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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.54 no.5 Campinas Sept./Oct. 2004
Intravenous isoflurane in lipid emulsion promotes cardiovascular and respiratory stability. Experimental model*
Isoflurano en emulsión lipídica por vía venosa promueve estabilidad cardiovascular respiratoria en modelo experimental
Lígia Andrade da Silva Telles Mathias, TSA, M.D.I; Luiz Piccinini Filho, M.D.II; José Carlos Rittes, TSA, M.D.III; Flávia Salles Souza, M.D.III; José Ricardo Pinotti Pedro, TSA, M.D.III; Wagner Cirillo, M.D.III; Joaquim Edson Vieira, TSA, M.D.IV
IDiretora do Serviço e Disciplina
de Anestesiologia, Irmandade Santa Casa de Misericórdia de São Paulo
e Faculdade de Ciências Médicas da S. Casa de SP
Responsável pelo Centro de Ensino e Treinamento, CET-SBA, ISCMSP
IIChefe do Serviço de Anestesiologia, Hospital Santa Isabel, São Paulo
IIIMédico Assistente, Serviço de Anestesiologia, Irmandade Santa Casa de Misericórdia de São Paulo
IVCoordenador do Centro para Desenvolvimento da Educação Médica, CEDEM da Faculdade de Medicina da Universidade de São Paulo
BACKGROUND AND OBJECTIVES:
Intravenous infusion of inhalation anesthetics may promote lung injury. Intravenous
halothane in lipid emulsion induces anesthesia with hemodynamic and respiratory
stability. This investigation aimed at establishing the induction dose of isoflurane
in 10% lipid emulsion and at observing cardiovascular and respiratory effects
in experimental anesthesia.
METHODS: This study involved 7 male piglets. Animals received intravenous propofol for invasive surgical preparations: femoral artery and jugular vein dissection and esophageal ecodopplercardiographic sensor. Heart rate (HR), electrocardiography (ECG), systolic (SBP), diastolic (DBP), mean (MBP) blood pressure and central venous pressure (CVP), cardiac index (CI) and bispectral index (BIS) were recorded. Inspired and expired gases fractions were continuously evaluated. Isoflurane lipid emulsion was injected until bispectral index had decreased to 40 ± 5 (BIS40). Animals were kept anesthetized and submitted to laparotomy for gastric suture.
RESULTS: Total volume to reach BIS40 was 25.6 ± 11.2 mL (2.56 mL isoflurane). Mean time to reach BIS40 was 15.6 ± 6.9 minutes. The higher the infusion rate the shorter the time to reach BIS40. Cardiovascular and respiratory conditions were stable throughout the experiment. Heart rate has increased with increased end tidal isoflurane.
CONCLUSIONS: Intravenous isoflurane in lipid emulsion has promoted bispectral index decrease, hemodynamic and respiratory stability and direct correlation with its expired fraction. Intravenous isoflurane in lipid emulsion may be a safe modality for this anesthetic delivery.
Key Words: ANESTHESIA, General: intravenous; ANESTHETICS, Volatile: isoflurane; ANIMAL: piglet; PHARMACOTECHNIQUE: lipid emulsion
JUSTIFICATIVA Y OBJETIVOS:
La administración venosa de anestésico inhalatorio pode causar lesión
pulmonar. Halotano en solución lipídica por vía venosa promueve
anestesia con estabilidad hemodinámica y respiratoria. Esta pesquisa buscó
establecer la dosis de inducción para emulsión lipídica de isoflurano
a 10% y observar las condiciones cardiovasculares y respiratorias, en anestesia
MÉTODO: Siete cerdos machos fueron seleccionados. Los animales recibieron infusión de propofol para las preparaciones quirúrgicas invasivas: disección de arteria femoral y vena yugular, sensor de ecodopplercardiografia en el esófago. Fueron registrados frecuencia cardíaca (FC), eletrocardiograma (ECG), presión arterial sistólica (PAS), diastólica (PAD), media (PAM), venosa central (PVC), índice cardíaco (IC), débito cardíaco (DC) e índice bispectral (BIS). Las fracciones inspirada e expirada de los gases respiratorios fueron analizadas continuamente. Iniciada infusión de la emulsión lipídica de isoflurano hasta el índice bispectral obtener valor de 40 ± 5 (BIS40). Los animales fueron mantenidos anestesiados y sometidos a laparotomía exploradora para sutura gástrica.
RESULTADOS: El volumen total infundido para obtener BIS40 fue 25,6 ± 11,2 ml (2,56 ml de isoflurano). El tiempo medio para alcanzar BIS40 fue 15,6 ± 6,9 minutos. Mayor velocidad de infusión redució el tiempo para los animales alcanzar BIS40. Condiciones cardiovasculares e respiratorias se mostraron estables durante la experimentación. La frecuencia cardíaca aumentó con la elevación de la fracción expirada del isoflurano.
CONCLUSIONES: La infusión venosa del isoflurano en solución emulsificada promovió disminución del índice bispectral, estabilidades hemodinámica y respiratoria y correlación directa con su fracción expirada. El uso del isoflurano en emulsión lipídica se puede constituir en modalidad segura de aplicación de este anestésico.
Among inherent complications of halogenate agents, inadvertent intravenous injection of inhalational anesthetics may promote direct lung injury with acute respiratory failure, cardiovascular instability and death 1-4. Animal experiments with intravenous halothane have induced diffuse pulmonary edema and multiple pulmonary hemorrhages as a consequence of direct lung injury 5,6.
In spite of highly severe complications after intravenous administration of inhalational anesthetics, the hypothesis of their use in lipid emulsions has been tested in animal models and even in human volunteers 7. However, this method would imply phlebitis and, similarly to other intravenous anesthetic agents, such as diazepam, propofol or etomidate, lipid emulsion could decrease the incidence of this adverse event without pharmacokinetic repercussions 8-10.
Johannesson et al. have experimentally investigated intravenous halothane in lipid emulsion and continuous infusion and have induced anesthesia with hemodynamic and respiratory stability and rapid anesthetic recovery, however observing some deaths with bolus injections 11.
New experimental models with intravenous isoflurane and halothane in lipid emulsion have suggested the possibility of this being an alternative to inhalational anesthesia. Cardiovascular stability and pharmacokinetic characteristics would indicate a similar profile for the same agent used as intravenous or inhalational anesthetics. However, intravenous route as alternative to anesthesia with inhalational agents has not found consensus in the literature 12-15.
So, in spite of interesting results shown by the literature, the use of emulsified inhalational agents for intravenous infusion still deserve the investigation of aspects such as lipid solutions, infusion rate and long-term exposure effects. The development of emulsified solutions with Brazilian technology may bring new approaches for intravenous anesthesia investigation.
This study aimed at determining the induction dose for 10% isoflurane lipid emulsion and at observing cardiovascular and respiratory conditions during experimental anesthesia.
After the animal experiment Ethics Committee, Faculdade de Ciências Médicas, Santa Casa de Misericórdia, São Paulo approval, 7 male piglets with estimated weight of 20 kg were selected for the study in the laboratory of the Surgical Technique Unit, Surgery Department. After a 12-hour fast, animals were premedicated with 15 mg muscular midazolam 30 minutes before the experiment.
Animals were placed in the supine position. Then, an ear vein was catheterized with 20G polyethylene device (Angiocath, Becton & Dickinson, Juiz de Fora) and ECG was installed in two leads. Soon after monitoring, denitrogenation was achieved with 100% oxygen and anesthesia was induced with 5 to 6 mg.kg-1 propofol.
Tracheal intubation was achieved with straight blade direct laryngoscopy for vocal folds visualization and tracheal tube installation. Animals were maintained under mechanical ventilation with circle system and low flow anesthesia machine, being ventilated in normocapnia with inspiratory mixtures of 50% oxygen and nitrous oxide. Peripheral pulse oximetry electrode was placed on the ear, bispectral index (BIS) electrode was placed on the front and end tidal CO2 (PETCO2) sensor was placed on the tracheal tube.
Animals received 100 to 130 µg.kg-1.min-1 propofol continuous infusion for invasive surgical preparations: femoral artery and jugular vein dissection and esophageal ecodopplercardiography sensor. Femoral artery was catheterized with number 10 Levinis probe and jugular vein was catheterized with double lumen catheter by Seldingers technique. Then, catheters and ecodoppler sensor were coupled to their transducers and heart rate (HR), ECG, systolic (SBP), diastolic (DPB), mean (MBP) and central venous (CVP) pressure, cardiac index (CI) and cardiac output (CO) were continuously monitored. Respiratory gases inspired and expired fractions were continuously analyzed by respiratory gases analyzer. Continuous infusion of 4 to 5 mL.kg-1.h-1 lactated Ringers solution was administered throughout the experiment.
Studied attributes were evaluated before isoflurane continuous infusion and then at 5-minute intervals for 60 minutes. After monitors installation, propofol was withdrawn until animals reached bispectral index above 85, when isoflurane in lipid emulsion was started (10% intralipid solution vol/vol, Cristália, São Paulo). Administration rate has followed bispectral pattern.
Induction dose was defined as the amount of isoflurane needed for BIS to reach 40 ± 5. After this, animals were maintained anesthetized with modified rate, if needed, to maintain BIS between 30 and 40 and to record studied variables. Hemodynamic stability and BIS maintenance for 15 minutes were considered indications of adequate anesthesia and, at this moment, coronary ligament was clamped for 30 s. This procedure would indicate anesthesia if followed by no change in HR and/or BP and no animals movement.
Data are presented in mean ± standard deviation. ANOVA for repeated measures was used to compare among investigated moments. Dunnets test was used to compare samples in which ANOVA was below the significance level.
Test considered as control the moment in which BIS has reached < 40 (BIS40). End tidal isoflurane and hemodynamic variables were correlated by Pearsons product. Values were considered different when p < 0.05 after correction for multiple comparisons.
Final group was made up of 7 male piglets. Mean weight was 25.1 ± 3.7 kg, total isoflurane volume infused to reach BIS40 was 25.6 ± 11.2 mL, resulting in a volume of 2.56 mL. Mean time for animals reaching BIS equal to or below 40 was 15.6 ± 6.9 minutes (Table I).
Ratio between volume infused per hour (infusion rate) and body weight shows a decreasing pattern (Figure 1), confirming the adopted model where higher infusion rate has decreased the time for animals reaching BIS < 40, regardless of animals weight (Figure 2).
Experiment has not exceeded 60 minutes counted as from beginning of intravenous administration of isoflurane intrepid mixture. Surgical procedure moment has varied among animals depending on the time to reach BIS 40. Cardiovascular conditions were stable throughout the 60 experimental minutes, including surgical procedure (Table II).
Heart rate changes were not statistically significant (p = 0.971) (Figure 3). Mean blood pressure throughout the experiment has not significantly changed (p = 0.839) (Figure 4). Blood pressure has not changed during evaluated moments (p = 1.000) (Figure 5). Cardiac index has significantly varied among moments (p = 0.040), however differences among means compared to initial values (pre) were not sufficiently high to result in Dunnets test significant difference (Figure 6).
Respiratory conditions were not changed in our experimental model (Table III). Mean oxygen saturation (SpO2) and end tidal CO2 (PETCO2) were not significantly changed. Only one animal has reached 87% SpO2 at 35 minutes of experiment (Figure 7). Comparison among studied moments has not shown significant differences (p = 0.604). Highest PETCO2 was 42 mmHg, while lowest was 14 mmHg; this latter however, may have been measurement error (Figure 8). Similarly, comparison among studied moments has not shown significant differences (p = 0.992).
End tidal isoflurane has significantly increased up to 15 minutes, with fluctuations during the experimental period (Figure 9). This variation was statistically significant among moments (p < 0.001), especially considering 15th minute measurement. Ifteenth minute was considered for comparison because this has been the mean time for animals reaching BIS40. However, considering the pre-infusion moment with zero rate and 15th and 50th minutes, variation has been statistically significant (p < 0.001) (Figure 10). Most significant variations were recorded at 15 minutes as compared to pre-infusion (p < 0.05) and to 50th minute (p < 0.05).
Ratio between isoflurane emulsified solution infusion rate and its expired fraction was stable, as expected from an agent whose higher excretion fraction is obtained by the respiratory system without metabolization (Figure 11).
The possible anesthetic agent systemic saturation in the experimental period of 60 minutes, considering the agent expired fraction, has not promoted mean blood pressure (Figure 12) and cardiac index (Figure 13) changes. However, heart rate has increased with increased end tidal isoflurane (Figure 14).
As from 30 minutes, animals were submitted to abdominal incision for laparotomy. There were no changes in evaluated parameters during this procedure.
Our results suggest that intravenous isoflurane in lipid emulsion may be a safe modality for the delivery of this drug.
Intravenous halogenates could be advantageous for associating their characteristics of complete anesthetic agent (analgesia, hypnosis and muscle relaxation) to elimination of specific ventilatory circuits. The independence of functional residual capacity during induction could be an additional benefit 13.
The possibility of adding lipid emulsion to inhalational anesthetics to allow their intravenous administration is not new 7. Although preliminary results were not encouraging 15, experimental models in species such as dogs, rats and swines have assured pharmacokinetic and cardiovascular stability to this infusion route 11-14.
Our results with this swine model have reproduced the stability suggested by previous studies. The experimental model adopted with piglets may be used both for emulsified isoflurane and for a comparative study of lipid solutions for propofol 14,16.
Oxygen peripheral saturation and end tidal CO2 were normal throughout the experiment, without significant changes, what suggests the maintenance of ventilatory and respiratory conditions. The ventilation model adopted in this experiment using flow below 1 L.min-1 (Linea A, Intermed, São Paulo, Brazil) may represent savings, especially for isoflurane, whose consumption may change according to fresh gases flow used 17.
Hemodynamic variables analysis has shown no significant changes in systolic, diastolic and mean blood pressure, heart rate and cardiac index, throughout the experiment. Although there are reports in the literature showing that inhalational isoflurane is associated to dose-dependent blood pressure decrease 18,19, this has not been confirmed by intravenous isoflurane in lipid solution. Results have shown stable MBP / PETISO ratio. Even with progressive PETISO increase, MBP has remained stable.
It is interesting to note that different authors have proposed myocardial function stability or decrease with inhalational isoflurane, desflurane and sevoflurane 18,20-22. In contrast, our results have shown unchanged cardiac index behavior, regardless of PETISO variations. A similar experiment in swine, using halothane in lipid emulsion has shown cardiac index stability and mean blood pressure decrease 14, while in dogs there has been myocardial contractility and mean blood pressure depression 11. So far, inhalational isoflurane has shown to have limited myocardial depression effects 23.
Inhalational isoflurane has been related to increased heart rate 18. Our experimental model has shown correlation between increased PETISO and increased heart rate. Inhalational isoflurane promotes significant transient and dose-dependent heart rate increase, effect also found in the adopted intravenous infusion model 24-26.
Intravenous isoflurane was stably correlated to its expired fraction, PETISO, evidencing its elimination by the respiratory system. Hemodynamic stability and the lack of interference with ventilatory parameters during intravenous isoflurane suggest the possibility of investigating induction doses spectrum, that is, the amount of liquid isoflurane diluted in lipid emulsion and the infusion rate needed to reach BIS40. Decreased bispectral index promoted by inhaled isoflurane does not seem to be directly correlated to hemodynamic changes 27.
To our knowledge, the effects of isoflurane dilution in lipid solution on its own blood solubility have not yet been studied. However, perfluorocarbon-based emulsifiers, oxygen carriers with partial and transient effects, increase inhalational anesthetics solubility 28. It is necessary to investigate whether similar effects are present when lipid solutions are used as inhalational anesthetic carriers.
In conclusion, intravenous isoflurane in 10% lipid solution (vol/vol) has promoted bispectral index decrease with maintenance of blood pressure and cardiac index, but with dose-dependent increase in heart rate. This studied infusion is directly correlated to its expired fraction, without however interfering with respiratory function values when under mechanical ventilation. Further studies are needed to investigate induction doses and safety of the formulation.
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Profª. Dra. Lígia Andrade da Silva Telles Mathias
Al. Campinas 139/41
01404-000 São Paulo, Brazil
Submitted for publication October 21, 2003
Accepted for publication March 17, 2004
* Received from Centro de Estudos em Anestesiologia "Roberto Simão Mathias" da Irmandade Santa Casa de Misericórdia de São Paulo (ISCMSP)