68 Ga-DOTATATE PET/CT in the Initial Diagnosis of Patients With Clinical, Imaging, and/or Biochemical Suspicion of a Neuroendocrine Tumor.

PURPOSE: The aim of this study was to assess the yield of somatostatin receptor PET in patients with clinical, imaging, and/or biochemical suspicion of a neuroendocrine tumor (NET). PATIENTS AND METHODS: This analysis includes patients referred for the initial diagnosis of an unconfirmed NET, as part of a prospective, single-arm registry study (NCT03873870) assessing the utility of 68 Ga-DOTATATE PET/CT in the management of NETs. Inclusion criteria to this cohort consisted of elevated biomarkers and/or clinical presentation suspicious for a NET, with negative conventional cross-sectional imaging, or presence of a lesion suspicious for a NET on conventional imaging, not amenable for biopsy. Patients with histological confirmation of a NET were excluded. RESULTS: There were 220 patients included between April 2019 and March 2022 with a mean age ± SD of 59.5 ± 16.1 years with biochemical, morphological, and/or clinical suspicion of a NET. Overall, 132/220 patients (60%) had a positive 68 Ga-DOTATATE PET/CT. 68 Ga-DOTATATE PET/CT confirmed a type 2 somatostatin receptor overexpressing tumor in 123/171 (71.9%) of patients with a radiographically suspicious abnormality. The positivity rate for pancreatic, small bowel/mesenteric, adrenal, and other sites was 78/96 (81.2%), 38/57 (66.7%), 7/7 (100%), and 1/11 (9.1%), respectively. 68 Ga-DOTATATE PET/CT was positive in 9/49 (18.4%) of those with a biochemical and/or clinical suspicion of a NET. CONCLUSIONS: 68 Ga-DOTATATE PET/CT is positive in nearly 3 of 4 patients with morphological suspicion of a NET, with the highest yield in those with pancreatic and small bowel or mesenteric masses, and in approximately 1 of 6 patients with biochemical and/or clinical suspicion of a NET.

Opioid use after outpatient elective general surgery: quantifying the burden of persistent use.

Purpose: Surgery is a major risk factor for chronic opioid use among patients who had not recently been prescribed opioids. This study identifies the rate of, and risk factors for, persistent opioid use following laparoscopic cholecystectomy and open inguinal hernia repair in patients not recently prescribed opioids. Methods: This retrospective population-based cohort study included all patients who had not been prescribed opioids in the 6 months prior to undergoing open inguinal hernia repair or laparoscopic cholecystectomy from January 2013 to July 2016 in Ontario. Opioid prescription was identified from the provincial Narcotics Monitoring System and data were obtained from the Institute for Clinical Evaluative Sciences. The primary outcome was persistent opioid use after surgery (3, 6, 9 and 12 months). Associated risk factors and prescribing patterns were also examined. Results: Among the 90,326 patients in the study cohort, 80% filled an opioid prescription after surgery, with 11%, 9%, 5% and 1% filling a prescription at 3, 6, 9 and 12 months, respectively. Significant variability was identified in the type of opioid prescribed (41% codeine, 31% oxycodone, 18% tramadol) and in regional prescribing patterns (mean prescription/region range, 135-225 oral morphine equivalents). Predictors of continued opioid use included age, female gender, lower income quintile and being operated on by less experienced surgeons. Conclusion: Most patients who undergo elective cholecystectomy and hernia repair will fill a prescription for an opioid after surgery, and many will continue to fill opioid prescriptions for considerably longer than clinically anticipated. There is important variability in opioid type, regional prescribing patterns and risk factors that identify strategic targets to reduce the opioid burden in this patient population.

Adrenal Cushing Syndrome Diagnosed During Pregnancy: Successful Medical Management With Metyrapone.

Adrenal Cushing syndrome during pregnancy is rare, and there is limited information on the effect and safety of metyrapone treatment both for mother and fetus. We present a 24-year-old woman diagnosed with adrenal Cushing syndrome at the end of the second trimester. We elected treatment with metyrapone titrated to 250 mg 3 times daily, resulting in good clinical response and maternal serum and saliva cortisol levels in the upper half of the normal pregnancy range. A healthy male infant was born at 35 weeks' gestation, with no clinical signs of adrenal insufficiency, this despite a low cortisol of 5 nmol/L on the first day of life. We measured metyrapone in maternal and umbilical cord blood samples, demonstrating fetal venous metyrapone levels similar to maternal venous concentration, and a fetal arterial cord concentration at about 60% of the fetal venous cord concentration. This case demonstrates that salivary cortisol levels may be used to monitor the effect of metyrapone on adrenal Cushing syndrome during pregnancy. We show, for the first time in humans, that metyrapone does cross the placenta and may suppress fetal cortisol production without necessarily causing clinical signs of adrenal insufficiency.

The Standardization of Outpatient Procedure (STOP) Narcotics: A Prospective Health Systems Intervention to Reduce Opioid Use in Ambulatory Breast Surgery.

BACKGROUND: During the past 15 years, opioid-related overdose death rates for women have increased 471%. Many surgeons provide opioid prescriptions well in excess of what patients actually use. This study assessed a health systems intervention to control pain adequately while reducing opioid prescriptions in ambulatory breast surgery. METHODS: This prospective non-inferiority study included women 18-75 years of age undergoing elective ambulatory general surgical breast procedures. Pre- and postintervention groups were compared, separated by implementation of a multi-pronged, opioid-sparing strategy consisting of patient education, health care provider education and perioperative multimodal analgesic strategies. The primary outcome was average pain during the first 7 postoperative days on a numeric rating scale of 0-10. The secondary outcomes included medication use and prescription renewals. RESULTS: The average pain during the first 7 postoperative days was non-inferior in the postintervention group despite a significant decrease in median oral morphine equivalents (OMEs) prescribed (2.0/10 [100 OMEs] pre-intervention vs 2.1/10 [50 OMEs] post-intervention; p = 0.40 [p < 0.001]). Only 39 (44%) of the 88 patients in the post-intervention group filled their rescue opioid prescription, and 8 (9%) of the 88 patients reported needing an opioid for additional pain not controlled with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) postoperatively. Prescription renewals did not change. CONCLUSION: A standardized pain care bundle was effective in minimizing and even eliminating opioid use after elective ambulatory breast surgery while adequately controlling postoperative pain. The Standardization of Outpatient Procedure Narcotics (STOP Narcotics) initiative decreases unnecessary and unused opioid medication and may decrease risk of persistent opioid use. This initiative provides a framework for future analgesia guidelines in ambulatory breast surgery.

Standardization of Outpatient Procedure (STOP) Narcotics: A Prospective Non-Inferiority Study to Reduce Opioid Use in Outpatient General Surgical Procedures.

BACKGROUND: There has been a dramatic rise in opioid abuse, and diversion of excess, unused prescriptions is a major contributor. We assess the impact of implementing a new standardized pain care bundle to reduce postoperative opioids in outpatient general surgical procedures. STUDY DESIGN: This study was designed to demonstrate non-inferiority for the primary end point: patient-reported average pain in the first 7 postoperative days. We prospectively evaluated 224 patients who underwent laparoscopic cholecystectomy or open hernia repair (inguinal, umbilical) pre-intervention to 192 patients post-intervention. We implemented a multimodal intra- and postoperative analgesic bundle, including promoting co-analgesia, opioid-reduced prescriptions, and patient education designed to clarify patient expectations. Patients completed a brief pain inventory at their first postoperative visit. Groups were compared using chi-square test, Mann-Whitney U test, and independent samples t-test, where appropriate. RESULTS: No difference was seen in average postoperative pain scores in the pre- vs post-intervention groups (2.3 vs 2.1 of 10; p = 0.12). The reported quality of pain control improved post-intervention (good/very good pain control in 69% vs 85%; p < 0.001). The median total morphine equivalents for prescriptions filled in the post-intervention group were significantly less (100; interquartile range 75 to 116 pre-intervention vs 50; interquartile range 50 to 50 post-intervention; p < 0.001). Only 78 of 172 (45%) patients filled their opioid prescription in the post-intervention group (p < 0.001), with no significant difference in prescription renewals (3.5% pre-intervention vs 2.6% post-intervention; p = 0.62). CONCLUSIONS: For outpatient open hernia repair and cholecystectomy, a standardized pain care bundle decreased opioid prescribing significantly and frequently eliminated opioid use, and adequately treating postoperative pain and improving patient satisfaction.

Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia.

BACKGROUND: Laparoscopic splenectomy is a second-line therapy for immune thrombocytopenia with a sustained success rate of 66%. In a climate of new available medical therapies for immune thrombocytopenia, the comparative safety and efficacy of laparoscopic splenectomy are worthy of attention. The purpose of this study is to identify factors predictive of laparoscopic splenectomy success that will enable preoperative prognostication. METHODS: A retrospective cohort study was conducted of patients undergoing laparoscopic splenectomy for immune thrombocytopenia. The data collected evaluated response to medical and surgical therapy, which was defined on a platelet level of 50 × 109/L with no bleeding events. Univariate and multivariate analyses were conducted to evaluate factors predictive of laparoscopic splenectomy success, with an additional subanalysis planned to assess for laparoscopic splenectomy safety in individuals ≥65 years. RESULTS: One hundred forty-one patients were reviewed. Operative outcomes showed a 3.6% conversion rate and 8.5% complication rate. Disease remission was achieved in 78.7% of patients. Response to initial corticosteroid therapy was associated with a laparoscopic splenectomy success rate of 90% and increased odds of surgical success by 5.58 over individuals with no response to corticosteroids. Age did not confer an increased risk of failure or complications. CONCLUSION: Laparoscopic splenectomy is a safe and effective intervention for immune thrombocytopenia regardless of age. Initial response to corticosteroids is associated with laparoscopic splenectomy success rate of 90% and improved odds of surgical success. Laparoscopic splenectomy should be the standard second-line therapy for immune thrombocytopenia, especially in patients responding to corticosteroids.

Early Rescue from Acute Severe Clostridium Difficile: A Novel Treatment Strategy.

BACKGROUND: Severe Clostridium difficile infections (CDI) can lead to significant impediments to effective treatment. We developed a novel treatment protocol utilizing bedside gastrointestinal lavage (GIL) for the management of patients with severe, complicated CDI. We describe the development and early outcomes of non-operative bedside GIL in hospitalized patients with severe, complicated CDI following the Idea, Development, Exploration, Assessment, Long Term Study (IDEAL) framework at the Idea stage. We compared our results with those of a cohort of patients managed with colectomy. METHODS: We conducted a retrospective cohort study of hospitalized patients with severe, complicated CDI who failed conventional medical therapy and were referred for surgical consultation at two academic tertiary-care hospitals between January 2009 and January 2015. After surgical assessment, the attending surgeon decided to proceed either with bedside GIL or directly to colectomy. Bedside GIL involved nasojejunal tube insertion followed by flushing with 8 L of polyethylene glycol 3350/electrolyte solution over 48 h. Both patient groups received standard medical treatment with vancomycin 500 mg q 6 h enterally and metronidazole 500 mg intravenously three times daily for 14 d. The main outcomes of interest were the incidence of colectomy, complications, and mortality rate. RESULTS: Nineteen and seventeen patients underwent GIL and direct colectomy, respectively. There were no significant differences between the groups in terms of demographics, American Society of Anesthesiologists class, disease severity, need for intensive care unit admission, mechanical ventilation, vasopressor use, serum lactate concentration, or proportion presenting with hypotension, acute kidney injury, or a white blood cell count >16,000/mcL or <4,000/mcL (p > 0.1). The in-hospital mortality rate was 26% (5/19) and 41% (7/17) for the GIL and colectomy groups, respectively (p = 0.35). Only one patient in the GIL group failed the protocol, requiring colectomy. There were no significant differences in complications in the two groups. CONCLUSIONS: Bedside GIL appeared to be safe for the treatment of patients with severe, complicated CDI who had failed conventional medical therapy. It did not appear to increase the risk of morbidity or death compared with the traditional strategy of proceeding directly to colectomy.

Successful percutaneous CT-guided microwave ablation of adrenal gland for ectopic Cushing syndrome.

Adrenocorticotropic hormone production by pancreatic neuroendocrine tumor (PNET) is rare and results in hyperstimulation of the adrenal gland to produce ectopic Cushing syndrome. Our case showcases the safety and effectiveness of percutaneous CT-guided microwave ablation of the adrenal gland in a 49-year-old female with PNET and hepatic metastases who presented with ectopic Cushing syndrome despite surgical resection of the primary pancreatic tumor and left adrenal gland. Prior to ablation, the right adrenal gland measured 4.3×1.6×2.0cm and the patient had malignant hypertension with elevated morning serum cortisol level (1976nmol/L). After microwave ablation of the right adrenal gland, the hypertension resolved and the cortisol level decreased dramatically (74nmol/L). As expected after successful treatment, the patient developed adrenal insufficiency and was placed on glucocorticoid and mineralocorticoid supplementation.

Roscoe R. Graham: An enduring legacy in the 21st century.

BACKGROUND: Modern advancements in surgery have led to a climate in which many classical techniques are becoming obsolete. However, the Graham patch technique for duodenal repair continues to be widely used as originally described in Dr Roscoe Reid Graham's 1937 article: an omental graft held in position over a duodenal perforation by three interrupted sutures. METHODS: Primary documents including original newspaper articles and wartime documents were retrieved from the University of Toronto Archives and Records. Contemporary case reports and journal publications were analyzed. A review of current literature on applications and modifications of the Graham patch was undertaken. DISCUSSION: Roscoe Graham received his education at the University of Toronto. After his surgical training, he joined the No. 4 General Hospital as a captain in World War I. Upon returning from duty, his surgical contributions were extensive. His achievements include the development of a procedure for rectal prolapse repair, the first insulinoma resection, and the pioneering of an omental patch technique for the treatment of perforated duodenal ulcers. He was an integral member of the Toronto medical community and reputed to be among North America's best surgeons. CONCLUSION: Although many surgical techniques described in the 20th century have been discarded in favor of new technological applications, Graham's original omental patch is still used across the world. In addition to providing an effective solution to perforated ulcer repair in both open and laparoscopic procedures, it has been adapted for use in traumatic solid organ injury. This article describes the life and career of Roscoe Reid Graham, highlights his medical contributions, and explores how his omental patch technique continues to be indispensable on the modern surgical stage.

Very early initiation of chemical venous thromboembolism prophylaxis after blunt solid organ injury is safe.

BACKGROUND: The optimal timing of initiating low-molecular weight heparin (LMWH) in patients who have undergone nonoperative management (NOM) of blunt solid organ injuries (SOIs) remains controversial. We describe the safety of early initiation of chemical venous thromboembolism (VTE) prophylaxis among patients undergoing NOM of blunt SOIs. METHODS: We retrospectively studied severely injured adults who sustained blunt SOI without significant intracranial hemorrhage and underwent an initial NOM at a Canadian lead trauma hospital between 2010 and 2014. Safety was assessed based on failure of NOM, defined as the need for operative intervention, in patients who received early (< 48 h) or late LMWH (≥ 48 h, or early discharge [< 72 h] without LMWH). RESULTS: We included 162 patients in our analysis. Most were men (69%), and the average age was 42 ± 18 years. The median injury severity score was 17, and splenic injuries were most common (97 [60%], median grade 2), followed by liver (57 [35%], median grade 2) and kidney injuries (31 [19%], median grade 1). Combined injuries were present in 14% of patients. A total of 78 (48%) patients received early LMWH, while 84 (52%) received late LMWH. The groups differed only in percent of high-grade splenic injury (14% v. 32%). Overall 2% of patients failed NOM, none after receiving LMWH. Semielective angiography was performed in 23 (14%) patients. The overall rate of confirmed VTE on imaging was 1.9%. CONCLUSION: Early initiation of medical thromboembolic prophylaxis appears safe in select patients with isolated SOI following blunt trauma. A prospective multicentre study is warranted.

Success of Urgent-Start Peritoneal Dialysis in a Large Canadian Renal Program.

UNLABELLED: ♦ BACKGROUND: Many patients start renal replacement therapy urgently on in-center hemodialysis via a central venous catheter, which is considered suboptimal. An alternative approach to manage these patients is to start them on peritoneal dialysis (PD). In this report, we describe the first reported Canadian experience with an urgent-start PD program. Additionally we reviewed the literature in this area. ♦ METHODS: In this prospective observational study, we report on our experience in a single academic center. This program started in July 2010. We included patients who initiated PD urgently, that is within 2 weeks of catheter insertion. We followed all incident PD patients until October 2013 for mechanical and infectious complications. Peritoneal dialysis catheters were inserted either percutaneously or laparoscopically and dialysis was initiated in either an inpatient or outpatient setting. ♦ RESULTS: Thirty patients were started on urgent PD during our study period. Follow-up ranged from 28 to 1,050 days. Twenty insertions (66.7%) were done percutaneously and 10 (33.3%) were laparoscopic. Dialysis was initiated within 2 weeks (range: 0-13 days, median = 6 days). Twenty-four patients (80%) started PD in an outpatient setting and 6 patients (20%) required immediate inpatient PD start. Three patients (10%) developed a minor peri-catheter leak during the first week of training that was managed conservatively. There were no episodes of peritonitis or exit-site/tunnel infection during the first 4 weeks post-insertion. Four patients (13.3%) from the percutaneous insertion group and 2 patients (6.7%) from laparoscopic insertions developed catheter dysfunction due to migration, which was managed by repositioning, without need for catheter replacement or modality switch. ♦ CONCLUSIONS: Our results are consistent with other studies in this area and demonstrate that urgent-start PD is an acceptable and safe alternative to hemodialysis in patients who need to start dialysis urgently without established dialysis access.

Daily Incision Cleansing with Alcohol Reduces the Rate of Surgical Site Infections: A Pilot Study.

Surgical site infections (SSIs) represent a significant source of preventable patient morbidity and hospital expense. Our objective was to assess the role of postoperative incisional alcohol cleansing in decreasing the rates of SSI as compared with standard care (control). Patients undergoing clean-contaminated abdominal operations at a single center were included. Prospectively collected data on control patients were compared with patients treated with daily postoperative alcohol-based surgical site cleansing (70% isopropyl alcohol) for the primary outcome of an SSI within the first 30 postoperative days. A total of 93 patients were included, 56 managed with standard care and 37 managed with the addition of daily alcohol cleansing. A significantly lower rate of SSI in the group managed with daily alcohol cleansing was observed (13% vs 32%, P = 0.04). This study suggests a role for adding daily incisional alcohol cleansing to further reduce the rate of SSIs.

Delayed hemorrhagic complications in the nonoperative management of blunt splenic trauma: early screening leads to a decrease in failure rate.

BACKGROUND: Delayed splenic rupture is the Achilles' heel of nonoperative management (NOM) for blunt splenic injury (BSI). Early computed tomographic (CT) scanning for features suggesting high risk of nonoperative failure, splenic pseudoaneurysms (SPAs), and arterial extravasation (AE), in concert with the appropriate use of splenic arterial embolization (SAE) is a viable method to reduce rates of failure of NOM. We report our 12-ear experience with a protocol for mandatory repeat CT evaluation at 48 hours and selective SAE. METHODS: A retrospective cohort analysis was performed on all consecutive adult trauma patients with BSI between 1995 and 2012. We evaluated an early/control (1995-1999) and a present/intervention (2000-2012) cohort in which SAE became available and 48-hour CT scans were implemented. RESULTS: The study included 773 patients (157 early vs. 616 present) with BSI. The proportion of patients managed nonoperatively (53% vs. 77%, p < 0.01) and overall splenic salvage rate (46% vs. 77%, p < 0.01) were improved in the present cohort. Among patients selected for NOM, there was a significant improvement in the failure rate of NOM (12% vs. 0.6%, p < 0.01) as well as in the length of hospital stay (8 days vs. 6 days, p < 0.01). Delayed development of SPA and/or AE was detected in 6% of BSI in the present cohort and was distributed among all grades of injury. CONCLUSION: The delayed development of SPA and AE is not an entirely rare event following BSI. Reevaluation with CT at 48 hours following admission and the use of SAE significantly decrease the failure rate of NOM. LEVEL OF EVIDENCE: Therapeutic study, level III.

The role of trauma team leaders in missed injuries: does specialty matter?

BACKGROUND: Previous studies have identified missed injuries as a common and potentially preventable occurrence in trauma care. Several patient- and injury-related variables have been identified, which predict for missed injuries; however, differences in rate and severity of missed injuries between surgeon and nonsurgeon trauma team leaders (TTLs) have not previously been reported. METHODS: A retrospective review was conducted on a random sample of 10% of all trauma patients (Injury Severity Score [ISS] > 12) from 1999 to 2009 at a Canadian Level I trauma center. Missed injuries were defined as those identified greater than 24 hours after presentation and were independently adjudicated by two reviewers. TTLs were identified as either surgeons or nonsurgeons. RESULTS: Of our total trauma population of 2,956 patients, 300 charts were randomly pulled for detailed review. Missed injuries occurred in 46 patients (15%). Most common missed injuries were fractures (n = 32, 70%) and thoracic injuries (n = 23, 50%). The majority of missed injuries resulted in minor morbidity with only 5 (11%) requiring operative intervention. On univariate analysis, higher ISS (p < 0.01), higher maximum Abbreviated Injury Scale (MAIS) score of the thorax (p < 0.01), and nonsurgeon TTL status were predictive of missed injuries (p = 0.02). Multivariable logistic regression revealed that, after adjustment for age, ISS, and severe head injuries, the presence of a nonsurgeon TTL was associated with an increased odds of missed injury (odds ratio, 2.15; 95% confidence interval, 1.10-4.20). CONCLUSION: Missed injuries occurred in 15% of patients. A unique finding was the increased odds of missed injury with nonsurgeon TTLs. Further research should be undertaken to explore this relationship, elucidate potential causes, and propose interventions to narrow this discrepancy between TTL provider types. LEVEL OF EVIDENCE: Therapeutic study, level IV. Prognostic and epidemiologic study, level III.

Compartment syndrome-induced microvascular dysfunction: an experimental rodent model.

BACKGROUND: Acute compartment syndrome (CS) is a limb-threatening disease that results from increased intracompartmental pressure. The pathophysiologic mechanisms by which this occurs are poorly understood. This study was designed to measure the effects of increased intracompartmental pressure on skeletal muscle microcirculation, inflammation and cellular injury using intravital videomicroscopy (IVVM) in a clinically relevant small animal model. METHODS: We induced CS in 10 male Wistar rats (175-250 g), using a saline infusion technique. Intracompartmental pressure was controlled between 30 and 40 mm Hg and maintained for 45 minutes. After fasciotomy, the extensor digitorum longus muscle was visualized using IVVM, and perfusion was quantified. We quantified leukocyte recruitment to measure the inflammatory response. We measured muscle cellular injury using a differential fluorescent staining technique. RESULTS: The number of nonperfused capillaries increased from 12.7 (standard error of the mean [SEM] 1.4 ) per mm in the control group to 30.0 (SEM 6.7) per mm following 45 minutes of elevated intracompartmental pressure (CS group; p = 0.031). The mean number of continuously perfused capillaries (and SEM) decreased from 78.4 (3.2) per mm in the control group to 41.4 (6.9) per mm in the CS group (p = 0.001). The proportion of injured cells increased from 5.0% (SEM 2.1%) in the control group to 16.3% (SEM 6.8%) in the CS group (p = 0.006). The mean number of activated leukocytes increased from 3.6 (SEM 0.7) per 100 µm(2) in the control group to 8.6 (SEM 1.8) per 100 µm(2) in the CS group (p = 0.033). CONCLUSION: Early CS-induced microvascular dysfunction resulted in a decrease in nutritive capillary perfusion and an increase in cellular injury and was associated with a severe acute inflammatory component.

Indomethacin reduces cell damage: shedding new light on compartment syndrome.

INTRODUCTION: Indomethacin may preserve tissue viability in compartment syndrome. The mechanism of improved tissue viability is unclear, but the anti-inflammatory effects may alter the relative contribution of tissue necrosis versus apoptosis to cellular injury. Existing studies have only considered indomethacin administration before induction of elevated intracompartment pressure. The purpose of this study was to determine the effect of timing of indomethacin administration on muscle damage in elevated intracompartment pressure and to assess apoptosis as a cause of tissue demise. METHODS: Twenty-four Wistar rats were randomized to elevated intracompartmental pressure (EICP) for either 45 or 90 minutes (30 mmHg). In the 45-minute cohort, indomethacin was withheld in Group 1 (CS45), given before induction of EICP in Group 2 (CS45Indo0), or given after 30 minutes of EICP/15 minutes before fasciotomy in Group 3 (CS45Indo30). In the 90-minute cohort, indomethacin was withheld in Group 4 (CS90) or given after 30 or 60 minutes of EICP in Groups 5 (CS90Indo30) and 6 (CS90Indo60). Intravital microscopy and fluorescent staining assessed capillary perfusion, cell damage, and inflammatory activation within extensor digitorum longus muscle. Apoptosis was assessed using spectrophotometric assessment of caspase levels. Groups 1 to 3 and 4 to 6 were compared using analysis of variance with P < 0.05 deemed significant. RESULTS: Perfusion and tissue viability improved in indomethacin-treated groups. Nonperfused capillaries decreased from Group 1 (CS45) (50.1 +/- 2.5) to Group 2 (CS45Indo0) (38.4 +/- 1.8) and Group 3 (CS45Indo30) (14.13 +/- 1.73) (P < 0.05). Similarly, Group 5 (CS90Indo30) and Group 6 (CS90Indo60) had 25% fewer nonperfused capillaries compared with Group 4 (CS90) (P < 0.0001). Group 2 (CS45Indo0) and Group 3 (CS45Indo30) showed fewer damaged cells (1% +/- 0.5% and 8.7% +/- 2%) compared with Group 1 (CS45) (20% +/- 14%) (P < 0.0001). Group 5 (CS90Indo30) showed decreased cell damage (13% +/- 1%) compared with Group 4 (CS90) (18% +/- 1%) (P < 0.01). Group 6 (CS90Indo60) also showed decreased cell damage (11% +/- 1%) compared with Group 4 (CS90) (18% +/- 1%); however, this difference was not significant (P > 0.05). Apoptotic activity was present with elevated intracompartment pressure. At 30 minutes, there were elevated caspase levels in Group 4 and Group 6 EICP groups (0.47 +/- 0.08) compared with control subjects (0.19 +/- 0.02) (P < 0.003). However, indomethacin-treated groups did not differ from control subjects with regard to caspase levels (P > 0.05). CONCLUSION: Indomethacin decreased cell damage and improved perfusion in elevated intracompartment pressure. The benefits of indomethacin were partially time-dependent; some improvement in tissue viability occurred regardless of timing of administration. Although apoptosis was common in elevated intracompartment pressure, the protective effect of indomethacin does not appear to be related to apoptosis. CLINICAL RELEVANCE: Adjuvant treatment with indomethacin may improve outcome in compartment syndrome.

Low-dose inhaled carbon monoxide attenuates the remote intestinal inflammatory response elicited by hindlimb ischemia-reperfusion.

Heme oxygenase (HO) represents the rate-limiting enzyme in the degradation of heme into carbon monoxide (CO), iron, and biliverdin. Recent evidence suggests that several of the beneficial properties of HO, may be linked to CO. The objectives of this study were to determine if low-dose inhaled CO reduces remote intestinal leukocyte recruitment, proinflammatory cytokine expression, and oxidative stress elicited by hindlimb ischemia-reperfusion (I/R). Male mice underwent 1 h of hindlimb ischemia, followed by 3 h of reperfusion. Throughout reperfusion, mice were exposed to AIR or AIR + CO (250 ppm). Following reperfusion, the distal ileum was exteriorized to assess the intestinal inflammatory response by quantifying leukocyte rolling and adhesion in submucosal postcapillary venules with the use of intravital microscopy. Ileum samples were also analyzed for proinflammatory cytokine expression [tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta] and malondialdehyde (MDA) with the use of enzyme-linked immunosorbent assay and thiobarbituric acid reactive substances assays, respectively. I/R + AIR led to a significant decrease in leukocyte rolling velocity and a sevenfold increase in leukocyte adhesion. This was also accompanied by a significant 1.3-fold increase in ileum MDA and 2.3-fold increase in TNF-alpha expression. Treatment with AIR + CO led to a significant reduction in leukocyte recruitment and TNF-alpha expression elicited by I/R; however, MDA levels remained unchanged. Our data suggest that low-dose inhaled CO selectively attenuates the remote intestinal inflammatory response elicited by hindlimb I/R, yet does not provide protection against intestinal lipid peroxidation. CO may represent a novel anti-inflammatory therapeutic treatment to target remote organs following acute trauma and/or I/R injury.