Cathepsin detection to identify malignant cells during robotic pulmonary resection.

Background: Intraoperative molecular imaging (IMI) uses a fluorescent probe to identify occult cancers. VGT-309 is a quenched activity-based probe that is activated in the presence of cathepsins, enzymes overexpressed in cancer cells, and detected by near-infrared (NIR) light. This study aims to evaluate the sensitivity and the positive predictive value (PPV) of robotic-assisted thoracic surgery (RATS) with intraoperative molecular imaging (RIMI) using VGT-309 to localize tumors using NIR light to detect areas with increased cathepsin activity. Our secondary outcome was to compare RIMI to video-assisted thoracic surgery (VATS) with intraoperative molecular imaging (VIMI). Methods: In a phase 2 clinical trial at the University of Pennsylvania, patients (n=10) with suspicious pulmonary lesions underwent RATS. First, white light was used followed by RIMI to identify tissues with increased cathepsin activity. Then, VIMI was performed to compare the sensitivity and PPV in identifying the cathepsin activity. The resected specimens were then evaluated for fluorescence and underwent histopathological analysis for cathepsin expression. Image analysis was performed using ImageJ software. Statistical analysis was conducted using IBM SPSS Statistics software. A P value of 0.05 or less was considered significant. Results: RATS with white light identified 6 out of the 10 pulmonary nodules, whereas adding RIMI identified an additional 4 more pulmonary nodules. RIMI and VIMI were able to detect the same 8/10 (80%) nodules. The addition of VIMI did not identify any lesions that RIMI may have missed. The mean fluorescence intensity of tumors visualized by RIMI was 115.81 A.U. [standard deviation (SD) =58.57] compared to 95.6 A.U. (SD =14.81) by VIMI (P=0.41). The mean tumor-to-background ratios (TBR) of tumors visualized by RIMI was 9.20 (SD =9.12) compared to 2.29 A.U. (SD =1.11) using VIMI (P=0.1). The sensitivity of RIMI and VIMI was 88.9% which was superior to that of RATS (55.6%). The PPV of RATS was 83.3% compared to 100% in RIMI and VIMI. Conclusions: RIMI is a valuable option for visualization of occult disease using VGT-309-guided IMI through identifying areas of increased cathepsin activity. In this small series, RIMI and VIMI showed clinical equivalence in sensitivity and PPV of detecting cathepsin activity.

Impact of Intraoperative Molecular Imaging after Fluorescent-Guided Pulmonary Metastasectomy for Sarcoma.

BACKGROUND: Intraoperative molecular imaging (IMI) has been shown to improve lesion detection during pulmonary sarcomatous metastasectomy. Our goal in this study was to evaluate whether data garnered from IMI-guided resection of pulmonary sarcoma metastasis translate to improved patient outcomes. STUDY DESIGN: Fifty-two of 65 consecutive patients with a previous history of sarcomas found to have pulmonary nodules during screening were enrolled in a nonrandomized clinical trial. Patients underwent TumorGlow the day before surgery. Data on patient demographics, tumor biologic characteristics, preoperative assessment, and survival were included in the study analysis and compared with institutional historical data of patients who underwent metastasectomy without IMI. p values < 0.05 were considered significant. RESULTS: IMI detected 42 additional lesions in 31 patients (59%) compared with the non-IMI cohort where 25% percent of patients had additional lesions detected using tactile and visual feedback only (p < 0.05). Median progression-free survival (PFS) for patients with IMI-guided pulmonary sarcoma metastasectomy was 36 months vs 28.6 months in the historical cohort (p < 0.05). IMI-guided pulmonary sarcoma metastasectomy had recurrence in the lung with a median time of 18 months compared with non-IMI group at 13 months (p < 0.05). Patients with synchronous lesions in the IMI group underwent systemic therapy at a statistically higher rate and tended to undergo routine screening at shorter interval. CONCLUSIONS: IMI identifies a subset of sarcoma patients during pulmonary metastasectomy who have aggressive disease and informs the medical oncologist to pursue more aggressive systemic therapy. In this setting, IMI can serve both as a diagnostic and prognostic tool without conferring additional risk to the patient.

Optimal Surgical Approach to Left Atrioesophageal Fistula After Catheter Radiofrequency Ablation.

Atrioesophageal fistula formation is a rare but formidable complication after catheter radiofrequency ablation for atrial fibrillation. We present 4 patients who underwent urgent primary intracardiac repair of the left atrium via sternotomy with central cardiopulmonary bypass and early aortic cross-clamp, followed by repair of the esophagus. We believe that this approach represents the safest strategy for addressing this morbid and often fatal complication.

A multi-institutional analysis of sternoclavicular joint coverage following osteomyelitis.

BACKGROUND: Sternoclavicular joint (SCJ) osteomyelitis is a rare pathology requiring urgent intervention. Several operative approaches have been described with conflicting reports. Here, we present a multi-institutional study utilizing multiple surgical pathways for SCJ reconstruction. METHODS: A multi-institutional retrospective cohort study was conducted to identify patients who underwent surgical repair for sternoclavicular osteomyelitis between 2008 and 2019. Patients were stratified according to reconstruction approach: single-stage reconstruction with advancement flap and delayed-reconstruction with flap following initial debridement. Demographics, operative approach, type of reconstruction, and postoperative outcomes were analyzed. RESULTS: Thirty-two patients were identified. Mean patient age was 56.2±13.8 years and 68.8% were male. The average body mass index (BMI) was 30.0±8.8 kg/m2. The most common infection etiologies were intravenous drug use and bacteremia (both 25%). Fourteen patients (43.8%) underwent one-stage reconstruction and 18 (56.2%) underwent delayed twostaged reconstruction. Both single and delayed-stage groups had comparable rates of reinfection (7.1% vs. 11.1%, respectively), surgical site complications (21.4% vs. 27.8%), readmissions (7.1% vs. 16.6%), and reoperations (7.1% vs. 5.6%; all P>0.05). The single-stage reconstruction group had a significantly lower BMI (26.2±5.7 kg/m2 vs. 32.9±9.1 kg/m2; P<0.05) and trended towards shorter hospital length of stay (11.3 days vs. 17.9 days; P=0.01). CONCLUSIONS: Both single and delayed-stage approaches are appropriate methods with comparable outcomes for reconstruction for SCJ osteomyelitis. When clinically indicated, a single-stage reconstruction approach may be preferable in order to avoid a second operation as associated with the delayed phase, and possibly shortening total hospital length of stay.

Factors associated with nodal metastasis in 2-centimeter or less non-small cell lung cancer.

OBJECTIVE: Lymph node involvement is an important determinant of treatment and prognosis in non-small cell lung cancer (NSCLC) and must be determined via surgical lymph node (LN) evaluation. However, lymphadenectomy is associated with multiple significant morbidities. Recent studies have suggested LN evaluation can be foregone in some or all patients with NSCLC ≤2.0 cm. Our objective was to identify whether these patients may be safely spared the morbidity of lymphadenectomy. METHODS: We undertook a retrospective study of patients treated for NSCLC ≤2.0 cm at a single institution from 2005 to 2017. We examined patient, demographic, and tumor variables for associations with LN metastases via univariable and multivariable analyses. RESULTS: In total, 555 patients met our inclusion criteria. Our primary independent variables included tumor size, histology, and histologic subtype. Although tumors ≤1 cm were less likely to have LN metastases than 1.1- to 2-cm tumors (6.8% vs 13.3%), there was no statistically significant difference. Histologic type was not associated with LN status. In an adenocarcinoma subgroup analysis, micropapillary predominant tumors were more likely to have LN metastases. All invasive mucinous adenocarcinomas and minimally invasive adenocarcinomas were N0. CONCLUSIONS: LN evaluation may be unnecessary in patients with minimally invasive adenocarcinoma or invasive mucinous adenocarcinomas ≤2.0 cm. However, this information is rarely available pre- or intraoperatively. Thus, we recommend LN evaluation always be performed when possible, even for subcentimeter NSCLC, unless the histology is absolutely certain. To our knowledge, this is the largest dataset published to study patients with NSCLC ≤2.0 cm.

Near-infrared intraoperative imaging for minimally invasive pulmonary metastasectomy for sarcomas.

BACKGROUND: Complete pulmonary metastasectomy for sarcoma metastases provides patients an opportunity for long-term survival and possible cure. Intraoperative localization of preoperatively identified metastases and identification of occult lesions can be challenging. In this trial, we evaluated the efficacy of near-infrared (NIR) intraoperative imaging using second window indocyanine green during metastasectomy to identify known metastases and to detect occult nodules. METHODS: Thirty patients with pulmonary nodules suspicious for sarcoma metastases were enrolled in an open-label, feasibility study (NCT02280954). All patients received intravenous indocyanine green (5 mg/kg) 24 hours before metastasectomy. Patients 1 through 10 (cohort 1) underwent metastasectomy via thoracotomy to assess fluorescence patterns of nodules detected by traditional methods (preoperative imaging and intraoperative visualization/bimanual palpation). After confirming reliability within cohort 1, patients 11 through 30 (cohort 2) underwent video-assisted thoracic surgery metastasectomy with NIR imaging. RESULTS: In cohort 1, 14 out of 16 preoperatively identified pulmonary metastases (87.5%) displayed tumor fluorescence. Nonfluorescent metastases were deeper than fluorescent metastases (2.1 cm vs 1.3 cm; P = .03). Five out of 5 metastases identified during thoracotomy displayed fluorescence. NIR imaging identified 3 additional occult lesions in this cohort. In cohort 2, 33 out of 37 known pulmonary metastases (89.1%) displayed fluorescence. Nonfluorescent tumors were deeper than 2.0 cm (P = .007). NIR imaging identified 24 additional occult lesions. Of 24 occult lesions, 21 (87.5%) were confirmed metastases and the remaining 3 nodules were lymphoid aggregates. CONCLUSIONS: NIR intraoperative imaging with indocyanine green (5 mg/kg and 24 hours before surgery) localizes known sarcoma pulmonary metastases and identifies otherwise occult lesions. This approach may be a useful intraoperative adjunct to improve metastasectomy.

Lung Cancer Screening in the Community Setting: Challenges for Adoption.

Secondary prevention of lung cancer by screening a high-risk population with low-dose CT (LDCT) of the chest has been shown to save lives. Our Institution offered a free screening program in 2013. The program was promoted through flyers, radio programs, face-to-face information sessions, and a multidisciplinary lung symposium. A lung navigator confirmed the eligibility of patients according to National Lung Screening Trial (NLST) criteria. Data were, prospectively, collected over a 12-month period using Lung-RADs (Lung Imaging Reporting and Data System). After one year, an online survey was sent out to all primary care and referring physicians in the network. One hundred and sixty-nine patients were found to be eligible for screening. Sixty-five per cent were black, 44 per cent white, 9 per cent Hispanic, and 6 per cent were Asian. Sixty per cent patients were referred by their physician. Thirty-one were Lung-RADs 1 (18.3%), 116 were Lung-RADs 2 (68.6%), 16 were Lung-RADs 3 (9.5%), and six were Lung-RADs 4 (3.6%). At the end of the study period, the survey showed that 100 per cent of the providers were aware of the screening program but 15 per cent never referred a patient. Time constraints and requirement for precertification were cited as potential barriers to referral. Twenty-six per cent of providers were unaware that LDCT was recommended by the U.S. Preventive Services Task Force on par with colonoscopy and mammography. The NLST showed that screening with LDCT could reduce lung cancer mortality by 20 per cent. Significant concerns exist about the generalizability of these results and the applicability of screening programs in the community.

Thoracic Surgery in Patients with AIDS.

The picture of human immunodeficiency virus (HIV)-infected patients has changed dramatically since the original description in 1981. The introduction of antiretroviral drugs in 1987 and combination antiretroviral therapy has decreased mortality by as much as 80%. We now see patients in their 60s and 70s, having lived decades with HIV and living a normal live. As outlined in the article, despite good viral control, patients with HIV may present with solid organ cancers earlier than noninfected patients and are also prone to other complications of their disease that may require the attention of a thoracic surgeon.

Multimodality approach to management of stage III non-small cell lung cancer.

Stage III non-small cell lung cancer represents a heterogeneous group of patients who are best managed with a multidisciplinary approach, including evaluation for surgical, radiation, and chemotherapeutic options.

Management of thoracic esophageal perforations.

OBJECTIVE: To assess our results of a prospective algorithm applied to patients with thoracic esophageal perforation. METHODS: A retrospective review of a prospective algorithm. Patients with esophageal perforation underwent an esophagram. If there was a contained esophageal perforation they were admitted, kept nothing by mouth, and restudied in 3-5 days. If the leak was not contained, they underwent operative repair. RESULTS: From 1/1998 to 6/2009 there were 81 patients. The gastrograffin swallow showed 56 patients had contained perforations and 25 did not. Twenty-two of the 25 patients with noncontained perforation underwent immediate operative repair (one patient refused surgery, two were not stable enough for the operating room); their morbidity was 68% and there were six (24%) operative mortalities. Median hospital length of stay (LOS) was 11 days (range, 2-120). Of the 56 patients with contained perforations, 26 were managed successfully without surgery. However, 30 of the patients initially treated nonoperatively eventually required operations due to new pleural effusion, mediastinal abscess, or conversion to noncontained perforation. Their morbidity was 41% and there were three operative mortalities (5%). On univariate analysis, these patients were more likely to have undergone previous esophageal procedures (surgical or dilation) (p=0.03), had new or increased pleural effusion (p=0.04), and had greater than 24h between diagnosis and treatment (p=0.02). Only greater than 24h between diagnosis and treatment remained a significant predictor on multivariate analysis. Their median hospital LOS was 21 days (range, 7-77). CONCLUSION: Contained thoracic esophageal perforations can usually be safely managed nonoperatively without significant morbidity or mortality. However, careful in-hospital monitoring is needed if surgery is not chosen.

The effect of inhibition of a major cell signaling pathway following trauma hemorrhage on hepatic injury and interleukin 6 levels.

HYPOTHESIS: Recent studies have shown that intracellular signaling pathways, such as the mitogen-activated protein kinases, play a pivotal role in the activation of the inflammatory response. We hypothesized that administration of a specific mitogen-activated protein kinase inhibitor, PD 98059, at the end of resuscitation following severe hemorrhagic shock can reduce the plasma levels of interleukin 6 (IL-6) and hepatocellular damage. DESIGN: Prospective controlled animal study. SETTING: Medical school-affiliated university hospital. INTERVENTIONS: Male Sprague-Dawley (275-325 g) rats underwent laparotomy (ie, soft tissue trauma) and were then bled to a mean arterial pressure of 40 mm Hg for approximately 90 minutes. The animals were then resuscitated with 4 times the bleed-out volume using Ringer lactate solution for 60 minutes. PD 98059, an inhibitor of extracellular signal-regulated kinases (ERKs) 1 and 2 (750 mmol/L), or vehicle (dimethyl sulfoxide and isotonic sodium chloride solution) was administered intravenously as a bolus at the end of resuscitation. MAIN OUTCOME MEASURES: At 24 hours after resuscitation or sham operation, plasma levels of IL-6 and alpha-glutathione S-transferase were determined with enzyme-linked immunosorbent assay and enzyme immunoassay, respectively. Moreover liver sections were stained with monoclonal antibody against the phosphorylated form of ERKs. RESULTS: At 24 hours following trauma hemorrhage and resuscitation, plasma levels of IL-6 and alpha-glutathione S-transferase were markedly elevated. Administration of PD 98059, however, reduced levels to sham values. Moreover, liver expression of phosphorylated ERKs was found in the cytosol and nuclear compartment of hepatocytes only following trauma hemorrhage. CONCLUSION: Administration of PD 98059 (ie, inhibition of intracellular signaling pathways) may represent a feasible approach to blunt the inflammatory response and improve outcome following traumatic injuries and hemorrhagic shock.

Metabolic disturbances in shock, and the role of ATP-MgCl2 and sex steroids.

Hemorrhage following accidental injuries is a common cause of death in the industrialized world. Moreover, the impact of elective surgery and solid organ transplantation sometimes results in low flow conditions similar to those seen following hemorrhagic shock. A shortage in O(2) availability, or hypoxia, leads to sequential changes in cell metabolism and morphology, including inflammatory responses and the expression of hypoxia-inducible transcription factor-1, which controls the cellular adaptation to hypoxia. These endogenous adaptive responses show that O(2) deprivation is not an unforeseen event for cells. The purpose of this review article is to discuss the pathophysiologic principles of shock and the metabolic alterations that cells undergo during low flow conditions. Moreover, the rationale for therapeutic intervention by administering ATP-MgCl(2) and sex steroids following shock and trauma will also be discussed.

Administration of progesterone after trauma and hemorrhagic shock prevents hepatocellular injury.

HYPOTHESIS: Administration of a single dose of progesterone following trauma and hemorrhage in progesterone-deficient rats would ameliorate the inflammatory response and hepatocellular damage. SETTING: A university laboratory. INTERVENTIONS: Ovariectomized female Sprague-Dawley rats (250-350 g; Charles River Laboratories, Wilmington, Mass) underwent a 5-cm midline laparotomy (ie, induction of soft tissue trauma), were bled to a mean arterial blood pressure of 35 mm Hg for about 90 minutes, and then were resuscitated using Ringer lactate solution. Progesterone (25 mg/kg of body weight) or vehicle was administered subcutaneously at the end of resuscitation. In additional animals, Kupffer cells were isolated following trauma, hemorrhage, and resuscitation and treated in vitro with progesterone, lipopolysaccharide, or both. MAIN OUTCOME MEASURES: Six hours following resuscitation, plasma tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) levels and liver myeloperoxidase activity were determined. Hepatocellular function (maximum velocity of indocyanine green clearance [Vmax] and the efficiency of the active transport or Michaelis-Menten constant [Km]) and plasma levels of transaminases were measured 20 hours after resuscitation. Kupffer cell IL-6 and TNF-alpha production were assessed. RESULTS: Plasma levels of TNF-alpha, IL-6, aspartate aminotransferase, and alanine aminotransferase, as well as hepatic myeloperoxidase activity were increased, whereas indocyanine green clearance was depressed in vehicle-treated rats following trauma-hemorrhage. Animals treated with progesterone showed significantly reduced levels of the TNF-alpha, IL-6, and transaminases as well as reduced myeloperoxidase activity in the liver. Progesterone-treated animals showed increased Vmax and Kmax values for indocyanine green. In vitro treatment of Kupffer cells with progesterone decreased TNF-alpha production but did not affect the production of IL-6. CONCLUSION: Progesterone administration following trauma-hemorrhage ameliorates the proinflammatory response and, subsequently, the hepatocellular injury via direct action on immunocompetent cells.

Progesterone administration after trauma and hemorrhagic shock improves cardiovascular responses.

OBJECTIVE: Studies have shown that female rats during the proestrus stage have significantly improved cell and organ functions after trauma-hemorrhage compared with male and ovariectomized females. This study investigated the hypothesis that progesterone can improve the depressed cardiovascular function in sex steroid-deficient female rats (i.e., ovariectomized females) after trauma-hemorrhage and resuscitation. DESIGN: Prospective study. SETTING: University laboratory. SUBJECTS: Ovariectomized female Sprague-Dawley rats (weight, 250-300 g). INTERVENTIONS: Rats underwent a 5-cm midline laparotomy (i.e., soft-tissue trauma), were bled to a mean arterial pressure of 35 mm Hg for approximately 90 mins, and were then resuscitated using Ringer's lactate. A single dose of progesterone (25 mg/kg of body weight) or vehicle was administered subcutaneously during resuscitation. MEASUREMENTS: At 20 hrs after trauma-hemorrhage or sham operation, cardiac output and heart performance and the circulating blood volume were assessed using the indocyanine green dilution technique and a left ventricular catheter. Furthermore, the binding activity of progesterone receptors in nuclear extracts of left ventricular tissue was determined. RESULTS: Cardiac output, heart performance, and circulating blood volume were significantly decreased in vehicle-treated animals after trauma-hemorrhage. Administration of progesterone significantly improved cardiac output and heart performance and increased the circulating blood volume. This was associated with an increased progesterone receptor activity in the left ventricular nuclear extracts. CONCLUSION: Because administration of progesterone after trauma-hemorrhage in sex steroid-deficient females improved cardiovascular responses, this hormone seems to be a useful adjunct for the treatment of cardiovascular depression in postmenopausal and ovariectomized female trauma patients.

Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms.

The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury. We hypothesized that alveolar macrophage (AMPhi) chemokine and cytokine release after hemorrhage and sepsis is regulated by NF-kappaB and MAPK. Adult male rats underwent soft tissue trauma and hemorrhagic shock (~90 min) followed by crystalloid resuscitation. Sepsis was induced by cecal ligation and puncture (CLP) 20 h after resuscitation. AMPhi were harvested, and TNF-alpha, IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNF-alpha levels were measured at 5 h after HCLP. Lung tissues were analyzed for activation of NF-kappaB, myeloperoxidase activity, and wet/dry weight ratio. In control animals, AMPhi were stimulated with LPS with or without inhibitors of NF-kappaB and MAPK. Serum TNF-alpha and IL-6 levels and spontaneous AMPhi TNF-alpha and MIP-2 release were elevated (P < 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation. Activation of NF-kappaB increased in lungs from the hemorrhage and CLP group compared with shams. Inhibition of NF-kappaB or the upstream MAPK significantly decreased LPS-stimulated AMPhi activation. Because enhanced release of inflammatory mediators by AMPhi may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions.

Mechanism of immune dysfunction in sepsis: inducible nitric oxide-meditated alterations in p38 MAPK activation.

BACKGROUND: After the onset of sepsis, there is a marked dysfunction in cell-mediated immunity that contributes to the morbidity and mortality seen in this condition. Although both nitric oxide (NO) from inducible NO synthase (iNOS) and the activation of p38 mitogen-activated protein kinase (p38 MAPK) appear to contribute to this immune dysfunction, the extent to which NO regulates p38 MAPK activity in sepsis remains unknown. METHODS: To examine this, we induced sepsis by cecal ligation and puncture (CLP) in iNOS knockout (iNOS -/-) or C57BL/6 control mice. Twenty-four hours after CLP or sham operation, splenic T cells and macrophages were isolated and then stimulated with monoclonal antibody against the T-cell marker CD3 (anti-CD3) or lipopolysaccharide. At 4 or 24 hours after stimulation, cytokine release was determined by enzyme-linked immunosorbent assay, and p38 MAPK phosphorylation (activation) was determined by immunoblotting with antibody specific to phosphorylated p38 MAPK. RESULTS: Splenic T-cell p38 MAPK activation and interleukin (IL)-10 release was increased by CLP, whereas Th1 cytokine (IL-2, interferon-gamma) release was depressed. iNOS gene deficiency inhibited p38 MAPK activation in splenic T cells taken from septic mice, and also suppressed IL-10 release in both sham and septic mice. Interestingly, although deficiency of iNOS restored IL-2 release after CLP, both sham and CLP T cells remained depressed in their ability to release interferon-gamma. Septic insult markedly suppressed C57BL/6 splenic macrophage release of proinflammatory agents tumor necrosis factor, IL-12, and IL-1, while augmenting the release of IL-10. However, although deficiency of iNOS concomitantly restored the ability to produce tumor necrosis factor while suppressing the rise in IL-10 release and p38 MAPK activation, it only partially restored IL-1 release and had no effect on IL-12 production seen after CLP. CONCLUSION: These data suggest that NO release from iNOS regulates aspects of sepsis-induced immune dysfunction by the activation of p38 MAPK.

Estrogen pretreatment protects males against hypoxia-induced immune depression.

Hypoxemia depresses cell-mediated immune functions in males, whereas proestrous females do not show such a depression. We hypothesized that elevated systemic estradiol levels in proestrous females prevent hypoxemia-induced immune depression. To study this hypothesis, male C3H/HeN mice were pretreated with 17 beta-estradiol (E(2), 40 microg/kg body wt sc) or vehicle for 3 days before induction of hypoxemia and again immediately before induction of hypoxia. The mice were subjected to hypoxemia (95% N(2)-5% O(2)) or sham hypoxemia (room air) for 60 min, and plasma and spleen cells were collected 2 h later. In vehicle-treated mice, splenocyte proliferation and interleukin-2 and interleukin-3 production were depressed after hypoxemia. E(2)-pretreated animals, however, displayed no such depression in splenic T cell parameters after hypoxemia. Splenic macrophage cytokine production was also depressed in vehicle-treated mice subjected to hypoxia, whereas it was normal in E(2)-pretreated mice. In summary, these findings indicate that administration of E(2) before hypoxemia prevented the depression of cell-mediated immune functions. Thus administration of 17 beta-estradiol in high-risk patients before major surgery might decrease hypoxemia-induced immune depression under those conditions.

Estradiol administration improves splanchnic perfusion following trauma-hemorrhage and sepsis.

HYPOTHESIS: The female sex steroid 17beta-estradiol improves immune functions following trauma-hemorrhage in rodent models. Therefore, we hypothesized that 17beta-estradiol administration following trauma-hemorrhage would also improve cardiac output, splanchnic perfusion, and oxygen utilization, even after the induction of subsequent sepsis. SETTING: A university laboratory. INTERVENTION: Male rats underwent midline laparotomy (ie, soft tissue injury). They were bled to a mean arterial pressure of 35 to 40 mm Hg for 90 minutes and resuscitated over 60 minutes with lactated Ringer solution. At the beginning of resuscitation, 17beta-estradiol (l mg/kg) or a vehicle was administered. At 20 hours after resuscitation, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). MAIN OUTCOME MEASURES: At 5 hours after CLP, cardiac performance (via a left ventricular catheter), cardiac output, and organ blood flow were determined using strontium 85 microspheres. Blood samples were collected from the femoral artery and jugular, portal, and renal veins to determine systemic and regional oxygen delivery and consumption. Moreover, circulating levels of 17beta-estradiol, its adrenal precursor dehydroepiandrosterone (DHEA), and corticosterone were assessed by enzyme-linked immunosorbent assay. RESULTS: Hemorrhage and subsequent sepsis significantly depressed cardiac performance, cardiac output, organ perfusion, and oxygen consumption. Estrogen did not restore cardiac output or systemic oxygen consumption; nonetheless, it restored the depressed intestinal perfusion. Rats treated with estrogen had significantly elevated levels of plasma 17beta-estradiol, but the levels of DHEA or corticosterone were not affected. CONCLUSIONS: The increase in gut perfusion could represent a potential mechanism for the salutary effects of 17beta-estradiol following trauma-hemorrhage. Because 17beta-estradiol improves systemic and intestinal perfusion after trauma-hemorrhage and induction of subsequent sepsis, this agent appears to be a promising adjunct for the treatment of trauma victims.