D. Nader

Blood product use in cardiac revascularization: comparison of on- and off-pump techniques.

BACKGROUND Cardiac revascularization on a beating heart avoids the side effects of cardiopulmonary bypass (eg, neurologic injury, hemodilution, and coagulopathy). We examined perioperative bleeding and use of blood products during coronary artery bypass grafting using either on-pump or off-pump techniques. METHOD The charts of 126 patients who had coronary artery bypass grafting were reviewed. Data from 66 patients revascularized off pump and 60 patients with cardiopulmonary bypass (on pump) were analyzed using unpaired Students t test. RESULTS Average age was 62.5 years in either group. More patients received heparin preoperatively in the off-pump group that resulted in mild elevation of preoperative partial thromboplastin time and activated clotting time (40.4 +/- 2.9 seconds and 150.1 +/- 5.3 seconds, respectively). However, the off-pump group had less perioperative (intraoperative or postoperative) bleeding (2312 +/- 212 mL versus 3251 +/- 155 mL, p < 0.05) and required fewer blood products compared with the on-pump group. Hemoglobin and platelets decreased more in the conventional on-pump group. CONCLUSIONS Avoiding cardiopulmonary bypass decreases perioperative bleeding and, consequently, reduces the use of blood products after coronary artery bypass grafting, which might result in fewer transfusion-related complications.

the Role of Tumor Necrosis Factor-α in the Pathogenesis of Aspiration Pneumonitis in Rats

Background Aspiration pneumonitis is characterized by proteinaceous pulmonary edema and acute infiltration of neutrophils into the alveolar space. This study examined the role of the proinflammatory cytokine, tumor necrosis factor-[Greek small letter alpha] (TNF-[Greek small letter alpha]), on the pathogenesis of the injury produced by the different components that may be present in the aspirate, acid, or gastric particles. Methods Rats were injured by intratracheal instillation of a vehicle containing acid or gastric particles. TNF-[Greek small letter alpha] concentration of bronchoalveolar lavage fluid was determined using a bioassay. upregulation of lung TNF-[Greek small letter alpha] mRNA was also measured. The effect of intratracheal anti-rat TNF-[Greek small letter alpha] treatment was assessed by lung protein permeability, blood gases, and lung myeloperoxidase activity. Results Injury vehicle alone and acid injury resulted in a small TNF-[Greek small letter alpha] peak 1–2 h after injury in the lavage fluid. Both particulate and acidic particulate groups produced a much more robust TNF-[Greek small letter alpha] signal that reached a plateau at 2–4 h after injury and declined at 8 h. Upregulation of TNF-[Greek small letter alpha] mRNA was only detected in the particulate-containing groups. Acidic particulate exposure yielded a synergistic increase in protein permeability and decrease in blood oxygenation. Anti-TNF-[Greek small letter alpha] treatment reduced protein permeability and myeloperoxidase activity and increased blood oxygenation in the groups exposed to only acid. Such treatment had no effect on either of the particulate containing injuries. Conclusions TNF-[Greek small letter alpha] is differentially manifested according to the components that make up the aspirate but the levels of TNF-[Greek small letter alpha] expression do not correlate with the severity of the resultant injury. However, the reduction in acid-induced lung injury by anti-TNF-[Greek small letter alpha] treatment indicates that TNF-[Greek small letter alpha] plays a role in the pathogenesis of aspiration pneumonitis.

PROGRESSIVE, SEVERE LUNG INJURY SECONDARY TO THE INTERACTION OF INSULTS IN GASTRIC ASPIRATION

This study examines lung injury and inflammation over 24 hours following intratracheal instillation of hydrochloric acid (acid), small nonacidic gastric particles (SNAP), or combined acid and small particles (CASP) in adult rats. The severity and duration of injury was significantly greater for CASP compared to acid or SNAP based on PaO2/FiO2, bronchoalveolar lavage (BAL) albumin, and BAL cell numbers. The inflammatory response associated with aspiration injury from CASP was distinct in several respects. Tumor necrosis factor (TNF)-alpha was greatly reduced in CASP compared to SNAP or acid, whereas interleukin (IL)-1beta was increased. Levels of cytokine-induced neutrophil chemoattractant (CINC)-1, monocyte chemoattractant protein (MCP)-1, and IL-10 in lavage were also significantly increased in animals injured with CASP compared to other forms of aspiration. Statistical analysis showed that BAL levels of IL-10 correlated most strongly with albumin leakage in aspiration-injured animals at 6 and 24 hours, followed by BAL levels of MCP-1. Additional cytokine cluster analyses indicated that levels of MCP-1 and CINC-1 in BAL from all injured animals were strongly correlated with inflammatory neutrophil numbers at 6 and 24 hours post aspiration, and that IL-10 levels in BAL were strongly correlated with inflammatory cell numbers at 24 hours. Preliminary blocking experiments showed that administration of anti-IL-10 antibody increased the albumin permeability index at 6 hours in SNAP and CASP animals, but anti-MCP-1 antibody did not affect the severity of injury. The results of this study support the possibility that different forms of aspiration are associated with identifiable cytokine profiles, and that specific cytokines, including IL-10 and MCP-1, may have utility as diagnostic or prognostic markers in clinical applications.□ This study examines lung injury and inflammation over 24 hours following intratracheal instillation of hydrochloric acid (acid), small nonacidic gastric particles (SNAP), or combined acid and small particles (CASP) in adult rats. The severity and duration of injury was significantly greater for CASP compared to acid or SNAP based on PaO2/FiO2, bronchoalveolar lavage (BAL) albumin, and BAL cell numbers. The inflammatory response associated with aspiration injury from CASP was distinct in several respects. Tumor necrosis factor (TNF)-α was greatly reduced in CASP compared to SNAP or acid, whereas interleukin (IL)-1β was increased. Levels of cytokine-induced neutrophil chemoattractant (CINC)-1, monocyte chemoattractant protein (MCP)-1, and IL-10 in lavage were also significantly increased in animals injured with CASP compared to other forms of aspiration. Statistical analysis showed that BAL levels of IL-10 correlated most strongly with albumin leakage in aspiration-injured animals at 6 and 24 hours, followed by BAL levels of MCP-1. Additional cytokine cluster analyses indicated that levels of MCP-1 and CINC-1 in BAL from all injured animals were strongly correlated with inflammatory neutrophil numbers at 6 and 24 hours post aspiration, and that IL-10 levels in BAL were strongly correlated with inflammatory cell numbers at 24 hours. Preliminary blocking experiments showed that administration of anti–IL-10 antibody increased the albumin permeability index at 6 hours in SNAP and CASP animals, but anti–MCP-1 antibody did not affect the severity of injury. The results of this study support the possibility that different forms of aspiration are associated with identifiable cytokine profiles, and that specific cytokines, including IL-10 and MCP-1, may have utility as diagnostic or prognostic markers in clinical applications.

Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain.

Background and Objectives Evidence implicates the pleiotropic cytokine tumor necrosis factor alpha (TNFα) in the pathogenesis of persistent pain. The present study employs a chronic constriction injury (CCI) model of neuropathic pain to examine TNFα production in the central nervous system (CNS) and in the periphery in this pain model. Methods CCI-induced hyperalgesia is assessed by measuring the nociceptive threshold using the hot-plate test. The development of hyperalgesia is correlated to levels of TNFα by assessing: bioactive TNFα in homogenates of sciatic nerves, cervical spinal cord, thoracolumbar spinal cord, as well as in plasma using the WEHI-13 variant cytotoxicity bioassay; and mRNA for TNFα in sections of locus coeruleus by in situ hybridization. Results We have previously demonstrated that TNFα bioactivity in the region of the brainstem containing the locus coeruleus is increased concurrent with the development of hyperalgesia, returning to baseline values by day 14, when hyperalgesia has ceased. Constitutive levels of TNFα are demonstrated in the plasma, sciatic nerves, and cervical and thoracolumbar spinal cord of control rats, sham-operated rats, and rats undergoing CCI. Levels of TNFα are significantly elevated in the injured sciatic nerve by day 8 postligature placement, concurrent with maximal hyperalgesia, and remain elevated when hyperalgesia has abated at day 14 postligature placement. Additionally, TNFα activity is increased in the thoracolumbar region of the spinal cord by day 4 postligature placement and remains elevated during hyperalgesia (day 8), as well as after hyperalgesia has dissipated (day 14). The increase in TNFα expression is specific to discrete regions of the CNS, rather than being the result of a systemic inflammatory response, since TNFα bioactivity in plasma is, in fact, decreased in rats undergoing CCI. Additionally, accumulation of mRNA specific for TNFα is significantly increased in neurons within a region of the brain containing the locus coeruleus at days 2, 8, and 14 postligature placement, contemporaneous with the development of hyperalgesia. Conclusions The increases in TNFα within regions of the brain and spinal cord that are associated with adrenergic neuron function, as well as with modulation of pain perception, and the time course and distribution of the increases in TNFα accumulation support a neuromodulatory role for TNFα within the CNS in the development and maintenance of neuropathic pain.

Role of macrophage inflammatory protein-2 in aspiration-induced lung injury.

Objective To determine the role of the chemokine, macrophage inflammatory protein (MIP)-2, in the pathogenesis of aspiration-induced lung injury in the rat. Design Prospective, randomized, controlled animal study. Setting University research laboratories. Subjects Adult, male Long-Evans rats. Interventions Anesthetized rats underwent induction of lung injury by well-described models of aspiration triggered by intratracheal delivery of acid alone, gastric particles alone, or the combination. After injury, induction of MIP-2 messenger RNA in whole lungs and immunoreactive MIP-2 in bronchoalveolar lavage (BAL) fluids was determined. The contribution of MIP-2 to BAL fluid chemotactic activity was defined by using an in vitro chemotaxis assay. The in vivo effect of blocking MIP-2 on pulmonary vascular leak, BAL fluid neutrophils, Pao2/Fio2 ratio, and alveolar-arterial oxygen tension gradient in acid-induced lung injury was determined. Measurements and Main Results Induction of MIP-2 messenger RNA and protein over time was observed in response to all three stimuli. A significant portion (25% to 41%) of the chemotactic activity in BAL fluids from injured rats was inhibited by anti-MIP-2 antibody. After acid injury, blocking of MIP-2 was associated with a 53% decrease in BAL fluid neutrophils and a 33% decrease in pulmonary vascular leak. Although acid injury both impaired oxygenation and increased venous admixture, in vivo blocking of MIP-2 was associated with improved oxygenation as well as decreased venous admixture. Conclusions MIP-2 was up-regulated during the development of aspiration-induced lung injury in rats. MIP-2 contributed to lung accumulation of neutrophils via a chemotactic mechanism. Although oxygenation and venous admixture are worsened by acid-induced lung injury in vivo, blocking of MIP-2 at the onset of injury improved these physiologic alterations. Because the aspiration event often is witnessed, chemokines may be valid therapeutic targets for inhibiting the subsequent inflammatory response.

Middle Ear Pressure Changes after Nitrous Oxide Anesthesia and Its Effect on Postoperative Nausea and Vomiting

Objectives/Hypothesis: This study was designed to explore the relationship between changes in middle ear pressure associated with inhalational anesthesia and the incidence of postoperative nausea and vomiting (PONV).

The hippocampus and TNF: Common links between chronic pain and depression

Major depression and chronic pain are significant health problems that seriously impact the quality of life of affected individuals. These diseases that individually are difficult to treat often co-exist, thereby compounding the patients disability and impairment as well as the challenge of successful treatment. The development of efficacious treatments for these comorbid disorders requires a more comprehensive understanding of their linked associations through common neuromodulators, such as tumor necrosis factor-α (TNFα), and various neurotransmitters, as well as common neuroanatomical pathways and structures, including the hippocampal brain region. This review discusses the interaction between depression and chronic pain, emphasizing the fundamental role of the hippocampus in the development and maintenance of both disorders. The focus of this review addresses the hypothesis that hippocampal expressed TNFα serves as a therapeutic target for management of chronic pain and major depressive disorder (MDD).

Clonidine Suppresses Plasma and Cerebrospinal Fluid Concentrations of Tnf-α During the Perioperative Period

The analgesic properties of &agr;2-agonists are well known. In experimental models, tumor necrosis factor (TNF)-&agr; regulates adrenergic responses in the brain. Constitutive TNF-&agr;, in brain regions involved in pain perception, is decreased after the administration of clonidine. We investigated patients undergoing lower-extremity revascularization. Seven patients were treated with clonidine 0.2 mg per os (low), and three patients received 0.4 mg per os clonidine (high) before surgery. Eight patients received placebo and served as controls. Continuous spinal anesthesia was provided by insertion of a pliable catheter into the subarachnoid space. Baseline plasma and cerebrospinal fluid (CSF) samples were obtained before injection of local anesthetic. Samples were analyzed for TNF-&agr; using a biologic assay. Systemic and central release of catecholamines were assessed by high-pressure liquid chromatography measurement of norepinephrine in plasma and CSF, vanillylmandelic acid and methoxy hydroxyl phenyl glycol in 24-h urinary excretion, respectively. Clonidine 0.2 mg pretreatment decreased TNF-&agr; concentrations both in plasma and CSF. Patients receiving clonidine had lower pain visual analog scale scores and required less morphine compared with the Placebo group (P < 0.01). Preoperative administration of clonidine decreased catecholamine release in the periphery, as well as in the central nervous system. A smaller norepinephrine concentration in plasma and CSF, and less secretion of vanillylmandelic acid (P < 0.01) and methoxy hydroxyl phenyl glycol in the urine, were observed. Larger dose clonidine (0.4 mg) resulted in no detectable TNF-&agr; in CSF. These results suggest that an interaction between TNF-&agr; and the function of adrenergic neurons in the central nervous system may contribute to the sedative and analgesic effects of adrenergic agonists.

Acute Kidney Injury and Death Associated With Renin Angiotensin System Blockade in Cardiothoracic Surgery: A Meta-analysis of Observational Studies

BACKGROUND Acute kidney injury (AKI) is a common complication after cardiovascular surgery. The use of renin angiotensin system (RAS) blockers preoperatively is controversial due to conflicting results of their effect on the incidence of postoperative AKI and mortality. STUDY DESIGN Meta-analysis of prospective or retrospective observational studies (1950 to January 2013) using MEDLINE, EMBASE, the Cochrane Library, conferences, and ClinicalTrials.gov, without language restriction. SETTING & POPULATION Patients undergoing cardiovascular surgery. SELECTION CRITERIA FOR STUDIES Retrospective or prospective studies evaluating the effect of preoperative use of RAS blockers in the development of postoperative AKI and/or mortality in adult patients. INTERVENTION Preoperative use of RAS blockers. RAS-blocker use was defined as long-term use of either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers until the day of surgery. OUTCOMES The primary outcome was the development of postoperative AKI; the secondary outcome was mortality. AKI was defined by different authors using different criteria. Death was ascertained in the hospital, at 30 days, or at 90 days in different studies. RESULTS 29 studies were included (4 prospective and 25 retrospective); 23 of these involving 69,027 patients examined AKI, and 18 involving 54,418 patients studied mortality. Heterogeneity was found across studies regarding AKI (I2 = 82.5%), whereas studies were homogeneous regarding mortality (I2 = 20.5%). Preoperative RAS-blocker use was associated with increased odds for both postoperative AKI (OR, 1.17; 95% CI, 1.01-1.36; P = 0.04) and mortality (OR, 1.20; 95% CI, 1.06-1.35; P = 0.005). LIMITATIONS Lack of randomized controlled trials, different definitions of AKI, different durations of follow-up used to analyze death outcome, and inability to exclude outcome reporting bias. CONCLUSIONS In retrospective studies, preoperative use of RAS blockers was associated with increased odds of postoperative AKI and mortality in patients undergoing cardiovascular surgery. A large, multicenter, randomized, controlled trial should be performed to confirm these findings.

The Predictive Value of Total Neutrophil Count and Neutrophil/ Lymphocyte Ratio in Predicting In-hospital Mortality and Complications after STEMI

Introduction: Leukocytosis, predominantly neutrophilia, has previously been described following ST elevation myocardial infarction (STEMI). The exact contribution of this phenomenon to the clinical outcome of STEMI is yet to be shown. We examined cellular inflammatory response to STEMI in the blood and its association with in-hospital mortality and/or adverse clinical events. Methods: In this cross-sectional study, 404 patients who were admitted with the diagnosis of acute STEMI at Madani Heart Hospital from March 2010 to March 2012 were studied. The complete blood cell count (CBC) was obtained from all patientswithin12-24 hours of the onset of symptoms. Total leukocytes were counted and differential count was obtained for neutrophils, lymphocytes and neutrophil/lymphocyte ratio (NLR) were evaluated. Association of cellular response with the incidence of post-MI mortality/complications was assessed by multiple logistic regression analyses. Results: In-hospital mortality and post-STEMI complication rate were 3.7% and 43.6%, respectively. Higher age (P=0.04), female gender (0.002), lower ejection fraction (P<0.001) and absolute neutrophil count (P=0.04) were predictors of mortality. Pump failure in the form of acute pulmonary edema or cardiogenic shock occurred in 35 (8.9%) of patients. Higher leukocyte (P<0.03) and neutrophil counts (P<0.03) and higher NLR (P=0.01) were predictors of failure. The frequency of ventricular tachyarrhythmias (VT/VF) at the first day was associated with higher neutrophil count (P<0.001) and higher NLR level (P<0.001). In multivariate analysis neutrophil count was an independent predictor of mortality (OR=2.94; 1.1-8.4, P=0.04), and neutrophil count [OR=1.1, CI (1.01-1.20), P=0.02], female gender [OR=2.34, CI (1.02-4.88), P=0.04] and diabetes [OR=2.52, CI (1.21-5.2), P=0.003] were independent predictors of heart failure. Conclusion: A single CBC analysis may help to identify STEMI patients at risk for mortality and heart failure, and total neutrophil count is the most valuable in predicting both.