Carolyn C. Snider

Effect of enteral feeding with eicosapentaenoic acid, γ-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome

OBJECTIVES Recent studies in animal models of sepsis-induced acute respiratory distress syndrome (ARDS) have shown that a low-carbohydrate, high-fat diet combining the anti-inflammatory and vasodilatory properties of eicosapentaenoic acid (EPA; fish oil), gamma-linolenic acid (GLA; borage oil) (EPA+GLA), and antioxidants improves lung microvascular permeability, oxygenation, and cardiopulmonary function and reduces proinflammatory eicosanoid synthesis and lung inflammation. These findings suggest that enteral nutrition with EPA+GLA and antioxidants may reduce pulmonary inflammation and may improve oxygenation and clinical outcomes in patients with ARDS. DESIGN Prospective, multicentered, double-blind, randomized controlled trial. SETTING Intensive care units of five academic and teaching hospitals in the United States. PATIENTS We enrolled 146 patients with ARDS (as defined by the American-European Consensus Conference) caused by sepsis/pneumonia, trauma, or aspiration injury in the study. INTERVENTIONS Patients meeting entry criteria were randomized and continuously tube-fed either EPA+GLA or an isonitrogenous, isocaloric standard diet at a minimum caloric delivery of 75% of basal energy expenditure x 1.3 for at least 4-7 days. MEASUREMENTS AND MAIN RESULTS Arterial blood gases were measured, and ventilator settings were recorded at baseline and study days 4 and 7 to enable calculation of PaO2/FIO2, a measure of gas exchange. Pulmonary neutrophil recruitment was assessed by measuring the number of neutrophils and the total cell count in bronchoalveolar lavage fluid at the same time points. Clinical outcomes were recorded. Baseline characteristics of 98 evaluable patients revealed that key demographic, physiologic, and ventilatory variables were similar at entry between both groups. Multiple bronchoalveolar lavages revealed significant decreases (approximately 2.5-fold) in the number of total cells and neutrophils per mL of recovered lavage fluid during the study with EPA+GLA compared with patients fed the control diet. Significant improvements in oxygenation (PaO2/FIO2) from baseline to study days 4 and 7 with lower ventilation variables (FIO2, positive end-expiratory pressure, and minute ventilation) occurred in patients fed EPA+GLA compared with controls. Patients fed EPA+GLA required significantly fewer days of ventilatory support (11 vs. 16.3 days; p = .011), and had a decreased length of stay in the intensive care unit (12.8 vs. 17.5 days; p = .016) compared with controls. Only four of 51 (8%) patients fed EPA+GLA vs. 13 of 47 (28%) control patients developed a new organ failure during the study (p = .015). CONCLUSIONS The beneficial effects of the EPA+GLA diet on pulmonary neutrophil recruitment, gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and the reduction of new organ failures suggest that this enteral nutrition formula would be a useful adjuvant therapy in the clinical management of patients with or at risk of developing ARDS.

Early evaluation of acute traumatic coagulopathy by thrombelastography

Posttraumatic coagulopathy is a major cause of morbidity. This prospective study evaluated the thrombelastography (TEG) system and PlateletMapping (Haemoscope Corporation, Niles, Ill) values posttrauma, and it correlated those values with transfusions and fatalities. After institutional review board approval, assays were performed on 161 trauma patients. One citrated blood sample was collected onsite (OS), and 1 citrate and 1 heparinized sample were collected within 1 h of arrival to the emergency department (ED). Paired and unpaired t-testing was performed for nominal data with chi square testing for categorical values. Except for a slight increase in clot strength (maximal amplitude (MA)), there were no significant changes from OS to the ED. None of the TEG parameters were significantly different for the 22 patients who required transfusion. PlateletMapping showed lower platelet adenosine diphosphate (ADP) responsiveness in patients who needed transfusions (MA = 22.7 +/- 17.1 vs MA = 35.7 +/- 19.3, P = 0.004) and a correlation of fibrinogen <100 mg/dL with fatalities (P = 0.013). For the 14 fatalities, TEG reaction (R) time was 3703 +/- 11,618 versus 270 +/- 393 s (P = < 0.001), and MA was 46.4 +/- 22.4 versus 64.7 +/- 9.8 mm (P < 0.001). Hyperfibrinolysis (percent fibrinolysis after 60 min (LY60) >15%) was observed in 3 patients in the ED with a 67% fatality rate (P = < 0.001 by chi-square testing). PlateletMapping assays correlated with the need for blood transfusion. The abnormal TEG System parameters correlated with fatality. These coagulopathies were already evident OS. The TEG assays can assess coagulopathy, platelet dysfunction, and hyperfibrinolysis at an early stage posttrauma and suggest more effective interventions.

Effects of eicosapentaenoic and γ-linolenic acid on lung permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats

OBJECTIVES Proinflammatory eicosanoids (cyclooxgenase and lipoxygenase metabolites of arachidonic acid) released by alveolar macrophages play an important role in endotoxin-induced acute lung injury. We investigated the effect of prefeeding rats for 21 days with enteral diets that provided the anti-inflammatory fatty acids, eicosapentaenoic acid and gamma-linolenic acid (derived from fish oil and borage oil, respectively), as compared with an n-6 fatty acid-enriched diet (corn oil) on the following: a) lung microvascular protein permeability, arterial blood pressure, and platelet and white blood cells in a model of endotoxin-induced acute lung injury; b) alveolar macrophage prostaglandin and leukotriene synthesis; and c) liver and alveolar macrophage phospholipid fatty acid composition. DESIGN Prospective, randomized, controlled, double-blind study. SETTING Research laboratory at a university medical center. SUBJECTS Male Long-Evans rats, weighing 250 g. INTERVENTIONS Rats were randomized into four dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day), containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, 20% fish and 5% borage oil, or 20% fish and 20% borage oil for 21 days. On day 22, lung microvascular protein permeability, mean arterial pressure, and platelet and white blood cell counts were determined for 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg). In a second group of prefed rats, the phospholipid fatty acid composition was determined in liver and alveolar macrophages. Alveolar macrophages were harvested by bronchoalveolar lavage and stimulated in vitro with a calcium ionophore (A23187), and the concentrations of leukotrienes B4 and B5, thromboxane A2, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were measured in a third group of prefed rats. MEASUREMENT AND MAIN RESULTS Lung permeability was greatest with corn oil and was significantly attenuated with 20% fish oil and 20% fish and 5% borage oil, and this effect approached significance with 20% fish and 20% borage oil (p = .06). The early and late hypotensive effects of endotoxin were attenuated with 20% fish oil, 20% fish and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Concentrations of leukotriene B4, prostaglandin E2, and thromboxane B2 released from A23187-stimulated alveolar macrophages were significantly lower with 20% fish oil and 20% fish and 20% borage oil, as compared with corn oil. The increase in lung microvascular protein permeability with 20% fish and 20% borage oil was not significantly different than the lung microvascular protein permeability that was found in animals receiving 20% fish oil (p = .20) and 20% fish and 5% borage oil (p = .31). Alveolar macrophage and liver phospholipid concentrations of arachidonic acid were lower, and the concentrations of eicosapentaenoic acid and docosahexaenic acid were higher, with 20% fish oil, and 5% borage oil, and 20% fish and 20% borage oil, as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, was increased with 20% fish and 20% borage oil, as compared with 20% fish oil and 20% fish and 5% borage oil. CONCLUSIONS The severity of pulmonary microvascular protein permeability and the degree of hypotension were reduced with fish or fish and borage oil diets, as compared with corn oil, in endotoxic rats. The reduced synthesis of the proinflammatory arachidonic acid-derived mediators, leukotriene B4, thromboxane B2, and prostaglandin E2 from stimulated alveolar macrophages was indicative of a decrease in arachidonic acid and an increase in eicosapentaenoic acid and docosahexaenoic acid in cell membrane phospholipids.

DIETARY FISH OIL AND FISH AND BORAGE OIL SUPPRESS INTRAPULMONARY PROINFLAMMATORY EICOSANOID BIOSYNTHESIS AND ATTENUATE PULMONARY NEUTROPHIL ACCUMULATION IN ENDOTOXIC RATS

OBJECTIVE Proinflammatory eicosanoids and cytokines are important mediators of local inflammation in acute lung injury. We determined if enteral nutrition with anti-inflammatory fatty acids, eicosapentaenoic acid, and gamma-linolenic acid would reduce the intrapulmonary synthesis of proinflammatory eicosanoids and cytokines and pulmonary neutrophil accumulation in a rat model of acute lung injury. DESIGN Prospective, randomized, controlled, double-blind study. SETTING Research laboratory at a university medical center. SUBJECTS Male Long-Evans rats (250 g). INTERVENTIONS Rats were randomly assigned to three dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day) containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, or 20% fish and 20% borage oil for 21 days. On day 22, bronchoalveolar lavage was performed 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg) or saline. Bronchoalveolar lavage fluid was analyzed for leukotriene B4, leukotriene C4/D4, thromboxane B2, prostaglandin E2, 6 keto-prostaglandin F1alpha, tumor necrosis factor (TNF)-alpha, and macrophage inflammatory protein-2 (MIP-2). Lung myeloperoxidase activity (a marker for neutrophil accumulation) and phospholipid fatty acid composition were also determined. MEASUREMENTS AND MAIN RESULTS Lung phospholipid concentrations of arachidonic acid were lower and the concentrations of eicosapentaenoic acid and docosahexaenoic acid were higher with fish oil and fish and borage oil as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, increased with fish and borage oil as compared with fish oil and corn oil. The levels of leukotriene B4, leukotriene C4/D4, 6-keto-prostaglandin F1alpha, and thromboxane B2 with corn oil were significantly increased with endotoxin as compared with saline. In contrast to the corn oil group, endotoxin did not significantly increase bronchoalveolar lavage levels of leukotriene B4, leukotriene C4/D4, and thromboxane B2 above those of saline-treated rats with fish oil and fish and borage oil. Lung myeloperoxidase activity was significantly increased in endotoxin-treated rats compared with those rats given saline in all dietary treatment groups. However, lung myeloperoxidase activity was significantly lower with either fish oil or fish and borage oil as compared with corn oil after endotoxin. Although endotoxin increased the levels of TNF-alpha and MIP-2 with all dietary treatment groups as compared with saline-treated rats, there were no significant differences in the levels of either cytokine between the dietary treatment groups. CONCLUSIONS These results indicate that dietary fish oil and fish and borage oil as compared with corn oil may ameliorate endotoxin-induced acute lung injury by suppressing the levels of proinflammatory eicosanoids (but not TNF-alpha or MIP-2) in bronchoalveolar lavage fluid and reducing pulmonary neutrophil accumulation.

Measurement of functional fibrinogen levels using the Thrombelastograph

STUDY OBJECTIVE To validate a Thromboelastograph (Haemoscope Corporation, Niles, IL) assay for functional fibrinogen. DESIGN Correlation study of the Thromboelastograph assay with two conventional fibrinogen assays by the standard Clauss method. SETTING Research laboratory of a university medical center. PARTICIPANTS AND INTERVENTIONS Blood samples were obtained from 19 healthy volunteers. MEASUREMENT AND MAIN RESULTS Thromboelastograph assays, using heparinized whole blood from 19 healthy donors, indicated that reptilase-XIIIa mixture (Activatorf)-generated clot shear elasticity in dynes per square centimeter (Gf) correlated with fibrinogen (mg/dL). Blood from four donors was used to define the contribution of hematocrit (Hct) to Gf by titration with platelet-rich plasma. The Gf versus Hct gave linear correlations (r2 = 0.746) with Gf = 1258 - 17.8 x % Hct. A commercial collection of 19 normal, 10 borderline, and one deficient for functional fibrinogen-citrated plasmas was assayed for Gf after recalcification using Activatorf. Of the 30 plasma samples, four were from factor X- or factor VII-deficient donors and one was from a coumadin-treated donor. There was a linear correlation of Activatorf Gf with functional fibrinogen (r2 = 0.940) with Gf = -730 + 9.21 x fibrinogen (mg/dL). CONCLUSION Thrombelastography with Activatorf may be used to determine fibrinogen levels in whole blood.

Measurement of patients' bivalirudin plasma levels by a Thrombelastograph® ecarin clotting time assay: A comparison to a standard activated clotting time

Standard activated clotting time (ACT) tests have a poor correlation to bivalirudin levels, leading to uncertainty regarding adequate anticoagulation in percutaneous coronary intervention patients. We tested a Thrombelastograph® (TEG®) ecarin clotting time (ECT) assay for sensitivity to bivalirudin using blood from 80 patients undergoing interventional cardiology procedures with bivalirudin anticoagulation. This was compared to a standard Hemochron ACT assay using diatomaceous earth. With the TEG® assay, the direct thrombin activator, ecarin, was used to initiate coagulation and measured as the reaction time. Plasma samples were evaluated for bivalirudin by a chromogenic assay at an independent hematological laboratory. Linear regression of the standard ACT versus bivalirudin level gave an r2 = 0.306 whereas the TEG® ECT gave a much higher r2 = 0.746 (both P < 0.0001). The TEG® ECT should prove more useful than the standard ACT for monitoring bivalirudin anticoagulation across the clinically therapeutic range.

A Perioperative Management Algorithm for Cardiac Rhythm Management Devices: The PACED-OP Protocol

Limited data are available regarding the perioperative management of cardiac rhythm management devices (CRMDs) exposed to intraoperative electromagnetic interference. We postulated that implementation of a simple, standardized approach to CRMD management using our own institutions Pacing And Cardioverting Electronic Devices peri‐Operative Protocol (the PACED‐OP protocol) would be associated with a reduction in the amount of device reprogramming without an increase in CRMD‐related complications.

Post interventional cardiology urinary thromboxane correlates with PlateletMapping® detected aspirin resistance

INTRODUCTION We have previously defined aspirin resistance detected by TEG PlateletMapping using arachidonic acid (AA). This aspirin resistance is observed as platelet activation (>20%) by AA in whole blood, even though the isolated platelets are inhibited by aspirin. This platelet activation in whole blood is due to a transcellular pathway mediated by platelets and leukocytes. METHODS To determine if this PlateletMapping assay of aspirin resistance on pre-procedure blood samples correlated with an in vivo response we assayed the first voided urine samples collected 2-8 hours post interventional cardiology procedures for 11-dehydro thromboxane B2. RESULTS AND CONCLUSIONS We detected 27 aspirin resistant patients out of a total of 81 (33%), in agreement with our previous study. All of these patients were on aspirin therapy, confirmed by a <20% aggregation response to AA by light transmission platelet aggregometry using isolated platelet rich plasma. Aspirin resistant patients urine samples (14 out of a total of 60 patients analyzed) contained significantly (P=0.008) higher 11-dehydro thromboxane B2 levels than the other 46 aspirin sensitive patients urine samples. Since our previous study implicated 12- and 15-lipoxygenases in this pathway, we also assayed for polymorphisms to determine any correlation with aspirin resistance. A correlation was found in a polymorphism affecting the lipoxygenase domain of platelet 12-lipoxygenase. This result indicates that aspirin resistance detected in whole blood by the TEG PlateletMapping assay correlates with a physiological consequence in terms of thromboxane formation. This is the first report of such a correlation.

A Comparison of VerifyNow® with PlateletMapping® -Detected Aspirin Resistance and Correlation with Urinary Thromboxane

BACKGROUND:Aspirin-resistant platelet activation in whole blood is attributable to a transcellular pathway not detected by isolated platelet aggregometry. Aspirin resistance as defined by urinary thromboxane levels is associated with increased risk for myocardial infarction or cardiac death. Whole blood point-of-care assays may also detect aspirin resistance. METHODS:We compared PlateletMapping® with VerifyNow® for detecting aspirin resistance in 200 patients undergoing invasive cardiac procedures. This included 10 patients not receiving aspirin therapy for comparison. The assay results were correlated with urinary 11-dehydro-thromboxane B2 collected 2 to 8 hours after the procedure. RESULTS:PlateletMapping detected aspirin resistance in 32% of patients. VerifyNow detected aspirin resistance in 6% of patients. A patient’s compliance with aspirin therapy was confirmed by a <20% aggregation response to arachidonic acid by light transmission aggregometry. Aspirin-resistant patients as determined by PlateletMapping had significantly (P < 0.001) higher urinary 11-dehydro-thromboxane B2 levels than aspirin-sensitive patients but significantly (P = 0.001) lower levels than patients not receiving aspirin therapy. There was no significant difference in urinary 11-dehydro-thromboxane B2 for aspirin-resistant compared with aspirin-sensitive patients as determined by VerifyNow, but the confidence intervals were wide. There was no significant correlation of resistance as defined by PlateletMapping with aspirin dose. However, there was significant increased aspirin sensitivity with clopidogrel (0.0006) or statin (0.004) cotherapies. There also was a significant correlation of smoking with aspirin resistance. CONCLUSIONS:These results indicate that PlateletMapping could be a useful point-of-care assay to identify aspirin-resistant patients for better perioperative risk stratification and management.

A randomized, placebo controlled, trial of preoperative sustained release Betamethasone plus non-controlled intraoperative Ketorolac or Fentanyl on pain after diagnostic laparoscopy or laparoscopic tubal ligation [ISRCTN52633712]

BackgroundGynecological laparoscopic surgery procedures are often complicated by postoperative pain resulting in an unpleasant experience for the patient, delayed discharge, and increased cost. Glucocorticosteroids have been suggested to reduce the severity and incidence of postoperative pain.MethodsThis study examines the efficacy of a sustained release betamethasone preparation to reduce postoperative pain and the requirement for pain relief drugs after either diagnostic laparoscopy or tubal ligation. Patients were recruited, as presenting, after obtaining informed consent. Prior to surgery, patients were randomly selected by a computer generated table to receive either pharmacy-coded betamethasone (12 mg IM Celestone™) or an optically identical placebo injection of Intralipid™ and isotonic saline mixture. The effect of non-controlled prophylactic intraoperative treatment with either fentanyl or ketorolac per surgeons orders was also noted in this study. Blood samples taken at recovery and at discharge times were extracted and analyzed for circulating betamethasone. Visual analog scale data on pain was gathered at six post-recovery time points in a triple blind fashion and statistically compared. The postoperative requirement for pain relief drugs was also examined.ResultsAlthough the injection achieved a sustained therapeutic concentration, no beneficial effect of IM betamethasone on postoperative pain or reduction in pain relief drugs was observed during the postoperative period. Indeed, the mean combined pain scores during the 2 hour postoperative period, adjusted for postoperative opioids as the major confounding factor, were higher approaching statistical significance (P = 0.056) in the treatment group. Higher pain scores were also observed for the tubal ligation patients relative to diagnostic laparoscopy. Intraoperative fentanyl treatment did not significantly lower the average pain score during the 2 hour postoperative period. Intraoperative ketorolac treatment significantly lowered (P = 0.027) pain scores and reduced the postoperative requirement for additional pain relief drugs.ConclusionsThere was a lack of efficacy of preoperative sustained release betamethasone in reducing postoperative pain despite maintaining a therapeutic concentration during the postoperative period. Intraoperative Ketorolac did afford some short-term pain relief in the postoperative period and reduced the need for additional pain relief drugs.