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1.
N Engl J Med ; 382(1): 29-40, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31893514

RESUMEN

BACKGROUND: Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. METHODS: We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. RESULTS: Three years after infusion, two participants (one who had received 6×1012 vector genomes [vg] per kilogram of body weight and one who had received 2×1013 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×1013 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×1013 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. CONCLUSIONS: Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×1013 vg per kilogram or 6×1013 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).


Asunto(s)
Dependovirus , Factor VIII/genética , Terapia Genética , Vectores Genéticos , Hemofilia A/terapia , Adulto , Biomarcadores , Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Estudios de Seguimiento , Terapia Genética/efectos adversos , Hemofilia A/complicaciones , Hemorragia/etiología , Hemorragia/prevención & control , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Transgenes , Adulto Joven
3.
Anaesthesia ; 75(2): 196-201, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31788791

RESUMEN

Mechanisms underlying loss of consciousness following propofol administration remain incompletely understood. The objective of this study was to compare frontal lobe electroencephalography activity and brainstem reflexes during intravenous induction of general anaesthesia, in patients receiving a typical bolus dose (fast infusion) of propofol compared with a slower infusion rate. We sought to determine whether brainstem suppression ('bottom-up') predominates over loss of cortical function ('top-down'). Sixteen ASA physical status-1 patients were randomly assigned to either a fast or slow propofol infusion group. Loss of consciousness and brainstem reflexes were assessed every 30 s by a neurologist blinded to treatment allocation. We performed a multitaper spectral analysis of all electroencephalography data obtained from each participant. Brainstem reflexes were present in all eight patients in the slow infusion group, while being absent in all patients in the fast infusion group, at the moment of loss of consciousness (p = 0.010). An increase in alpha band power was observed before loss of consciousness only in participants allocated to the slow infusion group. Alpha band power emerged several minutes after the loss of consciousness in participants allocated to the fast infusion group. Our results show a predominance of 'bottom-up' mechanisms during fast infusion rates and 'top-down' mechanisms during slow infusion rates. The underlying mechanisms by which propofol induces loss of consciousness are potentially influenced by the speed of infusion.


Asunto(s)
Anestésicos Intravenosos/administración & dosificación , Estado de Conciencia/efectos de los fármacos , Electroencefalografía/métodos , Lóbulo Frontal/efectos de los fármacos , Propofol/administración & dosificación , Adulto , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Método Simple Ciego , Factores de Tiempo , Adulto Joven
4.
Br J Anaesth ; 124(1): 35-43, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31607387

RESUMEN

BACKGROUND: Bleeding and transfusions affect mortality in aortic surgery. Although tranexamic acid significantly reduced bleeding in multiple settings, its role in major vascular surgery was never studied. The aim of this study was to determine if tranexamic acid reduces blood loss in open abdominal aortic aneurysm (AAA) surgery. METHODS: A total of 100 patients undergoing elective open AAA repair were randomised to receive tranexamic acid (a loading dose of 500 mg and a continuous infusion of 250 mg h-1) or placebo. The primary outcome was intraoperative blood loss, and the secondary outcomes were the number of patients receiving red blood cells, occurrence of thromboembolic events, and mortality. Data were analysed using the intention-to-treat principle. RESULTS: Fifty patients were randomised into each group. Median (inter-quartile range) intraoperative blood loss was 400 (300-1050) ml in the tranexamic acid group vs 500 (360-1000) ml in the placebo group (P=0.44). Transfusion rate was seven/50 (14%) in the tranexamic group vs 12/50 (24%) in the placebo group (P=0.20). No thrombosis was recorded. In a post hoc analysis, postoperative blood loss was reduced in the tranexamic group both at 4 h (60 [40-80] ml vs 100 [60-140] ml, P<0.001) and 24 h (180 [120-275] vs 275 [190-395] ml, P=0.003) after surgery. At 1 yr, three patients were dead, all in the placebo group (P=0.24) and all after 28 days. CONCLUSIONS: Tranexamic acid did not reduce intraoperative blood loss or blood transfusions in open AAA repair, although it may reduce postoperative blood loss without increasing adverse effects. CLINICAL TRIAL REGISTRATION: NCT02335359.


Asunto(s)
Antifibrinolíticos/uso terapéutico , Aneurisma de la Aorta/cirugía , Pérdida de Sangre Quirúrgica/prevención & control , Procedimientos Quirúrgicos Cardíacos/métodos , Ácido Tranexámico/uso terapéutico , Anciano , Antifibrinolíticos/efectos adversos , Aneurisma de la Aorta/mortalidad , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Transfusión Sanguínea/estadística & datos numéricos , Procedimientos Quirúrgicos Cardíacos/mortalidad , Método Doble Ciego , Transfusión de Eritrocitos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Tromboembolia/epidemiología , Tromboembolia/prevención & control , Ácido Tranexámico/efectos adversos
5.
J Surg Res ; 245: 604-609, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31499368

RESUMEN

BACKGROUND: Phosphatidylserine (PS) is a key cell membrane phospholipid normally maintained on the inner cell surface but externalizes to the outer surface in response to cellular stress. We hypothesized that PS exposure mediates organ dysfunction in hemorrhagic shock. Our aims were to evaluate PS blockade on (1) pulmonary, (2) renal, and (3) gut function, as well as (4) serum lysophosphatidic acid (LPA), an inflammatory mediator generated by PS externalization, as a possible mechanism mediating organ dysfunction. MATERIALS AND METHODS: Rats were either (1) monitored for 130 min (controls, n = 3), (2) hemorrhaged then resuscitated (hemorrhage only group, n = 3), or (3) treated with Diannexin (DA), a PS blocking agent, followed by hemorrhage and resuscitation (DA + hemorrhage group, n = 4). Pulmonary dysfunction was assessed by arterial partial pressure of oxygen, renal dysfunction by serum creatinine, and gut dysfunction by mesenteric endothelial permeability (LP). LPA levels were measured in all groups. RESULTS: Pulmonary: there was no difference in arterial partial pressure of oxygen between groups. Renal: after resuscitation, creatinine levels were lower after PS blockade with DA versus hemorrhage only group (P = 0.01). Gut: LP was decreased after PS blockade with DA versus hemorrhage only group (P < 0.01). Finally, LPA levels were also lower after PS blockade with DA versus the hemorrhage only group but higher than the control group (P < 0.01). CONCLUSIONS: PS blockade with DA decreased renal and gut dysfunction associated with hemorrhagic shock and attenuated the magnitude of LPA generation. Our findings suggest potential for therapeutic targets in the future that could prevent organ dysfunction associated with hemorrhagic shock.


Asunto(s)
Anexina A5/administración & dosificación , Fosfatidilserinas/antagonistas & inhibidores , Resucitación/métodos , Choque Hemorrágico/terapia , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Infusiones Intravenosas , Mucosa Intestinal/fisiopatología , Riñón/fisiopatología , Pulmón/fisiopatología , Lisofosfolípidos/sangre , Puntuaciones en la Disfunción de Órganos , Ratas , Choque Hemorrágico/sangre , Choque Hemorrágico/diagnóstico , Resultado del Tratamiento
6.
Br J Anaesth ; 124(2): 173-182, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31864721

RESUMEN

BACKGROUND: Syringe infusion pumps are used for the precise continuous administration of intravenous drugs. Their compliance and mechanical deficiencies have been found to cause considerable start-up delays, flow irregularities during vertical displacement, as well extensive delays of occlusion alarms at low infusion rates. The aim of this study was to evaluate the performance of several modern syringe infusion pumps at low infusion rates and the impact on drug concentration. METHODS: Seven currently marketed syringe infusion pump assemblies were assessed in an in vitro study during start-up, vertical displacement manoeuvres, and infusion line occlusion at a set flow rate of 1 ml h-1. The measured data were used as input for a pharmacokinetic simulation modelling plasma concentration during a standard neonatal continuous epinephrine infusion. RESULTS: The mean time from starting the infusion pump to steady-state flow varied from 89 to 1622 s. The zero-drug delivery time after lowering the pump ranged from 145 to 335 s. In all assemblies tested, occlusion alarm delays and measured flow irregularities during vertical displacement manoeuvres resulted in relevant deviations in plasma epinephrine concentration (>25%) as calculated by the pharmacokinetic simulation model. CONCLUSION: Problems with the performance of syringe infusion pump assemblies can have considerable impact on plasma drug concentration when highly concentrated short-acting cardiovascular drugs are administered at low flow rates. The problems, which affected all assemblies tested, are mainly related to the functional principle of syringe infusion pumps and will only partially be solved by incremental improvements of existing equipment.


Asunto(s)
Epinefrina/administración & dosificación , Bombas de Infusión , Infusiones Intravenosas/instrumentación , Modelos Biológicos , Atención Perioperativa/métodos , Jeringas , Diseño de Equipo , Humanos , Recién Nacido
7.
N Engl J Med ; 382(3): 211-221, 2020 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-31851795

RESUMEN

BACKGROUND: Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. METHODS: We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. RESULTS: A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. CONCLUSIONS: Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Receptor de Interferón alfa y beta/antagonistas & inhibidores , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Método Doble Ciego , Femenino , Glucocorticoides/uso terapéutico , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
8.
Pharm Res ; 37(1): 2, 2019 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-31823033

RESUMEN

PURPOSE: Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. METHODS: PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. RESULTS: Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. CONCLUSION: The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.


Asunto(s)
Bosentán/farmacocinética , Dioxanos/farmacocinética , Antagonistas de los Receptores de Endotelina/farmacocinética , Modelos Biológicos , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Receptores de Endotelina/metabolismo , Sulfonamidas/farmacocinética , Tetrazoles/farmacocinética , Bosentán/administración & dosificación , Dioxanos/administración & dosificación , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores de Endotelina/administración & dosificación , Humanos , Infusiones Intravenosas , Masculino , Dinámicas no Lineales , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Espectrometría de Masas en Tándem , Tetrazoles/administración & dosificación
9.
Khirurgiia (Mosk) ; (12): 84-90, 2019.
Artículo en Ruso | MEDLINE | ID: mdl-31825347

RESUMEN

AIM: To assess the effect of the modified infusion therapy regimen on the frequency of development of laboratory and clinical manifestations of fat embolism syndrome in patients after hip replacement. MATERIAL AND METHODS: The study was conducted in 80 patients (70 men and 10 women) who were admitted for planned revision hip arthroplasty. The criteria for not inclusion in the study were the presence of a traumatic brain injury, episodes of acute disturbance of blood supply (stroke) and diabetes mellitus in history. 40 patients of the main group during the operation were administered Gelofuzin and Sterofundin isotonic, and in the first day after the operation Remaxol and Sterofundin isotonic. Using the copy-steam method, a control group (n=40) out of 197 patients was selected by gender and age. In the control group, infusion therapy was carried out using a 0.9% NaCl solution. All patients underwent assessment of fat globulemia, water-electrolyte balance, acid-base status and oxygenation index - before surgery; 2, 24, 48, and 72 hours after the operation, on the third day, mental disorders were assessed using the Addenburg scale (ACE-R) for evaluating cognitive functions. RESULTS: All patients underwent hip joint endoprosthetics. In the group receiving the modified infusion therapy regimen, the results were significantly better, there were no statistically significant changes in the level of electrolytes (p=0.14), episodes of a decrease in the oxygenation index and cognitive dysfunction. In contrast to patients in the control group, where the level of chlorine and sodium was significantly higher, the number of fat globules with a diameter of more than 8 µm, as well as in two patients, the development of postoperative delirium with a decrease in the oxygenation index below 300 was observed. The causal relationship between the number of fat globules with a diameter of more than 8 microns and clinical manifestations of cerebral and pulmonary forms of fat embolism (r-Pirsen = -0.87 and -0.80, respectively). There were no statistically significant changes in platelet count, potassium concentration with indicators of fat globulemia and a scale of cognitive impairment. CONCLUSION: A high correlation of fatty globulemia with the development of respiratory and pulmonary dysfunction after hip replacement was determined. The inclusion of Gelofuzin, Sterofundin isotonic and Remaxol in intensive therapy provides a pronounced emulsifying effect on fat globules appearing in the bloodstream in the first hours after hip replacement, and effective prevention of potentially dangerous fat embolism.


Asunto(s)
Artroplastia de Reemplazo de Cadera/efectos adversos , Embolia Grasa/prevención & control , Gelatina/administración & dosificación , Fármacos Hematológicos/administración & dosificación , Succinatos/administración & dosificación , Embolia Grasa/etiología , Femenino , Humanos , Infusiones Intravenosas , Masculino , Compuestos Orgánicos/administración & dosificación , Reoperación
10.
Isr Med Assoc J ; 12(21): 812-816, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31814345

RESUMEN

BACKGROUND: The effect of repeated intravenous amantadine (IVAM) in advanced Parkinsonism has not been studied in depth. OBJECTIVES: To report the experience of our medical center with repeated IVAM infusions in patients with advanced Parkinsonism. METHODS: Thirty patients with advanced Parkinsonism of various etiologies were enrolled in an open-label retrospective study. All patients were treated with IVAM infusions in a neurological daycare center. Treatment was initiated with a loading dose of 200/400 mg per day for 5 days followed by a once-daily maintenance dose of 200/400 mg every 1 to 3 weeks. Patients and their caregivers participated in a structured interview and independently completed a clinical global impression of changes scale questionnaire on various motor and non-motor symptoms. RESULTS: Patient mean age was 73.3 ± 9.7 years, average disease duration was 6.2 ± 5.7 years, and mean Hoehn and Yahr score was 3.2 ± 0.84. Mean duration of the IVAM treatment was 15.1 ± 11.6 months. An improvement in general function was reported by 91% of the patients and 89% of the caregivers. Most of the patients reported improvement in tremor and rigidity, as well as in gait stability, freezing of gait, and reduced falls. The treatment was safe with few side effects. CONCLUSIONS: Our data suggest that repeated IVAM infusions could be an effective treatment against various motor symptoms and for improvement of mobility in patients with advanced Parkinsonism. Further randomized clinical trials with a larger sample size using objective measures are warranted to validate our results.


Asunto(s)
Accidentes por Caídas/prevención & control , Amantadina , Destreza Motora/efectos de los fármacos , Enfermedad de Parkinson , Recuperación de la Función/efectos de los fármacos , Anciano , Amantadina/administración & dosificación , Amantadina/efectos adversos , Progresión de la Enfermedad , Dopaminérgicos/administración & dosificación , Dopaminérgicos/efectos adversos , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Estudios Retrospectivos , Resultado del Tratamiento
11.
Epidemiol Psychiatr Sci ; 29: e79, 2019 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-31841104

RESUMEN

In March 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of esketamine for the treatment of resistant depression in adults. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations. While ketamine has not been approved for depression in the USA or in any other country, it has been used off-label in cases of severe depression. This commentary critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science.


Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Ketamina/uso terapéutico , Adulto , Antidepresivos/administración & dosificación , Depresión/diagnóstico , Trastorno Depresivo Resistente al Tratamiento/diagnóstico , Aprobación de Drogas , Medicina Basada en la Evidencia , Humanos , Infusiones Intravenosas , Ketamina/administración & dosificación , Estados Unidos , United States Food and Drug Administration
12.
Medicine (Baltimore) ; 98(51): e18311, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31860981

RESUMEN

BACKGROUND: Studies have shown the efficacy of norepinephrine in the treatment of maternal hypotension during cesarean section by comparing it to treatment with phenylephrine. However, few studies have compared the efficacy of norepinephrine to ephedrine. METHODS: Ninety-seven women undergoing elective cesarean section were administered norepinephrine at 4 µg/minute (group N; n = 48) or ephedrine at 4 mg/minute (group E; n = 49) immediately postspinal anesthesia, with an on-off titration to maintain systolic blood pressure (SBP) at 80% to 120% of baseline. A rescue bolus of 8 µg norepinephrine was given whenever SBP reached the predefined lower limit. Our primary outcome was the incidence of tachycardia. Secondary outcomes included the incidence of bradycardia, hypertension, hypotension, severe hypotension, hypotensive episodes, number of rescue top-ups, hemodynamic performance error including median performance error (MDPE), and median absolute performance error (MDAPE). Neonatal Apgar scores and umbilical arterial (UA) blood gas data were also collected. RESULTS: Women in group N experienced fewer cases of tachycardia (4.2% vs 30.6%, P = .002, odds ratio: 0.11 [95% confidence interval, CI: 0.02-0.47]), a lower standardized heart rate (HR) (70.3 ±â€Š11 vs 75 ±â€Š11, P = .04, difference: 4.7 ±â€Š2.2 [95% CI: 0.24-9.1]), and a lower MDPE for HR (1.3 ±â€Š9.6 vs 8.4 ±â€Š13.5 bpm, P = .003, difference: 3.1 ±â€Š1.8 [95% CI: -0.6-6.7]). In addition, the lowest or the highest HR was lower in group N compared to group E (both P < .05). Meanwhile, the standardized SBP in group N was lower than that in group E (P = .04). For neonates, the UA blood gas showed a higher base excess (BE) and a lower lactate level in group N compared to E (both P < .001). Other hemodynamic variables, maternal, and neonatal outcomes were similar. CONCLUSION: Infusion of 4 µg/minute norepinephrine presented fewer cases of tachycardia, less fluctuation and a lower HR compared to baseline values, as well as a less stressed fetal status compared to ephedrine infusion at 4 mg/minute. In addition, norepinephrine infusion presented a lower standardized SBP compared to ephedrine.


Asunto(s)
Anestesia Raquidea/métodos , Cesárea/efectos adversos , Efedrina/uso terapéutico , Hipotensión/prevención & control , Norepinefrina/uso terapéutico , Adulto , Anestesia Raquidea/efectos adversos , Presión Sanguínea/efectos de los fármacos , Cesárea/métodos , Método Doble Ciego , Efedrina/efectos adversos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipotensión/etiología , Infusiones Intravenosas , Norepinefrina/administración & dosificación , Embarazo
13.
Crit Care Resusc ; 21(4): 258-64, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31778632

RESUMEN

OBJECTIVE: To compare the physiological and biochemical effects of a single intravenous dose of furosemide or acetazolamide in critically ill patients. DESIGN: Single centre, pilot randomised controlled trial. SETTING: Large tertiary adult intensive care unit (ICU). PARTICIPANTS: Twenty-six adult ICU patients deemed to require diuretic therapy. INTERVENTION: Single dose of intravenous 40 mg furosemide or 500 mg acetazolamide. MAIN OUTCOME MEASURES: Data were collected on urine output, cumulative fluid balance, and serum and urine biochemistry for 6 hours before and 6 hours after diuretic administration. RESULTS: Study patients had a median age of 55 years (IQR, 50-66) and median APACHE III score of 44 (IQR, 37-52). Furosemide caused a much greater increase in-urine output and much greater median mass chloride excretion (121.7 mmol [IQR, 81.1-144.6] v 23.3 mmol [IQR, 20.4-57.3]; P < 0.01) than acetazolamide. Furosemide also resulted in a progressively more negative fluid balance while acetazolamide resulted in greater alkalinisation of the urine (change in median urinary pH, +2 [IQR, 1.75-2.12] v 0 [IQR, 0-0.5]; P = 0.02). In keeping with this effect, furosemide alkalinised and acetazolamide acidified plasma (change in median serum pH, +0.03 [IQR, 0.01-0.04] v -0.01 [IQR, -0.04 to 0]; P = 0.01; change in median serum HCO3-, +1.5 mmol/L [IQR, 0.75-2] v -2 mmol/L [IQR, -3 to 0]; P < 0.01). CONCLUSIONS: Furosemide is a more potent diuretic and chloriuretic agent than acetazolamide in critically ill patients, and achieves a threefold greater negative fluid balance. Compared with acetazolamide, furosemide acidifies urine and alkalinises plasma. Our findings imply that combination therapy might be a more physiological approach to diuresis in critically ill patients.


Asunto(s)
Acetazolamida/farmacología , Acetazolamida/farmacocinética , Enfermedad Crítica/terapia , Diuréticos/farmacología , Diuréticos/farmacocinética , Furosemida/farmacología , Furosemida/farmacocinética , Acetazolamida/administración & dosificación , Adulto , Anciano , Diuréticos/administración & dosificación , Electrólitos/sangre , Furosemida/administración & dosificación , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Proyectos Piloto , Resultado del Tratamiento , Urodinámica/efectos de los fármacos , Equilibrio Hidroelectrolítico/efectos de los fármacos
14.
N Engl J Med ; 381(24): 2293-2303, 2019 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-31774950

RESUMEN

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).


Asunto(s)
Alanina/análogos & derivados , Anticuerpos Monoclonales/uso terapéutico , Antivirales/uso terapéutico , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Ribonucleótidos/uso terapéutico , Adolescente , Adulto , Alanina/efectos adversos , Alanina/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Antivirales/efectos adversos , Niño , Preescolar , República Democrática del Congo/epidemiología , Brotes de Enfermedades , Ebolavirus/genética , Femenino , Fiebre Hemorrágica Ebola/mortalidad , Humanos , Lactante , Recién Nacido , Infusiones Intravenosas , Masculino , ARN Viral/sangre , Ribonucleótidos/efectos adversos , Método Simple Ciego , Adulto Joven
15.
N Engl J Med ; 381(22): 2103-2113, 2019 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-31774955

RESUMEN

BACKGROUND: The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. METHODS: In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death. RESULTS: A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant. CONCLUSIONS: In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).


Asunto(s)
Anticonvulsivantes/uso terapéutico , Levetiracetam/uso terapéutico , Fenitoína/análogos & derivados , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Benzodiazepinas/uso terapéutico , Niño , Preescolar , Método Doble Ciego , Resistencia a Medicamentos , Femenino , Humanos , Hipotensión/inducido químicamente , Infusiones Intravenosas , Inyecciones Intramusculares , Levetiracetam/efectos adversos , Masculino , Persona de Mediana Edad , Fenitoína/efectos adversos , Fenitoína/uso terapéutico , Ácido Valproico/efectos adversos , Adulto Joven
16.
J Surg Oncol ; 120(8): 1456-1461, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31680250

RESUMEN

BACKGROUND AND OBJECTIVES: Remifentanil infusion is used as an intraoperative anesthetic for thyroidectomy, but has been associated with acute opioid tolerance and hyperalgesia. A national shortage of remifentanil provided an opportunity to study postoperative pain in patients undergoing thyroidectomy. METHODS: Retrospective review of prospectively collected data from an outpatient surgery center. Primary analysis compared patients treated before and after remifentanil shortage. RESULTS: Median postoperative opioid consumption was 20 morphine milligram equivalents (MMEs) among those treated in the high-dose period and 15 MMEs in the low-dose period. Remifentanil/weight received was a significant predictor of requiring a postoperative narcotic (P = .006). Total non-remifentanil narcotics administered were equivalent but patients in the low dose period received higher amounts of intraoperative long-acting narcotics. CONCLUSIONS: Remifentanil infusion for thyroid surgery is associated with higher postoperative pain and postoperative narcotics requirement. While a hyperalgesia state is possible, shifting of longer-acting narcotics from intraoperative to postoperatively is also supported.


Asunto(s)
Analgésicos Opioides/administración & dosificación , Utilización de Medicamentos/estadística & datos numéricos , Dolor Postoperatorio/tratamiento farmacológico , Remifentanilo/administración & dosificación , Tiroidectomía , Adulto , Procedimientos Quirúrgicos Ambulatorios , Femenino , Humanos , Infusiones Intravenosas , Cuidados Intraoperatorios , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Alta del Paciente , Periodo Posoperatorio , Estudios Retrospectivos
17.
Intern Med ; 58(21): 3173-3178, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31685786

RESUMEN

Diffuse proliferative lupus nephritis (DPLN) is a serious organ complication. Drug resistance correlates with P-glycoprotein (P-gp) expression on activated lymphocytes. We encountered a refractory DPLN patient with expansion of peripheral CD69/CXCR3-co-expressing P-gp+CD4+ cells producing IL-2 and IL-6. Treatment with high-dose corticosteroid combined with biweekly intravenous cyclophosphamide pulse therapy (IVCY) failed to reduce the population of activated P-gp+CD4+ cells or control the disease activity. Methotrexate (MTX) with monthly IVCY reduced activated P-gp+CD4+ cells and improved the clinical symptoms, resulting in long-term remission and tapering of corticosteroids. MTX-IVCY combination therapy, which down-regulates the activated P-gp+CD4+ cell-mediated disease activity, may be useful for the treatment of refractory DPLN.


Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Metotrexato/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Intravenosa , Adulto , Esquema de Medicación , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Infusiones Intravenosas
19.
Medicine (Baltimore) ; 98(48): e17983, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31770207

RESUMEN

BACKGROUND: The anesthetic-sparing effect of dexmedetomidine has led to its use as a general adjuvant. The present study aimed to determine intravenous infusion of dexmedetomidine to epidural analgesia after open thoracotomy. METHODS: Forty-four patients scheduled for admission to the intensive care unit after open thoracotomy were divided into 2 groups. An epidural catheter was placed at T4 to T7. Thirty minutes before the end of thoracotomy, group D was injected with 0.3 µg/kg/h of dexmedetomidine and group C received an equal dose of normal saline. For patient-controlled epidural analgesia (PCEA), 150 mL of levobupivacaine 300 mg was infused at a rate of 1 mL/h, plus a bolus dose of 3 mL with a lockout time of 30 minutes. The primary outcome evaluated was analgesic efficacy using a visual analog scale (VAS) 48 hours postoperatively. Other outcomes included additional analgesic use, total consumed local analgesia via PCEA, sedation score, blood pressure, heart rate, arterial blood gases, patient satisfaction, and adverse effects. RESULTS: The VAS scores in group D were significantly lower than that in group C immediately, 1, 4, 12, 36, and 48 hours after admission to the intensive care unit (P = .016, .009, .015, .002, .001, and .042, respectively). The total dose of additional analgesic was also significantly lower in group D (P = .011). Patient satisfaction was higher in group D (P < .05). There were no significant differences in the other outcomes between groups. CONCLUSION: Intravenous infusion of dexmedetomidine amplifies thoracic epidural analgesic effect after open thoracotomy.


Asunto(s)
Analgesia Epidural/métodos , Analgésicos no Narcóticos/administración & dosificación , Dexmedetomidina/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Toracotomía/efectos adversos , Anciano , Analgesia Controlada por el Paciente/métodos , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Levobupivacaína/administración & dosificación , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Estudios Prospectivos , Vértebras Torácicas , Toracotomía/métodos , Resultado del Tratamiento
20.
Am Surg ; 85(10): 1171-1174, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31657318

RESUMEN

Avoiding excess fluid administration is necessary when managing critically ill surgical patients. The aim of this study was to delineate the current practices of IV electrolyte (IVE) replacement in a surgical ICU and quantify their contribution to the fluid balance (FB) status. Patients admitted to the surgical ICU over a six-month period were reviewed. Patients undergoing dialysis and those with ICU stay <72 hours were excluded. A total of 248 patients were included. The median age was 60 years, and 57 per cent were male. Overall, 1131 patient ICU days were analyzed. The median daily FB was 672 mL. IVEs were administered in 62 per cent of ICU days. In days that IVEs were used, negative FB was significantly less likely to be achieved (62% vs 69%, P = 0.02). The most commonly administered IVE was calcium (32% of ICU days); however, the largest volume of IVE was administered in the form of phosphorus (median 225 mL). Diuretics were administered in 17 per cent of ICU days. Patients who received diuretics were significantly more likely to receive IVE (70% vs 61%, P = 0.02). Administration of IVE may contribute to the daily positive FB of surgical ICU patients. Implementation of practices that can ameliorate this effect is encouraged.


Asunto(s)
Enfermedad Crítica , Electrólitos/administración & dosificación , Infusiones Intravenosas/métodos , Procedimientos Quirúrgicos Operativos , Equilibrio Hidroelectrolítico , Calcio/administración & dosificación , Diuréticos/administración & dosificación , Femenino , Fluidoterapia/efectos adversos , Fluidoterapia/métodos , Humanos , Infusiones Intravenosas/estadística & datos numéricos , Unidades de Cuidados Intensivos , Sulfato de Magnesio/administración & dosificación , Masculino , Persona de Mediana Edad , Fósforo/administración & dosificación , Potasio/administración & dosificación , Estudios Retrospectivos
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