Luis Otávio Esteves

Pharmacodynamic Evaluation and Physical/Chemical Analysis of Two Formulations of Propofol used in Target-Controlled Infusion

BACKGROUND AND OBJECTIVES There are several formulations of propofol available to the anesthesiologist for clinical use. The aim of this study was to analyze the physicochemical properties, pharmacodynamic effect, and pharmaceutical and clinical equivalence of the reference drug propofol as well as a similar formulation. METHOD Sixteen volunteers were enrolled in this randomized, double-blind, and paired study of Diprivan and Propovan formulations. Formulations were given as target-controlled infusion with target concentration of 3.0 μg.mL(-1) for 15 minutes. Variables studied were the area under the curve (AUC) of the bispectral index (BIS) graph regarding time, minimum BIS reached and time to reach it, and recovery time. The two formulations were sent to analysis of particle size of lipid emulsion, surface potential, and active principle quantification. RESULTS There was no difference between the formulations when comparing AUC, minimum BIS reached and time to reach it. The similar formulation recovery time was lower compared to the reference formulation (eight and 10 min, respectively, p=0.014). Mean particle size of lipid emulsion, surface potential, and active ingredient quantification were similar for both formulations. CONCLUSION There was no clinically significant difference between the use of propofol, reference Diprivan, and the similar Propovan during infusion. However, the recovery time was longer with the reference drug. Although analysis of both formulations studied show similar results regarding its physicochemical characterization, further studies should be conducted to justify this difference.

Clinical Evaluation of Two Ke0 in the same Pharmacokinetic Propofol Model: Study on Loss and Recovery of Consciousness

BACKGROUND AND OBJECTIVE The constant equilibrium between the plasma and effect site (ke0) is used by pharmacokinetic models to calculate a drug concentration in its site of action (Ce). It would be interesting if Ce of propofol was similar at loss and recovery of consciousness. The objective of this study was to evaluate the clinical performance of two different ke0 (fast = 1.21 min(-1), and slow = 0.26 min(-1)) in relation to Ce during loss and recovery of consciousness using Marsh pharmacokinetic model. METHODS Twenty healthy adult male volunteers participated in this study. In all volunteers propofol was administered as target-controlled infusion, Marsh pharmacokinetic model for fast ke0 and, at a different time, the same pharmacokinetic model with slow ke0 was used. Initially, propofol was infused with a serum target-controlled infusion of 3.0 μg.mL(-1). Loss of consciousness and recovery of consciousness were based on response to verbal stimulus. Ce was recorded at the moment of loss and recovery of consciousness. RESULTS On loss and recovery of consciousness, the Ce for fast ke0 was different (3.64 ± 0.78 and 1.47 ± 0.29 μg.mL(-1), respectively, p < 0.0001), while with slow ke0 the Ce was similar (2.20 ± 0.70 and 2.14 ± 0.43 μg.mL(-1), respectively, p = 0.5425). CONCLUSIONS Clinically, the slow ke0 (0.26 min(-1)) incorporated in the Marsh pharmacokinetic model showed better performance than the fast ke0 (1.21 min(-1)), since the calculated concentration of propofol at the effect site on loss and recovery of consciousness was similar.

Avaliação farmacodinâmica e análise físico-química de duas formulações de propofol usadas em infusão alvo-controlada

JUSTIFICATIVA E OBJETIVOS: Existem varias formulacoes de propofol para uso clinico a disposicao do anestesiologista. O objetivo desse estudo foi analisar as propriedades fisico-quimicas, o efeito farmacodinâmico e a equivalencia farmaceutica e clinica do farmaco referencia de propofol e uma formulacao similar. METODOS: Dezesseis voluntarios participaram desse estudo aleatorio, duplamente encoberto e pareado entre as formulacoes Diprivan® e Propovan®. As formulacoes foram administradas em regime de infusao alvo-controlada com concentracao-alvo de 3,0 µg.mL-1 por 15 minutos. As variaveis estudadas foram a area sob a curva (ASC) do grafico do indice bispectral (BIS) em relacao ao tempo, o BIS minimo atingido e o tempo para tal e o tempo de recuperacao. As duas formulacoes foram submetidas as analises de tamanho de particulas da emulsao lipidica, potencial de superficie e quantificacao de principio ativo. RESULTADOS: Nao houve diferenca entre as formulacoes quando se comparou a ASC, BIS minimo atingido e o tempo decorrido para tal. O tempo de recuperacao com a formulacao similar foi menor em relacao a referencia (oito e 10 min, respectivamente, p = 0,014). O tamanho medio de particulas da emulsao lipidica, potencial de superficie e a quantificacao de principio ativo foram semelhantes nas duas formulacoes. CONCLUSAO: Nao houve diferenca clinica significativa entre o uso de propofol referencia Diprivan® e seu similar Propovan® durante a infusao. Entretanto, o tempo de recuperacao foi mais prolongado com o farmaco referencia. Embora as analises com as duas formulacoes estudadas mostrarem resultados semelhantes quanto a sua caracterizacao fisico-quimica, outros estudos devem ser realizados para justificar tal diferenca.

Efficacy of Continuous S(+)-Ketamine Infusion for Postoperative Pain Control: A Randomized Placebo-Controlled Trial

Aim. A double-blind, randomized, placebo-controlled trial was designed to evaluate the efficacy of continuous intraoperative infusion of S(+)-ketamine under intravenous anesthesia with target-controlled infusion of remifentanil and propofol for postoperative pain control. Methods. Forty-eight patients undergoing laparoscopic cholecystectomy were assigned to receive continuous S(+)-ketamine infusion at a rate of 0.3 mg·kg−1·h−1 (n = 24, intervention group) or an equivalent volume of saline at the same rate (n = 24, placebo group). The same target-controlled intravenous anesthesia was induced in both groups. Pain was assessed using a 0 to 10 verbal numeric rating scale during the first 12 postoperative hours. Pain scores and morphine consumption were recorded in the postanesthesia care unit (PACU) and at 4 and 12 hours after surgery. Results. Pain scores were lower in the intervention group at all time points. Morphine consumption did not differ significantly between groups during PACU stay, but it was significantly lower in the intervention group at each time point after PACU discharge (P = 0.0061). At 12 hours after surgery, cumulative morphine consumption was also lower in the intervention group (5.200 ± 2.707) than in the placebo group (7.525 ± 1.872). Conclusions. Continuous S(+)-ketamine infusion during laparoscopic cholecystectomy under target-controlled intravenous anesthesia provided better postoperative pain control than placebo, reducing morphine requirement. Trial Registration. This trial is registered with ClinicalTrials.gov NCT02421913.

Avaliação clínica de duas ke0 no mesmo modelo farmacocinético de propofol: estudo da perda e recuperação da consciência

JUSTIFICATIVA Y OBJETIVOS: La constante de equilibrio entre el plasma y el sitio efector (ke0), se usa por los modelos farmacocineticos para prever la concentracion del farmaco en su region de accion (Ce). Seria interesante que el Ce de propofol fuese similar en la perdida y en la recuperacion de la conciencia. El objetivo de este estudio, fue evaluar el desempeno clinico de dos diferentes ke0 (rapida = 1,21 min-1 y lenta = 0,26 min-1), con relacion a la Ce durante la perdida y la recuperacion de la conciencia, usando el modelo farmacocinetico de Marsh. MeTODO: Participaron en este estudio, 20 voluntarios adultos sanos del sexo masculino. A todos los voluntarios se les administro propofol en regimen de infusion objeto controlada, modelo farmacocinetico de Marsh ke0 rapida y en otro momento, se uso el mismo modelo farmacocinetico con a ke0 lenta. Inicialmente, el propofol se infundio en concentracion-objeto plasmatica de 3,0 µg.mL-1. La perdida de la conciencia y la recuperacion de la conciencia estuvieron basadas en la respuesta al estimulo verbal. La Ce fue anotada en el momento de la perdida y de la recuperacion de la conciencia. RESULTADOS: En la perdida y en la recuperacion de la conciencia, la Ce por la ke0 rapida, fue diferente (3,64 ± 0,78 y 1,47 ± 0,29 µg.mL-1, respectivamente, p < 0,0001), mientras que con la ke0 lenta la Ce fue parecida (2,20 ± 0,70 y 2,13 ± 0,43 µg.mL-1, respectivamente, p = 0,5425). CONCLUSIONES: Desde el punto de vista clinico, la ke0 lenta (0,26 min-1) incorporada al modelo farmacocinetico de Marsh, presento un mejor desempeno que la ke0 rapida (1,21 min-1), pues la concentracion de propofol prevista en su region de accion en la perdida y en la recuperacion de la conciencia fue similar.

Estudo comparativo entre indução rápida e lenta de propofol em infusão alvo-controlada: concentração de propofol prevista no local de ação. Ensaio clínico aleatório

BACKGROUND AND OBJECTIVE studies have shown that rate of propofol infusion may influence the predicted propofol concentration at the effect site (Es). The aim of this study was to evaluate the Es predicted by the Marsh pharmacokinetic model (ke0 0.26min(-1)) in loss of consciousness during fast or slow induction. METHOD the study included 28 patients randomly divided into two equal groups. In slow induction group (S), target-controlled infusion (TCI) of propofol with plasma, Marsh pharmacokinetic model (ke0 0.26min(-1)) with target concentration (Tc) at 2.0-μg.mL(-1) were administered. When the predicted propofol concentration at the effect site (Es) reached half of Es value, Es was increased to previous Es + 1μg.mL(-1), successively, until loss of consciousness. In rapid induction group (R), patients were induced with TCI of propofol with plasma (6.0μg.ml(-1)) at Es, and waited until loss of consciousness. RESULTS in rapid induction group, Tc for loss of consciousness was significantly lower compared to slow induction group (1.67±0.76 and 2.50±0.56μg.mL(-1), respectively, p=0.004). CONCLUSION the predicted propofol concentration at the effect site for loss of consciousness is different for rapid induction and slow induction, even with the same pharmacokinetic model of propofol and the same balance constant between plasma and effect site.

Case of anaphylaxis induced by rocuronium treated with sugammadex

First, I would like to congratulate the authors for the article entitled “Case of Anaphylaxis Induced by Rocuronium Treated with Sugammadex”, recently published in the Revista Brasileira de Anestesiologia (Brazilian Journal of Anesthesiology). While reading the article, two points deserving some considerations were noted. First, an anaphylactic reaction was reported after rocuronium administration; however, as described by the author himself, it is impossible to differentiate an anaphylactic from an anaphylactoid reaction based only on clinical data. Differential diagnosis is made by laboratory tests. The author cited an article reporting a similar case in which differential diagnosis was made, and thus the term “anaphylaxis” may use. The second observation relates to the time of medications used. In the third paragraph of the Case Report section, it is reported that immediately after intubation signs of a possible allergic reaction were noted and treatment initiated. Doses of epinephrine (0.30 mg) were used, repeated every 5 minutes, totaling 1.5 mg of this medication. In the next paragraph, the authors report that 700 mg of sugammadex were used 5 minutes after administration of rocuronium, followed by another dose of epinephrine (0.30 mg). Finally, in the fifth paragraph of the Discussion section, it is reported that sugammadex was administered 25 minutes after rocuronium. Thus, it is clear that there is an inconsistency in the administration times of medications and, hence, in total dose of adrenaline. Due to the great importance of the subject and high mortality of this complication, data description requires accuracy in order to become an aid tool for future cases.

Total intravenous anesthesia (TIVA) in an infant with Werdnig-Hoffmann disease: case report

Resumen: Esteves LO – Anestesia Venosa Total (AVT) en Lactante con Enfer - medad de Werdnig-Hoffmann. Relato de Caso. Rev Bras Anestesiol 2010; 60:2:170-175.Fue con un gran interes que lei el articulo “Anestesia Venosa Total (AVT) en Lactante con Enfermedad de Werdnig-Hoffmann. Relato de Caso”, de Resende y col. 1 , publicado en esta revista. Y de hecho quiero, en primer lugar, felicitar a los autores por la iniciativa. Sin embargo, dos puntos me llamaron la atencion. El primero, se refiere a la definicion de lactante, la cual abarca el periodo de 1 a 12 meses de edad. A partir de los 12 meses, se define como preescolar o apenas como nino. En el articulo, el autor coloca la edad del paciente como de 1 ano, pero no especifica meses o dias. Tal vez, ese paciente tenga mas de 12 meses y entonces la definicion de lactante seria inadecuada. El segundo y el mas importante de mis cuestionamientos, versa sobre la tecnica usada y sobre el titulo del articulo. En el titulo, se uso la expresion “anestesia venosa total”, pero en el relato se dijo que, ademas del propofol y del remifentanil, la anestesia se mantuvo con oxigeno y N