodding residents into or out of research, with residents who do research and those who do not found in equal proportions at each level of indebtedness (P=.80).Sex seems to play little or no role in the research paths taken by surgical residents in New England, with 55% of women and 63% of men planning or participating in research (P=.10). There were no significant sex differences in either the type of research (64% of women vs 58% of men chose basic science and 30% of women vs 29% of men chose clinical research, respectively [P=.40]), or the length or timing of research.Surgical residents of both sexes seem to share similar rationales for pursuing research, with the exception of the desire to take a break from residency: 79% of women and only 55% of men (P=.001) cited this as a factor with either some or significant influence. Among those residents who elect against doing research, significantly more women than men cite lack of interest as a factor of some or significant influence (35% of women vs 20% of men said it was a significant influence [P=.03]). Female and male surgical residents who do research also have similar productivity: 69% of women and 71% of men who have completed a research elective have 1 or more publications (P=.40).There was no association between parenthood and research: 58% of surgical residents with children have done or plan to do research, compared with 61% of residents who have no children (P=.60).Ten (56%) of the 18 responding programs had more than 25 residents (large programs) and 8 (44%) had fewer than 25 residents (small programs) (Table 2). Significantly more residents have done or plan to do research in larger programs than in smaller programs. Residents in larger programs are also more likely to choose basic science research, while residents in smaller programs are more likely to choose clinical research.Residents in larger programs also planned or spent longer periods in research, with the majority (64%) choosing 2 years or more; conversely, the majority of residents (59%) in small programs plan or spend 6 months or less (Table 2).Reasons for or against engaging in research during residency differ by the size of a resident's program, with 68% of those choosing to do research in larger programs citing the need for a break from clinical work as a deciding factor (22% cited this as a significant influence; 46%, some influence), whereas only 23% of those in smaller programs cited that as a factor (P=.001). Additionally, 86% of those in larger programs vs 70% in smaller programs cited the benefits of research experience in helping them to obtain a fellowship (P=.02). Conversely, 38% of those residents in smaller programs who have chosen not to engage in research cited lack of availability in their programs as a factor of some (23%) or significant (15%) influence in their decision (P=.001).Among residents who had completed their research period, those in larger programs were more likely to have published at least one article (50% vs 26%) (P=.03). When productivity was defined more specifically as one publication per year of research, there was no difference in the productivity of men (54%) and women (48%) (P=.90), nor between those with a medical degree (56%) and those with an advanced degree (52%) (P=.90). Those residents who pursued research believing that it would enhance their fellowship opportunities were neither more nor less productive than their peers (50% vs 48%) (P=.70).COMMENTInterest and participation in research is strong among residents in New England surgical training programs. The majority of residents have completed or are planning research, and most have committed or plan significant time—2 years or more—to this effort.Most residents are productive, with more than two thirds publishing at least 1 article. The fact that 31% of residents who have completed research have published nothing to date, however, seems excessive. It may be that some still have work in progress, or that a subset of residents are missing a key part of the research experience—that the mentoring relationship has not been successful for these residents.Most residents choose research for appropriate reasons: to initiate an academic career and/or to determine whether they have an appetite or aptitude for research. Most influential in the decision to pursue research was a sense that a research background would contribute positively in the fellowship application process, reflecting the view that fellowship programs select applicants more likely to be academic surgeons. The likelihood of performing additional research during fellowship was not a dissuasion from research during general surgery residency. Most residents do not feel compelled by their programs to take research time.Among those residents not planning research work, lack of interest was the most common rationale. More than half had engaged in research prior to residency, suggesting that their prior research experience was sufficient for career goals, or possibly that it was an unsatisfactory experience.Overall, only 6% felt that lack of research opportunity was a significantly negative influence on their decision against research; but more than a third of residents in small programs indicated this was an influence on their decision not to engage in research. It is not clear from this study whether this difference between small and large program residents is a result of differences purely in opportunity or resident self-selection—that is, residents select programs that reflect their level of interest in research and vice versa. Whether these residents would do research, and what type, if available, is unanswered by this study. Significant differences in the type and duration of research between larger and smaller programs may reflect differences in the availability of basic science research mentors and opportunities. Program directors should discuss this issue with residents in career planning sessions.For small programs, or for those programs in which interest and performance in research varies from one PGY cohort to the next, finding residents to replace those who depart for research may be difficult or impossible. Faculty with available research positions should be aware that a potential source of trainees may exist, untapped, in smaller New England programs. One way to maximize resident opportunity and satisfaction may be establishment of a regional clearinghouse of research opportunities. Such a system would provide regionwide dissemination of information regarding available research opportunities, and allow matching of residents with research opportunities in their area of interest.Personal debt has previously been identified as a major concern among New England surgical residents.Although 51% of our respondents indicated personal debt exceeding $50 000, indebtedness seems to have no influence on the decision of whether to engage in research: few surgical residents in New England are dissuaded from spending time in research because of the pressure to finish training and repay their outstanding debt, nor do they consider the opportunity to earn money moonlighting as a significant reason to take research time.It is not clear from these results how to interpret the finding that taking a break from residency is more important to residents from large programs. It may well be that the residents in large programs feel more isolated or anonymous, with less support than that in a smaller, more tightly knit, resident cohort. It may also be that resident work hours, not addressed in this survey, may be more taxing in large programs. Program directors should be aware of this rationale among residents and should counsel residents not to select a research elective solely for this purpose.No differences were apparent between male and female surgical residents in terms of the proportions who choose to pursue research during residency, the type of research they choose to engage in, or productivity. Although twice as many male as female residents had children, parenthood per se was not a factor in whether residents choose research. Women are significantly more likely than men to cite seeking a break from residency as a rationale for research. Since having children during residency and postponing family plans has been found to be significant concerns of female surgical residents, one might anticipate that women would desire completion of surgical training without additional time being taken for research. This runs counter to our finding in this study that taking a research period to get a break from residency was a prominent rationale for female residents. Program directors should be aware of this dichotomy, as it may contribute to even greater stress among female residents. The finding that lack of interest in research is a significantly more influential factor among women than men in the decision not to pursue research may reflect women's perception of a "glass ceiling" in academic medicine.CONCLUSIONSMost surgical residents in New England plan or perform some research and publish their work. Primary among their reasons for doing so is an intellectual interest in research. Results of the current study confirm the conventional wisdom that residents who choose to do research while in clinical training intend to pursue academic careers; in addition, they believe that research experience in training provides them an advantage in obtaining fellowships.Significant differences in the type and duration of research exist between larger and smaller programs, and may reflect differing priorities among residents, as well as differences in the extent of research opportunities available to them. Further study is needed to determine whether resident aspirations for an academic career are borne out in the acquisition of fellowships, continued research productivity, and faculty appointment.WWSoubaKKTanabeMAGaddBLSmithMSBushmanAttitudes and opinions toward surgical research: a survey of surgical residents and their chairpersons.Ann Surg.1996;223:377-383.MSLessinMDKleinDoes research during general surgery residency correlate with academic pursuits after pediatric surgery residency?J Pediatr Surg.1995;30:1310-1313.JCDunnECLaiCMBrooksBEStabileEWFonkalsrudThe outcome of research training during surgical residency.J Pediatr Surg.1998;33:362-364.SGGabramLWAllenPJDeckersSurgical residents in the 1990s: issues and concerns for men and women.Arch Surg.1995;130:24-28.John A. Mannick, MD, Boston, Mass:Dr Stewart and his associates have done a real New England survey of the participation of surgical residents in research. They were fortunate to receive the cooperation of almost all of the surgical residency programs in our area. The response from the residents they pooled was absolutely outstanding—about 80% of them responded. This in itself is a real accomplishment, considering the harried life most residents lead.The investigators divided the residencies, as you have seen, into 2 categories: those with more than 25 residents and those with fewer than 25 residents. They found that the participation in research during residency was greater in the larger programs, which is perhaps not surprising, although the percentages were not vastly different: 65% participated in the larger programs and 45% in the smaller programs. What was notably different was the period spent in research, with the majority of residents in the larger programs planning to spend 2 years or more in research and only 4% of those in the smaller programs planning such a long time in the laboratory or in clinical research. Residents from smaller programs were also much more likely to be involved in clinical research only. The longer time spent in research by residents from the larger programs was also reflected in a greater number of publications per resident in these programs.Now I don't really have any argument with the authors' techniques or with their conclusions and I honestly don't have any substantive questions to ask them. What they did not attempt to do was to answer the question of whether participation in research during residency is of real benefit to the subsequent careers of the individuals involved, and I am not sure that is an answer that they were likely to be able to get. I share their prejudice that research during residency is a good thing, even if the individual never intends to make research a part of his or her career after residency. If one has had the opportunity to do a clinical research project, for example, and to write it up for publication, the experience will almost certainly translate into a greater ability to critically evaluate publications in the surgical literature throughout one's career. Whether every resident would benefit from time spent in a basic research laboratory during the course of residency training is, in my mind, far less clear. As the present authors rightly conclude, this probably depends on the individual's professional goals. It also seems very likely that the larger residency programs in our area are more geared to training individuals for positions in academic surgery, where a period of laboratory research during residency may prove invaluable in jump starting an academic career. However, for an individual who is committed to a career in the practice of clinical surgery, I am not at all sure that 2 years in a basic research laboratory during residency is the best use of that individual's time.What the present authors have documented is that there is considerable variability in the residency programs in our area with regard to resident participation in basic research. Some programs, such as the one I recently directed, which are focused on training people for academic careers lie at one extreme, while those programs dedicated entirely to training expert clinical practitioners lie at the other, with many programs lying somewhere in between.Dr Stewart:I thank Dr Mannick for those comments. We thank all of the program directors out there who helped with this project; we did get an excellent response. I also agree with you on the fact that the question not answered in this is whether or not research has any bearing on future careers, which is actually the second phase of what this research project is going to be: the first portion asking residents their feelings and research participation and the second looking at practicing surgeons from New England to see what their careers are now and how they will correlate research experience with academic practice in the future.I also share the concept that writing and publishing an article is a very valuable portion of this experience and should be emphasized.Finally, I agree with you that the timing of research of 6 months vs 2 years was not meant to indicate that more is better. For some individuals, doing 6 months of research is probably more valuable than doing 2 years if their future career is only to do general practice surgery.Claude H. Organ, Jr, MD, Oakland, Calif:I rise to discuss this because I will have the opportunity to exercise my discretion when it comes across my desk, but I want to support the concepts being fostered here. I think it has proved its case over the years. The practices that we have today have been dictated by the research of yesterday. Tomorrow will be no different. We have a little different approach. We do not demand that the residents go for the research experience. It's voluntary, not in the voluntary jesuitical sense but truly voluntary. We insist that they have shown evidence in clinical maturation in terms of their decision-making skills, their technical skills and their knowledge base principally around the American Board of Surgery In-Training Examination. If they are doing well in those categories, they may apply for the research experience. This is run by myself and Gerry Peskin, who was formerly a member of the New England Surgical Society. We do not feel that we owe it to them but that they have to earn it. This has proven to work well for us. We consistently have 6 or 8 people working full time in laboratories throughout the country. There are a lot of research positions in training programs that are going unused and we found this to be a very helpful thing in terms of their own knowledge base. We believe they are better clinical surgeons when they return. They certainly have positioned themselves better for fellowships and future residencies. One remarkable experience I just had was with a young man named Brian Cain (finishing with us this year) who was in Alden Harkins' laboratory for 2 years and, incredibly, wrote 48 papers in peer-reviewed journals. I rise in support of this experience. It ought to be voluntary and we should not make this mandatory for these candidates.Dr Stewart:Thank you, Dr Organ. I've met Dr Cain. He is a very bright young man and has much too big of a curriculum vitae for his level. Do you have any record through this process of selecting residents for research? Do you have a higher rate of residents staying on the academic track following their research?This study was supported in part by a grant from the Harvard Medical School and Beth Israel Deaconess Mount Auburn Institute for Education and Research, Boston, Mass (Drs Stewart and Stone and Ms Doyle).Presented at the 80th Annual Meeting of the New England Surgical Society, Newport, RI, September 25, 1999.Corresponding author: Michael D. Stone, MD, Department of Surgery, Harvard Medical School and the Beth Israel Deaconess Medical Center, 110 Francis St, Suite 3A, Boston, MA 02215 (e-mail: [email protected]).
Frumiento, Carmine; Abajian, J. Christopher; Vane, Dennis W.
doi: 10.1001/archsurg.135.4.445pmid: 10768710
HypothesesUse of spinal anesthesia is safe and effective in an outpatient population of preterm infants undergoing inguinal hernia repair (IHR) and eliminates routine postoperative hospital admission for apnea monitoring.MethodsFrom October 1982 through October 1997, all preterm (gestational age [GA], ≤37 weeks), high-risk (preterm infants whose postconceptual age at surgery [PCAS] is <60 weeks) infants undergoing IHR with spinal anesthesia were studied prospectively. No exclusions were made for preexisting conditions. Elective IHRs and incarcerated hernias were both considered. A postoperative apnea rate was calculated and compared with published postoperative apnea rates in preterm infants after receiving general anesthesia.ResultsFor 269 IHRs performed, 262 spinal anesthetic placements (97.3%) were successful in 259 infants; 246 placements were achieved on the first attempt and 16 on the second. The mean GA was 32 weeks (GA range, 24-37 weeks); mean PCAS, 43.7 weeks (PCAS range, 33.4-59.3 weeks); and mean birth weight, 1688 g (weight range, 540-3950 g). Two hundred six patients (78.6 %) did not require supplemental anesthesia; 56 (21.4%) did: 34 received intravenous anesthesia; 6, general; 12, local; and 4, other regional. One hundred fifty-three infants had a history of apnea. Thirteen episodes of apnea were noted in 13 infants (4.9%) following the 262 procedures; all 13 were inpatients undergoing concomitant therapy for apnea (mean GA, 28 weeks; PCAS, 42.9 weeks). Four of these infants received supplemental anesthesia. This apnea rate is significantly lower than the published rate (10%-30%) (P=.01). One hundred three infants underwent IHR on an outpatient basis, 39 of whom had a history of apnea. None of these developed apnea postoperatively. The mean birth weight of this group was 2091 g (weight range, 710-3693 g); mean GA, 33 weeks (GA range, 25-37 weeks); and mean PCAS, 44.3 weeks (PCAS range, 35.4-59.2 weeks). All 103 patients were discharged home the day of surgery. Average time from room entry to incision was 26.3 minutes, which is similar to anesthesia induction time for patients receiving general anesthesia. Average time from bandaging to leaving room was 1 minute, less than usual time for patients receiving general anesthesia.ConclusionsSpinal anesthesia is safe, effective, and eliminates the need for postoperative hospital admission in an outpatient population of preterm infants undergoing IHR. This results in considerable cost savings without compromising quality of care.INGUINAL HERNIAS are common in preterm infants, occurring in up to 38% of infants whose birth weight is between 751 g and 1000 g and in 16% of those whose birth weight is between 1001 g and 1250 g.Because infants with inguinal hernia face a relatively high risk of incarcerated hernia and bowel obstruction, preterm infants undergo inguinal hernia repair (IHR) shortly after becoming medically stable.Most pediatric surgeons perform these IHRs with general anesthesia.Multiple studies have demonstrated that preterm (gestational age [GA], ≤37 weeks), high-risk (preterm infants whose postconceptual age at surgery [PCAS] is <60 weeks) infants are at high risk of postoperative apnea.This high incidence of apnea has resulted in the routine hospital admission of infants after receiving general anesthesia for IHR to monitor for postoperative apnea.Since 1977, our institution has been using spinal anesthesia on patients younger than 1 year undergoing surgery below the umbilicus. Abajian et alpublished their experience with 78 infants who received spinal anesthesia for various surgical procedures, 36 of whom were preterm and high risk. This study reported no incidence of apnea in infants who received spinal anesthesia. In a prospective study of 136 preterm infants younger than 60 weeks PCAS who received spinal anesthesia for various surgical procedures, Sartorelli et aldemonstrated a postoperative apnea rate of 0.8%. We have since continued to expand our experience and now routinely use spinal anesthesia in both our inpatient and outpatient population of preterm infants undergoing IHR. We hypothesized that spinal anesthesia is both safe and effective in an outpatient population of preterm, high-risk infants undergoing IHR and eliminates routine postoperative hospital admission for apnea monitoring.PATIENTS, MATERIALS, AND METHODSDuring a 15-year period (October 1982 through October 1997), all preterm, high-risk infants at our institution undergoing IHR with spinal anesthesia, or infants who had undergone attempted spinal anesthetic placement for IHR, were included in this study. No patients were excluded for methylxanthine use or any preexisting conditions, such as cardiac, neurological, or respiratory anomalies. All patients were prospectively studied, and the information pertaining to the infant's medical histories (technical data regarding the surgery, operating times, operating room treatments [need for administration of medications or need for airway control by intubation], and postoperative follow-up) was gathered and placed into a database.All patients underwent surgery at a single institution (Fletcher Allen Healthcare/University of Vermont Hospital, Burlington). All patients in the study were scheduled to undergo IHR, including elective unilateral and bilateral repairs and emergent incarcerated hernia repairs. In addition, some patients also underwent circumcisions at the same time. Informed consent for the administration of spinal anesthesia was obtained prior to surgery from patients' parents. Use of spinal anesthesia was attempted in all patients. This study included inpatients, day of surgery admission patients (DOSA), and outpatients. All patients were monitored postoperatively for apnea and bradycardia. Apnea/bradycardia monitors were used for most inpatients and some outpatients for 24 to 48 hours postoperatively. Apnea was defined as cessation of respiration for 20 seconds or longer, while bradycardia was defined as a pulse less than 80 beats per minute for at least 20 seconds. Outpatients were observed in the postanesthesia care unit prior to discharge and had their oxygen saturation monitored. All inpatient apneic or bradycardiac events were responded to appropriately and recorded. Infants were followed up by the attending surgeon (D.W.V.), either in his office within 2 weeks or in the hospital postoperatively. Parents of outpatients were specifically questioned about any witnessed apnea episodes.The lumbar puncture was accomplished with a standard spinal anesthesia tray as described by Abajian et al.A hyperbaric solution was made with 0.5 mg/kg of 1% tetracaine hydrochloride mixed with an equivalent amount of 10% dextrose in a 1-mL syringe. If the procedure was expected to last longer than 30 minutes, 0.02 mL of 1:1000 epinephrine bitartrate solution was added to the syringe. Electrocardiographs and temperature and blood pressure monitors were all attached to the patient prior to positioning the patient in the lateral decubitus or sitting posture with the chin extended. The infant's back was cleansed with iodophor solution, and a skin wheel was raised using 1% procaine. A 22- or 25-gauge disposable stiletted spinal needle was used to perform the lumbar puncture at the most readily palpable interspace below the third lumbar vertebra. Once free flow of cerebrospinal fluid was obtained, the tetracaine-dextrose solution was administered. There was no attempt to aspirate the cerebrospinal fluid.The infants were monitored for cessation of lower extremity movement, which occurred usually within 2 minutes. At that time, the patients had a lower extremity intravenous (IV) needle placed. A pinch was used to determine the sensory level of the patient while receiving anesthesia. Infants were comforted by the anesthesiologists during the procedure to prevent excessive upper extremity motion and were given a 10% glucose solution by bottle if they seemed hungry.A review of all of the literature was performed to obtain published apnea rates in preterm, high-risk infants after receiving general anesthesia for IHR.We then compared our overall apnea episodes with the published data using binomial comparison.RESULTSFor 269 IHRs, 262 spinal anesthetic placements were successful in 259 infants. One hundred thirty of these IHRs were previously reported by Sartorelli et al.Seven IHRs were started with the patient receiving other regional or general anesthesia; these 7 cases were not considered for further evaluation in our study. Three of 259 infants underwent 2 procedures; 1 experienced apnea following reoperation. This apnea episode was counted once since the procedures were more than 2 days apart, and the infant had no episodes of apnea during the time between the 2 procedures. A summary of the data for all infants participating in this study is given in Table 1. The mean GA of all infants included in the study was 32 weeks (GA range, 24-37 weeks); mean birth weight, 1688 g (weight range, 540-3950 g); mean PCAS, 43.7 weeks (PCAS range, 33.4-59.3 weeks); and mean weight at time of surgery, 3418 g (weight range, 1360-7103 g). The mean dose of tetracaine hydrochloride administered was 0.57 mg/kg (dose range, 0.25-1.40 mg/kg). One hundred fifty-four procedures were performed on infants who had a history of apnea. Apnea/bradycardia monitors were used for 117 inpatients and 6 outpatients. One hundred three outpatient, 149 inpatient, and 10 DOSA procedures were performed. Twenty-one infants had a history of congenital heart anomalies.Table 1. Data Summary for All Infants Entered in Study*CharacteristicNo. (%)Procedures (N=262)†Attempted placement of spinal anesthetic269 (102.7)Inpatient procedures149 (56.9)Outpatient procedures103 (39.3)DOSA procedure10 (3.9)Procedures on patients with apnea history154 (58.7)Followed with apnea/bradycardia monitor123 (46.9)Congenital heart anomalies21 (8.0)Mean (Range)PatientsGestational age, wk32 (24-37)Postconceptual age, wk43.7 (33.4-59.3)Birth weight, g1688 (540-3950)Weight at surgery, g3417.9 (1360-7103)Tetracaine hydrochloride dose, mg/kg0.57 (0.25-1.40)*DOSA indicates day of surgery admission.†No. of patients, 259.Adequate spinal anesthetic level was obtained following the first dose of tetracaine in 246 (91.4%) of 269 procedures (Table 2). An additional 17 patients underwent attempted placement of a repeated dose of spinal anesthetic, successful in 16. Therefore, 262 (97.3%) of 269 procedures were started with the patient receiving spinal anesthesia. The mean elapsed time between the infant entering the operating room to an incision being made was 26 minutes (time range, 14-50 minutes); this includes all failed or repeated spinal anesthetic administration.Table 2. Results of Spinal Anesthesia for Inguinal Hernia RepairsCharacteristic*No. (%)Total No. of procedures269Adequate spinal anesthesia administration, first dose246 (91.4)Repeated spinal anesthesia administration17 (6.3)Successful repeated spinal anesthesia administration16 (6.0)Procedures started with spinal anesthesia262 (97.3)Supplemental anesthesiaNone206 (78.6)Intravenous34 (12.9)Local12 (4.5)General6 (2.2)Epidural3 (1.1)Caudal1 (0.3)Intraoperative eventsNone205 (78.2)Fussy infant42 (16.0)High spinal (no intubation)8 (3.0)High spinal (intubation)0 (0)Bradycardia4 (1.5)Vomiting1 (0.3)Malperfusion1 (0.3)Oxygen desaturation0 (0)Apnea1 (0.3)Operative treatmentsNone222 (84.7)Vagolytics5 (1.9)Supplemental oxygen6 (2.2)Sedation26 (9.9)Other†3 (1.1)*Mean (range) time before incision, 26 minutes (14-50 minutes); duration of anesthesia, 151 minutes (45-250 minutes); and operative time, 48 minutes (15-130 minutes).†See the "Results" section.Supplemental anesthesia was not necessary for 206 (78.6%) of 262 procedures (Table 2) and was necessary for 56 procedures (21.4%). Intravenous supplementation was administered during 34 procedures, consisting of fentanyl citrate, diazepam, and/or midazolam hydrochloride. Local anesthetic supplementation was used in 12 procedures—6 patients received general anesthesia and 4, other regional supplementation. The mean duration of spinal anesthesia effectiveness was 151 minutes (time range, 45-250 minutes), while the mean operating time was 48 minutes (time range, 15-130 minutes). The infants usually remained in the operating room following application of the bandage for less than 1 minute.Two hundred forty seven procedures were performed with no serious intraoperative events (Table 2). Of 8 infants with high spinals, none required intubation. Four infants experienced bradycardia in the operating room; 2 of these infants received vagolytics. One infant vomited and another was reported to have malperfusion. There were no reported episodes of oxygen desaturation, although 1 infant was reported to have a perioperative episode of apnea on transport after surgery.Operating room treatments were not required for 222 procedures (Table 2). Five patients required vagolytics, and 6 required supplemental oxygen by blow-by. No fluid bolus or vasopressors were required by any infant. Sedation was administered during 26 procedures, and 3 infants had "other" treatments documented on their data form. One of these 3 received midazolam and local anesthetic, while a second was given nitrous oxide supplementation during the surgery. The third patient was an infant from the neonatal intensive care unit who suffered severe bronchopulmonary dysplasia and was oxygen dependent at the time of surgery. In the operating room, the patient experienced bradycardia and was treated with vagolytics. On transport back to the neonatal intensive care unit following surgery, he was noted to be "fussy" and was given midazolam. Shortly thereafter, he became bradycardiac and apneic, requiring resuscitation and intubation (GA, 26 weeks; PCAS, 40.7 weeks; birth weight, 966 g; and weight at surgery, 2075 g).Eight patients experienced bradycardia following IHR. All were inpatients and the episodes were self-limiting; bradycardia resolved without intervention. Thirteen patients experienced at least 1 episode of apnea at some point during their postoperative hospitalization, including the case of perioperative respiratory arrest. All patients who experienced apnea were inpatients who had a fairly extensive hospital course prior to IHR and were undergoing concomitant treatment for apnea at the time of surgery. Two of these 13 required IV anesthesia supplementation, and 2 received general anesthesia for supplementation.The mean birth weight of the 13 patients who experienced apneic episodes postoperatively was 1006 g (weight range, 540-1420 g) (Table 3). Their mean GA was 28 weeks (GA range, 24-34 weeks); mean PCAS, 42.9 weeks (PCAS range, 35.0-51.0 weeks); mean tetracaine hydrochloride dose, 0.66 mg/kg (dose range, 0.39 to 1.13 mg/kg); and mean weight at time of surgery, 2335 g (weight range, 1840 to 3310 g). The overall apnea rate following 262 attempted inguinal herniorrhaphies with spinal anesthetic was 4.9% (13/262). Eliminating the 6 procedures requiring general anesthetic supplementation, the apnea rate drops to 4.2% (11/256 ). One hundred eight of these high-risk, preterm infants had no history of apnea, and none experienced apnea postoperatively. There were no deaths in our inpatient population.Table 3. Characteristics of Infants With Apnea Episodes*CharacteristicMean (Range)Birth weight, g1006 (540-1420)Tetracaine hydrochloride dose, mg/kg0.66 (0.39-1.13)Weight at surgery, g2336 (1840-3310)Gestational age, wk28 (24-34)PCAS, wk42.9 (35.0-51.0)*Thirteen (4.9%) of 262; all 13 had a history of apnea. The apnea rate minus the procedures using general anesthesia is 11 (4.2%) of 256. PCAS indicates postconceptual age at surgery.During the past 15 years, our institution has performed few IHRs with general anesthesia on preterm infants, so we compared our rates of apnea in preterm infants after receiving spinal anesthesia with rates of apnea reported in the literature in preterm infants after receiving general anesthesia. We found 8 studies that examined apnea rates in preterm infants after receiving general anesthesia undergoing surgery with a PCAS younger than 60 weeks.There is no consensus on an exact apnea rate in preterm infants after receiving general anesthesia. Some studies either do not give the exact definition of apnea or define it as cessation of breathing for 15 seconds or longer. We chose to define apnea as cessation of breathing for at least 20 seconds, which appears to be the more commonly accepted definition in the literature. While there is no accepted exact rate for true 20-second apnea, most will agree that it is likely between 10% to 30% in this high-risk population. After review of these studies, we feel that an overall apnea rate of 10% following general anesthesia for IHR in preterm, high-risk infants is a conservative estimate. An analysis of our apnea rate (4.9%; 99% confidence interval, 2.2-9.5) following IHR with spinal anesthesia in this population was significantly lower than the conservative estimate of 10% from the literature.There were 103 outpatients participating in this study who underwent 103 procedures. Data on this group are summarized in Table 4. Thirty-nine of these patients had a history of apnea, and 7 had a history of congenital heart problems. The mean GA of this group was 33 weeks (GA range, 25-37 weeks); mean PCAS, 44.4 weeks (PCAS range, 35.4-59.3 weeks); mean birth weight, 2091 g (weight range, 710-3693 g); mean weight at time of surgery, 4061 g (weight range, 1818-7000 g); and mean dose of tetracaine hydrochloride administered, 0.53 mg/kg (dose range, 0.39 to 0.91 mg/kg).Table 4. Characteristics of Outpatients Undergoing Inguinal Hernia Repairs With Spinal AnesthesiaCharacteristic*No. (%)Total procedures and outpatients103 (100)History of apnea39 (37.8)Congenital heart problems15 (14.5)Adequate spinal anesthesia administration, first dose97 (94.1)Repeated spinal anesthesia administration†6 (5.9)Supplemental anesthesiaNone83 (80.5)Intravenous17 (16.5)Local3 (2.9)Intraoperative eventsNone72 (69.9)Fussy infant20 (19.4)Bradycardia2 (1.9)Apnea0 (0)High spinal (no intubation)8 (7.7)High spinal (intubation)0 (0)Malperfusion1 (0.9)Intraoperative treatmentsNone81 (78.6)Vagolytics4 (3.8)Sedation14 (13.5)Vasopressors0 (0)Fluid bolus0 (0)Supplemental oxygen4 (3.8)Other0 (0)*Mean (range) gestational age, 33 weeks (25-37 weeks); postconceptual age at surgery, 44.4 weeks (35.4-59.3 weeks); birth weight, 2091 g (710-3693 g); weight at surgery, 4061 g (1818-7000 g); and tetracaine hydrochloride dose, 0.53 mg/kg (0.39-0.91 mg/kg).†All successful.Ninety-seven patients received adequate spinal anesthesia following the first dose, while 6 patients needed a repeated administration of spinal anesthesia. Eighty-three patients needed no anesthetic supplementation, while 17 patients received IV supplementation. An additional 3 infants required local anesthesia. Seventy-two infants in the outpatient group were noted to have no intraoperative events. Twenty patients were classified as being "fussy." There were no cases of apnea in this group, and 2 patients did experience an episode of bradycardia. In 1 case, a decreased heart rate occurred, which was successfully treated with atropine sulfate and blow-by oxygen. The remainder of this patient's course was uneventful, and the patient did not have a history of apnea and/or bradycardia. In the second case, a short episode of bradycardia was witnessed, which resolved spontaneously, and no treatment was instituted. This patient did have a history of apnea and/or bradycardia. Eight patients were reported to have had a high spinal; none required intubation. One case of malperfusion was reported, which resolved spontaneously.Twenty-two of 103 infants had intraoperative treatments instituted at some point during IHR. Four patients received vagolytics, while 14 required IV sedation. An additional 4 patients also received supplemental oxygen by blow-by. No patients required either vasopressors or fluid boluses.All outpatients were discharged home following a 1- to 6-hour stay in the postanesthesia care unit. All were followed up in the attending surgeon's office within 1 week. There were no reported episodes of apnea following discharge. Table 5gives the increasing number of outpatients undergoing IHR at our institution. There was no mortality in this group and no morbidity directly related to the anesthetic. Table 6gives data on all our inpatients and DOSA patients to allow comparison to the outpatients in terms of birth weight, PCAS, GA, surgery weight, and tetracaine dose.Table 5. Outpatient Inguinal Hernia RepairsTime PeriodTotal No. of PatientsNo. (%) of OutpatientsOct 1982-Oct 1987604 (6.6)Nov 1987-Oct 19929442 (44.6)Nov 1992-Oct 199710857 (52.7)Table 6. Inpatients and Day of Surgery Admission Patients*CharacteristicMean (Range)Gestational age, wk30 (24-37)PCAS, wk42.6 (33.4-59.3)Birth weight, g1415 (540-3950)Weight at surgery, g2987.5 (1360.0-7103.0)Tetracaine hydrochloride dose, mg/kg0.59 (0.25-1.40)*No. of procedures, 159. PCAS indicates postconceptual age at surgery.COMMENTThe number of preterm infants who present with inguinal hernias has increased with advances in neonatal care. Peevy et alfound the incidence of inguinal hernias to be higher than 30% in infants with birth weights less than 1000 g. Early repair has been advocated owing to the high risk of incarcerated hernia and associated complications.A survey by the Section on Surgery of the American Academy of Pediatricsfound that general anesthesia was used by 70% of the pediatric surgeons polled to perform IHR in high-risk infants. If the surgery was to be performed in an outpatient setting, 69% of surgeons delay the procedure until a PCAS of at least 50 weeks. An additional 15% of surgeons never perform IHRs on an outpatient basis.The risk of apnea in preterm infants receiving general anesthesia has been investigated by numerous reports in the literature.Numerous factors have been implicated as the cause of apnea in preterm infants, including airway obstruction, anemia, diminished respiratory drive, hypothermia, diaphragmatic fatigue, and residual effects of anesthetics.While there is no consensus on the exact incidence of apnea in preterm infants who receive general anesthesia, the rate is likely between 10% to 30%. This has made the routine hospital admission of preterm infants after undergoing IHR with general anesthesia or the delay of repair necessary, as evidenced by the American Academy of Pediatrics survey.A study by Abajian et alin 1984 sparked an interest in spinal anesthesia as an alternative to general anesthesia in this high-risk population. Since that time, numerous other studies have been published examining the risk of apnea in preterm infants after receiving spinal anesthesia.Veverka et aldescribed 84 preterm, high-risk patients who underwent IHR with spinal anesthesia with no episodes of apnea. Webster et alreported that 5 infants of 44 who had received spinal anesthesia for IHR had apneic episodes. However, all 5 infants had received supplemental inhalation anesthesia. Sartorelli et alprospectively evaluated 136 preterm, high-risk infants who underwent various surgical procedures, 130 of which were inguinal herniorrhaphies. One patient (0.8%) experienced apnea postoperatively. This study led directly to the routine use of spinal anesthesia for outpatients in this high-risk population at our institution.Our study builds on the work of Sartorelli et al. We have now prospectively studied 259 preterm, high-risk infants who underwent IHR with spinal anesthesia. To our knowledge, this is the largest reported series of IHRs using spinal anesthesia in this population. This also includes the largest reported series of outpatient IHRs in preterm infants receiving spinal anesthesia. Analysis of this study demonstrates that the risk of apnea in preterm infants after receiving spinal anesthesia is significantly lower than reported apnea rates in preterm infants after receiving general anesthesia.All infants experiencing an apneic episode after receiving spinal anesthesia in our study were inpatients with a recent history of apnea who were undergoing concomitant therapy for apnea at the time of surgery. None of the outpatients were observed to have an apneic episode, and this group included 39 infants with a history of apnea. No outpatients received general anesthetic supplementation for their surgery, and none were actively experiencing apneic episodes while at home prior to surgery. This would suggest that preterm, high-risk infants who are medically ready to be at home are at little or no increased risk of experiencing apnea postoperatively after receiving spinal anesthesia for IHR. Thus, using spinal anesthesia eliminates routine overnight hospital admission in this population for apnea monitoring, assuming general anesthetic supplementation was not required, and reduces the stress imposed on the family. There is little if any additional cost incurred during the procedure from the use of spinal anesthesia compared with general anesthesia. Any additional operating room time at the beginning of the procedure is usually made up for at the end of the procedure since no time is spent waiting to extubate the infant. However, the elimination of routine overnight hospital admission for preterm infants after receiving general anesthesia provides the most considerable overall cost savings at our institution.A recent editorial in a newsletter from the Society for Pediatric Anesthesia supported the routine use of general anesthesia for repair of asymptomatic inguinal hernia in medically stable, preterm infants.The arguments proposed were as follows:The effectiveness of regional anesthesia in preventing postoperative apnea remains inconclusive.Regional anesthesia is technically difficult and not reliable in prematurely born infants.The flexibility, technical ease, and reliability of general anesthesia makes it cost effective (improved economic outcome).Our experience with spinal anesthesia in this population refutes each of these claims.Our data demonstrate that the risk of apnea in preterm infants after receiving spinal anesthesia is significantly lower than the apnea rate in preterm infants after receiving general anesthesia. Our low apnea rate was in accord with multiple other smaller studies.In addition, the only infants who experienced apnea in our study were those who were hospitalized at the time of their surgery and undergoing therapy and monitoring for apnea. None of our 103 outpatients reported any apnea following surgery with spinal anesthesia. All were discharged home. Spinal anesthesia clearly reduces the overall risk of anesthetic-associated apnea in preterm, high-risk infants undergoing IHR and likely eliminates apnea in patients who have been discharged from the hospital and are stable at home prior to IHR.Ninety-seven percent of our procedures were started with the patient receiving spinal anesthesia, and 206 patients (78.6%) did not require any anesthesia supplementation. Of the infants who received supplementation, 46 (82%) required either local or IV. If spinal anesthesia was inadequate and the patient was already prepared for surgery, it was up to the discretion of the anesthesiologist to administer IV sedation or general anesthesia for supplementation. The average duration of spinal anesthesia effectiveness was 3 times longer than the average operative time, thus allowing more than enough time to complete the IHR. In instances during which effective spinal anesthesia is not obtained, general anesthesia can be administered, and the surgeon may proceed with the understanding that the infant's risk of apnea is now significant, and postoperative hospital admission is generally required for apnea monitoring. However, our complete spinal anesthesia failure rate (unable to begin procedure while patient is receiving spinal anesthesia) was 0% in our outpatient population (n=103) and only 2.7% overall in the study.Use of spinal anesthesia for IHR in preterm, high-risk infants is cost-effective at our institution. An increase in operating room time owing to the delay in starting surgery while waiting for spinal anesthesia administration is usually made up for at the end of the procedure since there is no need to wait until the infant awakes. In addition, since the study by Sartorelli et al,we routinely perform this procedure on an outpatient basis. We do not postpone the procedure until the infant is at an older PCAS, as is sometimes done to reduce the risk of apnea when general anesthesia is used on an outpatient basis. This reduces the risk of incarcerated hernia or associated complications that sometimes occur when surgery is postponed and at the same time eliminates routine postoperative hospital admission. With a minimum daily room and monitoring charge of $630 at our institution, use of spinal vs general anesthesia has resulted in a minimum reduction in charges of $64 890 for our 103 outpatients. This does not consider the financial strain as well as the emotional stress that is imposed on families in a rural state such as Vermont when a child is hospitalized far from home.There are 2 areas in which this study may be criticized. The first is the lack of patient randomization between a general anesthesia control group and a spinal anesthesia test group, thereby requiring the use of historical controls. The second is the lack of home apnea monitoring following outpatient surgery, leading to possible underdetecting of apneic episodes, although none of these episodes were of clinical significance.The routine use of spinal anesthesia in preterm, high-risk infants at our institution for surgery below the umbilicus dates back to the late 1970s. Abajian et alsuggested that spinal anesthesia reduces the risk of postoperative apnea in preterm, high-risk infants. We continue to use spinal anesthesia routinely for surgery below the umbilicus in infants and feel strongly that it reduces the risk of postoperative apnea in a high-risk population. Since we rarely plan IHRs with general anesthesia and have a high success rate in obtaining effective spinal anesthesia, a control group at our institution would require many years to accrue. As cited earlier, numerous prospective studies have reviewed the risk of apnea in preterm infants undergoing IHR. While there is no consensus on an exact apnea rate, we compared our apnea rate with the most conservative reasonable estimates cited in all of the literature.Only a handful of our outpatients used apnea/bradycardia monitors at home following surgery. Prior work by Sartorelli et alon inpatients who were virtually all followed up with apnea/bradycardia monitors demonstrated that there was no increased risk of apnea in preterm infants after receiving spinal anesthesia for IHR if inhalation anesthetics were not required for supplementation. Since that time, we have routinely performed IHRs on an outpatient basis. There were no outpatients who underwent IHR with spinal anesthesia who were scheduled for a DOSA, and this included 15 infants who may be considered higher risk secondary to congenital heart anomalies. All outpatients had oxygen saturation monitoring while in the postanesthesia care unit prior to discharge. No apnea events were witnessed either in the postanesthesia care unit or at home, and no infant experienced any event requiring readmission or reevaluation in the emergency department following discharge. This cohort of outpatients is considered a high-risk group for postoperative apnea after receiving general anesthesia, as was our inpatient population in our earlier experiences. The fact that they did not have any episodes of respiratory compromise is owing to the anesthetic used for their surgery.CONCLUSIONThis study provides further evidence that spinal anesthesia is effective in reducing or eliminating the risk of postoperative apnea following IHR in high-risk inpatient and outpatient populations of preterm infants. We have also demonstrated that for IHRs, spinal anesthesia is technically feasible and successful in most infants for whom it is attempted. In addition, we have demonstrated that the use of spinal anesthesia eliminates the need for routine postoperative hospital admission after IHR in a high-risk, preterm population of outpatient infants. We use spinal anesthesia for nearly all IHRs for this population, and if the infant has been stable at home prior to surgery, then we feel comfortable discharging these infants home as long as supplemental inhalation anesthesia was not required. Spinal anesthesia is thus both safe and effective in an outpatient population of high-risk, preterm infants undergoing IHR and eliminates routine postoperative admission for apnea monitoring.KJPeevyFASpeedCJHoffEpidemiology of inguinal hernia in preterm neonates.Pediatrics.1986;77:246-247.FJRescorlaJLGrosfeldInguinal hernia repair in the perinatal period and early infancy: clinical considerations.J Pediatr Surg.1984;19:832-837.ESWeinerRJTouloukianBMRodgersHernia survey of the Section on Surgery of the American Academy of Pediatrics.J Pediatr Surg.1996;31:1166-1169.DJStewardPreterm infants are more prone to complications following minor surgery than are term infants.Anesthesiology.1982;56:304-306.LMPLiuCJCoteGGNishanLife-threatening apnea in infants recovering from anesthesia.Anesthesiology.1983;59:506-510.LGWelbornNRamirezTHOhPostanesthetic apnea and periodic breathing in infants.Anesthesiology.1986;65:658-661.CDKurthARSpitzerAMBroennleJJDownesPostoperative apnea in preterm infants.Anesthesiology.1987;66:483-488.LGWelbornLJRiceRSHannallahLMBroadmanUERuttimanRFinkPostoperative apnea in former preterm infants: prospective comparison of spinal and general anesthesia.Anesthesiology.1990;72:838-842.JHMeloneMZSchwartzKRTTysonOutpatient inguinal herniorrhaphy in premature infants: is it safe?J Pediatr Surg.1992;27:203-208.SMaliviyaJSwartzJLermanAre all preterm infants younger than 60 weeks postconceptual age at risk for post anesthetic apnea?Anesthesiology.1993;78:1076-108.CJCoteAZaslavskyJJDownesPostoperative apnea in former preterm infants after inguinal herniorrhaphy.Anesthesiology.1995;82:809-822.JCAbajianRWPMellishAFBrowneFMPerkinsDHLambertJEMazuzan JrSpinal anesthesia for surgery in the high risk infant.Anesth Analg.1984;63:359-363.KHSartorelliJCAbajianJMKreutzDWVaneImproved outcome utilizing spinal anesthesia in high-risk infants.J Pediatr Surg.1992;27:1022-1025.GAGregoryDJStewardLife threatening perioperative apnea in the ex-"preemie."Anesthesiology.1983;59:495-498.RAHoganACBryanMHBryanThe effects of sleep state on intercostal muscle activity and RC motion [abstract].Physiologist.1976;19:243.CDKurthMDLebardAssociation of postoperative apnea, airway obstruction, and hypoxemia in former premature infants.Anesthesiology.1991;75:22-26.LGWelbornRSHannallahLCNaomiAnemia and postoperative apnea in former preterm infants.Anesthesiology.1991;74:1003-1006.TJVeverkaDNHenryMJMilroySpinal anesthesia reduces the hazards of apnea in high-risk infants.Am Surg.1991;57:531-534.ACWebsterJDMcKishnieCFKenyonDGMarshallSpinal anesthesia for inguinal hernia repair in high-risk neonates.Can J Anaesth.1991;38:281-286.CDKruthGeneral anesthesia is the best method for former prematures undergoing inguinal hernia repair [editorial].Soc Pediatr Anesth Newslett.1997;10:6-8.Albert W. Dibbins, MD, Portland, Me:For the first time someone has been brave enough to take a group of premature infants who have been successfully treated for apnea and say that spinal anesthesia will reduce the risk of postoperative apnea to the point where they can successfully be done as outpatients. Dr Abajian and the pediatric surgeons at Vermont, Dr Allen Browne, Dr Paul Mellish, Dr Vane, and Dr Kenneth Sartorelli have been pioneers in the use of spinal anesthesia in infants. We started to do this 10 years ago. Spinal anesthesia is ideal for these infants. We have not yet begun to do the babies who are under 45 weeks of postconceptual age who have been prematures with histories of apnea as outpatients.We are in the same position as many others in the audience are in; we have not had the courage to try it. This paper proves conclusively that this can be done. However, my strong bias is that this is not for everyone. This is for experienced pediatric anesthesiologists and pediatric surgeons. When we began to do this 10 years ago, our failure rate for spinals was reasonably high. At that point, we had 1 formally trained pediatric anesthesiologist. We now have 4, which makes our lives much easier, and we are always sure that we have one of these anesthesiologists when we have a premature infant who needs an inguinal hernia.It is ideal to repair these infants before they go home, but some of them are discharged without being repaired. Then they come back with hernias, and some of them are very large hernias. Some of them are difficult. The sacs are very large. The cord structures are splayed out around the sac, and it's not a simple thing to do. So I think while this can be used appropriately in situations in which there are pediatric anesthesiologists and pediatric surgeons who are used to doing a large amount of infants with hernias, I don't think it's applicable to the general population.The message is that the baby who is medically ready to go home or who is medically ready to be at home can be done as an outpatient. One needs to know what the status of each infant is. I would like to ask Dr Vane what he does if the spinal cannot be done. What do you do about the baby? Do you then bring the baby into the hospital and try again the next day if you can get on the operating room schedule? Do you ever make a decision if you miss the spinal that it would be too much of a problem for the parents because they have already given up a day of work to do this that you use a general anesthetic in the baby and put them to sleep?Donald Hight, MD, Hartford, Conn:This study takes a tremendous relationship between the pediatric surgeons and your anesthesiologists. They have to know the surgeon as you do the anesthesiologist. There are some surgeons quite honestly who couldn't do some of these large hernias within the time frame that a typical spinal anesthetic will afford. You're operating within a significant time constraint. It's not like a general anesthetic, which can go on for an extended period of time. I'd like to emphasize the fact that neonatal hernia repairs are a very highly specialized procedure. The success of this form of management involves a relationship between anesthesia and the pediatric surgeon in order to carry this out safely.Robert J. Touloukian, MD, New Haven, Conn:My question has to do with the need for conversion to general anesthesia after an initial attempt at spinal either prior to beginning the operation or for a failed spinal during the course of the procedure. We believe it remains the surgeon's responsibility to determine the adequate level of anesthesia needed to proceed with the operation. I noticed that there were very few conversions during the course of the procedure and the point, of course, is that the surgeon has to move along quickly to complete the case within the allotted time period. Would you comment on the issue of determining the adequate level of anesthesia before beginning the case?Dr Vane:The conversion rate is low. Essentially the majority of the conversions are done prior to the operation being started. The routine length for the anesthetic is about 2 hours. The issue addressed by all of the surgeons is that you really probably shouldn't be tackling these cases unless you know what you're doing in a premature infant. The hernias can be extremely difficult to do. In this age group, it is common to do bilateral approaches, at least for us and if you're taking more than an hour for the first side, I think you may want to abort and wait. I always do the most symptomatic side first and then subsequently can wait. I have not had to personally stop the case. My partner has in one situation. Converting is important if something goes wrong. You find something bizarre and that can be done, although I have to tell you that the conversion rate was higher in the early part of our study. We have only converted one in 10 years now that I've been at Vermont, so that's going down dramatically with more experience.As to who does the anesthetic, there is no question there has to be a technically adept surgeon, otherwise you're going to be in a disaster if the spinal is wearing off and you're still working on the first side and so again it should be probably reserved to the technically trained pediatric surgeons. However, for the anesthesiologists, I have to tell you Dr Dibbins, we also have 4 pediatric anesthesiologists, but at night if a kid comes in, sometimes I'll get stuck with an adult anesthesiologist, and it's what they do. They just have to do it. I just don't really tolerate them not putting a spinal in, and they over the course of time listen to the surgeon. Remember, medical students are doing spinal taps on these babies up in the neonatal intensive care unit, and so it's not that hard. I do think adult anesthesiologists can do it.Presented at the 80th Annual Meeting of the New England Surgical Society, Newport, RI, September 25, 1999.Corresponding author: Dennis W. Vane, MD, Department of Surgery, University of Vermont, Fletcher 4, MCHV Campus, 111 Colchester Ave, Burlington, VT 05401 (e-mail: [email protected]).
Akbari, Cameron M.; Pomposelli, Jr, Frank B.; Gibbons, Gary W.; Campbell, David R.; Pulling, Michele C.; Mydlarz, Darius; LoGerfo, Frank W.
doi: 10.1001/archsurg.135.4.452pmid: 10768711
HypothesisDespite the success of infrainguinal arterial bypass in diabetic limb and foot salvage, optimism remains guarded because of purported high late mortality and limb loss in patients with diabetes.DesignInception cohort, with minimum 5-year follow-up.SettingTertiary referral center.PatientsEight hundred forty-three consecutive patients undergoing lower extremity arterial reconstruction from July 1, 1990, through July 31, 1993.InterventionInfrainguinal arterial bypass with vein graft.Main Outcome MeasuresGraft patency, limb salvage, and survival.ResultsA total of 962 vein grafts (843 patients) were performed; 795 grafts (82.6%) were performed in patients with diabetes (DM group) and 167 (17.4%) in nondiabetic patients (NDM group). Average age was 68.4 years, and was lower in the DM group (66.2 [range, 27-92 years] vs 70.5 years [range, 37-96 years]) (P=.005). In-hospital 30-day perioperative mortality was 1.4%, lower in the DM group (0.9% vs 4.2%) (P=.005). The target vessel was more frequently infrageniculate in the DM group (87% vs 77%; P=.002). Five-year primary and secondary graft patencies were 74.7% (DM group, 75.6%; NDM group, 71.9%; P=.80) and 76.2% (DM group, 77.0%; NDM group, 73.6%; P=.90), respectively. The 5-year overall limb salvage rate was 87.1%, also unaffected by diabetes (DM group, 87.3%; NDM group, 85.4%; P=.80). Survival at 5 years was 58.1% overall and virtually identical in the DM (58.2%) and NDM groups (58.0%).ConclusionsDiabetes mellitus does not influence late mortality, graft patency, or limb salvage rates after lower extremity arterial reconstruction. Concern for long-term mortality and limb loss in diabetic patients is unwarranted and should not prevent aggressive attempts at limb salvage.AWARENESS of the pathophysiological features of vascular disease in diabetes,coupled with technical advances in extreme distal arterial reconstructionand an aggressive approach to diabetic foot problems,has led to improved limb and foot salvage in patients with diabetes.Despite this success, there remains a guarded optimism about long-term function and survival in these patients, particularly toward diabetic patients with peripheral arterial disease. Higher rates of lower extremity amputation,increased incidence and severity of coronary artery disease,and higher cardiovascular mortalityare well-recognized in diabetic patients. The misconception of "diabetic small-vessel disease" has been refuted but still appears in the literature.Considered together, these may suggest poorer outcome in treated patients or, even worse, may completely discourage any aggressive treatment in these patients.Previous studies from our institution have demonstrated successful limb salvageand functional outcomefollowing distal arterial reconstruction in diabetic patients, with low perioperative morbidity and mortality rates. In an effort to better define the long-term outcome of these patients, we herein present our experience with a cohort of diabetic and nondiabetic patients undergoing lower extremity revascularization, with follow-up of at least 5 years.PATIENTS AND METHODSSince January 1990, data from every patient undergoing vascular surgery at our institution have been entered prospectively into a computerized vascular registry. We reviewed the data on all consecutive patients who underwent infrainguinal arterial bypass with vein graft at the Deaconess Hospital, Boston, Mass, from July 1, 1990, through July 31, 1993.Patient demographics, associated atherosclerotic risk factors, and indication for operation were entered into the database at the time of surgery. Operative details were recorded by the attending surgeon. Perioperative death and complications were also documented. Follow-up generally consisted of an early postoperative visit (usually at 1 month), then every 3 months for the first year and every 6 to 12 months thereafter. All follow-up visits were recorded into the registry. Graft patency was determined by results of physical and handheld continuous-wave Doppler examinations. Ankle-brachial indices were measured on selected patients during the follow-up visits. Duplex scanning graft surveillance was used in selective cases. Further follow-up was obtained from office records and telephone interviews.Statistical analysis was performed using a commercially available computer program (Stat View; Abacus Systems, Berkeley, Calif). Primary patency (grafts patent from initial surgery without any subsequent intervention), secondary patency (all grafts remaining patent), limb salvage (all or part of the foot remaining), and survival rates were calculated using the actuarial life table method.Differences were calculated using the log-rank test. Categorical variables were compared using the χ2test, and continuous variables were compared using the ttest. Statistical significance was considered at P<.05.RESULTSA total of 962 vein grafts were performed on 843 patients; 795 grafts (82.6%) were performed in patients with diabetes (DM group) and 167 (17.4%) in nondiabetic patients (NDM group). Patient demographic data and concomitant cardiovascular risk factors are presented in Table 1. Patients in the DM group were younger at presentation than those in the NDM group, and coexisting coronary artery disease and a history of heart failure were also more common among DM group patients. A greater proportion of NDM group patients were active or previous cigarette smokers, and revision bypass grafts were also more common in NDM group patients.Table 1. Demographics*GroupsPDM (n=795)NDM (n=167)Mean age (range), y66.2 (27-92)70.5 (37-96).005SexMale495 (62.3)100 (59.9).70Female300 (37.7)67 (40.1).60Tobacco useCurrent140 (17.6)51 (30.5)NAFormer444 (55.8)86 (51.5)NANever211 (26.5)30 (18.0).02Hypertension471 (59.2)95 (56.9).72Coronary artery disease383 (48.2)58 (34.7).001Congestive heart failure150 (18.9)11 (6.6)<.001Revision or reoperation134 (16.9)40 (24.0).03*DM indicates diabetic; NDM, nondiabetic; and NA, not applied. Unless otherwise indicated, data are given as number (percentage) of grafts.Tissue loss (gangrene or ulcer) was the predominant indication for operation in both groups (Table 2), but was more common among the DM group. In fact, in the DM group, claudication or rest pain was an indication in only 6.5%. Asymptomatic failing grafts were also uncommon among both groups, presenting in only 5.5% of the entire group.Table 2. Indications for Operation*GroupsPDM (n=795)NDM (n=167)Claudication34 (4.3)24 (14.4)NARest pain20 (2.5)10 (6.0)NATissue loss728 (91.2)127 (76.0).007†Failing graft, asymptomatic13 (1.6)6 (3.6)NA*DM indicates diabetic; NDM, nondiabetic; and NA, not applied. Data are given as number (percentage) of grafts.†P<.01 for tissue loss vs claudication or rest pain.Operative details regarding graft location and type of conduit are presented in Table 3. In-hospital perioperative mortality was 1.4%, and was lower in the DM than in the NDM group (0.9% vs 4.2%; P=.005). Grafts originating from the popliteal artery were more common in the DM group, consistent with the pattern of arterial vascular disease in diabetes. The dorsalis pedis artery was used as the outflow site in nearly one third of DM group patients, again reflecting the differing patterns of disease in both groups. Overall, bypass grafts to the infrapopliteal and inframalleolar arteries were more common among DM group patients (P<.01). A variety of venous conduits and configurations were used in both patient populations (Table 3).Table 3. Graft Location and Type of Conduit*GroupsDM (n=795)NDM (n=167)Inflow arteryCommon femoral409 (51.4)96 (57.5)Superficial femoral or profunda126 (15.8)36 (21.6)Popliteal213 (26.8)20 (12.0)Tibial3 (0.4)0 (0)Previous graft44 (5.5)15 (9.0)Outflow arteryAbove-knee popliteal79 (9.9)25 (15.0)Below-knee popliteal108 (13.4)35 (21.0)Tibial228 (28.7)54 (32.3)Peroneal83 (10.4)22 (13.2)Dorsalis pedis243 (30.6)13 (7.8)Plantar or tarsal28 (3.5)4 (2.4)Previous graft26 (3.3)14 (8.4)ConduitIn situ saphenous vein218 (27.4)30 (18.0)Reversed saphenous vein149 (18.7)31 (18.6)Nonreversed saphenous vein261 (32.8)69 (41.3)Arm vein100 (12.6)18 (10.8)Composite67 (8.4)19 (11.4)*DM indicates diabetic; NDM, nondiabetic. Data are given as number (percentage) of grafts. Because of rounding, percentages may not all total 100.Follow-up continued at least 5 years on all patients. Cumulative 5-year primary graft patency was 74.7% overall, with no difference between groups (DM group, 75.6%; NDM group, 71.9%; P=.80) (Figure 1). The secondary graft patency rate was 76.2% for the entire cohort, and was also similar between groups (DM group, 77.0%; NDM group, 73.6%; P=.90) (Figure 2).Figure 1.Cumulative primary patency rates of vein grafts in diabetic (DM group) and nondiabetic patients (NDM group).Figure 2.Cumulative secondary patency rates of vein grafts in diabetic (DM group) and nondiabetic patients (NDM group).Primary graft patency varied according to outflow site. Five-year patency was 86.1% for grafts placed to the popliteal artery, 76.9% for tibial (anterior and posterior tibial artery) and peroneal grafts, 69.7% for dorsalis pedis grafts, and 56.8% for grafts placed to the tarsal and plantar arteries (P=.003 for popliteal vs dorsalis pedis and tarsal-plantar grafts). The conduit also had a dominant effect on primary patency, with arm vein (AV) grafts having lower patency rates compared with in situ (ISSV), translocated nonreversed (NRSV), and reversed saphenous vein (RSV) grafts. Primary patency rates were 55.4% for AV, 78.1% for ISSV, and 82.1% for NRSV-RSV grafts (P=.002 for AV vs ISSV and NRSV-RSV grafts).Five-year limb salvage and survival rates were virtually identical in both groups (Figure 3and Figure 4). The overall limb salvage rate was 87.1% (DM group, 87.3%; NDM group, 85.4%; P=.80). Survival at 5 years was 58.1% in the entire cohort (DM group, 58.2%; NDM group, 58.0%; P=.94).Figure 3.Limb salvage up to 5 years among patients with (DM group) and without diabetes (NDM group).Figure 4.Five-year diabetic (DM group) and nondiabetic patient (NDM group) survival rates.COMMENTPrevious clinical and epidemiological studies have confirmed that diabetes mellitus is a strong risk factor for atherosclerotic coronary,cerebrovascular,and peripheral vascular disease,as well as a higher cardiovascular mortality rate,compared with the general population. In addition, the relative risk for lower extremity amputation is 40 times higher among patients with diabetes.It may appear, therefore, that long-term prognosis is worse among diabetic patients with overt peripheral vascular disease when compared with their nondiabetic counterparts. In our study, however, we have demonstrated long-term bypass graft patency, limb salvage, and survival rates to be comparable between DM and NDM groups with peripheral vascular disease.Despite a higher incidence of coexisting coronary disease and congestive heart failure, in-hospital mortality was approximately 1% in the DM group. This may result from our recognition of the patterns of cardiac disease in diabetes, specifically, a higher incidence of silent coronary ischemiaand a predisposition to congestive heart failure.We therefore have adopted an aggressive approach toward invasive perioperative cardiac monitoring in this population and continue to advocate its use.The anatomic pattern of vascular disease in diabetes has been well describedand is characterized by atherosclerosis of the infrageniculate arteries with relative sparing of the pedal arteries, which has allowed for successful arterial reconstruction to these vessels. Our study confirms this finding. The dorsalis pedis artery was the most common outflow site among the DM group, and short bypass grafts originating from the popliteal artery were also more common among the DM group.Five-year primary and secondary graft patency rates were similar between groups. In addition, there was virtually no difference between the primary patency rate (74.7%) and the secondary patency rate (76.2%) for all grafts. This likely results from the fact that most grafts did not undergo routine duplex surveillance. Because stenoses in some grafts may not have been detected because of our selective surveillance routine, secondary patency rates might have been higher if routine duplex scanning of all grafts had been performed regularly. However, despite a selective (not routine) surveillance, primary and secondary graft patency rates were comparable to those of other reports.In addition, the 5-year primary patency rate of the dorsalis pedis grafts (69.7%) was virtually identical to the patency rate (68%) previously reported from our institution.Arm vein grafts had lower patency rates when compared with saphenous vein grafts. This is consistent with previous reports,including the experience reported from our institution.The reasons for this difference are multiple and probably not related to any flaw in the intrinsic biology of arm veins.The arm veins have often received previous venipunctures or cannulations, with resultant injury and scarring. Angioscopy and careful preparation of the conduit can detect and diminish the sequelae of these injuries, which probably contribute to acute and delayed graft failure. Despite this lower patency, however, patency rates are superior to those of prosthetic grafts, and we continue to advocate AV grafts as the first alternative to ipsilateral saphenous vein, particularly in diabetic patients. Contralateral saphenous vein has been seldom used in our largely diabetic population for several reasons. In our previous series, we found that contralateral saphenous vein is present in only 38% of the patients who required AV grafts. More important, we and othershave found diabetes to be a strong risk factor for subsequent contralateral bypass, approaching 60% at 3 years, and have therefore reserved its use for subsequent need.Although more than 90% of the DM group presented with tissue loss, limb salvage was 87.3% at 5 years, similar to that achieved in the NDM group. This results from our continued adherence to the fundamentals of diabetic foot management: prompt control of infection and surgical drainage, evaluation for ischemia, prompt arterial reconstruction, and subsequent secondary procedures on the fully vascularized foot.Success with extreme distal arterial reconstruction has enhanced our ability to perform direct foot-sparing surgery,such as metatarsal resections and osteotomies, and has allowed for direct soft tissue coverage or even free-flap procedures in select cases.Most important, we have found that patients with diabetes and peripheral vascular disease have the same survival rate at 5 years as nondiabetic patients with peripheral vascular disease. Although multiple reports have noted 5-year survival of 30% to 60% among all patients with critical leg ischemia,our study suggests that survival rates after revascularization are identical between both groups. The comparable long-term graft patency, limb salvage, and survival rates all strongly emphasize that patients with diabetes and peripheral vascular disease should expect the same quantity and quality of life as nondiabetic patients with peripheral vascular disease, and the presence of diabetes should never deter aggressive attempts at limb salvage.CMAkbariFWLogerfoDiabetes and peripheral vascular disease.J Vasc Surg.1999;30:373-384.NECameronMACotterThe relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications.Diabetes Metab Rev.1994;10:189-224.FWLoGerfoJDCoffmanVascular and microvascular disease of the foot in diabetes.N Engl J Med.1984;311:1615-1619.FWLoGerfoVascular disease, matrix abnormalities, and neuropathy: implications for limb salvage in diabetes mellitus.J Vasc Surg.1987;5:793-796.RACohenDysfunction of vascular endothelium in diabetes mellitus.Circulation.1993;87:V67-V76.FBPomposelli JrSJJepsenGWGibbonsEfficacy of the dorsalis pedis bypass for limb salvage in diabetic patients.J Vasc Surg.1990;11:745-752.CMAkbariFWLoGerfoSaphenous vein bypass to pedal arteries in diabetic patients.In: Yao JST, Pearce WH, eds. Techniques in Vascular and Endovascular Surgery. East Norwalk, Conn: Appleton & Lange; 1998:227-232.GMCaputoPRCavanaghJSUlbrechtGWGibbonsAWKarchmerAssessment and management of foot disease in patients with diabetes.N Engl J Med.1994;331:854-860.JLMillsWCBeckettSMTaylorThe diabetic foot.South Med J.1991;84:970-974.CMAkbariFBPomposelli JrThe diabetic foot.In: Perler B, Becker G, eds. 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Vascular Surgery. 4th ed. Philadelphia, Pa: WB Saunders; 1995:794-814.ATGentileRWLeeGLMonetaLMTaylorJMEdwardsJMPorterResults of bypass to the popliteal and tibial arteries with alternative sources of autogenous vein.J Vasc Surg.1996;23:272-280.TJHolzenbeinFBPomposelli JrAMillerResults of a policy with arm veins used as the first alternative to an unavailable ipsilateral greater saphenous vein for infrainguinal bypass.J Vasc Surg.1996;23:130-140.FWLoGerfoCMAkbariArm vein grafts for lower extremity arterial reconstruction.In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery. 4th ed. St Louis, Mo: Mosby–Year Book. In press.WCTarryDBWalshNJOBirkmeyerMFFillingerRMZwolakJLCronenwettFate of the contralateral leg after infrainguinal bypass.J Vasc Surg.1998;27:1039-1048.JDormandyLHeeckSVigThe fate of patients with critical leg ischemia.Semin Vasc Surg.1999;12:142-147.David B. Pilcher, MD, Burlington, Vt:This is a careful analysis of one of the largest bypass series studied, perhaps only surpassed by Leather's 1853 in situ grafts. In 1971 the group from the Deaconess presented a smaller series, and concluded graft patency rates and symptomatic improvement are similar in diabetic and nondiabetic patients. The same thing we heard today, a much smaller group. They also concluded that the operative and long-term survival was worse in the diabetic patients, something that we're told today has changed.Many series have supported the view that graft patency is not adversely affected by diabetes. Perhaps we're trading off the iliac and proximal femoral disease in the nondiabetics for the distal pattern frequently ending above the ankle, evident in diabetics. In that 1971 group from the Deaconess, late survival at 7 years was 37% in the diabetics compared to 50% in nondiabetics. The diabetics had a 41% rate of myocardial infarctions, and that's a place where we've made a significant benefit in the survival rate. And we're told that since now the survival rate is the same between the diabetics and the nondiabetics at 58%, that therefore we shouldn't be concerned. But you know, if you look at the life table for insurance statistics, 68-year-old people (the average age of your group) should have a 17-year life expectancy. Certainly different than your 42% mortality. What you're saying, more appropriately, is that we should be concerned about the mortality in both the diabetic and the nondiabetic groups and that there is room for improvement there.The limb salvage rates you have are excellent in these difficult patients. This would particularly be so in a group of diabetics who were dialysis dependent, where the group of Veith showed a 25% amputation rate. How many of your patients were on dialysis, and do you think that dialysis-dependent diabetic patients are a different animal than just the diabetic patient?In summary then, I agree that you've shown what many others have shown: that diabetes does not influence the graft patency and late mortality compared to nondiabetics who are undergoing vascular bypasses. There is room for improvement in both the diabetic and the nondiabetic patients when the 5-year mortality that you're talking about is 42%.Carl E. Bredenberg, MD, Portland, Me:The results are excellent. Parenthetically, I wish I had a better understanding of the interrelationship of atherosclerosis and diabetes and, for example, why this more peripheral distribution of the occlusive process in the infrageniculate arteries that characterize it. My specific question, however, is the very difficult group of diabetic patients who are renal dialysis patients and how many of your patients were on dialysis that required limb salvage, reconstruction, or, briefly, what is your approach to those patients, and how aggressive are you in that very difficult group?Dr Akbari:First, insofar as long-term survival is concerned, it is remarkably similar in the 2 groups, and despite quite a few advances in the treatment of cardiovascular disease, the heart remains as the No. 1 cause of death in these patients. Reports still document anywhere from a 30% to 60% long-term 5-year mortality in patients undergoing lower extremity revascularization, which points to the nature of the disease, that is, atherosclerosis affecting all vessels. What is important—and the take-home message here—is that patients with diabetes don't differ significantly from patients without diabetes who require lower extremity revascularization. We clearly know that the odds are stacked against these patients from the get-go, insofar as they do have vascular disease, a systemic process.What about the patients with renal failure and on hemodialysis? Renal failure patients continue to constitute anywhere from 10% to 15% of our practice. And multiple studies have shown that graft patency rates are not influenced by the presence of renal failure, but long-term survival and wound healing rates are. What do we do with the difficult patient who has a very, very large defect in the foot and is on dialysis? Well, obviously if that patient has no chance for rehabilitation, with no chance for wound healing, then consideration should perhaps be given to an amputation. But more and more, we're seeing patients with renal failure which includes patients who have previously undergone kidney transplantation. The disease is the same, and if in those patients we're talking about a small ulcer on the foot, then every effort should be made towards limb salvage.The real consideration should be given to young patients with diabetes whom we might be looking at with grim eyes and saying their chance for long-term survival is poor. It's just not the case. Most of these patients have the exact same prognosis as patients without diabetes who need revascularization.Presented at the 80th Annual Meeting of the New England Surgical Society, Newport, RI, September 25, 1999.Corresponding author: Cameron M. Akbari, MD, 110 Francis St, Suite 5B, Boston, MA 02215 (e-mail: [email protected]).
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