The role of sealants for achieving anastomotic hemostasis in vascular surgery.

BACKGROUND: During vascular interventions, connections that link arteries, veins, or synthetic grafts, which are known as an 'anastomosis', may be necessary. Vascular anastomoses can bleed from the needle holes that result from the creation of the anastomoses. Various surgical options are available for achieving hemostasis, or the stopping of bleeding, including the application of sealants directly onto the bleeding vessels or tissues. Sealants are designed for use in vascular surgery as adjuncts when conventional interventions are ineffective and are applied directly by the surgeon to seal bleeding anastomoses. Despite the availability of several different types of sealants, the evidence for the clinical efficacy of these hemostatic adjuncts has not been definitively established in vascular surgery patients. OBJECTIVES: To evaluate the benefits and harms of sealants as adjuncts for achieving anastomotic site hemostasis in patients undergoing vascular surgery. SEARCH METHODS: The Cochrane Vascular Information Specialist conducted systematic searches of the following databases: the Cochrane Vascular Specialised Register via the Cochrane Register of Studies; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE via Ovid; Embase via Ovid ; and CINAHL via EBSCO. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for clinical trials. Reference lists of included trials and relevant reviews were also searched. The latest search date was 6 March 2023. SELECTION CRITERIA: We included randomized controlled trials that compared fibrin or synthetic sealant use with alternative interventions (e.g. manual compression, reversal of anticoagulation) for achieving anastomotic-site hemostasis in vascular surgery procedures. We included participants who underwent the creation of an anastomosis during vascular surgery. We excluded non-vascular surgery patients. DATA COLLECTION AND ANALYSIS: We have used standard Cochrane methods. Our primary outcomes were time to hemostasis, failure of hemostatic intervention, and intraoperative blood loss. Our secondary outcomes were operating time, death from bleeding complications up to 30 days, postoperative bleeding up to 30 days, unplanned return to the operating room for bleeding complications management up to 30 days, quality of life, and adverse events. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We found 24 randomized controlled trials that included a total of 2376 participants who met the inclusion criteria. All trials compared sealant use with standard care controls, including oxidized cellulose, gelatin sponge, and manual compression. All trials were at high risk of performance bias, detection bias, and other sources of bias. We downgraded the certainty of evidence for risk of bias concerns, inconsistency, imprecision and possible publication bias. Combining data on time to hemostasis showed that sealant use may reduce the mean time to hemostasis compared to control (mean difference (MD) -230.09 seconds, 95% confidence interval (CI) -329.24 to -130.94; P < 0.00001; 7 studies, 498 participants; low-certainty evidence). Combining data on failure of hemostatic intervention showed that sealant use may reduce the rate of failure compared to control, but the evidence is very uncertain (risk ratio (RR) 0.46, 95% CI 0.35 to 0.61; P < 0.00001; 17 studies, 2120 participants; very low-certainty evidence). We did not detect any clear differences between the sealant and control groups for intraoperative blood loss (MD -32.69 mL, 95% CI -96.21 to 30.83; P = 0.31; 3 studies, 266 participants; low-certainty evidence); operating time (MD -18.72 minutes, 95% CI -40.18 to 2.73; P = 0.09; 4 studies, 436 participants; low-certainty evidence); postoperative bleeding (RR 0.78, 95% CI 0.59 to 1.04; P = 0.09; 9 studies, 1216 participants; low-certainty evidence), or unplanned return to the operating room (RR 0.27, 95% CI 0.04 to 1.69; P = 0.16; 8 studies, 721 participants; low-certainty evidence). No studies reported death from bleeding or quality of life outcomes. AUTHORS' CONCLUSIONS: Based on meta-analysis of 24 trials with 2376 participants, our review demonstrated that sealant use for achieving anastomotic hemostasis in vascular surgery patients may result in reduced time to hemostasis, and may reduce rates of hemostatic intervention failure, although the evidence is very uncertain, when compared to standard controls. Our analysis showed there may be no differences in intraoperative blood loss, operating time, postoperative bleeding up to 30 days, and unplanned return to the operating room for bleeding complications up to 30 days. Deaths and quality of life could not be analyzed. Limitations include the risk of bias in all studies. Our review has demonstrated that using sealants may reduce the time required to achieve hemostasis and the rate of hemostatic failure. However, a significant risk of bias was identified in the included studies, and future trials are needed to provide unbiased data and address other considerations such as cost-effectiveness and adverse events with sealant use.

General versus loco-regional anesthesia for endovascular aortic aneurysm repair.

BACKGROUND: Aortic aneurysms occur when the aorta, the body's largest artery, grows in size, and can occur in the thoracic or abdominal aorta. The approaches to repair aortic aneurysms include directly exposing the aorta and replacing the diseased segment via open repair, or endovascular repair. Endovascular repair uses fluoroscopic-guidance to access the aorta and deliver a device to exclude the aneurysmal aortic segment without requiring a large surgical incision. Endovascular repair can be performed under a general anesthetic, during which the unconscious patient is paralyzed and reliant on an anesthetic machine to maintain the airway and provide oxygen to the lungs, or a loco-regional anesethetic, for which medications are administered to provide the person with sufficient sedation and pain control without requiring a general anesthetic. While people undergoing general anesthesia are more likely to remain still during surgery and have a well-controlled airway in the event of unanticipated complications, loco-regional anesthesia is associated with fewer postoperative complications in some studies. It remains unclear which anesthetic technique is associated with better outcomes following the endovascular repair of aortic aneurysms. OBJECTIVES: To evaluate the benefits and harms of general anesthesia compared to loco-regional anesthesia for endovascular aortic aneurysm repair. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was 11 March 2022. SELECTION CRITERIA: We searched for all randomized controlled trials that assessed the effects of general anesthesia compared to loco-regional anesthesia for endovascular aortic aneurysm repairs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: all-cause mortality, length of hospital stay, length of intensive care unit stay. Our secondary outcomes were: incidence of endoleaks, requirement for re-intervention, incidence of myocardial infarction, quality of life, incidence of respiratory complications, incidence of pulmonary embolism, incidence of deep vein thrombosis, and length of procedure. We planned to use GRADE methodology to assess the certainty of evidence for each outcome. MAIN RESULTS: We found no studies, published or ongoing, that met our inclusion criteria. AUTHORS' CONCLUSIONS: We did not identify any randomized controlled trials that compared general versus loco-regional anesthesia for endovascular aortic aneurysm repair. There is currently insufficient high-quality evidence to determine the benefits or harms of either anesthetic approach during endovascular aortic aneurysm repair. Well-designed prospective randomized trials with relevant clinical outcomes are needed to adequately address this.

The influence of diabetes on temporal trends in lower extremity revascularisation and amputation for peripheral artery disease: A population-based repeated cross-sectional analysis.

AIM/HYPOTHESIS: To describe the influence of diabetes on temporal changes in rates of lower extremity revascularisation and amputation for peripheral artery disease (PAD) in Ontario, Canada. METHODS: In this population-based repeated cross-sectional study, we calculated annual rates of lower extremity revascularisation (open or endovascular) and amputation (toe, foot or leg) related to PAD among Ontario residents aged ≥40 years between 2002 and 2019. Annual rate ratios (relative to 2002) adjusted for changes in diabetes prevalence alone, as well as fully adjusted for changes in demographics, diabetes and other comorbidities, were estimated using generalized estimating equation models to model population-level effects while accounting for correlation within units of observation. RESULTS: Compared with 2002, the Ontario population in 2019 exhibited a significantly higher prevalence of diabetes (18% vs. 10%). Between 2002 and 2019, the crude rate of revascularisation increased from 75.1 to 90.7/100,000 person-years (unadjusted RR = 1.10, 95% CI = 1.07-1.13). However, after adjustment, there was no longer an increase in the rate of revascularisation (diabetes-adjusted RR = 0.98, 95% CI = 0.96-1.01, fully-adjusted RR = 0.94, 95% CI = 0.91-0.96). The crude rate of amputation decreased from 2002 to 2019 from 49.5 to 45.4/100,000 person-years (unadjusted RR = 0.78, 95% CI = 0.75-0.81), but was more pronounced after adjustment (diabetes-adjusted RR = 0.62, 95% CI = 0.60-0.64; fully-adjusted RR = 0.58, 95% CI = 0.56-0.60). CONCLUSIONS/INTERPRETATION: Diabetes prevalence rates strongly influenced rates of revascularisation and amputation related to PAD. A decrease in amputations related to PAD over time was attenuated by rising diabetes prevalence rates.

Drug-eluting balloon angioplasty versus uncoated balloon angioplasty for the treatment of in-stent restenosis of the femoropopliteal arteries.

BACKGROUND: Stents are placed in the femoropopliteal arteries for numerous reasons, such as atherosclerotic disease, the need for dissection, and perforation of the arteries, and can become stenosed with the passage of time. When a stent develops a flow-limiting stenosis, this process is known as "in-stent stenosis." It is thought that in-stent restenosis is caused by a process known as "intimal hyperplasia" rather than by the progression of atherosclerotic disease. Management of in-stent restenosis may include performing balloon angioplasty, deploying another stent within the stenosed stent to force it open, and creating a bypass to deliver blood around the stent. The role of drug-eluting technologies, such as drug-eluting balloons (DEBs), in the management of in-stent restenosis is unclear. Drug-eluting balloons might function by coating the inside of stenosed stents with cytotoxic chemicals such as paclitaxel and by inhibiting the hyperplastic processes responsible for in-stent restenosis. It is important to perform this systematic review to evaluate the efficacy of DEB because of the potential for increased expenses associated with DEBs over uncoated balloon angioplasty, also known as plain old balloon angioplasty (POBA). OBJECTIVES: To assess the safety and efficacy of DEBs compared with uncoated balloon angioplasty in people with in-stent restenosis of the femoropopliteal arteries as assessed by criteria such as amputation-free survival, vessel patency, target lesion revascularization, binary restenosis rate, and death. We define "in-stent restenosis" as 50% or greater narrowing of a previously stented vessel by duplex ultrasound or angiography. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to November 28, 2017. Review authors also undertook reference checking to identify additional studies. SELECTION CRITERIA: We included all randomized controlled trials that compared DEBs versus uncoated balloon angioplasty for treatment of in-stent restenosis in the femoropopliteal arteries. DATA COLLECTION AND ANALYSIS: Two review authors (AK, WA) independently selected appropriate trials and performed data extraction, assessment of trial quality, and data analysis. The senior review author (AD) adjudicated any disagreements. MAIN RESULTS: Three trials that randomized a combined total of 263 participants met the review inclusion criteria. All three trials examined the treatment of symptomatic in-stent restenosis within the femoropopliteal arteries. These trials were carried out in Germany and Austria and used paclitaxel as the agent in the drug-eluting balloons. Two of the three trials were industry sponsored. Two companies manufactured the drug-eluting balloons (Eurocor, Bonn, Germany; Medtronic, Fridley, Minnesota, USA). The trials examined both anatomical and clinical endpoints. We noted heterogeneity in the frequency of bailout stenting deployment between studies as well as in the dosage of paclitaxel applied by the DEBs. Using GRADE assessment criteria, we determined that the certainty of evidence presented was very low for the outcomes of amputation, target lesion revascularization, binary restenosis, death, and improvement of one or more Rutherford categories. Most participants were followed up to 12 months, but one trial followed participants for up to 24 months.Trial results show no difference in the incidence of amputation between DEBs and uncoated balloon angioplasty. DEBs showed better outcomes for up to 24 months for target lesion revascularization (odds ratio (OR) 0.05, 95% confidence Interval (CI) 0.00 to 0.92 at six months; OR 0.24, 95% CI 0.08 to 0.70 at 24 months) and at six and 12 months for binary restenosis (OR 0.28, 95% CI 0.14 to 0.56 at six months; OR 0.34, 95% CI 0.15 to 0.76 at 12 months). Participants treated with DEBs also showed improvement of one or more Rutherford categories at six and 12 months (OR 1.81, 95% CI 1.02 to 3.21 at six months; OR 2.08, 95% CI 1.13 to 3.83 at 12 months). Data show no clear differences in death between DEBs and uncoated balloon angioplasty. Data were insufficient for subgroup or sensitivity analyses to be conducted. AUTHORS' CONCLUSIONS: Based on a meta-analysis of three trials with 263 participants, evidence suggests an advantage for DEBs compared with uncoated balloon angioplasty for anatomical endpoints such as target lesion revascularization (TLR) and binary restenosis, and for one clinical endpoint - improvement in Rutherford category post intervention for up to 24 months. However, the certainty of evidence for all these outcomes is very low due to the small number of included studies and participants and the high risk of bias in study design. Adequately powered and carefully constructed randomized controlled trials are needed to adequately investigate the role of drug-eluting technologies in the management of in-stent restenosis.

Smart(phone) Learning Experience Among Vascular Trainees Using a Response System Application.

OBJECTIVES: Smartphones have become the most important personal technological device. M-learning is learning through mobile device educational technology. We aim to assess the acceptability of a smartphone learning experience among the vascular trainees and determine if results could inform formal teaching efforts. METHODS: A survey of the vascular trainees at a single center was conducted following a trial of smartphone learning experience. A vascular fellow used a smartphone response system application (Polltogo, Inspirapps Inc.) to send a daily multiple-choice question to the vascular residents for 20 consecutive working days. The application allows for only one attempt from each user, and the answers are registered anonymously. However, each participant receives instant feedback on his/her response by viewing the correct answer after answering each question along with a distribution of answers among other users. RESULTS: A total of 9 trainees participated in the trial, and all of them filled a posttrial survey. All the trainees possessed smartphones. The majority (78%) were not aware of the concept of m-learning. The mobile engagement score (number of answers received divided by total possible answers) was 145/180 (81%). All the trainees were "satisfied" or "very satisfied" with the experience, and the same number stated that they were "likely" or "very likely" to use this technology in the future. The majority (89%) agreed that such an application could assist them in preparing for their board examination. On 3 occasions, 75% or more of the participating trainees answered the multiple-choice question incorrectly, which resulted in addressing the relevant topics in the unit's weekly teaching conference. CONCLUSION: Using smartphones for education is acceptable among the vascular trainees, and the trial of a response system application with instant written feedback represents a novel method for using smartphones for collaborative learning. Such an application can also inform program directors and surgical trainers of their trainees' learning needs.

Just leg pain? Think again: What health leaders must know about peripheral arterial disease.

Approximately 800,000 Canadians have Peripheral Arterial Disease (PAD). Peripheral arterial disease is also a leading cause of limb amputation. Yet public and clinical awareness of PAD is very limited. This article discusses the "Just Leg Pain? Think Again" awareness campaign the Canadian Association of Wound Care has launched in response. This article also summarizes PAD risk factors, screening, linkage with diabetes, treatment and care interventions, PAD care innovations, and the need for policy leadership on this issue.

Si vous pensez que c'est juste un mal de jambe détrompez-vous: ce que les leaders en santé doivent savoir sur la maladie artérielle périphérique.

Environ 800 000 Canadiens ont une maladie artérielle périphérique (MAP), une cause majeure d'amputation. Pourtant, le public et les cliniciens connaissent très peu cette maladie. Le présent article traite de la campagne de sensibilisation Si vous pensez que c'est juste un mal de jambe… détrompez-vous que l'Association canadienne du soin des plaies a lancée pour contrer cette tendance. Il porte également sur les facteurs de risque et le dépistage de la MAP, son lien avec le diabète, son traitement et ses soins, ses innovations en matière de soins de la MAP et la nécessité de faire preuve de leadership sur le plan des politiques.

Physical rehabilitation of the critically ill trauma patient in the ICU.

OBJECTIVES: To 1) review the existing evidence for early mobilization of the critically ill patients in the ICU with polytrauma; 2) provide intensivists with an introduction to the biomechanics, physiology, and nomenclature of injuries; 3) summarize the evidence for early mobilization in each anatomic area; and 4) provide recommendations for the mobilization of these patients. DATA SOURCES: A literature search of the MEDLINE and EMBASE databases for articles published in English between 1980 and 2011. STUDY SELECTION: Studies pertaining to physical therapy and rehabilitation in trauma patients were selected. Articles were excluded if they dealt with pediatrics, geriatrics, burn injuries, isolated hand injuries, chronic (i.e., not acute) injuries, nontraumatic conditions, and pressure/decubitus ulcers, were in a language other than English, were published only in abstract form, were letters to the editor, were case reports, or were published prior to 1980. DATA EXTRACTION: Reviewers extracted data and summarized results according to anatomical areas. DATA SYNTHESIS: Of 1,411 titles and abstracts, 103 met inclusion criteria. We found no articles specifically addressing the rehabilitation of polytrauma patients in the ICU setting or patients with polytrauma in general. We summarized the articles addressing the role of mobilization for specific injuries and treatments. We used this evidence, in combination with biologic rationale and physician and surgeon experience and expertise, to summarize the important considerations when providing physical therapy to these patients in the ICU setting. CONCLUSIONS: There is a paucity of evidence addressing the role of early mobilization of ICU patients with polytrauma and patients with polytrauma in general. Evidence for the beneficial role of early mobilization of specific injuries exists. Important considerations when applying a strategy of early physical therapy and mobilization to this distinctive patient group are summarized.

Hypertonic saline resuscitation from hemorrhagic shock does not impair the neutrophil response to intraabdominal infection.

BACKGROUND: Hypertonic saline (HTS) has been proposed as a resuscitation strategy following trauma based on its ability to prevent organ dysfunction by exerting immunosuppressive effects on inflammatory cells, including neutrophils. Because these cells are central to the innate response to bacteria, we hypothesized that hypertonic treatment for hemorrhagic shock might alter the host response to bacterial contamination of the peritoneal cavity and therefore render the host more susceptible to invasive infection. METHODS: Male Sprague-Dawley rats were subjected to hemorrhagic shock and resuscitated with either lactated Ringer solution (RL) or HTS. After intraperitoneal injection of feces, Escherichia coli, or lipopolysaccharide, peritoneal neutrophil accumulation and bacterial clearance were studied. In some studies, lipopolysaccharide as an inflammatory stimulus was injected into both the peritoneal cavity and the lungs. RESULTS: Peritoneal neutrophil accumulation in response to each of the stimuli did not differ between RL- and HTS-resuscitated animals. Whereas emigration into the peritoneum activated neutrophils, there was no difference between resuscitation strategies, consistent with the finding that bacterial clearance did not differ between groups. Although peritoneal neutrophil sequestration was unaffected by resuscitation type, HTS still was able to prevent lung neutrophil accumulation compared to RL treatment. CONCLUSIONS: HTS resuscitation did not impair the host response to bacterial contamination of the peritoneal cavity. However, the ability of HTS to prevent lung neutrophil accumulation in this setting persisted. These findings suggest that peritoneal bacterial contamination should not be considered a contraindication to the use of HTS in the trauma setting associated with hemorrhagic shock.

Intensive care of the patient following open abdominal aortic surgery.

PURPOSE OF REVIEW: Abdominal aortic aneurysms still require open repair despite the advances that endovascular aneurysm repair has made in treating patients with significant operative risk. Older patients with significant comorbidities require open repair of their complex aneurysms when they fail to meet anatomic criteria for endovascular aneurysm repair. This review discusses the physiologic insult of abdominal aortic surgery. It aims to address which patients are the highest risk of postoperative morbidity, and advances in their intensive care unit management to reduce such morbidity. RECENT FINDINGS: Advanced age, chronic health dysfunction, emergency surgery, and multiple organ failure are independent predictors of postoperative mortality. Myocardial ischemia is the largest contributor to patient morbidity, with any rise in postoperative cardiac troponin I predicting increased in-hospital myocardial infarction and mortality. Highest-risk patients benefit most from optimizing perioperative cardiac status with beta-blockade. Perioperative treatment with fenoldopam may improve renal outcome. Tracheostomy to aid in weaning is associated with increased mortality but may improve outcome in patients with preoperative chronic obstructive pulmonary disease. SUMMARY: Demographic trends indicate that open aortic surgery will continue to be performed on older patients with complex aneurysms. Identifying patients at risk and optimizing their postoperative risk factors will improve outcomes.

Oxidant-induced priming of the macrophage involves activation of p38 mitogen-activated protein kinase through an Src-dependent pathway.

BACKGROUND: Resuscitated hemorrhagic shock predisposes patients to the development of organ dysfunction, particularly to lung injury. Ischemia/reperfusion during shock is believed to prime the immune system for an exaggerated inflammatory response to a second delayed stimulus. We previously reported an in vitro model of oxidant-induced priming of the macrophage to lipopolysaccharide (LPS) involves the Src family of tyrosine kinases. Because the Src family has been shown to activate the p38 mitogen-activated protein kinase (MAPK) pathway, we hypothesize that LPS signaling after oxidant stress involves the p38 pathway and is activated by Src kinases. METHODS: The murine macrophage cell line, Raw 264.7, was first incubated with H(2)O(2) 100 micromol/L for 1 hour and then with low dose LPS 0.01 microg/mL for 5 to 45 minutes. In a separate experiment, the cells were pretreated with PP2 or SB203580, a specific inhibitor of the Src family and p38 respectively. The phosphorylation of p38, representative of its activation, was assessed in whole cell lysates by use of Western blotting. NF-kappaB translocation was detected by immunofluorescence with anti-p65 antibody. RESULTS: There is a time dependent earlier activation of p38 by oxidant stress. H(2)O(2) augmented the LPS-induced p38 phosphorylation. The Src inhibitor, PP2, prevented only the LPS-induced earlier phosphorylation after oxidant stress and had no effect on LPS activation of p38 alone. The p38 inhibitor had no effect in preventing NF-kappaB translocation in either the LPS- or H(2)O(2)/LPS-exposed cells. CONCLUSIONS: Oxidant stress generated during global ischemia/reperfusion activates p38 MAPK in an Src-dependent manner. Oxidants seem to alter the LPS-induced activation of p38. P38 does not seem to have a direct role in leading to oxidant-induced NF-kappaB translocation but may affect other oxidant-induced transcription factors. This altered pathway provides an alternative avenue to target therapy during the oxidant-induced priming of the macrophage induced by trauma resuscitation.

Hypertonic resuscitation of hemorrhagic shock upregulates the anti-inflammatory response by alveolar macrophages.

BACKGROUND: Resuscitated hemorrhagic shock predisposes patients to the development of acute respiratory distress syndrome (ARDS). Hypertonic saline (HTS) has been shown to inhibit immune cell activation in response to lipopolysaccharide (LPS) in vitro and to reduce lung damage when used for resuscitation of hemorrhagic shock in vivo. We hypothesize that HTS resuscitation of hemorrhagic shock may exert this anti-inflammatory effect by modulating alveolar macrophage function leading to an altered balance between the proinflammatory and the counter-inflammatory response. METHODS: A 2-hit rat model of shock resuscitation was used. Alveolar macrophages were harvested by bronchoalveolar lavage (BAL), and tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were quantified in the cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Alternatively, 1 hour after resuscitation, animals received endotracheal LPS followed by endotracheal anti-IL-10 neutralizing antibody. Lung injury was determined by measuring BAL neutrophil counts 4 hours after LPS in vivo administration. RESULTS: Systemic administration of HTS significantly modulates the responsiveness of alveolar macrophages. Specifically, HTS resuscitation inhibited LPS-induced TNF-alpha production while enhancing IL-10 release in response to LPS administered ex vivo and in vivo. Anti-IL-10 antibody in vivo partially reversed the lung protective effect of HTS resuscitation. CONCLUSIONS: HTS resuscitation exerts an immunomodulatory effect on alveolar macrophages by shifting the balance of pro- and counter-inflammatory cytokine production in favor of an anti-inflammatory response. The in vivo data suggest a causal role for HTS-induced augmented IL-10 as protective. These findings suggest a novel mechanism for the in vivo salutary effect of HTS resuscitation on lung injury after resuscitated hemorrhagic shock.

Impaired activation of mitogen-activated protein kinases after hemorrhagic shock.

BACKGROUND: Patients sustaining major trauma are at risk of developing organ dysfunction. We have previously shown that resuscitated hemorrhagic shock primes for increased lung injury in response to lippolysaccharide (LPS), in part by preventing upregulation of the counterinflammatory cytokine IL-10. Because the mitogen-activated protein kinase (MAPK) family is known to participate in LPS signaling, we hypothesized that altered upstream signaling through these kinases might contribute to impaired LPS-simulated IL-10 release after shock and resuscitation. METHODS: Rats were bled to a mean arterial pressure of 40 mm Hg and maintained for 1 hour, then resuscitated. Alveolar macrophages were retrieved at the end of resuscitation and exposed to LPS (0.5 microg/mL). Western blotting for p38, extracellular-regulated protein kinase, and c-Jun NH2-terminal kinase was performed on whole cell lysates. In some studies, the alveolar macrophages were preincubated with the p38 inhibitor or the extracellular-regulated protein kinase inhibitor before LPS stimulation. IL-10 levels were measured by enzyme-linked immunosorbent assay. RESULTS: LPS caused an early activation in all members of the MAPK family, whereas antecedent shock both delayed and attenuated the LPS induction. To discern whether this reduction in LPS-stimulated MAPK activation after shock might contribute to reduced IL-10, specific inhibitors were used. Inhibition of p38 MAPK completely inhibited LPS-induced IL-10 production, whereas blockade of extracellular-regulated protein kinase pathway had no effect. CONCLUSIONS: Shock resuscitation impairs LPS-induced activation of the members of the MAPK family. For the critical counterinflammatory cytokine IL-10, inhibition of p38 activation appears to contribute to the reduced levels of this cytokine in response to LPS. This study provides in vitro evidence for altered signaling through p38 MAPK, as a mechanism leading to failed upregulation of a counterinflammatory cytokine, and thus the propagation of an unrestrained proinflammatory state. Restoration of normal signaling may represent an effective strategy to reverse this effect.

25% Albumin modulates adhesive interactions between neutrophils and the endothelium following shock/resuscitation.

BACKGROUND: Polymorphonuclear neutrophil (PMN) sequestration in the lung is a hallmark of acute respiratory distress syndrome (ARDS). We have shown that 25% Albumin (A25) resuscitation attenuates lung injury after hemorrhagic shock and lipopolysaccharide (LPS) exposure by reducing lung leukosequestration. We hypothesize that this protective property is mediated by alteration of neutrophil-endothelial cell adhesive interactions. MATERIALS AND METHODS: A 2-hit rodent model of shock resuscitation was used. CD11b and L-selectin were measured using flow cytometry in rat and human neutrophils ex vivo. Intercellular adhesion molecule-1 (ICAM-1) levels were measured by Northern blot and immunohistochemistry. RESULTS: Resuscitation with A25 attenuated the increase in PMN CD11b expression in Ringer's lactate (RL) resuscitated animals at end resuscitation and at 4-hour post-LPS. While PMN L-selectin levels remained stable in RL treated animals, A25 resuscitation resulted in a significant decrease in surface L-selectin expression at 4-hour post-LPS. ICAM-1 lung endothelial cell mRNA, was increased in RL resuscitated animals, however reduced with A25 use by 51%. The LPS induced ICAM-1 endothelial cell protein expression was also prevented with A25 resuscitation. Antioxidant property of albumin was shown to play a critical role in altering CD11b expression. CONCLUSIONS: The A25 exerts its lung-protective activity at various levels including altering the interaction between neutrophils and endothelial cells via suppressed expression of adhesion molecules. These findings suggest a novel role for A25 as an anti-inflammatory agent in PMN-mediated diseases such as ARDS.