Cardiac output and the pharmacology of general anesthetics: a narrative review

The relationship between cardiac output and anesthetic drugs is important to anesthesiologists, since cardiac output determines the speed with which a drug infused into the bloodstream reaches its target and the intensity of the drug's effect. But rather than focus on how anesthetic drugs affect cardiac output, this narrative review focuses on how changes in cardiac output affect the pharmacokinetics and pharmacodynamics of general anesthetics during the three phases of anesthesia. At induction, an increase in cardiac output shortens both the onset time of propofol for hypnosis and the neuromuscular blocking effect of rapid-acting neuromuscular blockers, favoring the conditions for rapid sequence intubation. During maintenance, changes in cardiac output are followed by opposite changes in the drug plasma concentration of anesthetic drugs. Thus, an increase in cardiac output followed by a decrease in the plasma concentration of the anesthetic could expose the patient to a real risk of intraoperative awakening, which can be avoided by increasing the dose of hypnotic drugs. At emergence, an increase in cardiac output secondary to an increase in pC02 allows for a more rapid recovery from anesthesia. The pC02 can be increased by adding CO2 to the respiratory circuit, lowering the ventilatory rate, or placing the patient on partial rebreathing. Finally, the reversal action of sugammadex for rocuronium-induced neuromuscular block can be shortened by increasing the cardiac output.

La relación entre el gasto cardíaco y los fármacos anestésicos es importante para los anestesiólogos puesto que el gasto cardíaco determina la velocidad con la cual un medicamento que se infunde al torrente sanguíneo llega a su diana y la intensidad del efecto del agente. Pero en lugar de concentrarnos en cómo los fármacos anestésicos afectan el gasto cardíaco, esta revisión narrativa se enfoca en cómo los cambios en el gasto cardíaco afectan la farmacocinética y la farmacodinámica de los agentes anestésicos generales durante las tres fases de la anestesia. En el momento de la inducción, un incremento en el gasto cardíaco acorta tanto el tiempo de inicio del efecto del propofol para la hipnosis como el efecto del bloqueo neuromuscular causado por los bloqueadores neuromusculares de acción rápida, favoreciendo las condiciones para la intubación de secuencia rápida. Durante la fase de mantenimiento, los cambios en el gasto cardíaco vienen seguidos de cambios opuestos en la concentración plasmática del medicamento de los agentes anestésicos. Por lo tanto, un aumento del gasto cardíaco, seguido de una reducción en la concentración plasmática del anestésico, podría exponer al paciente a un riesgo real de despertar intraoperatorio, lo cual puede evitarse aumentando la dosis de los fármacos hipnóticos. En la educción, un aumento en el gasto cardíaco secundario al incremento en el pCO2 permite una recuperación más rápida de la anestesia. El pCO2 puede aumentar agregando CO2 al circuito de la respiración, reduciendo la tasa ventilatoria, o colocando al paciente en re-inhalación parcial. Finalmente, la acción de reversión de sugammadex en caso de bloqueo neuromuscular inducido por rocuronio, puede acortarse aumentando el gasto cardíaco.

Evaluation of a closed-loop intravenous total anesthesia delivery system with BIS monitoring compared to an open-loop target-controlled infusion (TCI) system: randomized controlled clinical trial / Evaluación de un sistema de administración de Anestesia Total Intravenosa en lazo cerrado con neuromonitoría, comparado con un sistema de lazo abierto de infusión controlada por objetivo (TCI): Ensayo clínico controlado

Abstract Introduction: Intravenous general anesthesia is an anesthetic technique that can be administered with TCI (target-controlled infusion) or closed-loop systems. The authors designed an automatic delivery system using clinical variables such as bispectral index (BIS), heart rate, and blood pressure. Objective: To evaluate the clinical and technical performance of this controller by comparing it to a TCI system. Methods: This was a single-blind, randomized, controlled clinical trial in which 150 patients were recruited: 75 for the TCI group and 75 for the closed loop with BIS. Clinical performance was determined according to the mean percentage of time spent in the BIS range of 40 to 60 during anesthetic maintenance. In addition, adequate intraoperative analgesia, technical performance, intraoperative awakening, and intraoperative recall were evaluated. Results: The primary outcome showed a mean BIS time between 40 and 60 for the closed loop of 75.24% (± 15.78) versus 59.5% (± 20.3) for the TCI system, with an absolute difference of 15.8%, 95% confidence interval (CI): 9.9 to 21.65, P < 0.0001. The mean time in intraoperative analgesia was 82.4% (25.1) in closed loop and 70.77% (± 32.8) in TCI, with a difference of 4.76 (95% CI: 2.23-21.06), P = 0.016. There was no difference in intraoperative recall. Conclusion: The closed-loop system was better at maintaining a BIS in the range of 40 to 60 during a general anesthetic than the open system or TCI.

Resumen Introducción: La anestesia total endovenosa es una técnica anestésica que puede administrarse con sistemas de TCI (Target Controlled Infusión) o de lazo cerrado. Los autores diseñaron un sistema de administración automática empleando variables clínicas como índice biespectral (BIS), frecuencia cardiaca y presión arterial. Objetivo: Evaluar el desempeño clínico y técnico de este controlador, comparándolo con un sistema de TCI. Métodos: Este fue un ensayo clínico controlado, aleatorizado y de ciego único, en el cual se reclutaron 150 pacientes: 75 en el grupo de TCI y 75 en lazo cerrado con BIS. El desempeño clínico fue determinado de acuerdo al porcentaje promedio de tiempo de permanencia en el rango de BIS entre 40-60 durante el mantenimiento anestésico. Adicionalmente se evaluó analgesia intraoperatoria adecuada, desempeño técnico, despertar intraoperatorio y recuerdo intraoperatorio. Resultados: Para el desenlace primario se encontró un tiempo promedio de BIS entre 40-60 para el lazo cerrado de un 75.24% (+/-15.78) vs. 59.5% (+/- 20.3) para el sistema TCI, con una diferencia del 15.8%, IC del 95%: 9.9 a 21.65, p < 0.0001. El promedio de tiempo en analgesia intraoperatoria adecuada fue del 82.4% (25.1) en lazo cerrado y 70.77% (+/- 32.8) en TCI, con una diferencia de 4.76 (IC del 95%: 2.23 a 21.06), p=0.016. No hubo diferencias en recuerdo intraoperatorio. Conclusión: El sistema de lazo cerrado fue mejor para mantener un BIS en rango de 40-60 durante un acto anestésico que el sistema abierto o TCI.

Remifentanilo versus propofol con infusión controlada a objetivo en sitio efecto para la sedación de pacientes durante procedimientos endoscópicos gastrointestinales: ensayo clínico controlado aleatorizado / Remifentanil vs. propofol controlled infusion for sedation of patients undergoing gastrointestinal endoscopic procedures: A clinical randomized controlled clinical trial

Contexto: La administración de sedación con sistemas de infusión controlada a objetivo (TCI) podría ofrecer una alternativa segura para el manejo del malestar de los pacientes llevados a procedimientos endoscópicos gastrointestinales. Sin embargo, no se conoce qué medicamento de los disponibles para TCI es el más apropiado. El objetivo del estudio fue comparar remifentanilo y propofol en TCI para la sedación de pacientes durante procedimientos endoscópicos gastrointestinales. Materiales y métodos: Sesenta y nueve pacientes que requerían un procedimiento endos-cópico gastrointestinal fueron asignados aleatoriamente a recibir una TCI en sitio efecto (TCIe) de remifentanilo (n = 30) o propofol (n = 39). El desenlace primario fue la satisfacción del paciente. Los desenlaces secundarios incluyeron la satisfacción del gastroenterólogo, se compararon las proporciones de eventos adversos entre los 2 grupos (ocurrencia de arritmias cardiacas, depresión respiratoria leve, depresión respiratoria mayor, bradicardia, hipotensión, dolor, náuseas o vómitos, y ausencia de amnesia) y el nivel de consciencia. Número de registro retrospectivo: NCT01746641. Resultados: Las medianas (rango) de satisfacción del paciente entre remifentanilo y propofol fueron 1 (1-2) y 2 (1-4), respectivamente (Chi², p< 0,001). Se encontraron diferencias en la ocurrencia de dolor durante el procedimiento (mediana 2 vs. 1, Chi², p = 0,042), náuseas o vómito (4 vs. 0, Chi², p = 0,01), y ausencia de amnesia (29 vs. 10, Chi², p<0,001) entre remifentanilo y propofol, respectivamente. Para las otras variables estudiadas no se encontraron diferencias estadísticamente significativas entre los grupos. Conclusión: El propofol en TCIe parece ser un medicamento adecuado para la sedación de pacientes durante procedimientos endoscópicos gastrointestinales, y presentó menores efectos adversos y mayor satisfacción del paciente. Es probable que con la sinergia de estos 2 medicamentos se pudiera lograr disminuir aún más los efectos adversos.

Background: Target controlled infusion (TCI) for the administration of anesthesia may provide a safe alternative for managing the discomfort of patients undergoing gastrointestinal endoscopic procedures. However, the most appropriate drug available for TCI is yet to be established. The objective of this trial was to comparemifentanil vs. propofol in TCI for sedating patients during GI endoscopy. Materials and methods: Sixty-nine patients requiring GI endoscopies were randomly distributed to receive remifentanil (n = 30) or propofol (n = 39) TCI at the effect site (e). The primary outcome was patient’s satisfaction. Secondary outcomes included the gastroenterologist satisfaction, comparison of the percentage of adverse events between the two groups (occurrence of arrhythmias, major respiratory depression, bradycardia, hypotension, pain, nausea or vomiting and absence of amnesia), and the level of awareness. Retrospective registration number is NCT01746641 at Clinicaltrials.gov. Results: The mean (range) of patient satisfaction with remifentanil vs propofol was 1 (1-2) and 2 (1-4), respectively ([1]2, p < 0,001). Pain during the procedurewas found to differ between remifentanil and propofol (mean 2 vs. 1, [1]2, p = 0,042), nausea or vomiting (4 vs. 0, [1]2, p = 0,01), and absence of amnesia (29 vs. 10, [1]2, p < 0,001), respectively. No statistically significant differences were found between the two groups. Conclusion: Propofol in TCI seems to be an adequate agent for sedation of patients undergoing GI endoscopic procedures, with less adverse effects and higher patient satisfaction. Most likely, the combination of these two drugs may be synergistic and further reduce any adverse effects.

Metabolic and oxidative effects of sevoflurane and propofol in children undergoing surgery for congenital heart disease / Efeitos metabólicos e oxidativos do sevoflurano e do propofol em crianças portadoras de cardiopatia congênita submetidas à cirurgia

PURPOSE: To evaluate the metabolic and oxidative effects of sevoflurane and propofol in children undergoing surgery for correction of congenital heart disease. METHODS: Twenty children with acyanotic congenital heart disease, scheduled for elective cardiac surgery with cardiopulmonary bypass, age range 1 day to 14 years were randomly assigned to 2 groups: Group GP, programmed to receive total intravenous anesthesia with propofol and group GS scheduled to use balanced anesthesia with sevoflurane. Exclusion criteria were cyanotic heart disease or complex, association with other malformations, severe systemic diseases, infection or children undergoing treatment and palliative or emergency surgery. Blood samples were collected at three different time-points: T0, after radial artery cannulation, T1, 30 minutes after cardiopulmonary bypass (CPB) launch and T2, at the end of procedure. Parameters analyzed included thiobarbituric acid-reactive substance (TBARS), glutathione (GLN), lactate and pyruvate plasmatic concentrations. RESULTS: TBARS, GSH, lactate and pyruvate concentrations did not change significantly by Friedman´s test. Lactate/pyruvate ratio (L/P) was >10 in both groups. There was a moderate Pearson correlation for TBARS, in T1 (r=0.50; p=0.13) e T2 (r=0.51;p=0.12). Pearson correlation was high between groups during CPB (T1) for lactate (r=0.68; p=0.02), pyruvate (r=0.75; p=0.01) and L/P ratio (r=0.83; p=0.003). CONCLUSION: Anesthetic techniques investigated in this study showed a similar pattern, with no increase in metabolic substrates and oxidative stress during surgical correction of congenital heart defects in non-cyanotic children.

OBJETIVO: Avaliar os efeitos metabólicos e oxidativos da anestesia com sevoflurano ou propofol em crianças portadoras de cardiopatia congênita, submetidas à cirurgia eletiva. MÉTODOS: Vinte crianças com cardiopatia congênita acianótica, agendadas para a cirurgia cardíaca eletiva com circulação extracorpórea (CEC), idades 1 dia-14 anos, foram distribuídas aleatoriamente em dois grupos: Grupo GP (anestesia venosa total com propofol) e grupo GS (anestesia balanceada com sevoflurano). Critérios de exclusão foram: doença cardíaca cianótica ou complexa, associação com outras malformações, doença sistêmica grave, infecção ou crianças submetidas a tratamento e cuidados paliativos ou cirurgia de emergência. Amostras de sangue foram coletadas em três horários diferentes: T0, após a canulação da artéria radial, T1, 30 minutos após o início da CEC e T2, no final do procedimento. Parâmetros analisados: substâncias reativas ao ácido tiobarbitúrico (TBARS), glutationa (GLN), lactato e piruvato. RESULTADOS: As concentrações de TBARS, GSH, lactato e piruvato não foram diferentes (teste de Friedman). A razão Lactato/piruvato (L/P) foi >10 em ambos os grupos. Houve uma correlação de Pearson moderada no TBARS, em T1 (r = 0,50, p = 0,13) e T2 (r = 0,51, p = 0,12). A correlação de Pearson foi alta entre os grupos durante a CEC (T1) para lactato (r=0,68, p=0,02), piruvato (r=0,75, p=0,01) e relação L/P (r =0,83, p=0,003). CONCLUSÃO: As técnicas anestésicas investigadas mostraram um padrão semelhante, sem aumento de substratos metabólicos ou do estresse oxidativo durante a correção cirúrgica de cardiopatias congênitas em crianças acianóticas.

Efeito do propofol associado à efedrina no tempo de latência do cisatracúrio / Effect of propofol in combination with ephedrine upon the onset time of cisatracurium

OBJETIVOS: Este estudo teve por objetivo avaliar a eficácia da efedrina na prevenção dos efeitos hemodinâmicos induzidos pela associação do propofol e do remifentanil, assim como os efeitos sobre o tempo de latência do cisatracúrio. MÉTODOS: Sessenta pacientes com idade entre 18 e 52 anos, estado físico ASA I ou II, foram divididos em três grupos, aleatoriamente: G I - propofol 1 por cento; G II - propofol 1 por cento + efedrina 0,5 mg.ml-1 e G III - propofol 1 por cento + efedrina 1,0 mg.ml-1 (velocidade de infusão igual a 180 ml.h-1), até a perda da consciência. Administrou-se remifentanil (0,5 mg.kg-1.min-1) e cisatracúrio na dose de 0,15 mg.kg-1. Foram registrados os dados demográficos, os sinais vitais (PAS, PAM, PAD, FC e SpO2) e o tempo de latência do cisatracúrio. RESULTADOS: Os grupos foram homogêneos com relação aos dados demográficos. Houve diminuição estatisticamente significativa dos valores de PAS, PAM, PAD e FC, um e três minutos após a administração do propofol, porém sem significado clínico importante e sem diferença entre os grupos. As medianas para os tempos de latência do cisatracúrio foram: 178 s (G2 e G3) e 183 s (G1), mas sem diferença significante entre os grupos. CONCLUSÃO: Não houve diminuição clinicamente importante dos parâmetros hemodinâmicos avaliados nos grupos que receberam ou não a efedrina e o tempo de latência do cisatracúrio foi o mesmo para os diferentes grupos.

OBJECTIVE: The onset time of neuromuscular blocking drugs is partially determined by circulatory factors, including muscle blood flow and cardiac output. The aim of the present paper was to: 1) compare the haemodynamic effects of adding different doses of ephedrine to an induction dose of propofol and remifentanil. 2) onset time of cisatracurium. METHODS: Sixty patients were randomly allocated into three groups: G1 - 1 percent propofol; G2 - 1 percent propofol + 0.5 mg.ml-1 ephedrine and G3 - 1 percent propofol + 1.0 mg.ml-1 ephedrine. All patients received continuous infusion of remifentanil (0.5 mg.kg-1.min-1). The rate of propofol infusion was 180 ml.h-1 until loss of consciousness and a loading dose of cisatracurium (0.15 mg.kg-1) was then given. After induction of anesthesia, the ulnar nerve was stimulated supramaximally every 10s, and the evoked twitch response of the adductor pollicis was recorded by accelerometry. RESULTS: There was no statistical difference between groups with respect to age, weight, dose of propofol administered and onset time of cisatracurium (tables 1, 2). Heart rate, SpO2, systolic, diastolic and mean blood pressures were compared at 1 and 3 min post-induction. There were statistical differences in HR, SAP, DAP and MAP, without significant adverse clinical effects. CONCLUSIONS: There were no clinically important decreases in the hemodynamic parameters evaluated in the groups receiving ephedrine or not, and the onset time of cisatracurium was the same for all groups.

Anestesia en la ventana aorto-pulmonar

Se realiza un estudio retrospectivo de 9 niños menores de 2 años operados de ventana aorto-pulmonar en el Cardiocentro del Hospital Pediátrico Docente "William Soler", durante el período de 1986 a 1994. El fentanyl fue el agente más utilizado en la inducción de la anestesia (8 pacientes, 89 %) y se empleó en todos los pacientes durante el mantenimiento, lo que aportó gran estabilidad hemodinámica. Las complicaciones encontradas fueron el síndrome de bajo gasto cardíaco, broncoespasmo, hipertensión pulmonar y arritmias cardíacas. En todos los pacientes se utilizó el protocolo para el manejo de la hipertensión pulmonar. No hubo fallecidos durante el transoperatorio ni en el posoperatorio inmediato.

A retrospective study of 9 children under 2 operated on of aorto-pulmonary window at the Heart Center of "William Soler" Pediatric Teaching Hospital from 1986 to 1994 was conducted. Fentanyl was the most used agent in the induction of anesthesia (8 patients, 89 %) and it was administered to all patients during maintenance, which made possible a great hemodynamic stability. The complications found were the syndrome of low cardiac output, bronchospasm, pulmonary hypertension and cardiac arrhythmias. The protocol for the management of pulmonary hypertension was used with all patients. Deaths were not reported either during the transoperative or in the immediate postoperative.