Outcome of intravenous thrombolysis in stroke patients weighing over 100 kg.

Background: Intravenous thrombolysis with alteplase for ischemic stroke is fixed at a maximal dose of 90 mg for safety reasons. Little is known about the clinical outcomes of stroke patients weighing >100 kg, who may benefit less from thrombolysis due to this dose limitation. Methods: Prospective data on 1,479 consecutive stroke patients treated with intravenous alteplase in six Swiss stroke units were analyzed. Presenting characteristics and the frequency of favorable outcomes, defined as a modified Rankin scale (mRS) score of 0 or 1, a good outcome (mRS score 0-2), mortality and symptomatic intracranial hemorrhage (SICH) were compared between patients weighing >100 kg and those weighing ≤100 kg. Results: Compared to their counterparts (n = 1,384, mean body weight 73 kg), patients weighing >100 kg (n = 95, mean body weight 108 kg) were younger (61 vs. 67 years, p < 0.001), were more frequently males (83 vs. 60%, p < 0.001) and more frequently suffered from diabetes mellitus (30 vs. 13%, p < 0.001). As compared with patients weighing ≤100 kg, patients weighing >100 kg had similar rates of favorable outcomes (45 vs. 48%, p = 0.656), good outcomes (58 vs. 64%, p = 0.270) and mortality (17 vs. 12%, p = 0.196), and SICH risk (1 vs. 5%, p = 0.182). After multivariable adjustment, body weight >100 kg was strongly associated with mortality (p = 0.007) and poor outcome (p = 0.007). Conclusion: Our data do not suggest a reduced likehood of favorable outcomes in patients weighing >100 kg treated with the current dose regimen. The association of body weight >100 kg with mortality and poor outcome, however, demands further large-scale studies to replicate our findings and to explore the underlying mechanisms.

Strokes in the anterior circulation: comparison between bridging and intravenous thrombolysis.

BACKGROUND AND PURPOSE: To compare safety and efficacy of bridging approach with intravenous (IV) thrombolysis in patients with acute anterior strokes and proximal occlusions. PATIENTS AND METHODS: Consecutive patients with ischemic anterior strokes admitted within a 4 h 30 min window in two different centers were included. The first center performed IV therapy (alteplase 0.6 mg/kg) during 30 min and, in absence of clinical improvement, mechanical thrombectomy with flow restoration using a Solitaire stent (StS); the second carried out IV thrombolysis (alteplase 0.9 mg/kg) alone. Only T, M1 or M2 occlusions present on CT angiography were considered. Endpoints were clinical outcome and mortality at 3 months. RESULTS: There were 63 patients in the bridging and 163 in the IV group. No significant differences regarding baseline characteristics were observed. At 3 months, 46% (n = 29) of the patients treated in the combined and 23% (n = 38) of those treated in the IV group had a modified Rankin scale (mRS) of 0-1 (P < 0.001). A statistical significant difference was observed for all sites of occlusion. In a logistic regression model, National Institute of Health Stroke Scale (NIHSS) and bridging therapy were independent predictors of good outcome (respectively, P = 0.001 and P = 0.0018). Symptomatic hemorrhage was documented in 6.3% vs 3.7% in the bridging and in the IV group, respectively (P = 0.32). There was no difference in mortality. CONCLUSIONS: Our results suggest that patients treated with a bridging approach were more likely to have minimal or no deficit at all at 3 months as compared to the IV treated group.

ASTRAL-R score predicts non-recanalisation after intravenous thrombolysis in acute ischaemic stroke.

Intravenous thrombolysis (IVT) as treatment in acute ischaemic strokes may be insufficient to achieve recanalisation in certain patients. Predicting probability of non-recanalisation after IVT may have the potential to influence patient selection to more aggressive management strategies. We aimed at deriving and internally validating a predictive score for post-thrombolytic non-recanalisation, using clinical and radiological variables. In thrombolysis registries from four Swiss academic stroke centres (Lausanne, Bern, Basel and Geneva), patients were selected with large arterial occlusion on acute imaging and with repeated arterial assessment at 24 hours. Based on a logistic regression analysis, an integer-based score for each covariate of the fitted multivariate model was generated. Performance of integer-based predictive model was assessed by bootstrapping available data and cross validation (delete-d method). In 599 thrombolysed strokes, five variables were identified as independent predictors of absence of recanalisation: Acute glucose > 7 mmol/l (A), significant extracranial vessel STenosis (ST), decreased Range of visual fields (R), large Arterial occlusion (A) and decreased Level of consciousness (L). All variables were weighted 1, except for (L) which obtained 2 points based on β-coefficients on the logistic scale. ASTRAL-R scores 0, 3 and 6 corresponded to non-recanalisation probabilities of 18, 44 and 74 % respectively. Predictive ability showed AUC of 0.66 (95 %CI, 0.61-0.70) when using bootstrap and 0.66 (0.63-0.68) when using delete-d cross validation. In conclusion, the 5-item ASTRAL-R score moderately predicts non-recanalisation at 24 hours in thrombolysed ischaemic strokes. If its performance can be confirmed by external validation and its clinical usefulness can be proven, the score may influence patient selection for more aggressive revascularisation strategies in routine clinical practice.

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.

Predictability of refraction following immediate sequential bilateral cataract surgery (ISBCS) performed under general anesthesia

Abstract Background: To evaluate the predictability of refraction following immediate sequential bilateral cataract surgery (ISBCS) performed under general anaesthesia. Methods: This is a retrospective review of all ISBCS performed at Kantonsspital Winterthur, Switzerland, between April 2000 and September 2013. The case notes of 250 patients were reviewed. Patients having full refraction reported (110 patients/220 eyes) were included. 210 (95 %) eyes had a straight forward phacoemulsification with posterior chamber intraocular lens implantation, seven eyes had a planned extracapsular cataract extraction (ECCE); three eyes had an intracapsular cataract extraction. Results: Both eyes of 110 patients (64 women, 46 men) with a mean age of 79.0 years, standard deviation (SD) ±11.4 (range 26 to 97 years) were included. Median preoperative best corrected visual acuity (BCVA) was 0.5 LogMAR in the first eye, the interquartile range (IQR) was [0.4, 1.2]; 0.7 LogMAR in the second eye with IQR [0.4, 1.8]. At one month, the median BCVA was 0.2 LogMAR, IQR [0.1, 0.3] in the first eye, median BCVA was 0.1 LogMAR and IQR [0.0, 0.5] in the second eye. There were 3 eyes (3 %) that lost 3 lines or more in BCVA at one month (control vs. pre-operatively). In all three cases, poor visual acuity had been recorded pre-operatively (>1 LogMAR). Achieved refraction was within ±1.0 D of the target in 83 % of eyes. There were only 5 % (n = 6) of cases where if delayed sequential bilateral extraction had been performed could potentially intraocular lens (IOL) choice have been adjusted, in four of these cases, target refraction was within ±1.0 D in the second eye. Conclusions: ISBCS performed under general anaesthesia achieves target refraction in 83 % of eyes after consideration of complications, ocular co-morbidities and systemic restrictions. In the majority of cases where IOL power calculation could be considered, the achieved refraction of the second surgical eye was within ±1.0 D of intended refraction. This undermines the utility of IOL power adjustments in the second surgical eye. Keywords: Cataract, Cataract surgery, Immediate sequential bilateral cataract surgery

Incidence and consequence of major bleeding in primary percutaneous intervention for ST-elevation myocardial infarction in the era of radial access: an analysis of the international randomized Acute myocardial infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up trial.

AIMS: The aims of the study are to compare the outcome with and without major bleeding and to identify the independent correlates of major bleeding complications and mortality in patients described in the ATOLL study. METHODS: The ATOLL study included 910 patients randomly assigned to either 0.5 mg/kg intravenous enoxaparin or unfractionated heparin before primary percutaneous coronary intervention. Incidence of major bleeding and ischemic end points was assessed at 1 month, and mortality, at 1 and 6 months. Patients with and without major bleeding complication were compared. A multivariate model of bleeding complications at 1 month and mortality at 6 months was realized. Intention-to-treat and per-protocol analyses were performed. RESULTS: The most frequent bleeding site appears to be the gastrointestinal tract. Age >75 years, cardiac arrest, and the use of insulin or >1 heparin emerged as independent correlates of major bleeding at 1 month. Patients presenting with major bleeding had significantly higher rates of adverse ischemic complications. Mortality at 6 months was higher in bleeders. Major bleeding was found to be one of the independent correlates of 6-month mortality. The addition or mixing of several anticoagulant drugs was an independent factor of major bleeding despite the predominant use of radial access. CONCLUSIONS: This study shows that major bleeding is independently associated with poor outcome, increasing ischemic events, and mortality in primary percutaneous coronary intervention performed mostly with radial access.

Total intravenous anaesthesia with propofol-racemic ketamine and propofol-S-ketamine: a comparative study and haemodynamic evaluation in dogs undergoing ovariohysterectomy

Total intravenous anaesthesia (TIVA) with propofol and ketamine proved to be very satisfactory from a clinical point of view. This blind randomised controlled trial was designed to compare induction and maintenance of anaesthesia under continuous infusion of propofol-racemic ketamine (PRK) with that of propofol-S-ketamine (PSK) and evaluate their haemodynamic, metabolic and ventilatory effects. Seven female dogs undergoing ovariohysterectomy were involved in each group. Anaesthesia was induced: in Group PRK, with propofol (4.0mg kg-1) and racemic ketamine (2.0mg kg-1) intravenous (i.v.), followed by i.v. infusion of propofol (initial dose of 0.5mg kg-1 min-1) and racemic ketamine (0.2mg kg-1 min-1); in Group PSK, with propofol (4.0mg kg-1) and S-ketamine (1.0 mg kg¹) i.v., followed by i.v. infusion of propofol (initial dose of 0.5mg kg-1 min-1) and S-ketamine (0.1mg kg-1 min-1). Parameters were assessed before anaesthesia and in 6 time points after induction. In both groups, heart rate increased significantly at all time points. There was a slight decrease in systemic blood pressure, cardiac output and cardiac index in both groups. The systolic index decrease significantly and intense respiratory depression was observed in all groups, making assisted ventilation necessary.

Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

The increasing use of nanotechnologies in advanced therapies has allowed the observation of specific adverse reactions related to nanostructures. The toxicity of a novel liposome formulation of meglumine antimoniate in dogs with visceral leishmaniasis after single dose has been investigated. Groups of 12 animals received by the intravenous route a single dose of liposomal meglumine antimoniate (group I [GI], 6.5 mg Sb/kg), empty liposomes (GII) or isotonic saline (GIII). Evaluation of hematological and biochemical parameters showed no significant changes 4 days after administration. No undesired effects were registered in the GIII. However, adverse reactions were observed in 67.7% of dogs from both groups that received liposomal formulations. The side effects began moments after bolus administration and disappeared during the first 15 minutes after treatment. Prostation, sialorrhea and defecation were the most frequent clinical signs, registered in 33.3% and 41.6 % of animals from the groups GI and GII, respectively. Tachypnea, mydriasis, miosis, vomiting and cyanosis were also registered in both groups. The adverse reactions observed in this study were attributed to the activation of the complement system by lipid vesicles in a phenomenon known as Complement Activation-Related Pseudoallergy (CARPA). The influence of the physical-chemical characteristics of liposomal formulation in the triggering of CARPA is discussed.

Metabolic profile and ruminal and abomasal pH in sheep subjected to intravenous ranitidine

Resumo: Brazilian sheep production has intensified, predisposing sheep to an increased incidence of digestive disorders, such as abomasal ulcers. Ranitidine is used to prevent and treat this disease; however, there is little information on the parenteral use of this drug in adult ruminants. Few data exist on the concomitant metabolic changes and the behavior of the digestive system associated with its use. For this study, five healthy male sheep with ruminal and abomasal cannulas were used. A 5x5 Latin square experiment with a 2x2+1 factorial arrangement of the treatments was performed. Sheep treated with drug doses of 1 or 2mg/kg ranitidine administered intravenously every 8 or 12 hours were compared with the control group, was treated intravenously with 1 mL of physiological solution per 25 kg every 12 hours. Higher total protein concentrations, hemoglobin levels, as well as increased aspartate aminotransferase activity and increased abomasal pH for up to 150 min following drug administration were observed in all animals that received the drug, regardless of dose and frequency. The animals treated every 12 hours showed a decrease in leukocyte number compared with the control group and with the animals treated every 8 hours. Increased serum creatinine concentrations were observed in the animals treated every 8 hours. Treatments of 1mg/kg every 8 hours and 2mg/kg every 12 hours increased the red blood cell count and decreased the serum pepsinogen. All protocols studied were safe for healthy sheep, but 1mg/kg ranitidine every 8 hours and 2mg/kg ranitidine every 12 hours were the most effective protocols for gastric protection.

Evaluation of cardiopulmonary parameters and recovery from anesthesia in cougars (Puma concolor) anesthetized with detomidine/ketamine and isoflurane or sevoflurane

Abstract: The aim of this study was to assess the cardiopulmonary effects, the onset time after the administration of a detomidine/ketamine combination, and the recovery from anesthesia of cougars (Puma concolor) anesthetized with detomidine/ketamine and isoflurane or sevoflurane for abdominal ultrasound imaging. Fourteen animals were randomly allocated into two experimental groups: GISO (n=7) and GSEVO (n=7). Chemical restraint was performed using 0.15mg/kg detomidine combined with 5mg/kg ketamine intramuscularly; anesthesia induction was achieved using 2mg/kg propofol intravenously and maintenance with isoflurane (GISO) or sevoflurane (GSEVO). The following parameters were assessed: heart rate, respiratory rate, systolic and diastolic arterial blood pressure, mean arterial blood pressure, oxyhemoglobin saturation, rectal temperature, central venous pressure, and end-tidal carbon dioxide. The time to sternal recumbency (TSR) and time to standing position (TSP) were also determined. There was not statistically significant difference for the cardiopulmonary variables or TSP whereas TSR was significantly shorter in GSEVO. The time to onset of anesthesia was 11.1±1.2 minutes and 11.3±1.8 minutes for GISO and GSEVO, respectively. The anesthesia of cougars with detomidine/ketamine and isoflurane or sevoflurane was conducted with safety, cardiopulmonary stability, and increased time to sternal recumbency in the GISO group.

A chromatographic method for the production of a human immunoglobulin G solution for intravenous use

Immunoglobulin G (IgG) of excellent quality for intravenous use was obtained from the cryosupernatant of human plasma by a chromatographic method based on a mixture of ion-exchange, DEAE-Sepharose FF and arginine Sepharose 4B affinity chromatography and a final purification step by Sephacryl S-300 HR gel filtration. The yield of 10 experimental batches produced was 3.5 g IgG per liter of plasma. A solvent/detergent combination of 1% Tri (n-butyl) phosphate and 1% Triton X-100 was used to inactivate lipid-coated viruses. Analysis of the final product (5% liquid IgG) based on the mean for 10 batches showed 94% monomers, 5.5% dimers and 0.5% polymers and aggregates. Anticomplementary activity was 0.3 CH50/mg IgG and prekallikrein activator levels were less than 5 IU/ml. Stability at 37ºC for 30 days in the liquid state was satisfactory. IgG was stored in flasks (2.5 g/flask) at 4 to 8ºC. All the characteristics of the product were consistent with the requirements of the 1997 Pharmacopée Européenne.

Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant

The objective of this prospective study was to evaluate the efficacy and complications of the use of an intraocular sustained-release ganciclovir implant for the treatment of active cytomegalovirus (CMV) retinitis in AIDS patients. Thirty-nine eyes of 26 patients were submitted to ocular surgery. All patients underwent complete ocular examination before and after surgery. The surgical procedure was always done under local anesthesia using the same technique. The mean time for the surgical procedure was 20 min (range, 15 to 30 min). The average follow-up period was 3.7 months. Of all patient, only 4 presented recurrence of retinitis after 8, 8, 9 and 2 months, respectively. Three of them received a successful second implant. All 39 eyes of the 26 patients presented healing of retinitis as shown by clinical improvement evaluated by indirect binocular ophthalmoscopy and retinography. Retinitis healed within a period of 4 to 6 weeks in all patients, with clinical regression signs from the third week on. Six (15.4%) eyes developed retinal detachment. None of the patients developed CMV retinitis in the contralateral eye. The intraocular implant proved to be effective in controlling the progression of retinitis for a period of up to 8 months even in patients for whom systemic therapy with either ganciclovir or foscarnet or both had failed. The intraocular sustained-release ganciclovir implant proved to be a safe new procedure for the treatment of CMV retinitis, avoiding the systemic side effects caused by the intravenous medications and improving the quality of life of the patients.

HIV-1 subtypes among intravenous drug users from two neighboring cities in São Paulo State, Brazil

In order to assess the molecular epidemiology of HIV-1 in two neighboring cities located near the epicenter of the HIV-1 epidemics in Brazil (Santos and São Paulo), we investigated 83 HIV-1 strains obtained from samples collected in 1995 from intravenous drug users. The V3 through V5 region of the envelope of gp 120 was analyzed by heteroduplex mobility analysis. Of the 95 samples, 12 (12.6%) were PCR negative (6 samples from each group); low DNA concentration was the reason for non-amplification in half of these cases. Of the 42 typed cases from São Paulo, 34 (81%, 95% confidence limits 74.9 to 87.0%) were B and 8 (19%, 95% confidence limits 12.9 to 25.0%) were F, whereas of the 41 typed cases from Santos, 39 (95%, 95% confidence limits 91.6 to 98.4%) were B and 2 (5%, 95% confidence limits 1.6 to 8.4%) were C. We therefore confirm the relationship between clade F and intravenous drug use in São Paulo, and the presence of clade C in Santos. The fact that different genetic subtypes of HIV-1 are co-circulating indicates a need for continuous surveillance for these subtypes as well as for recombinant viruses in Brazil.

Respiratory mechanics and morphometric changes during anesthesia with ketamine in normal rats

Ketamine is believed to reduce airway and pulmonary tissue resistance. The aim of the present study was to determine the effects of ketamine on the resistive, elastic and viscoelastic/inhomogeneous mechanical properties of the respiratory system, lungs and chest wall, and to relate the mechanical data to findings from histological lung analysis in normal animals. Fifteen adult male Wistar rats were assigned randomly to two groups: control (N = 7) and ketamine (N = 8). All animals were sedated (diazepam, 5 mg, ip) and anesthetized with pentobarbital sodium (20 mg/kg, ip) or ketamine (30 mg/kg, ip). The rats were paralyzed and ventilated mechanically. Ketamine increased lung viscoelastic/inhomogeneous pressure (26%) compared to the control group. Dynamic and static elastances were similar in both groups, but the difference was greater in the ketamine than in the control group. Lung morphometry demonstrated dilation of alveolar ducts and increased areas of alveolar collapse in the ketamine group. In conclusion, ketamine did not act at the airway level but acted at the lung periphery increasing mechanical inhomogeneities possibly resulting from dilation of distal airways and alveolar collapse.