Comparison of surgical outcomes for colostomy closure performed by acute care surgeons versus a dedicated colorectal surgery service.

BACKGROUND: Despite colostomy closure being a common procedure, it remains highly morbid. Previous literature suggests that complication rates, including surgical site infections, intra-abdominal abscess, and anastomotic failures, reach as high as 50%. With the creation of a dedicated colorectal service, colostomy reversals have been largely migrated from the acute care surgery services. This study analyzes the differences in outcomes in colostomy closures performed between colorectal surgeons and acute care surgeons. METHODS: We retrospectively analyzed our experience with 127 colostomy closures performed in our hospital system by acute care surgeons and colorectal surgeons from 2016 through 2020. Demographic data, operative data, and outcomes such as abscess formation, anastomotic leak, and readmission were analyzed. Multivariate regression analysis was performed for intraabdominal abscesses and anastomotic leaks. RESULTS: In total, 71 colostomy closures were performed by colorectal surgeons (56%) and 56 by acute care surgeons (43%). The majority of colostomy reversals were after Hartmann's procedure for perforated diverticulitis. No differences in demographics were identified, except for a shorter interval to closure in the acute care surgeons group (10.0 vs 7.2 months; P = .049). Two (3.6%) acute care surgeon patients required colorectal surgeon consultation during the definitive repair. Regression analysis identified body mass index (odds ratio 2.43; P = .001), male gender (odds ratio -2.39; P = .18), and colorectal surgeons (odds ratio -2.28; P = .025) as significant risk factors for anastomotic leak. CONCLUSION: Analysis of the current series identified female gender and increased body mass index as higher risk, while procedures performed by colorectal surgeons were at decreased risk for anastomotic leak. Our study identified colostomy reversals performed by a dedicated colorectal service decreased the rate of anastomotic leak.

Long-Term Clinical Outcomes of an Antibiotic-Coated Non-Cross-linked Porcine Acellular Dermal Graft for Abdominal Wall Reconstruction for High-Risk and Contaminated Wounds.

BACKGROUND: Abdominal wall reconstruction in high-risk and contaminated cases remains a challenging surgical dilemma. We report long-term clinical outcomes for a rifampin-/minocycline-coated acellular dermal graft (XenMatrix™ AB) in complex abdominal wall reconstruction for patients with a prior open abdomen or contaminated wounds. METHODS: Patients undergoing abdominal wall reconstruction at our institution at high risk for surgical site occurrence and reconstructed with XenMatrix™ AB with intent-to-treat between 2014 and 2017 were included. Demographics, operative characteristics, and outcomes were collected. The primary outcome was hernia recurrence. The secondary outcomes included length of stay, surgical site occurrence, readmission, morbidity, and mortality. RESULTS: Twenty-two patients underwent abdominal wall reconstruction using XenMatrix™ AB during the study period. Two patients died while inpatient from progression of their comorbid diseases and were excluded. Sixty percent of patients had an open abdomen at the time of repair. All patients were from modified Ventral Hernia Working Group class 2 or 3. There were a total of four 30-day infectious complications including superficial cellulitis/fat necrosis (15%) and one intraperitoneal abscess (5%). No patients required reoperation or graft excision. Median clinical follow-up was 38.2 months with a mean of 35.2 +/- 18.5 months. Two asymptomatic recurrences and one symptomatic recurrence were noted during this period with one planning for elective repair of an eventration. Follow-up was extended by phone interview which identified no additional recurrences at a median of 45.5 and mean of 50.5 +/-12.7 months. CONCLUSION: We present long-term outcomes for patients with high-risk and contaminated wounds who underwent abdominal wall reconstruction reinforced with XenMatrix™ AB to achieve early, permanent abdominal closure. Acceptable outcomes were noted.

Operative Microwave Ablation for the Multimodal Treatment of Neuroendocrine Liver Metastases.

Background and Purpose: Operative microwave ablation (MWA) is a safe modality for treating hepatic tumors. The aim of this study is to present our 10-year, single-center experience of operative MWA for neuroendocrine liver metastases (NLM). Methods: A single-institution retrospective review of patients who underwent operative MWA for NLM was performed (2008-2018). Demographics, primary tumor site, operative approach, combined surgical operations, and carcinoid symptoms were recorded. Clinical outcomes for major complications, readmission, and mortality were analyzed 30 days postoperatively. Postablation imaging was evaluated for incomplete ablation/missed lesions, and surveillance imaging reviewed for local, regional, and metastatic recurrence. Results: Of the 50 patients (166 targeted lesions) who received MWA for NLM, 41 (82%) were treated with a minimally invasive approach, and 22 (44%) underwent MWA concomitant with hepatectomy and/or primary tumor resection. Within the study cohort 70% of patients were treated with curative intent with a 77% (27/35) success rate. Carcinoid symptoms were reported in 40% (20/50) of patients preoperatively, and MWA treatment improved symptoms in 19/20 patients. Incomplete ablation occurred in 1/166 treated lesions. Recurrence-free survival at 1 and 5 years was 86% and 28%, respectively. Overall survival at 1 and 5 years was 94% and 70%, respectively (median follow-up 32 months, range 0-116 months). Conclusion: Operative MWA is a versatile modality, which can be safe and effectively performed alone or combined with hepatectomy for NLM, preferably using a minimally invasive approach, to achieve symptom control and possibly improve survival.

Effect of Margin Status on Survival After Resection of Hilar Cholangiocarcinoma in the Modern Era of Adjuvant Therapies.

INTRODUCTION: Studies have shown that for patients with hilar cholangiocarcinoma (HC), survival is associated with negative resection margins (R0). This requires increasingly proximal resection, putting patients at higher risk for complications, which may delay chemotherapy. For patients with microscopically positive resection margins (R1), the use of modern adjuvant therapies may offset the effect of R1 resection. METHODS: Patients at our institution with HC undergoing curative-intent resection between January 2008 and July 2019 were identified by retrospective record review. Demographic data, operative details, tumor characteristics, postoperative outcomes, recurrence, survival, and follow-up were recorded. Patients with R0 margin were compared to those with R1 margin. Patients with R2 resection were excluded. RESULTS: Seventy-five patients underwent attempted resection with 34 (45.3%) cases aborted due to metastatic disease or locally advanced disease. Forty-one (54.7%) patients underwent curative-intent resection with R1 rate of 43.9%. Both groups had similar rates of adjuvant therapy (56.5% vs. 61.1%, P = .7672). Complication rates and 30 mortality were similar between groups (all P > .05). Both groups had similar median recurrence-free survival (R0 29.2 months vs. R1 27.8 months, P = .540) and median overall survival (R0 31.2 months vs. R1 38.8 months, P = .736) with similar median follow-up time (R0 29.9 months vs. R1 28.5 months, P = .8864). CONCLUSIONS: At our institution, patients undergoing hepatic resection for HC with R1 margins have similar recurrence-free and overall survival to those with R0 margins. Complications and short-term mortality were similar. This may indicate that with use of modern adjuvant therapies obtaining an R0 resection is not an absolute mandate.

Prognostic impact of the Bismuth-Corlette classification: Higher rates of local unresectability in stage IIIb hilar cholangiocarcinoma.

BACKGROUND: The Bismuth-Corlette (BC) classification is used to categorize hilar cholangiocarcinoma by proximal extension along the biliary tree. As the right hepatic artery crosses just behind the left bile duct, we hypothesized that BC IIIb tumors would have a higher likelihood of local unresectability due to involvement of the contralateral artery. METHODS: A retrospective review of a prospectively maintained database identified patients with hilar cholangiocarcinoma taken to the operating room for intended curative resection between April 2008 and September 2016. Cases were assigned BC stages based on preoperative imaging. RESULTS: Sixty-eight patients were included in the study. All underwent staging laparoscopy after which 16 cases were aborted for metastatic disease. Of the remaining 52 cases, 14 cases were explored and aborted for locally advanced disease. Thirty-eight underwent attempt at curative resection. After excluding cases aborted for metastatic disease, the chance of proceeding with resection was 55.6% for BC IIIb staged lesions compared to 80.0% of BC IIIa lesions and to 82.4% for BC I-IIIa staged lesions (P < 0.05). About 44.4% of BC IIIb lesions were aborted for locally advanced disease versus 17.6% of remaining BC stages. CONCLUSIONS: When hilar cholangiocarcinoma is preoperatively staged as BC IIIb, surgeons should anticipate higher rates of locally unresectable disease, likely involving the right hepatic artery.

Modifying Interhospital Hepatopancreatobiliary Transfers Based on Predictive Analytics: Moving from a Center of Excellence to a Health-Care System of Excellence.

Regionalization of complex surgical care has increased interhospital transfers to quaternary centers within large health-care systems. Risk-based patient selection is imperative to improve resource allocation without compromising care. This study aimed to develop predictive models for identifying low-risk patients for transfer to a fully integrated satellite hepatopancreatobiliary (HPB) service in the northeast region of the health-care system. HPB transfers to the quaternary center over 15 months from hospitals in proximity to the satellite HPB center. A predictive tool was developed based on simple pretransfer variables and outcomes for 30-day major complications (Clavien grade ≥ 3), readmission, and mortality. Thresholds for "low risk" were set at different SDs below mean for each model. Predictive models were developed from 51 eligible northeast region patient transfers for major complications (Brier score 0.1948, receiver operator characteristic (ROC) 0.7123, P = 0.0009), readmission (Brier score 0.0615, ROC 0.7368, P = 0.0020), and mortality (Brier score 0.0943, ROC 0.7989, P = 0.0023). Thresholds set from 2 SD below the mean for all models identified 2 as "low risk." Adjusting the threshold for the serious complication model to only 1 SD below the mean increased the "low-risk" cohort to five patients. These models demonstrate an easy-to-use tool to assist surgeons in identifying low-risk patients for diversion to a fully integrated satellite center. Improved interhospital transfers within a region could begin a transition from centers of excellence toward health-care systems of excellence.

Minimally Invasive Surgical Management as Effective First-Line Treatment of Large Pyogenic Hepatic Abscesses.

Management of pyogenic hepatic abscesses (PHA) varies among surgeons and institutions. Recent studies have advocated for first-line percutaneous drainage (PD) of all accessible hepatic abscesses, with surgery reserved as rescue only. Our study aimed to internally validate an established multimodal algorithm for PHA at a high-volume hepatopancreatobiliary center. Patients treated by the hepatopancreatobiliary service for PHA were retrospectively reviewed from 2008 through 2018. The algorithm defined intended first-line treatment as antibiotics for type I abscesses (<3 cm), PD for type II (≥3, unilocular), and surgical intervention (minimally invasive drainage or resection, when possible) for type III (≥3 cm, multilocular). Outcomes were compared between patients who received first-line treatment following the algorithm versus alternate therapy. Of 330 patients with PHA, 201 met inclusion criteria. Type III abscesses had significantly lower failure following algorithmic approach with surgery compared with PD (4% vs 28%, P = 0.018). Type II abscesses failed first-line PD in 27 per cent (13/48) with 11 patients requiring surgical rescue, whereas first-line surgery failed in only 13 per cent (2/15). No deaths occurred after any surgical intervention, and there was no statistical difference in major complications between first-line surgical intervention and PD for type II or III abscesses. These results support the algorithmic approach and demonstrate that minimally invasive surgical intervention is a safe and effective modality for large PHA. We recommend that select patients with large, complex abscesses should be considered for a first-line minimally invasive surgical approach depending on surgical experience and available resources.

Clinically Meaningful Laboratory Protocols Reduce Hospital Charges Based on Institutional and ACS-NSQIP® Risk Calculators in Hepatopancreatobiliary Surgery.

Postoperative laboratory testing is an underrecognized but substantial contributor to health-care costs. We aimed to develop and validate a clinically meaningful laboratory (CML) protocol with individual risk stratification using generalizable and institution-specific predictive analytics to reduce laboratory testing and maximize cost savings for low-risk patients. An institutionally based risk model was developed for pancreaticoduodenectomy and hepatectomy, and an ACS-NSQIP®-based model was developed for distal pancreatectomy. Patients were stratified in each model to the CML by individual risk of major complications, readmission, or death. Clinical outcomes and estimated cost savings were compared with those of a historical cohort with standard of care. Over 34 months, 394 patients stratified to the CML for pancreaticoduodenectomy or hepatectomy saved an estimated $803,391 (44.4%). Over 13 months, 52 patients stratified to the CML for distal pancreatectomy saved an estimated $81,259 (30.5%). Clinical outcomes for 30-day major complications, readmission, and mortality were unchanged after implementation of either model. Predictive analytics can target low-risk patients to reduce laboratory testing and improve cost savings, regardless of whether an institutional or a generalized risk model is implemented. Broader application is important in patient-centered health care and should transition from predictive to prescriptive analytics to guide individual care in real time.

Efficacy of a Laparoscopic Saline-Coupled Bipolar Sealer in Minimally Invasive Hepatobiliary Surgery.

Hepatic resection presents unique surgical challenges to reduce blood loss during parenchymal division. The development of saline-coupled bipolar devices, in which hemostasis is achieved at lower temperatures than electrocautery or other bipolar sealing devices, have been employed for open hepatic resection. Saline-coupled bipolar devices have now become available for minimally invasive use. The goals of this study were to evaluate the feasibility and safety of a laparoscopic saline-coupled bipolar device for minimally invasive hepatectomy. Seventeen patients (median age 66 years, range 36-81) were consented for inclusion and enrolled. Patient demographics, intraoperative data, and surgeon feedback were collected. Seven robot-assisted partial hepatectomies, 9 laparoscopic partial hepatectomies, and 1 laparoscopic cholecystectomy with liver abscess resection were performed. Average operating time was 222 ± 33 minutes (median 188 minutes; range 61-564 minutes) with no difference between robotic versus laparoscopic time. Successful seals were achieved in all cases following application of 150 to 200 J energy (average 179 ± 3 J, average time to achieve a successful seal 9.3 ± 2.7 minutes). Estimated blood loss was 362 ± 74 mL (median 300 mL, range 5-1200 mL) and 3/17 patients received intraoperative blood transfusion. No bile leaks were detected in any of the patients. Median length of stay was 5 days (range 1-20 days), and there were no readmissions within 30 days. Postoperative morbidity occurred in 5/17 patients, all of which were Clavien Grade 1. There was no mortality within 90 days or complications requiring a return to the operating room, and there were no liver-specific morbidities. These data suggest the laparoscopic Aquamantys device represents a useful device for use in minimally invasive liver resection.

Experimental High-Frequency Irreversible Electroporation Using a Single-Needle Delivery Approach for Nonthermal Pancreatic Ablation In Vivo.

PURPOSE: To investigate the feasibility of single-needle high-frequency irreversible electroporation (SN-HFIRE) to create reproducible tissue ablations in an in vivo pancreatic swine model. MATERIALS AND METHODS: SN-HFIRE was performed in swine pancreas in vivo in the absence of intraoperative paralytics or cardiac synchronization using 3 different voltage waveforms (1-5-1, 2-5-2, and 5-5-5 [on-off-on times (µs)], n = 6/setting) with a total energized time of 100 µs per burst. At necropsy, ablation size/shape was determined. Immunohistochemistry was performed to quantify apoptosis using an anticleaved caspase-3 antibody. A numerical model was developed to determine lethal thresholds for each waveform in pancreas. RESULTS: Mean tissue ablation time was 5.0 ± 0.2 minutes, and no cardiac abnormalities or muscle twitch was detected. Mean ablation area significantly increased with increasing pulse width (41.0 ± 5.1 mm2 [range 32-66 mm2] vs 44 ± 2.1 mm2 [range 38-56 mm2] vs 85.0 ± 7.0 mm2 [range 63-155 mm2]; 1-5-1, 2-5-2, 5-5-5, respectively; p < 0.0002 5-5-5 vs 1-5-1 and 2-5-2). The majority of the ablation zone did not stain positive for cleaved caspase-3 (6.1 ± 2.8% [range 1.8-9.1%], 8.8 ± 1.3% [range 5.5-14.0%], and 11.0 ± 1.4% [range 7.1-14.2%] cleaved caspase-3 positive 1-5-1, 2-5-2, 5-5-5, respectively), with significantly more positive staining at the 5-5-5 pulse setting compared with 1-5-1 (p < 0.03). Numerical modeling determined a lethal threshold of 1114 ± 123 V/cm (1-5-1 waveform), 1039 ± 103 V/cm (2-5-2 waveform), and 693 ± 81 V/cm (5-5-5 waveform). CONCLUSIONS: SN-HFIRE induces rapid, predictable ablations in pancreatic tissue in vivo without the need for intraoperative paralytics or cardiac synchronization.

Cholangitis: Causes, Diagnosis, and Management.

Acute cholangitis remains a potentially lethal disease if not appropriately diagnosed in a timely fashion. Modern diagnostic and therapeutic modalities have greatly decreased mortality from acute cholangitis. This article aims to provide an up-to-date synopsis of empirically tested diagnostic criteria as well as an overview of the expanding interventions available.

Retrospective Validation of an Algorithmic Treatment Pathway for Necrotizing Pancreatitis.

The role of surgical intervention for necrotizing pancreatitis has evolved; however, no widely accepted algorithm has been established to guide timing and optimal modality in the minimally invasive era. This study aimed to retrospectively validate an established institutional timing- and physiologic-based algorithm constructed from evidence-based guidelines in a high-volume hepatopancreatobiliary center. Patients with necrotizing pancreatitis requiring early (≤six weeks from symptom onset) or delayed (>six weeks) surgical intervention were reviewed over a four-year period (n = 100). Early intervention was provided through laparoscopic drain-guided retroperitoneal debridement (n = 15) after failed percutaneous drainage unless they required an emergent laparotomy (due to abdominal compartment syndrome, bowel necrosis/perforation, or hemorrhage) after which conservative, sequential open necrosectomy was performed (n = 47). Robot-assisted (n = 16) versus laparoscopic (n = 22) transgastric cystgastrostomy for the delayed management of walled-off pancreatic necrosis was compared, including patient factors, operative characteristics, and 90-day clinical outcomes. Major complications after early debridement were similarly high (open 25% and drain-guided 27%), yet 90-day mortality was low (open 8.5% and drain-guided 7.1%). Patient and operative characteristics and 90-day outcomes were statistically similar for robotic versus laparoscopic transgastric cystogastrostomy. Our evidence-based algorithm provides a stepwise approach for the management of necrotizing pancreatitis, emphasizing minimally invasive early and late interventions when feasible with low morbidity and mortality. Robot-assisted transgastric cystogastrostomy is an acceptable alternative to a laparoscopic approach for the delayed treatment of walled-off pancreatic necrosis.

The impact of intraoperative goal-directed fluid therapy on complications after pancreaticoduodenectomy.

INTRODUCTION: Optimal fluid balance is critical to minimize anastomotic edema in patients undergoing pancreaticoduodenectomy. We examined the effects of decreased fluid administration on rates of postoperative pancreatic leak and delayed gastric emptying. METHODS: Retrospective study of 105 patients undergoing pancreaticoduodenectomy at a single institution from January 2015 through July 2016. Stroke volume variation (SVV) was tracked and titrated during the procedure. A comparative analysis of postoperative complications was performed between patients with a median SVV < 12 during the extirpative and reconstructive phases of the procedure compared with patients with an SVV ≥ 12. RESULTS: Of 64 patients who met selection criteria, 42 (65.6%) had a SVV < 12 and 22 (34.4%) had a SVV ≥ 12. Patients with an SVV ≥ 12 during the extirpative phase of the procedure had lower rates of postoperative pancreatic leaks compared to patients with an SVV < 12 (5.9% vs 21.3%)). Patients with an SVV ≥ 12 during the extirpative phase had lower rates of postoperative delayed gastric emptying compared to patients with an SVV < 12 (41.2% vs 46.8%). CONCLUSION: Goal-directed fluid restriction before the reconstructive phase of pancreaticoduodenectomy may contribute to lower postoperative rates of pancreatic leak and delayed gastric emptying.

Endocannabinoid degradation inhibition improves neurobehavioral function, blood-brain barrier integrity, and neuroinflammation following mild traumatic brain injury.

Traumatic brain injury (TBI) is an increasingly frequent and poorly understood condition lacking effective therapeutic strategies. Inflammation and oxidative stress (OS) are critical components of injury, and targeted interventions to reduce their contribution to injury should improve neurobehavioral recovery and outcomes. Recent evidence reveals potential protective, yet short-lived, effects of the endocannabinoids (ECs), 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl-ethanolamine (AEA), on neuroinflammatory and OS processes after TBI. The aim of this study was to determine whether EC degradation inhibition after TBI would improve neurobehavioral recovery by reducing inflammatory and oxidative damage. Adult male Sprague-Dawley rats underwent a 5-mm left lateral craniotomy, and TBI was induced by lateral fluid percussion. TBI produced apnea (17±5 sec) and a delayed righting reflex (479±21 sec). Thirty minutes post-TBI, rats were randomized to receive intraperitoneal injections of vehicle (alcohol, emulphor, and saline; 1:1:18) or a selective inhibitor of 2-AG (JZL184, 16 mg/kg) or AEA (URB597, 0.3 mg/kg) degradation. At 24 h post-TBI, animals showed significant neurological and -behavioral impairment as well as disruption of blood-brain barrier (BBB) integrity. Improved neurological and -behavioral function was observed in JZL184-treated animals. BBB integrity was protected in both JZL184- and URB597-treated animals. No significant differences in ipsilateral cortex messenger RNA expression of interleukin (IL)-1ß, IL-6, chemokine (C-C motif) ligand 2, tumor necrosis factor alpha, cyclooxygenase 2 (COX2), or nicotinamide adenine dinucleotide phosphate oxidase (NOX2) and protein expression of COX2 or NOX2 were observed across experimental groups. Astrocyte and microglia activation was significantly increased post-TBI, and treatment with JZL184 or URB597 blocked activation of both cell types. These findings suggest that EC degradation inhibition post-TBI exerts neuroprotective effects. Whether repeated dosing would achieve greater protection remains to be examined.

Alcohol abuse and the injured host: dysregulation of counterregulatory mechanisms review.

Traumatic injury ranks as the number one cause of death for the younger than 44 years age group and fifth leading cause of death overall (www.nationaltraumainstitute.org/home/trauma_statistics.html). Although improved resuscitation of trauma patients has dramatically reduced immediate mortality from hemorrhagic shock, long-term morbidity and mortality continue to be unacceptably high during the postresuscitation period particularly as a result of impaired host immune responses to subsequent challenges such as surgery or infection. Acute alcohol intoxication (AAI) is a significant risk factor for traumatic injury, with intoxicating blood alcohol levels present in more than 40% of injured patients. Severity of trauma, hemorrhagic shock, and injury is higher in intoxicated individuals than that of sober victims, resulting in higher mortality rates in this patient population. Necessary invasive procedures (surgery, anesthesia) and subsequent challenges (infection) that intoxicated trauma victims are frequently subjected to are additional stresses to an already compromised inflammatory and neuroendocrine milieu and further contribute to their morbidity and mortality. Thus, dissecting the dynamic imbalance produced by AAI during trauma is of critical relevance for a significant proportion of injured victims. This review outlines how AAI at the time of hemorrhagic shock not only prevents adequate responses to fluid resuscitation but also impairs the ability of the host to overcome a secondary infection. Moreover, it discusses the neuroendocrine mechanisms underlying alcohol-induced hemodynamic dysregulation and its relevance to host defense restoration of homeostasis after injury.

Hypertonic saline resuscitation enhances blood pressure recovery and decreases organ injury following hemorrhage in acute alcohol intoxicated rodents.

BACKGROUND: Acute alcohol intoxication (AAI) impairs the hemodynamic and arginine vasopressin (AVP) counter-regulation to hemorrhagic shock (HS) and lactated Ringer's solution (LR) fluid resuscitation (FR). The mechanism of AAI-induced suppression of AVP release in response to HS involves accentuated nitric oxide (NO) inhibitory tone. In contrast, AAI does not prevent AVP response to increased osmolarity produced by hypertonic saline (HTS) infusion. We hypothesized that FR with HTS during AAI would enhance AVP release by decreasing periventricular nucleus NO inhibitory tone, subsequently improving mean arterial blood pressure (MABP) and organ perfusion. METHODS: Male Sprague-Dawley rats received a 15-hour alcohol infusion (2.5 g/kg + 0.3 g/kg/h) or dextrose (DEX) before HS (40 mm Hg × 60 minutes) and FR with HTS (7.5%, 4 ml/kg) or LR (2.4 × blood volume removed). Organ blood flow was determined, and brains were collected for NO content at 2 hours after FR. RESULTS: HTS improved MABP recovery in AAI (109 vs. 80 mm Hg) and DEX (114 vs. 83 mm Hg) animals compared with LR. This was associated with higher (>60%) circulating AVP levels at 2 hours after FR compared with those detected in LR animals in both groups. Neither AAI alone nor HS in DEX animals resuscitated with LR altered organ blood flow. In AAI animals, HS and FR with LR reduced blood flow to the liver (72%), small intestine (65%), and large intestine (67%) compared with shams. FR with HTS improved liver (threefold) and small intestine (twofold) blood flow compared with LR in AAI-HS animals. The enhanced MABP response to HTS was prevented by pretreatment with a systemic AVP V1a receptor antagonist. HTS decreased periventricular nucleus NO content in both groups 2 hours after FR. CONCLUSION: These results suggest that FR with HTS in AAI results in the removal of central NO inhibition of AVP, restoring AVP levels and improving MABP and organ perfusion in AAI-HS.

Augmented central nitric oxide production inhibits vasopressin release during hemorrhage in acute alcohol-intoxicated rodents.

Acute alcohol intoxication (AAI) attenuates the AVP response to hemorrhage, contributing to impaired hemodynamic counter-regulation. This can be restored by central cholinergic stimulation, implicating disrupted signaling regulating AVP release. AVP is released in response to hemorrhage and hyperosmolality. Studies have demonstrated nitric oxide (NO) to play an inhibitory role on AVP release. AAI has been shown to increase NO content in the paraventricular nucleus. We hypothesized that the attenuated AVP response to hemorrhage during AAI is the result of increased central NO inhibition. In addition, we predicted that the increased NO tone during AAI would impair the AVP response to hyperosmolality. Conscious male Sprague-Dawley rats (300-325 g) received a 15-h intragastric infusion of alcohol (2.5 g/kg + 300 mg·kg(-1)·h(-1)) or dextrose prior to a 60-min fixed-pressure hemorrhage (∼40 mmHg) or 5% hypertonic saline infusion (0.05 ml·kg(-1)·min(-1)). AAI attenuated the AVP response to hemorrhage, which was associated with increased paraventricular NO content. In contrast, AAI did not impair the AVP response to hyperosmolality. This was accompanied by decreased paraventricular NO content. To confirm the role of NO in the alcohol-induced inhibition of AVP release during hemorrhage, the nitric oxide synthase inhibitor, nitro-l-arginine methyl ester (l-NAME; 250 µg/5 µl), was administered centrally prior to hemorrhage. l-NAME did not further increase AVP levels during hemorrhage in dextrose-treated animals; however, it restored the AVP response during AAI. These results indicate that AAI impairs the AVP response to hemorrhage, while not affecting the response to hyperosmolality. Furthermore, these data demonstrate that the attenuated AVP response to hemorrhage is the result of augmented central NO inhibition.

Delayed resuscitation with physostigmine increases end organ damage in alcohol intoxicated rats.

Previous studies from our laboratory have identified a role for blunted central sympathetic activation in the acute alcohol intoxication (AAI)-induced impairment of the counterregulatory response to hemorrhagic shock (HS). Immediate fluid resuscitation (FR) with acetylcholinesterase inhibitors restores the neuroendocrine and pressor responses to FR in AAI + HS. We hypothesized this intervention would remain beneficial after delay and that restoration of mean arterial blood pressure (MABP) during FR would attenuate organ damage. Male Sprague-Dawley rats received a primed constant alcohol infusion (2.5 g · kg + 0.3 g · kg · h for 15 h) or isocaloric dextrose (DEX) before HS (40 mmHg for 60 min) and FR with lactated Ringer's (LR) solution ± physostigmine (PHYS; 100 µg · kg) immediately or after a 60-min delay after HS. Immediate LR solution elevated MABP in DEX + HS. Acute alcohol intoxication delayed the initial MABP recovery. Delayed LR solution did not further increase MABP in DEX- or AAI + HS. LR solution + PHYS increased MABP in DEX- and AAI + HS after immediate and delayed FR. No differences were noted in markers of organ dysfunction (alanine aminotransferase [ALT], aspartate aminotransferase, blood urea nitrogen, creatinine) after DEX + HS, and this was unaltered by immediate or delayed LR solution + PHYS. Acute alcohol intoxication + HS increased ALT, which was attenuated by immediate LR solution + PHYS. In contrast, delayed LR solution + PHYS exacerbated tissue injury in AAI + HS, as reflected by increased ALT, aspartate aminotransferase, blood urea nitrogen, creatinine, and liver protein carbonylation over time-matched LR solution. In conclusion, PHYS enhanced blood pressure recovery independent of time of FR and presence of AAI. However, in AAI + HS, delayed LR solution + PHYS accentuated organ damage and dysfunction. These findings suggest that although enhancing the sympathetic response can improve hemodynamic recovery during AAI, it may compromise tissue perfusion and enhance tissue injury.

Estrogen increases the sensitivity of ovariectomized rats to the disruptive effects produced by antagonism of D2 but not D1 dopamine receptors during performance of a response learning task.

Estrogen impairs performance on some striatum-sensitive tasks of learning and memory. Evidence indicates that it may have these impairing effects by creating a bias to use hippocampally based strategies to solve tasks whether or not it is advantageous to do so. Estrogen may also exert direct effects in the striatum to affect performance on striatum-mediated procedural memory tasks. In spite of the robust effects that estrogen exerts on nigrostriatal dopaminergic neurons, the role of dopamine in the estrogen-induced effects on procedural memory tasks remains unexplored. The goal of the present study was to assess the independent and interactive effects of estrogen and dopamine antagonists on a striatum-mediated response learning task. Adult rats were ovariectomized and implanted with Silastic capsules containing 25% estradiol diluted in cholesterol or 100% cholesterol. Rats were trained to receive food rewards in an elevated plus maze by making a specified response (right or left turn). Following acquisition, dose-effect curves were determined for the D(1) dopamine receptor antagonist, SCH 23390, and the D(2) dopamine receptor antagonist, eticlopride. Estrogen did not significantly affect acquisition of the task and had no significant effect on the ability of SCH 23390 to disrupt performance on the task. However, estrogen significantly increased the sensitivity of the rats to the error-increasing effects of eticlopride. These results indicate that estrogen may differentially interact with D(1) and D(2) dopamine receptors to affect response learning. They also suggest that in addition to creating a bias to use hippocampally based strategies to solve tasks, estrogen may affect performance on procedural memory tasks through direct action on dopaminergic functioning.