N-Halamine Biocidal Materials with Superior Antimicrobial Efficacies for Wound Dressings.

This work demonstrated the successful application of N-halamine technology for wound dressings rendered antimicrobial by facile and inexpensive processes. Four N-halamine compounds, which possess different functional groups and chemistry, were synthesized. The N-halamine compounds, which contained oxidative chlorine, the source of antimicrobial activity, were impregnated into or coated onto standard non-antimicrobial wound dressings. N-halamine-employed wound dressings inactivated about 6 to 7 logs of Staphylococcus aureus and Pseudomonas aeruginosa bacteria in brief periods of contact time. Moreover, the N-halamine-modified wound dressings showed superior antimicrobial efficacies when compared to commercially available silver wound dressings. Zone of inhibition tests revealed that there was no significant leaching of the oxidative chlorine from the materials, and inactivation of bacteria occurred by direct contact. Shelf life stability tests showed that the dressings were stable to loss of oxidative chlorine when they were stored for 6 months in dark environmental conditions. They also remained stable under florescent lighting for up to 2 months of storage. They could be stored in opaque packaging to improve their shelf life stabilities. In vitro skin irritation testing was performed using a three-dimensional human reconstructed tissue model (EpiDerm™). No potential skin irritation was observed. In vitro cytocompatibility was also evaluated. These results indicate that N-halamine wound dressings potentially can be employed to prevent infections, while at the same time improving the healing process by eliminating undesired bacterial growth.

Inter- and intramolecular mechanisms for chlorine rearrangements in trimethyl-substituted N-chlorohydantoins.

The antimicrobial compounds 1-chloro-3,5,5-trimethylhydantoin and 3-chloro-1,5,5-trimethylhydantoin (1 and 2, respectively) have been synthesized and examined via a joint experimental and computational study. The measured rate of loss of oxidative chlorine in the absence and presence of exposure to UVA irradiation determined 2 to be less stable than 1. An interesting migration reaction was observed during UVA irradiation that featured the production of chlorine rearrangement and dechlorinated compounds. Two novel hydrogen atom transfer reaction (HATR) mechanisms have been proposed: (1) an intramolecular process in which a hydrogen atom undergoes a series of sigmatropic shifts, and (2) an intermolecular pathway in which a radical abstracts a hydrogen atom from a neighboring molecule. Density functional theory (DFT) calculations at the UB3LYP/6-311G++(2d,p) theory level have been employed to elucidate the preferred reaction pathway. Both proposed HATR mechanisms predicted 2 to possess a lower free energy of activation, ΔG(‡), relative to 1 in accordance with the experimental stability measurements. However, the intermolecular route had an overall lower absolute ΔG(‡) and was more consistent with measured product ratios in solution. The intermolecular reaction pathway, unlike the intramolecular route, also predicted the lack of formation of a migration product featuring a Cl covalently bonded to a methylene group at the 5-position of the hydantoin moiety, which was verified by NMR experiments.

N-halamine surface coating for mitigation of biofilm and microbial contamination in water systems for space travel.

A copolymer termed HASL produced from monomeric units of 2-acrylamido-2-methyl-1-(5-methylhydantoinyl)propane (HA) and of 3-(trimethoxysilyl)propyl methacrylate (SL) has been coated onto stainless steel and Inconel™ substrates, which upon halogenation with either aqueous oxidative chlorine or bromine, became antimicrobial. It has been demonstrated that the halogenated stainless steel and Inconel™ substrates were effective in producing 6 to 7 log inactivations of Staphylococcus aureus and Escherichia coli O157:H7 within about 10 min, and in prevention of Pseudomonas aeruginosa biofilm formation over a period of at least 72 h on the stainless steel substrates. Upon loss of halogen, the HASL coating could be re-charged with aqueous halogen. The HASL coating was easily applied to the substrates via a simple dip-coating method and was reasonably stable to contact with water. Both chlorinated substrates could be loaded with at least 6 × 1016 oxidative Cl atoms per cm2 and maintained a loading of greater than 1 × 1016 chlorine atoms per cm2 for a period of 3-7 days while agitated in aqueous solution. After loss of chlorine to a level below 1 × 1016 atoms per cm2, the substrates could be recharged to the 6 × 1016 Cl atoms per cm2 level for at least 5 times over a 28 day period. The new antimicrobial coating technology has potential for use in a variety of important applications, particularly for water treatment and storage on spacecraft.

N-halamine biocidal coatings via a layer-by-layer assembly technique.

Two N-halamine copolymer precursors, poly(2,2,6,6-tetramethyl-4-piperidyl methacrylate-co-acrylic acid potassium salt) and poly(2,2,6,6-tetramethyl-4-piperidyl methacrylate-co-trimethyl-2-methacryloxyethylammonium chloride) have been synthesized and successfully coated onto cotton fabric via a layer-by-layer (LbL) assembly technique. A multilayer thin film was deposited onto the fiber surfaces by alternative exposure to polyelectrolyte solutions. The coating was rendered biocidal by a dilute household bleach treatment. The biocidal efficacies of tested swatches composed of treated fibers were evaluated against Staphylococcus aureus and Escherichia coli. It was determined that chlorinated samples inactivated both S. aureus and E. coli O157:H7 within 15 min of contact time, whereas the unchlorinated control samples did not exhibit significant biocidal activities. Stabilities of the coatings toward washing and ultraviolet light exposure have also been studied. It was found that the stability toward washing was superior, whereas the UVA light stability was moderate compared to previously studied N-halamine moieties. The layer-by-layer assembly technique can be used to attach N-halamine precursor polymers onto cellulose surfaces without using covalently bonding tethering groups which limit the structure designs. In addition, ionic precursors are very soluble in water, thus promising for biocidal coatings without the use of organic solvents.

Effect of mixed flavonoids, n-3 fatty acids, and vitamin C on oxidative stress and antioxidant capacity before and after intense cycling.

Consumption of plant flavonoids, antioxidants, and n-3 fatty acids is proposed to have many potential health benefits derived primarily through antioxidant and anti-inflammatory activities. This study examined the effects of 1,000 mg quercetin + 1,000 mg vitamin C (QC); 1,000 mg quercetin, 1,000 mg vitamin C, 400 mg isoquercetin, 30 mg epigallocatechin gallate, and 400 mg n-3 fatty acids (QFO); or placebo (P), taken each day for 2 wk before and during 3 d of cycling at 57% W(max) for 3 hr, on plasma antioxidant capacity (ferricreducing ability of plasma [FRAP], oxygen-radical absorbance capacity [ORAC]), plasma oxidative stress (F(2)-isoprostanes), and plasma quercetin and vitamin C levels. Thirty-nine athletes were recruited and randomized to QC, QFO, or P. Blood was collected at baseline, after 2 wk supplementation, immediately postexercise, and 14 hr postexercise. Statistical design used a 3 (groups) × 4 (times) repeated-measures ANOVA with post hoc analyses. Plasma quercetin was significantly elevated in QC and QFO compared with P. Plasma F(2)-isoprostanes, FRAP, and vitamin C were significantly elevated and ORAC significantly decreased immediately postexercise, but no difference was noted in the overall pattern of change. Post hoc analyses revealed that the QC and QFO groups did not exhibit a significant increase in F(2)-isoprostanes from baseline to immediately postexercise compared with P. This study indicates that combining flavonoids and antioxidants with n-3 fatty acids is effective in reducing the immediate postexercise increase in F(2)-isoprostanes. Moreover, this effect occurs independently of changes in plasma antioxidant capacity.

Dynamics and predisposition of respiratory viral co-infections in children and adults.

OBJECTIVES: The epidemiology of respiratory co-infection pairings is poorly understood. Here we assess the dynamics of respiratory viral co-infections in children and adults and determine predisposition for or against specific viral pairings. METHODS: Over five respiratory seasons from 30 November 2013 through 6 June 2018, the mono-infection and co-infection prevalence of 13 viral pathogens was tabulated at The Cleveland Clinic. Employing a model to proportionally distribute viral pairs using individual virus co-infection rate with prevalence patterns of concurrent co-circulating viruses, we compared predicted occurrence with observed occurrence of 132 viral pairing permutations using binomial analysis. RESULTS: Of 30 535 respiratory samples, 9843 (32.2%) were positive for at least one virus and 1018 (10.8%) of these were co-infected. Co-infected samples predominantly originated from children. Co-infection rate in paediatric population was 35.0% (2068/5906), compared with only 5.8% (270/4591) in adults. Adenovirus C (ADVC) had the highest co-infection rate (426/623, 68.3%) while influenza virus B had the lowest (55/546, 10.0%). ADVC-rhinovirus (HRV), respiratory syncytial virus A (RSVA)-HRV and RSVB-HRV pairings occurred at significantly higher frequencies than predicted by the proportional distribution model (p < 0.05). Additionally, several viral pairings had fewer co-infections than predicted by our model: notably metapneumovirus (hMPV)-parainfluenza virus 3, hMPV-RSVA and RSVA-RSVB. CONCLUSIONS: This is one of the largest studies on respiratory viral co-infections in children and adults. Co-infections are substantially more common in children, especially under 5 years of age, and the most frequent pairings occurred at a higher frequency than would be expected by random. Specific pairings occur at altered rates compared with those predicted by proportional distribution, suggesting either direct or indirect interactions result between specific viral pathogens.

Long-term impact of respiratory viral infection after pediatric lung transplantation.

To evaluate the epidemiology and to investigate the impact of RVI on chronic allograft rejection after pediatric lung transplantation, a retrospective study of pediatric lung transplant recipients from 2002 to 2007 was conducted. Association between RVI and continuous and categorical risk factors was assessed using Wilcoxon rank-sum tests and Fisher's exact tests, respectively. Association between risk factors and outcomes were assessed using Cox proportional hazards models. Fifty-five subjects were followed for a mean of 674 days (range 14-1790). Twenty-eight (51%) developed 51 RVI at a median of 144 days post-transplant (mean 246; range 1-1276); 41% of infections were diagnosed within 90 days. Twenty-five subjects developed 39 LRI, and eight subjects had 11 URI. Organisms recovered included rhinovirus (n = 14), adenovirus (n = 10), parainfluenza (n = 10), influenza (n = 5), and RSV (n = 4). Three subjects expired secondary to their RVI (two adenovirus, one RSV). Younger age and prior CMV infection were risks for RVI (HR 2.4 95% CI 1.1-5.3 and 17.0; 3.0-96.2, respectively). RVI was not associated with the development of chronic allograft rejection (p = 0.25) or death during the study period. RVI occurs in the majority of pediatric lung transplant recipients, but was not associated with mortality or chronic allograft rejection.

Compared to CPAP extubation to non-invasive ventilation is associated with higher risk of bronchopulmonary dysplasia in extremely low birth weight infants.

OBJECTIVE: While non-invasive ventilation (NIV) has been associated with improved extubation rates, its impact on bronchopulmonary dysplasia (BPD) remains unclear. METHOD: In this retrospective, chart review study of infants admitted to the Cleveland Clinic, we aimed to compare the incidence of BPD among extremely low birth weight (ELBW) infants extubated to continuous positive pressure (CPAP) versus those extubated to NIV via RAM cannula or biphasic CPAP. Data collected included demographics, ventilatory modes, extubation data, and presence of complications. Infants extubated to either CPAP or NIV were compared using Wilcoxon rank- sum and Chi-square tests, and data were corrected using logistic regression models. Data are presented as medians. RESULTS: A total of 120 infants were included, of whom 62% were extubated to NIV. The incidence of BPD was significantly lower in the CPAP group vs NIV (57% vs. 78%, p = 0.011). Infants in the CPAP group were heavier (birth weight (BWT) of 833 vs 724 grams, p = 0.005), more mature (gestation age (GA) 27 vs 25 weeks, p <  0.001) and were extubated significantly earlier (2 vs 8 days, p <  0.001). After adjusting for BWT and GA, NIV continued to be significantly associated with higher incidence of BPD among those extubated on the first day of life (odds ratio 5.9; 95% CI: 1.2-29.1, p = 0.029). CONCLUSION: This study concludes that, as compared to CPAP, early use of NIV is associated with higher risk of BPD in ELBW infants. Further investigation using prospective studies is recommended to validate these findings.

Respiratory viral infections within one year after pediatric lung transplant.

To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the first post-transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1 year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using Wilcoxon's rank-sum and chi(2) tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the first year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; P<0.01). Viruses detected included adenovirus (n=25), influenza (n=9), respiratory syncytial virus (n=21), parainfluenza virus (n=19), enterovirus (n=4), and rhinovirus (n=22). In a multivariable model for time to first RVI, etiology other than cystic fibrosis (CF), younger age, and no induction therapy were independently associated with risk of RVI. Cytomegalovirus serostatus and acute rejection were not associated with RVI. RVI was independently associated with decreased 12-month survival (hazard ratio 2.6, 95% confidence interval 1.6-4.4). RVI commonly occurs after pediatric lung transplantation with risk factors including younger age and non-CF diagnosis. RVI is associated with decreased 1-year survival.

Why does Kevlar decompose, while Nomex does not, when treated with aqueous chlorine solutions?

Kevlar and Nomex are high-performance polymers which have wide varieties of applications in daily life. Recently, they have been proposed to be biocidal materials when reacted with household bleach (sodium hypochlorite solution) because they contain amide moieties which can be chlorinated to generate biocidal N-halamine functional groups. Although Nomex can be chlorinated without any significant decomposition, Kevlar decomposes under the same chlorination conditions. In this study, two mimics for each of the polymers were synthesized to simulate the carboxylate and diaminophenylene components of the materials. It was found that the p-diaminophenylene component of the Kevlar mimic is oxidized to a quinone-type structure upon treatment with hypochlorous acid, which then decomposes. However, such a mechanism for the Nomex mimic is not possible. In this paper, based upon these observations, a plausible answer will be provided to the title question.

Effects of in-utero exposure to selective serotonin reuptake inhibitors and venlafaxine on term and preterm infants.

OBJECTIVE: We hypothesized that in-utero SSRI exposure affects Apgar scores and immediate post-delivery oxygen requirements. STUDY DESIGN: SSRI in-utero exposure was assessed retrospectively in preterm neonates ≥ 28 weeks gestation and term neonates. Primary outcome was Apgar <7 at five minutes and delivery room oxygen requirements. Secondary endpoints included one-minute Apgar, length of stay, birth weight, and NICU admission. RESULTS: Fifty-one preterm and 117 term neonates were exposed to a SSRI; mostly to sertraline. Pre-term SSRI-exposed neonates had 4.1 times higher delivery room oxygen requirements. One minute Apgar <7 was 3.5 times higher and NICU admission 5 times higher 95% CI (1.3-19) in SSRI-exposed term neonates. Higher doses of sertraline had associated adverse outcomes. CONCLUSION: In-utero SSRI exposure was associated with increased neonatal care at birth, differences in Apgar scores compared with controls, and increased NICU admissions. Higher sertraline doses were associated with poorer outcomes.

N-halamine/quat siloxane copolymers for use in biocidal coatings.

A series of copolymers incorporating N-halamine siloxane and quaternary ammonium salt siloxane units has been prepared. The primary function of the quat units was to render the siloxane copolymers soluble in water. The copolymers have been coated onto cotton swatches and evaluated for biocidal efficacy against Staphylococcus aureus and Escherichia coli O157:H7. It was determined that both N-halamine and quat functional groups were effective against S. aureus, but only the N-halamine units were effective against Escherichia coli O157:H7. The copolymers should be useful for applications for which aqueous media is preferred over organic solvents to be used during coating procedures.

Synthesis and antimicrobial applications of 5,5'-ethylenebis[5-methyl-3-(3-triethoxysilylpropyl)hydantoin].

A novel, durable, long lasting, N-halamine siloxane monomer precursor, 5,5'-ethylenebis[5-methyl-3-(3-triethoxysilylpropyl)hydantoin] has been prepared and characterized by (1)H-NMR and FTIR for the purpose of functionalizing the surfaces of various materials. In this work, the precursor N-halamine moiety was attached by siloxane covalent bonding to surfaces of cotton fibers. Simulated laundering tests indicated that the chlorinated N-halamine structure could survive many repeated home launderings. The materials were rendered biocidal after exposure to oxidative halogen solutions, i.e. dilute household bleach. Once chlorinated, these materials were biocidal against Staphylococcus aureus and Escherichia coli. Upon loss of the halogen from either long-term use or consumption by the microbes on the surfaces, they could be simply recharged by further exposure to dilute bleach to regain biocidal activity.

Electrohydraulic shock wave decalcification of stenotic aortic valves: postmortem and intraoperative studies.

Decalcification of stenotic aortic valves is limited by the difficulty in removing sufficient calcium to restore valve function without cusp perforation. The present study demonstrates that electrohydraulic shock waves generated by a hand-held lithotriptor fragmented the calcifications contained within the cusps of four necropsy specimens of stenotic aortic valves. The electrohydraulic shock waves appeared to create a cleavage plane between the valve tissue and the fragmented calcific deposits, allowing the fragmented calcified masses to be removed without cusp perforation. Five patients with severe aortic stenosis also underwent successful aortic valve decalcification augmented by electrohydraulic shock waves generated with the hand-held lithotriptor, without significant complication. The shock waves permitted removal, from the aortic valve, of calcium that had not been removed by mechanical means. These results indicate that the addition of electrohydraulic shock waves to mechanical aortic valve decalcification may facilitate successful decalcification in patients undergoing operative treatment for aortic stenosis and may allow patients to avoid the need for aortic valve replacement.

Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group.

OBJECTIVES: This study was designed to assess outcome in patients with diabetes who received thrombolytic therapy and to determine whether differences in angiographic characteristics may account for the worse outcome observed in diabetic patients. BACKGROUND: Patients with diabetes are known to have a worse outcome after acute myocardial infarction than that of patients without diabetes. METHODS: Clinical and angiographic characteristics of the 148 patients with diabetes and the 923 patients without diabetes in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trials were examined and analyzed. RESULTS: Patients with diabetes tended to be older (median age 59 vs. 56 years) and to have a higher incidence of hypertension and hyperlipidemia and a lower incidence of cigarette smoking. Patients with diabetes had significantly more severe anatomic disease (66% vs. 46% had multivessel disease, p < 0.0001), similar global left ventricular ejection fraction (49% vs. 51%) and worse noninfarct zone ventricular function (-0.13 vs. 0.32 SD/chord, p = 0.02) than that of nondiabetic patients. Angiographic patency rates at 90 min after thrombolytic therapy were similar in patients with and without diabetes (initial 90-min patency 71% vs. 70%). Diabetic patients had nearly twice the in-hospital mortality rate (11% vs. 6%, p < 0.02) and a higher incidence of pulmonary edema (11% vs. 4%, p = 0.001). Diabetic women had an especially high in-hospital mortality rate (21%). No retinal hemorrhages were observed. Although diabetes as an unadjusted variable was predictive of in-hospital (p < 0.02) and long-term (p = 0.003) mortality, after adjustment for baseline clinical and angiographic characteristics, diabetes was not found to have an independent influence on mortality. CONCLUSIONS: Patients with diabetes after myocardial infarction have a worse outcome than that of patients without diabetes despite similar rates of infarct vessel patency. However, diabetes was not found to be an independent risk factor for increased mortality. These findings suggest that diabetes itself is not a major risk factor for poor early outcome after thrombolytic therapy for myocardial infarction; rather, the secondary effects such as more extensive coronary artery disease account for the worse outcome.

Increased risk of non-Q wave myocardial infarction after directional atherectomy is platelet dependent: evidence from the EPIC trial. Evaluation of c7E3 for the Prevention of Ischemic Complications.

OBJECTIVES: We sought to determine the effects of platelet glycoprotein IIb/IIIa receptor blockade on adverse outcomes, especially non-Q wave myocardial infarction, in patients undergoing directional atherectomy in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. BACKGROUND: Randomized trials comparing directional atherectomy with percutaneous transluminal coronary angioplasty (PTCA) have demonstrated modest benefits favoring atherectomy but at a cost of increased acute ischemic complications, notably non-Q wave myocardial infarction. The mechanism for this excess risk is unknown. METHODS: Of 2,038 high risk patients undergoing coronary intervention in the EPIC trial, directional atherectomy was performed in 197 (10%). Patients randomly received the chimeric glycoprotein IIb/IIIa antibody 7E3 (c7E3), as a bolus or a bolus and 12-h infusion or placebo. Study end points included death, myocardial infarction, repeat intervention or bypass surgery. RESULTS: Patients undergoing directional atherectomy had a lower baseline risk for acute complications but had a higher incidence of any myocardial infarction (10.7% vs. 6.3%, p = 0.021) and non-Q wave myocardial infarction (9.6% vs. 4.9%, p = 0.006). Bolus and infusion of c7E3 reduced non-Q wave myocardial infarctions by 71% after atherectomy (15.4% for placebo vs. 4.5% for bolus and infusion, p = 0.046). Non-Q wave myocardial infarction rates after PTCA were not affected by c7E3, although Q wave myocardial infarctions were reduced from 2.6% to 0.8% (p = 0.017). CONCLUSIONS: The EPIC trial confirmed the increased risk of non-Q wave myocardial infarction with directional atherectomy use compared with PTCA. A bolus and 12-h infusion of the glycoprotein IIb/IIIa receptor inhibitor c7E3 abolished this excess risk. Directional atherectomy-related non-Q wave myocardial infarction appears to be platelet aggregation dependent.

Comparison of time domain and frequency domain variables from the signal-averaged electrocardiogram: a multivariable analysis.

The relative values of the unprocessed signal-averaged electrocardiogram (ECG) and time domain analysis and frequency domain analysis of the signal-averaged ECG were compared in 36 patients with sustained monomorphic ventricular tachycardia and a remote myocardial infarction, in 29 asymptomatic patients with a remote myocardial infarction and in 23 normal subjects. Area ratios of the energy spectra derived from fast Fourier transform analysis were calculated using six separate 140 ms intervals starting at 0, 40, 50 and 60 ms after QRS onset; 40 and 50 ms before QRS end and a variable length interval starting 40 ms before QRS end and extending to the T wave. Total filtered QRS duration, late potential duration and root mean square voltage of the terminal QRS complex were measured from the filtered vector magnitude signal-averaged ECG. The total QRS duration was also measured from the X, Y, Z leads of the unfiltered signal-averaged ECG. Seven variables were significantly different in univariate tests between myocardial infarction patients with and without ventricular tachycardia: three fast Fourier transform area ratios with the sampling interval starting at 1) QRS onset (p = 0.007), 2) 40 ms after QRS onset (p = 0.02), and 3) 60 ms after QRS onset (p less than 0.0001); and all four time domain variables at 1) total filtered QRS duration (p less than 0.0001), 2) late potential duration (p = 0.0001), 3) root mean square terminal QRS voltage (p = 0.0001), and 4) QRS duration from the unprocessed signal-averaged ECG (p less than 0.0001). Of these seven variables, only the fast Fourier transform area ratio starting at QRS onset was significantly different between patients with myocardial infarction without ventricular tachycardia and normal subjects. In multi-variable analysis, the total filtered vector magnitude QRS duration, a time domain variable that includes the late potential, was the only independent factor that separated patients with myocardial infarction with and without associated ventricular tachycardia.

Accelerated plasminogen activator dose regimens for coronary thrombolysis. The TAMI-7 Study Group.

To determine the clinical profile and efficacy of accelerated recombinant tissue-type plasminogen activator (rt-PA) dose regimens, five different strategies of thrombolytic therapy in a total of 232 patients were systematically evaluated in the setting of acute myocardial infarction. The fifth strategy involved a combination of accelerated rt-PA and intravenous urokinase (regimen E). A weight-adjusted dose of 1.25 mg/kg body weight of tissue plasminogen activator over 90 min (regimen C) yielded the highest coronary patency rate (83%) at acute angiography. The associated in-hospital reocclusion rate for this regimen was low (4%). An exaggerated (60-min) dosage regimen yielded an inferior coronary patency rate (63%). Combination therapy (regimen E) was associated with a 72% patency rate and 3% reocclusion rate. Marginal improvement in global ejection fraction and regional wall function was demonstrated with all strategies by predischarge catheterization. Bleeding complications were most common at the periaccess site and were not different from those in previous experiences reported with conventional 3-h dosing regimens. Measurements of baseline, 30-min and 3-h levels of tissue plasminogen activator, fibrinogen and fibrin(ogen) degradation products were obtained. At 3 h, fibrinogen levels of less than 1 g/liter were demonstrated with combination therapy (regimen E) as well as with regimen C. Major clinical outcomes including death, reocclusion and reinfarction also showed a tendency to be less common with regimen C. Therefore, although accelerated dose regimens of rt-PA do not reliably yield acute coronary patency rates greater than 85%, an acute coronary patency rate of approximately 85% can be approached.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of the need for early acute intervention in patients treated conservatively after thrombolytic therapy for acute myocardial infarction. TAMI-5 Study Group.

This study sought to determine whether clinical variables can be used to identify patients at high risk of recurrent spontaneous myocardial ischemia or hemodynamic compromise during the 1st 4 days after intravenous thrombolysis for acute myocardial infarction. Of 288 patients randomly assigned to a conservative postthrombolysis strategy, 54 (19%) required urgent cardiac catheterization within 24 h; 75 (26%) underwent urgent cardiac catheterization within 4 days of admission. Of the clinical variables examined by multiple logistic regression analysis, only patient age and anterior wall myocardial infarction correlated with the need for urgent cardiac catheterization (p = 0.0016 and p = 0.017, respectively). Compared with recombinant tissue-type plasminogen activator or urokinase monotherapy, combination therapy with these agents was associated with a lower need for acute intervention during the 1st 24 h after admission, but the difference did not reach statistical significance (14% for combination therapy vs. 21% for each agent alone, p = 0.30). Of the 75 patients undergoing urgent coronary angiography, only 39% had an occluded infarct-related artery. Emergency coronary angioplasty was performed in 49% of the patients and coronary artery bypass graft surgery was performed urgently in 3%. Despite these interventions, the need for urgent cardiac catheterization was associated with an in-hospital mortality rate of 7% (vs. 3% in the group not requiring urgent angiography, p = 0.36); mean left ventricular ejection fraction was 50.5 +/- 11% (vs. 54.3 +/- 10.8%, p = 0.12) and regional infarct zone wall motion was -2.68 +/- 1.07 SD/chord (vs. -2.46 +/- 1.19 SD/chord; p = 0.44).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of benefit of combination thrombolytic therapy for acute myocardial infarction: a quantitative angiographic and hematologic study.

OBJECTIVES: The goal of this study was to lend insight into the mechanisms responsible for the beneficial effects of combination thrombolytic therapy. BACKGROUND: Combination thrombolytic therapy for acute myocardial infarction has been associated with less reocclusion and fewer in-hospital clinical events than has monotherapy. METHODS: Infarct-related quantitative coronary dimensions and hemostatic protein levels were evaluated in 287 patients with acute myocardial infarction during the early (90-min) and convalescent (7-day) phases after administration of recombinant tissue-type plasminogen activator (rt-PA), urokinase or combination rt-PA and urokinase. RESULTS: Minimal lumen diameter was similar in the 90-min and 7-day phases after treatment with rt-PA, urokinase and combination rt-PA and urokinase (0.72 +/- 0.45 mm, 0.62 +/- 0.53 mm and 0.75 +/- 0.58 mm, respectively, at 90 min, p = 0.16; and 1.05 +/- 0.56 mm, 1.12 +/- 0.72 mm and 0.94 +/- 0.54 mm, respectively, at 7 days, p = 0.22). In-hospital clinical event and reocclusion rates were less frequent in patients receiving combination therapy than in those receiving monotherapy (25% vs. 38% and 32% for rt-PA and urokinase, respectively, p = 0.084; and 3% vs. 13% and 9% for rt-PA and urokinase, respectively, p = 0.03), but these events were unrelated to early or late coronary dimensions. Patients receiving combination therapy or urokinase monotherapy had significantly higher peak fibrin degradation products (1,307 +/- 860 and 1,285 +/- 898 micrograms/ml vs. 435 +/- 717 micrograms/ml, respectively, p < 0.0001) and lower nadir fibrinogen levels (0.85 +/- 1.00 and 0.75 +/- 0.53 g/liter vs. 1.90 +/- 0.86 g/liter, respectively, p < 0.0001) than did those receiving rt-PA monotherapy. Peak fibrinogen degradation products indirectly correlated (p = 0.004) and baseline (p = 0.026) and nadir (p = 0.089) fibrinogen levels directly correlated with reocclusion. CONCLUSIONS: Lower in-hospital clinical event and reocclusion rates observed with combination thrombolytic therapy may relate to systemic hematologic factors rather than to the residual lumen obstruction after thrombolysis.