Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Morphology and anatomy of shoot, root, and propagation systems in Hoffmannseggia glauca.

Hoffmannseggia glauca is a perennial weed that has tubers and root-borne buds. Some authors only consider root tubers without mentioning root-borne buds, while others consider that more anatomic studies become necessary to determine the origin of these structures and to interpret their behaviour. The objectives are: to study the growth form of the plant in order to analyze the ontogeny of its propagation organs, and to study its shoot and root anatomical characters that affect water conductivity. Hoffmannseggia glauca was collected in Argentina. Development of its shoot and root systems was observed. Shoots and roots were processed to obtain histological slides. Macerations were prepared to study vessel members. Primary and lateral roots originate buds that develop shoots at the end of the first year. In winter, aerial parts die and only latent buds at soil surface level and subterranean organs remain. In the following spring, they develop innovation shoots. Roots show localized swellings (tuberous roots), due to a pronounced increase of ray thickness and parenchymatous proliferation in the root center. Root vessel members are wider than those of aerial and subterranean shoots. Early development of an extensive root system, presence of root borne buds, anatomic and physiological specialization of innovation shoots, capability of parenchymatous rays to originate buds and tuberous roots, and high water transport efficiency in subterranean organs lead Hoffmannseggia glauca to display higher colonization potential than other species.

Congenital bilateral coronary-to-pulmonary artery fistulas.

Rare, congenital bilateral coronary-to-pulmonary artery fistulas in an older woman, one originating from the proximal right coronary artery and the other from a distal left main coronary artery and draining to the proximal main pulmonary artery, were successfully dissected, identified, and ligated proximally and also closed distally on a beating heart with cardiopulmonary bypass standby.

Lorazepam and midazolam in the intensive care unit: a randomized, prospective, multicenter study of hemodynamics, oxygen transport, efficacy, and cost.

OBJECTIVES: To evaluate and compare the clinical efficacy, impact on hemodynamic and oxygen transport variables, safety profiles, and cost efficiency of sedation and anxiolysis with lorazepam vs. continuous infusion of midazolam in critically ill, intensive care unit patients. DESIGN: Multicenter, prospective, randomized, open-label study. SETTING: Teaching hospitals. PATIENTS: Ninety-five critically ill, mechanically ventilated patients with fiberoptic pulmonary artery catheters in place were randomly assigned to receive short-term (8 hrs) sedation with either intermittent intravenous injection lorazepam (group A, n = 50) or continuous intravenous infusion midazolam (group B, n = 45) titrated to clinical response. MEASUREMENTS AND MAIN RESULTS: The severity of illness, demographic characteristics, levels of anxiety and agitation, hemodynamic parameters, oxygen transport variables, quality of sedation, nursing acceptance, and laboratory chemistries reflecting drug safety were recorded. There were no significant differences with regard to demographic data, hemodynamic and oxygen transport variables, or levels of anxiety/agitation between the two groups at baseline, 5 mins, 30 mins, and 4 and 8 hrs after administration of sedation. There were no significant differences in the quality of sedation or anxiolysis. Midazolam-treated patients used significantly larger amounts of drug for similar levels of sedation and anxiolysis (14.4 +/- 1.2 mg/8 hrs vs. 1.6 +/- 0.1 mg/8 hrs, p = .001). Both drugs were safely administered and patient and nurse satisfaction was similar. CONCLUSIONS: Sedation and anxiolysis with lorazepam and midazolam in critically ill patients is safe and clinically effective. Hemodynamic and oxygen transport variables are similarly affected by both drugs. The dose of midazolam required for sedation is much larger than the dose of lorazepam required for sedation, and midazolam is therefore less cost-efficient.

Comparison of antegrade with antegrade/retrograde cold blood cardioplegia for myocardial revascularization.

There has been increasing interest in the use of retrograde coronary sinus perfusion for delivery of cardioplegic solution during myocardial revascularization. Despite evidence of improved cardiac protection, it is unclear if a combined antegrade/retrograde approach to myocardial preservation offers significant clinical benefits. One hundred twenty patients undergoing elective 1st-time coronary bypass surgery for 3-or-more-vessel disease received aortic root, antegrade cold blood cardioplegia (Group I, n=52) or combined antegrade/retrograde cardioplegia via coronary sinus cannulation (Group II, n=68). All preoperative variables were similar, including age, severity of coronary artery disease, functional status, and ejection fraction. Intraoperative and postoperative variables, including the degree of hypothermia, temperature of infusion solution, number of bypass grafts, defibrillation attempts and spontaneous return to sinus rhythm, the use of intraaortic balloon pump counterpulsation, and inotropic support during weaning from cardiopulmonary bypass, were not statistically different. Cardioplegia infusion time was longer in Group II than in Group I (2.5 +/- 0.8 vs 1.7 +/- 0.7 min, p < 0.05). The postoperative cardia output, electrocardiographic and cardiac enzyme evidence of ischemia, the need for temporary pacing, and 30-day morbidity were similar for both groups. The data indicate that in this non-risk-stratified group of patients, the route of cardioplegia administration is not a determinant of clinical outcome.

Descending thoracic aortomyoplasty: a technique for clinical application.

BACKGROUND: Descending thoracic aortomyoplasty is a form of skeletal muscle-powered cardiac assistance. Its use in clinical settings has been limited by the ligation of intercostal arteries necessary to complete a circumferential wrap of the aorta with the latissimus dorsi. METHODS: This study assessed the feasibility and the efficacy of aortomyoplasty constructed with a modified latissimus dorsi. A pericardial patch was attached to the latissimus dorsi and divided around the preserved intercostal arteries. Nine alpine goats (37 +/- 2 kg) underwent descending aortomyoplasty using this technique. All intercostal arteries were preserved. After a 6-week recovery period, the animals underwent a 6-week, incremental electrical conditioning program. After 90 postoperative days, animals were examined under anesthesia with the myostimulator on and off. RESULTS: Aortomyoplasty activation resulted in augmentation of mean diastolic aortic pressure by 16.0 +/- 0.9 mm Hg (23%). Significant improvements in cardiac index (40%), stroke volume index (37%), left ventricular stroke work index (49%), and mean arterial pressure (19%) were noted. An intravascular sonographic probe placed in the descending aorta revealed circumferential compression of the aorta during counterpulsation. Mean cross-sectional aortic area was reduced by 51.8%, from 210.1 +/- 7.1 to 108.9 +/- 6.7 mm2 during aortomyoplasty activation (p < 0.05). Histologic analysis confirmed the long-term patency of intercostal arteries. CONCLUSIONS: Descending aortomyoplasty, modified with an interposing patch of pericardium, effectively transfers skeletal muscle force across the aortic wall and assists cardiac function. This technique allows preservation of all aortic branches, and with this novel approach, the clinical utility of aortomyoplasty can now be explored.

Predictors of stroke after cardiac surgery.

From January 1, 1988 to September 30, 1993, 44 of 2,455 patients undergoing cardiac surgery for acquired heart disease at our institution sustained an intraoperative or postoperative cerebrovascular accident (CVA). Demographic data, atherosclerosis risk factors, past medical history, cardiac catheterization reports, and intraoperative findings were retrospectively reviewed. The highest rate of CVA was in the sub-group of patients undergoing simultaneous myocardial revascularization and carotid endarterectomy (18.2%). The lowest rate was in a group of patients who underwent aortic valve replacement (0.9%). Severe aortic arch atherosclerosis with the presence of atheromatous material or calcinosis at the cannulation site was identified intraoperatively in 43.2% of patients with neurological complications and in 5% of the group without CVA (x2 = 18.1, p = 0.0001). Of 44 patients with CVA, 13.6% had a history of preoperative completed stroke. CPB time was 90.1 +/- 4.9 min vs. 71.6 +/- 3.7 min (p = 0.004), and aortic cross-clamping time was 54.5 +/- 3.2 min compared to 39.8 +/- 2.7 min (p = 0.001) in groups with and without postoperative stroke, respectively. Hypertension was an independent risk factor of postoperative CVA (x2 = 9.5, p = 0.02), but age was not. Neurological complications correlated with high operative mortality (38.6%) and prolonged postoperative hospital stays (35.1 +/- 5.3). These data describe predictors for the development of post-cardiopulmonary bypass CVA and identify a high-risk subgroup for neurological events. The preoperative recognition of risk factors is an essential step toward the reduction of morbidity and mortality.

Latissimus dorsi and serratus anterior dynamic descending aortomyoplasty for ischemic cardiac failure.

Dynamic descending aortomyoplasty for cardiac assistance is a form of extraaortic, skeletal muscle-driven counterpulsation. Controversy exists regarding its clinical applicability and the most suitable muscle autograft for the procedure. Specifically, the ligation of intercostal vessels required for descending aortomyoplasty may not be tolerated clinically. This study compared the hemodynamic profiles and long-term function of latissimus dorsi (LD) aortomyoplasty to a split serratus anterior (SA) descending aortomyoplasty in which all intercostal vessels were preserved. Descending aortomyoplasty was performed in 11 goats. In 5, the SA was harvested and its distal end divided, facilitating a wrap of the aorta without ligation of intercostal arteries. In 6, the LD was used as a circumferential aortic wrap. At 90 days, an occluder placed on the left anterior descending artery created an ischemic event. Hemodynamic studies with and without assistance were performed in the ischemic and nonischemic states. Latissimus dorsi aortomyoplasty improved cardiac output 24% and 5.6%, stroke volume 29% and 66%, left ventricular stroke work index 30% and 166%, and coronary flow 4% and 3% in the normal and ischemic heart, respectively. Serratus anterior aortomyoplasty improved cardiac output 36% and 10%, stroke volume 42.8% and 13.5%, left ventricular stroke work index 64% and 21%, and coronary flow 8% and 4.3%, in the normal and ischemic heart, respectively. Two of the SA autografts were fibrotic and nonfunctional at 3 months. Aortomyoplasty with either SA or LD muscle improves cardiac function in the normal and ischemic heart. However, divided SA is associated with a higher rate of fibrosis and may be less suitable for the procedure.

Mandatory seatbelts: epidemiologic, financial, and medical rationale from the Colorado matched pairs study.

In what approximated a controlled clinical trial for efficacy of seatbelts, the Colorado matched pairs study examined 256 crashes meeting the following criteria: driver plus front-seat passenger, one belted (SB) and one nonbelted (NSB) occupant, and at least one occupant injured. Nearly half (119 of 256) of the SB partners escaped injury, while only 16% (41 of 256) of the NSB group were as fortunate. To ascertain a differential effect the 160 pairs discordant for injury were analyzed. The relative odds for injury in the SB group was 0.34 (95% Cl: 0.24, 0.49) of that in the NSB group. Likewise, relative odds for any medical costs in the SB group was reduced to 0.24 (95% Cl: 0.14, 0.43) and for hospitalization to 0.29 (95% Cl: 0.10, 0.80). Sixty-five percent of the SB group had no medical costs in contrast to only 29% of the NSB group. Altogether the NSB group accounted for 76% of the medical costs and 72% of the hospitalizations. This study establishes the effectiveness of seatbelts in reducing nonfatal injuries using epidemiologic, financial, and medical data.

Release of von Willebrand factor antigen (vWF:Ag) and eicosanoids during acute injury to the isolated rat lung.

It has been suggested that the von Willebrand factor antigen (vWF:Ag) may be a clinical marker for pulmonary endothelial cell injury. An ELISA was developed for the measurement of rat vWF:Ag. Rat lungs were isolated and perfused with a recirculating, blood-free, physiologic salt solution. Circulating levels of vWF:Ag and the eicosanoids thromboxane B2 (TXB2) and prostaglandin 6-keto F1-alpha (6-keto PGF1 alpha) were measured before and after different forms of insult. The addition of phospholipase C (PLC) or hydrogen peroxide (H2O2) to the perfusate caused lung damage as manifested by pulmonary artery pressure increase and pulmonary edema. This was paralleled by significant release of vWF:Ag, TXB2, and 6-keto PGF1 alpha. Increased hydrostatic pressure caused pulmonary edema without vWF:Ag and eicosanoid release. The addition of vasopressin to the perfusate caused vWF:Ag release but no lung injury and no release of eicosanoids. It is concluded that in the rat model, vWF:Ag release is a nonspecific marker for lung injury.

Neutrophils contribute to TNF induced myocardial tolerance to ischaemia.

Sublethal endotoxin (ETX) pretreatment of rats induces protection from cardiac ischaemia-reperfusion injury. This protective state is associated with increased endogenous myocardial catalase activity. Since tumour necrosis factor (TNF) is one mediator of ETX effects, we hypothesized that (TNF) pretreatment of the rat (30 micrograms/kg ip) 36 h prior to cardiac ischaemia-reperfusion could induce myocardial protection. We found that TNF administration increased both myocardial tolerance to ischaemia reperfusion injury (modified Langendorff, buffer perfusion, global, normothermic ischaemia) and myocardial catalase activity at 36 h. Moreover, we found that 6 h after TNF administration, myocardial hydrogen peroxide (H2O2, assessed by aminotriazole-H2O2 inactivation of catalase) and myocardial neutrophil accumulation (assessed by histology) were both increased. When neutrophil function was inhibited either by neutrophil depletion (vinblastine) or by ibuprofen treatments of the rat before TNF, the protection previously apparent at 36 h was blocked. We conclude that TNF can induce myocardial resistance to ischaemia reperfusion injury. This protection is related to prior tissue neutrophil accumulation and concomitant increases in H2O2 levels.

Cardiac 5'-nucleotidase activity increases with age and inversely relates to recovery from ischemia.

The metabolic basis for the enhanced tolerance of immature hearts to ischemia remains to be elucidated. Loss of high-energy phosphate nucleotides occurs during ischemia/reperfusion in mature (adult) hearts through the breakdown of adenosine triphosphate, diphosphate, and monophosphate (nondiffusible) to adenosine (freely diffusible). However, previous work has shown that after ischemia nondiffusible nucleotides are better retained by immature (neonatal) hearts than by mature hearts. The enzyme responsible for the conversion of adenosine monophosphate to adenosine is 5'-nucleotidase. We therefore hypothesized lower activity of this enzyme in neonatal than in adult myocardium. The purposes of this study were (1) to document 5'-nucleotidase activities in neonatal and adult rabbit myocardium and (2) to correlate differences of 5'-nucleotidase activity with functional recovery from ischemia. Neonatal (5- to 10-day-old) and adult (4- to 6-month-old) rabbit hearts were isolated and perfused (retrograde Langendorff). A left ventricular balloon measured functional parameters. Hearts were subjected to 20 minutes of global 37 degrees C ischemia and 10 minutes of reperfusion followed by freeze clamping. Tissue homogenates were assayed for 5'-nucleotidase by the linked formation of nicotinamide-adenine dinucleotide at 340 nm (Arkesteijn method). Postischemic recovery of developed pressure was 86% +/- 3% in neonates (n = 5) versus 38% +/- 3% in adults (n = 8) (mean +/- standard deviation) (p less than 0.01). 5'-Nucleotidase activity was 4400 +/- 1208 nmol/min/gm in neonates (n = 5) versus 13,938 +/- 830 nmol/min/gm in adults (n = 8) (mean +/- standard deviation) (p less than 0.01). We conclude that (1) 5'-nucleotidase activity is 68% lower in neonatal than in adult myocardium and (2) functional recovery after ischemia inversely relates to 5'-nucleotidase activity.

Extracellular flush solution that contains blood, mannitol, albumin, and prostacyclin protects rat lungs from six hours of ischemia.

We have used an isolated rat lung model to compare the quality of preservation of different flush techniques with each other and with topical cooling alone. Lung injury was assessed by recording lung weights after reperfusion after 4 and 6 hours of ischemia. The flush solutions studied were intracellular (Collins-Sacks), traditional extracellular, extracellular with low potassium plus dextran, and extracellular containing blood, mannitol, albumin, and prostacyclin (Wallwork's solution). Flushing with Wallwork's solution before both 4 and 6 hours of ischemia gave superior protection from lung edema after reperfusion over all the other methods.

Oxygen metabolite effects on creatine kinase and cardiac energetics after reperfusion.

Noninvasive 31P nuclear magnetic resonance measurements indicate that during the initial reperfusion phase myocardial tissue contents of phosphocreatine (PCr) recover rapidly, while ATP levels remain low and recover slowly. There is also a burst of H2O2 during the first 10 min of reperfusion, as indicated by the in vivo inactivation of catalase that occurs only when H2O2, and the inactivator 3-aminotriazole (AMT), are simultaneously present. Neither H2O2 production nor CK inactivation was discernable after ischemia alone. In excitable tissue the PCr and ATP pools are equilibrated by the enzyme creatine kinase (CK), but myocardial CK activity is decreased by 20% after reperfusion, though not by simple washout. Extrapolating from the well-known air sensitivity of CK, we find that limited exposure in vitro to small concentrations of H2O2 can markedly diminish CK activity. We postulate that failure of certain CK isoenzymes at energy-using termini may decouple the relative rates of PCr production and ATP regeneration and hence cause elevated PCr-to-ATP ratios. The assumptions of 1) CK equilibrium during the reperfusion period to calculate free ADP levels and 2) cardiac recovery deduced from the elevation of PCr levels may require reexamination.

Antiarrhythmic surgery.

Medically refractory tachyarrhythmias remain a significant clinical problem. The indications for surgical intervention in this challenging patient population continue to expand. Advances in noninvasive detection of patients at risk, as well as expanding electrophysiologic testing, continue to help define patients best served by surgical therapy. Refinements in surgical techniques, including rapid computerized intraoperative arrhythmia mapping, have made operative therapy safer and more effective. This review describes recent observations and advances in surgical therapy for supraventricular and ventricular tachyarrhythmias.