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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.56 no.4 Campinas Set./Aug. 2006
Anesthetic induction after treated hemorrhagic shock: experimental study comparing ketamine and etomidate*
Inducción anestésica después del tratamiento del choque hemorrágico: estudio experimental eomparando la cetamina y el etomidato
Adilson O. FragaI; Luiz Marcelo Sá Malbouisson, TSAII; Ricardo PristIII; Maurício Rocha e SilvaIV; José Otávio Costa Auler Júnior, TSAV
Assistente do Serviço de Anestesiologia do InCor da FMUSP
IIDoutor em Ciências pela USP. Especialista em Terapia Intensiva AMIB; Médico Assistente do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do InCor HCFMUSP
IIIDoutor em Medicina Veterinária USP Médico da Divisão de Experimentação HCFMUSP
IVProfessor Titular Deptº de Cardiopneumologia da FMUSP; Diretor da Divisão Experimental do InCor HCFMUSP
VProfessor Titular da Disciplina de Anestesiologia da FMUSP; Especialista em Terapia Intensiva AMIB. Diretor do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do InCor HCFMUSP
OBJECTIVES: Bleeding causing hemorrhagic shock usually requires surgical
treatment under general anesthesia. Anesthetic drugs may further compromise
hemodynamics. The objective was to compare the hemodynamic effects of ketamine
and etomidate during anesthetic induction in dogs submitted to an experimental
model of hemorrhagic shock and resuscitation.
METHODS: Thirty-two mongrel dogs were submitted to a pressure-controlled hemorrhagic shock, resuscitation and anesthetic induction model. After achieving the target pressure of 40 mmHg, they were randomly assigned in two groups according to the resuscitation fluid to be used: NaCl 0.9% (32 mL.kg-1) and NaCl 7.5% (4 mL.kg-1). After volume infusion, these groups were reassigned according to anesthetic drug used: GI) NaCl 0.9% and ketamine; GII) NaCl 7.5% and ketamine; GIII) NaCl 0.9% and etomidate; and GIV) NaCl 7.5% and etomidate. Hemodynamic measurements were obtained at five moments: (M0) baseline; (M1) after bleeding to shock; (M2) after volume expansion; (M3) 5 minutes after anesthetic induction; (M4) 15 minutes after anesthetic induction. Statistical analysis was performed using Student t test and two way ANOVA. Value of p lower than 0.05, was considered significant.
RESULTS: After shock, both solutions restored hemodynamics to baseline values. Independently of anesthetic agent or expansion solution used, mean arterial pressure remained unaltered for all groups after induction. Central venous pressure, heart rate, pulmonary capillary wedge pressure and pulmonary vascular resistance index increased significantly after ketamine infusion. Cardiac index, systemic vascular resistance index and oxygen transport variables remained stable in all groups.
CONCLUSIONS: Etomidate or ketamine were able to maintain hemodynamic stability in dogs undergoing severe hemorrhagic shock treated with NaCl 0.9% or NaCl 7.5%.
Key Words: ANIMALS: dogs; COMPLICATIONS: hemorrhagic shock; DRUGS: etomidate, ketamine; THERAPEUTIC: volemic resuscitation; VOLEMIA: 0.9% saline solution, 7.5% NaCl.
Y OBJETIVOS: El sangramiento que conlleva al choque hemorrágico generalmente
necesita un tratamiento quirúrgico bajo anestesia general. A su vez,
los anestésicos pueden comprometer más las condiciones hemodinámicas.
El objetivo de este estudio fue el de comparar los efectos hemodinámicos
de la cetamina y del etomidato durante la inducción anestésica
en perros sometidos a un modelo experimental de choque hemorrágico y
MÉTODO: Treinta y dos perros mestizos fueron sometidos al choque hemorrágico presión-controlada, reanimación e inducción anestésica. Después de alcanzar la presión objeto de 40 mmHg ellos fueron divididos aleatoriamente en dos grupos de acuerdo con el líquido usado en la resucitación: NaCl a 0.9% (32 mL.kg-1) y NaCl a 7,5% (4 mL.kg-1). Después de la infusión de volumen, esos grupos fueron divididos nuevamente de acuerdo con el anestésico utilizado: GI) NaCl a 0.9% y cetamina; GII) NaCl a 7.5% y cetamina; GIII) NaCl a 0.9% y etomidato; y GIV) NaCl a 7.5% y etomidato. Mediciones hemodinámicas fueron obtenidas en cinco momentos: (M0) inicial; (M1) después del desarrollo del choque hemorrágico; (M2) después de la administración de soluciones; (M3) 5 minutos después de la inducción anestésica; (M4) 15 minutos después de la inducción anestésica. Se hizo el análisis estadístico usando el Student t test y two-way ANOVA. Fueron considerados significativos valores de p menores que 0,05.
RESULTADOS: Después de la instalación del choque, los dos sueros reestablecieron los estándares hemodinámicos a los valores iniciales. Independiente del anestésico o del solución utilizada, después de la inducción anestésica la presión arterial media permaneció inalterada en todos los grupos. La presión venosa central, frecuencia cardiaca, presión capilar pulmonar y el índice de resistencia pulmonar vascular aumentaron significativamente después de la administración de cetamina. El índice cardíaco, el índice de resistencia vascular sistémica y el transporte de oxígeno permanecieron estables en todos los grupos.
CONCLUSIONES: El etomidato o la cetamina fueron capaces de mantener la estabilidad hemodinámica en los perros que sufrieron choque hemorrágico severo y que fueron tratados con NaCl a 0,9% o NaCl a 7,5%.
Hemorrhagic shock due to trauma is an important cause of emergency hospital admission. Surgical intervention to control bleeding is often necessary, and anesthetic induction may cause further hemodynamic imbalance due to vasodilatation and myocardial depression. In such patients, vigorous crystalloid infusion using either isotonic or hypertonic crystalloid solutions has been used for initial resuscitation in emergency departments before the surgical intervention1,2. Hypertonic saline has been demonstrated in experimental and clinical studies to be efficient to restore hemodynamic stability after hemorrhagic shock3-5, but isotonic saline continues to be the main fluid used during initial resuscitation of hemorrhagic shock1. Controversy also remains regarding the optimal choice of an anesthetic induction drug that will minimally interfere with the hemodynamic state mainly in traumatized hypovolemic patients6,7. In 1990, Haskins et al. studied the effects of ketamine in a model of hypovolemic dogs and observed that it adequately maintained cardiovascular function, preserved oxygen transport, and causes only transient respiratory depression8. Based on these data, ketamine has been considered one option for the induction of anesthesia in hypovolemic patients in emergency situations. Etomidate, another anesthetic agent, has been considered safe for use in critically ill patients, because autonomic nervous system reflexes are preserved as well as myocardial contractility6. Despite the widespread use of both anesthetic agents in cases of unstable circulation, few studies have compared these drugs in experimental models of hemorrhagic shock and their interactions with normal saline and hypertonic sodium chloride used to treat hemorrhagic shock8-10.
The purpose of this study was to compare the hemodynamic effects of ketamine and etomidate in dogs submitted to a model of hemorrhagic shock, after being resuscitated with normal saline or hypertonic sodium chloride (NaCl 7.5%) solutions.
This study was approved by the Hospital Ethics Committee and was in agreement with the international rules for animal experimental research. The study was performed in 32 male mongrel dogs, weighing between 15 and 20 kg. Dogs were fasted for 12 hours before the study, with free access to water.
To avoid possible influence with different anesthetics the animals were prepared under sedation with thiopental (15 mg.kg-1), and mechanical ventilation twenty-four hours before the experiment. A 7-French pulmonary artery catheter (Baxter Healthcare Corp., Irvine, CA, USA) was inserted via the right internal jugular vein and positioned in the pulmonary artery under fluoroscopic visualization. Small gauge polyethylene catheters (P260) filled with 10 Ul.mL-1 heparin were inserted, by dissection, into both femoral arteries and veins. The arterial catheters were used to measure the systemic arterial pressure, remove blood, and collect arterial blood sample as well as for drug administration and volume expansion. All catheters were firmly secured and tunneled subcutaneously and exteriorized in the dorsal region of each animal for later use. After all vascular accesses were obtained, 50 UI.kg-1 heparin was administered via the central venous route and the animals were subsequently extubated and allowed to recover during 24 hours with free access to water. After this period of resting, the dogs were pre-medicated with morphine (0.4 mg.kg-1) one hour before the transportation to experimentation room, where the main study was carried out.
Arterial and mixed venous oxygen (PaO2, PvO2), carbon dioxide (PaCO2, PvCO2) tensions and plasmatic sodium (Na+) level, as well as the arterial and mixed venous pH values, were measured using a blood-gas analyzer (Gas Analyzer ABL Radiometer, Copenhagen). All measurements were corrected for body temperature, and the sodium bicarbonate concentration and base excess were calculated for each animal. Hemoglobin concentrations (Hb) were also determined. The mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) were measured using pressure transducers, by means of the Acknowledge MP 100 (Biopac Systems Inc, Goleta, CA). Cardiac output (CO) was measured using the standard thermodilution technique. The measure was repeated five times, and the average value was divided by body surface area to obtain the cardiac index (CI). Systemic and pulmonary vascular resistances, arterial and mixed venous blood oxygen contents (CaO2 and CvO2), the venous admixture, oxygen consumption (VO2), oxygen delivery, and oxygen utilization ratio were all calculated from measured values utilizing conventional equation.
The model of hemorrhagic shock used was the one described by Prist et al.11. In this model, the animal was submitted to continuous bleeding throughout the procedure, and a small blood sample was removed each minute. The prevailing pressure during the last 30 seconds (30s) of the minute prior to each bleeding event was used to establish the blood volume to be removed during the first 30s of the next minute. Thus, the volume of the blood sample corresponds to the previous MAP. The described model is derived from a standard situation in which the removal of an initial blood volume of 25 mL.min-1 from 17.5-kg dogs with a MAP of 100 mmHg corresponds to a blood loss of 100 mL.min-1 for a 70 kg adult with the same MAP. The different animal weights or MAP variations were taken into consideration for determining the rate of bleeding according to the following conditions:
- The MAP was determined during the 5 minutes preceding the beginning of hemorrhage;
- An initial bleeding volume (VbO) was adjusted to the actual body weight;
Since the target of shock is the achievement of a mean arterial pressure of 40 mmHg during bleeding, individual variation in total shed blood volume is expected in order to maintain the same MAP.
The animals were studied in relation to diverse hemodynamic variables assessed at five experimental times, considered from M0 - baseline to M4:
(M1) After bleeding (hemorrhagic shock);
(M2) After volume expansion (normal and hypertonic sodium chloride solutions);
(M3) 5 minutes after infusion of anesthetic agent (etomidate or ketamine) and tracheal intubation;
(M4) 15 minutes after infusion of anesthetic agent;
The experimental procedure is shown in the Figure 1. After obtaining the baseline hemodynamic measurements (M0), all animals were submitted to hemorrhagic shock as described in hemorrhage protocol section. After achieving the target mean arterial pressure of 40 mmHg, 30 minutes after the beginning of the experiment (M1), new hemodynamic measurements were obtained and blood samples were collected. At this moment, the animals were divided in two groups according to expansion solution they were assigned to receive: 16 dogs received NaCl 0.9% (32 mL.kg-1) and 16 received NaCl 7.5% (4 mL.kg-1) during ten minutes. The volumes of normal and hypertonic saline solution were chosen in order to give the same NaCl load to both groups. After volemic expansion (M2), other hemodynamic measurements were obtained and arterial and venous blood samples collected. In the next step, each group was further split in two subgroups assigned to receive either etomidate (1 mg.kg-1, N = 8) or ketamine (4 mg.kg-1, n = 8) as anesthetic induction agent, followed by tracheal intubation. M3 and M4 measures were collected 5 and 15 minutes after anesthetic injection respectively. After M2, the four groups of animals were labeled as GI) NaCl 0.9% and ketamine; GII) NaCl 7.5% and ketamine; GIII) NaCl 0.9% and etomidate; and GIV) NaCl 7.5% and etomidate.
Statistical analyses were performed using the SPSS 10 statistical package (SPSS Inc., Cary, Ca). One-way analysis of variance (ANOVA) was used to compare weight, body surface area and total blood loss among the four groups. Two-way ANOVA for repeated measures followed by Student-Newmann post-hoc test when indicated was used to analyze the hemodynamic parameters. A p value of < 0.05 was considered statistically significant. All data are presented as mean ± SD.
During baseline (M0) and M1, all animals were submitted to the same experimental procedures and data collection. For statistical analysis they were considered as a single group. During M2, for the statistical analysis, the animals were divided in two groups according to the fluid infusion: 16 animals received NaCl 0.9% and 16 animals received NaCl 7.5%. After M2, each group of 16 animals was divided again in two subgroups (n = 8) according to the anesthetic drug, etomidate or ketamine. During M3 and M4, the groups, as previously defined GI) NaCl 0.9% and ketamine; GII) NaCl 7.5% and ketamine; GIII) NaCl 0.9% and etomidate; and GIV) NaCl 7.5% and etomidate were submitted to statistical analysis.
Table I summarizes characteristics of the animals, including body weight, body surface area, and volume of blood removed. Values for body surface area and shed blood volume did not significantly differ between groups.
As shown in the Figures 2, 3 and 4, hemodynamic signals of severe blood loss were observed. Compared to baseline (M0), significant decreases in CVP, MAP, CI, PCWP and MPAP (p < 0.001) and significant increases in PVRI and SVRI (p < 0.001) were observed, while HR remained unaltered. Parameters, representing oxygen delivery (DO2), and oxygen consumption (VO2) decreased significantly (p < 0.001), while a significant increase in oxygen extraction (OERO2) (p < 0.001) was observed.
After intravascular expansion (M2) either with normal saline or hypertonic sodium chloride, almost all parameters were restored to baseline (Figures 2 and 3). After resuscitation, MAP was slightly lower when compared to baseline measurement in both groups, although without statistical significance. As shown in figures 2 and 3, both normal and hypertonic saline infusions restored MPAP and PVRI compared to initial values, being slightly greater in hypertonic treated animals, but without significant differences between groups. Heart rate remained unaltered in both groups. VO2, DO2 increased and O2ER decreased significantly following the administration of both solutions without difference between groups (Figure 4). As shown in Table II, there was a significant increase in plasma sodium levels in the group treated with NaCl 7.5% solution when compared to pre-infusion values (153.1 ± 4.5 mEq/L vs. 142 ± 3.8 mEq/L, p < 0.001) and when compared to the NaCl 0.9% solution treated group (153.1 ± 4.5 mEq/L vs. 143.1 ± 3 mEq/L, p < 0.001). This difference remained elevated until the end of experimental protocol.
MAP remained unaltered in all groups following anesthetic induction using either ketamine or etomidate (Figure 2). CVP increased in the NaCl 7.5% treated group branch that received ketamine when compared to others. As shown in figure 2 and 3, PCWP, MPAP, and PVRI significantly increased in the animals anesthetized with ketamine, but decreased in the animals treated with etomidate at five (M3) and 15 minutes (M4) after anesthetic injection. HR increased significantly in the ketamine treated groups, but decreased following etomidate infusion (Figure 3). CI and SVRI (Figure 3) remained stable in all groups after anesthetic administration. After fluid resuscitation, either with NaCl 7.5% or NaCl 0.9%, oxygen transport index, oxygen consumption index and oxygen extraction were restored to baseline levels and remained unaltered after anesthetic induction with both drugs in M3 and M4 (Figure 4).
The main results of this study were: 1) either normal saline or hypertonic saline solutions in doses calculated to offer the same load of salt reversed hemorrhagic shock 2) after hemorrhagic shock animals treated with hypertonic saline solution presented a slight increase in the values of MPAP and PVRI when compared to the normal saline group 3) after resuscitation, neither ketamine nor etomidate significantly interfered with hemodynamic parameters and oxygen transportation.
In this study, we aimed to simulate a clinical situation that is commonly encountered during the treatment of patients with severe trauma, when large volumes of crystalloid are given to reestablish hemodynamics and oxygen transport in the emergency room before anesthetic induction for surgical treatment. The effects of interaction between the kind of volume expansion solution and the anesthetic induction drug have never been studied before. As an attempt to avoid the confounding effects on hemodynamics of thiopental infusion and mechanical ventilation necessary during vascular catheterization, the animal preparation took place 24 hours prior to the experiment. In the experimental model of hemorrhagic shock used in this study11, the mean bleeding during the study (30.4 mL.kg-1) and subsequent state of hypovolemic shock with hemodynamic alterations were comparable to those reported in the literature8,9. A small dose of morphine as premedication was administered to the animal's one hour before the main experiment. The aim of morphine administration was to keep animals quiet during transport to the experimentation room, positioning in the experiment table and during the hemorrhage phase, when they were still awake. One criticism to our study could be raised about the influence of morphine on the hemodynamic parameters, but according to the literature the doses employed do not seem to produce any significant hemodynamic effect12.
As previously described in the literature13,14, after the pressure-controlled hemorrhagic shock induction, a significant decrease in the MAP, CI, PCWP, MPAP and in oxygen transport and consumption, as well as an increase in the SVRI and PVRI were observed. As expected, both solutions were equally effective in the resuscitation of hemorrhagic shock. Acute hemodilution with both solutions would explain how MAP and SVRI tended to be lower than baseline after resuscitation. These results were similar to those reported by several authors13-15. Both solutions in doses calculated to offer the same load of salt equally restored PCWP and CVP baseline levels, in contrast to the data previously reported by Prist et al, that found a greater increase in CVP of animals resuscitated with hypertonic saline solution16. One of the most consistent effects of hypertonic solutions in hemorrhagic shock models has been an increase in the arterial pressure and cardiac output attributed to fluid shift from extravascular to intravascular compartment5. Although the same load of salt was given to both groups, a greater volume of water was infused in the NaCl 0.9% group. This may explain the difference in plasma sodium concentration observed after fluid infusion in both groups and is in concordance with results from other studies11,14. Systemic vascular resistance significantly decreased very similarly following the infusion of both solutions. Rapid infusion of hypertonic solution is known to induce profound vasodilatation, as previously reported by Kien et al.17. The prolonged infusion time used in our study (10 minutes) may explain the absence of this effect in our animals. On the other hand, the PVRI decrease after NaCl 0.9% solution infusion was greater then after NaCl 7.5%. A reinforcement of hypoxic pulmonary vasoconstriction after hypertonic saline solution infusion, as suggested by Bellezza et al.18, would explain the observed increase in PVRI. These authors found that hypertonic saline dextran solution, as replacement fluid in isovolemic hemodilution, increased the magnitude of hypoxic pulmonary vasoconstriction in piglets, whereas a dextran solution reduced it. This fact may be explained by the slightly higher values of mean pulmonary arterial pressure in dogs treated with NaCl 7.5% solution. Despite the effects of hypertonic solution on pulmonary circulation, both solutions effectively and similarly restored oxygen delivery and consumption in shocked animals.
After anesthetic induction, we observed that ketamine promoted a significant increase in CVP, PAP, PVRI, PCWP and HR, which could be related to the ketamine-induced sympathetic activation. These findings were consistent with the results of other authors using similar experimental model19. On the other hand, etomidate infusion did not result in significant alterations in such hemodynamic parameters9. Despite the hemodynamic derangements in filling pressures and HR with ketamine, mean arterial pressure, CI and SVRI remained stable in all groups after anesthesia induction. It has been described that ketamine may cause a dose-dependent decrease in MAP when administered to severely hypovolemic animals without prior volume expansion20, due to as myocardial depressor effect, despite the ketamine-induced sympathetic activation. The administration of ketamine to swine and dogs submitted to hypovolemic shock was associated with a significant fall in the MAP, 5 minutes after drug administration8,21. In hypovolemic dogs, low doses (10 mg.kg-1) seem to stimulate the cardiovascular system, leading to tachycardia, While high doses of ketamine (20 mg.kg-1) may cause profound myocardial depression with bradycardia20. In this study, ketamine was only injected after correction of the hypovolemic shock with normal or hypertonic saline solutions. The adequate fluid replacement along with the increase in sympathetic tonus induced by ketamine would explain the stability of MAP and CI. The effect of ketamine on the sympathetic system might theoretically induce an increase on SVRI9, and the maintenance of MAP, even in the presence of a low CI. Interestingly, SVRI was comparable in all groups. This is probably due to the adequate fluid reposition, which might have counterbalanced marginal hemodynamic effects of the anesthetic agents.
A significant increase in the PCWP was observed in animals that received ketamine, when compared to the groups that received etomidate. We could hypothesize that the increase in HR associated to sympatheticinduced increase in contractility would promote some degree of diastolic dysfunction along with the sympathetic-mediated elevation of PAP would increase PCWP. The PVRI significantly increased in animals treated with ketamine while animals receiving etomidate experienced a less-than-statistically significant decrease in the PVRI. These results are in agreement with other experiments using ketamine as anesthetic induction agent9,21-23. In hypertonic solution treated animals, reinforcement of hypoxic pulmonary vasoconstriction could contribute to the increase of PVRI18. Unfortunately, we cannot confirm the hypothesis of additive effects, since PVRI was not different in ketamine anesthetized animals that were resuscitated either with normal or hypertonic saline solution. On the other hand, the non-significant decrease in PVRI in the etomidate groups could reflect vasodilatation due to an absence of sympathetic activation. This is accordance with data from some experimental studies in hypovolemic state models that documented a decrease in PVRI after etomidate infusion. The authors attributed the decrease in PVRI to a reduction in sympathetic tone induced by this agent9.
In conclusion, after hemorrhagic shock, animals treated with hypertonic saline presented a slight increase in the values of PAP and PVRI when compared to normal saline group. Ketamine treated groups (saline and hypertonic) presented a discrete but statistically significant increase in PCWP, MPAP, HR and PVRI without clinical relevant effects. Neither ketamine nor etomidate significantly interfered with the oxygen transport status. Due to the difference of species it is difficult to transfer this scenario to the human traumatized patient who may require anesthesia or surgical procedures after rescue and reanimation. However, the findings of minor hemodynamic derangement observed with both anesthetic agents in our experimental study may be worthy of consideration when patients are required to have surgery after adverse situations that cause severe hemorrhagic shock such as trauma of civilian or military casualties caused by firearms.
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Dr. José Otávio Costa Auler Júnior
Av. Enéas de Carvalho Aguiar, 44
05403-000 São Paulo, SP
Submitted for publication
24 de outubro de 2005
Accepted for publication 28 de abril de 2006
* Received from da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP. Tese de Mestrado apresentada na FMUSP.