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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.1 Campinas Jan./Feb. 2005
LETTERS TO THE EDITOR
Intravenous isoflurane in lipid emulsion promotes respiratory cardiovascular stability in experimental model
It was with great interest and pleasure that I read the above-mentioned paper published in our prestigious Journal. I would like to congratulate authors for the enviable idea of carrying out such interesting and novel study. Concerned with conceptual aspects, I have the following considerations:
1) The first "Discussion" paragraph mentions what the authors have described as "complete anesthetic", to name likely halogenate actions, among them: analgesia, hypnosis and muscle relaxation, which are known anesthetic components.
A major contributions of intravenous anesthesia, especially as from the 90s, was the introduction of the concept of "compartmentation" of anesthetic components. As from Prys-Roberts' definition - 1982 1-8, anesthetic components started to be described and understood in a very unique way. Hypnotics are given to promote hypnosis, analgesics to promote analgesia and neuromuscular blockers to promote muscle relaxation. Currently, muscle relaxation is considered anesthetic coadjuvant and no longer a component. Hypnosis, here understood as unconsciousness, may be promoted with intravenous or inhalational drugs.
Inhalational agents have different and still poorly understood action mechanisms. Their activities and effects have always been monitored as from a clinical outcome, such as decreased blood pressure, which historically has been related to "anesthetic depth"- concentration in which there is pressure response block after noxious stimulation (MAC-BAR). For many years, blood pressure was an excellent "anesthetic depth" monitor and it is unquestionable that "deep anesthesia" directly promotes blood pressure decrease.
With the advent of specific cortical component monitors, such as BIS, the correlation of blood pressure and "anesthetic depth" started to be questioned and early studies were published correlating "depth" to BIS 4 .
Invariably, "deep and superficial anesthesia" monitored by BIS, are not followed by respective hemodynamic changes 7. It is believed that hemodynamic changes have little to do with adequate anesthesia, but rather represent trauma-induced autonomic changes.
Inhalational anesthetics may suppress these autonomic responses maintaining low blood pressure during noxious stimulation, but this has nothing to do with analgesia. It is a function of their action on myocardial depression, vasodilation, etc. Even in high doses, all other autonomic response components are released, such as sweating, catecholamine and steroids release, among others. The lack of motor response, after high inhalational anesthetic concentrations, is solely the result of reflex arc blockade.
There is no action whatsoever on opioid receptors or on any other mechanism described in the literature to explain analgesic action of inhalational agents. What is described is absence of motor response and attenuation of autonomic response which, in fact, is poor. For many years this has been interpreted as analgesia. Currently, with the advent of BIS and Entropy, what we see is that analgesics do not change bispectral index but rather decrease post-trauma entropy values and motor response 4.
On the other hand, clinical hypnotic doses do not change entropy but rather bispectral indices and do not change motor response. Halogenate agents act by blocking motor response after noxious stimulation by acting on reflex arc but this action is only seen when hypnotic concentrations are reached, that is, in the presence of unconsciousness2. A decerebrated animal is able to move the paw after noxious stimulation, but will not do so if under analgesic effect. This amplifies analgesics action spectrum because it explains that analgesia is not just motor response blockade.
As to inhalational agents-induced muscle relaxation, there is no recent publication justifying such statement. No halogenate acts on endplate leading to muscle relaxation. The only drugs able to do so are those directly acting on endplate - neuromuscular blockers. Again, observed relaxation is merely clinical and visual, but when a monitor is installed, TOF result is 100%.
2) Analysis of Results:
It calls the attention that figures data illustrate what has happened to all seven animals in means, until figure 10. From figure 11 on, data refer only to "13 different moments", which are not clear. Which moments are these? How were they chosen and why weren't they done based on seven animals means, for example, as the others? This might have led a hasty conclusion. Increased heart rate as a direct function of halogenate expired fraction, according to figure 14, was interpreted by authors as response to increased halogenate expired fraction.
The fact is that the correlation had a too low index for the conclusion to be drawn - just 0.1987. Couldn't HR have increased due to other factors, such as surgical stimulation? The same is true for cardiac index, which was also increased and, coincidentally, to higher values during laparotomy. Figure 12 and Figure13 are, in my opinion, adequately interpreted, because the conclusion was that there was no correlation between expired fraction and MBP (Figure 12) or between expired fraction and cardiac index (Figure 13). Both correlations had low values (0.038 and 0.0009, respectively) confirming authors conclusions.
3) The assertive that isoflurane-induced decreased bispectral indices does not seem to correlate with hemodynamic changes is, in my opinion, also correct, since the correlation of these variables with BIS is really poor as described by Struys 7 and according to what I have already described in item 1 of this comment. So, in intravenous anesthesia, we do not correlate anesthetic administration to hemodynamic measurements. Patients awaken with unchanged blood pressure and heart rate!
4) Kissin, Prys-Roberts and Gelman have reported in the book Intravenous Anesthesia 8, that the term "Anesthetic Depth" could be inadequate and that "Anesthetic State" would be result of a wide spectrum of pharmacological actions, with each drug acting on its anatomic substrate. Stress response attenuation is promoted not only by analgesia and sensory block but rather by the synergism among all drugs. Anesthetic components have such different actions that a study published in 2003 9 has shown that propofol concentration in which patients awakened would not vary as a consequence of fentanyl concentrations, which ranged from 0.8 to 3 ng.mL-1.
Patients awakened with propofol concentrations between 1.6 and 1.8 µg.mL-1, regardless of fentanyl concentration. Postoperative differences would appear on pain scores. Patients awakening with higher fentanyl concentrations had lower pain scores, however with a higher incidence of apnea. When patients awakened with lower concentrations, pain scores were higher and the incidence of apnea lower. It has been proposed that ideal concentration, that is, residual analgesia associated to low incidence of respiratory depression should be 2 ng.mL-1 fentanyl. Interesting this study, because authors have shown what had already been described by Miller - perioperative analgesia promoted by fentanyl concentrations below 2 ng.mL-1 is mild, and patients are able to spontaneously ventilate with concentrations as low as these.
5) So, I believe that any scientific research line involving new drugs should target specific action drugs - with specific and well defined anatomic action substrates - because this helps the development of monitors that are so helpful. The advent of BIS has decreased in 85% the incidence of intraoperative awaraness, as referred during the World Congress, and this is a huge conquest. This monitor is a classic example - it solely monitors the cortical component, that is, the activity of the hypnotic agent. Analgesia decreases stimuli afference to cortex. This decreases the need for hypnotics to promote unconsciousness but does not suppress hypnotics or analgesics administration. There is a joke saying that the "Goose is an animal able to swim, fly and run but everything is poorly done".
Hoping to having contributed to improve anesthetic concepts and definitions, I would like to congratulate the authors for their elegant study which has given us an excellent example of the development of experimental studies which are so important to improve Anesthesiology. Congratulations!
Fernando Squeff Nora, TSA, M.D.
01. Prys-Roberts C - Anesthesia: a practical or impractical construct. Br J Anaesth, 1987;59:1341-1345.
02. Heier T, Steen PA - Assessment of anesthesia depth. Acta Anaesthesiol Scand, 1996;40:1087-1100.
03. Schneider G, Sebel PS - Monitoring depth of anaesthesia. Eur J Anaesthesiol, 1997;15:(Supll4):21-28.
04. Glass PS, Bloom M, Kearse L et al - Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane and alfentanil in healthy volunteers. Anesthesiology, 1997;86:836-847.
05. Kissin I - Depth of anesthesia and bispectral index monitoring, 2000;90:1114-1117.
06. Rampill IJ - Monitoring depth of anaesthesia. Anesth Analg, 2001;14:649-653.
07. Struyz MM, De Smet T, Versichelen LF et al - Comparison of closed-loop controlled administration of propofol using Bispectral Index as the controlled variable versus "standard practice" controlled administration. Anesthesiology, 2001;95:6-17.
08. Flaishon R, Lang E, Sebel PS - Monitoring the adequacy of intravenous anesthesia, em: White PF - Intravenous Anesthesia. Editora Willians & Wilkins, 1997;27:545-564.
09. Iwakiri H, Nagata O, Matsukawa T et al - Effect-site concentration of propofol for recovery of consciousness is virtually independent of fentanyl effect-site concentration. Anesth Analg, 2003;96: 1651-1655.
Thank you for the opportunity of sending this message. I would also like to thank the careful and enriching comments of Dr. Fernando Squeff Nora - Chairman SARGS. Little has to be added to them, which only add to the above mentioned investigation proposal.
As an explanation, I like to answer the perspicacious observation of item 2) of your letter, about "13 different moments" which do not seem clear in the text. Dr. Squeff Nora is right when he talks about clarity deficiency, which could have been a semantic mistake we are held responsible for. Data in figures 11, 12, 13 and 14 are means observed for the seven animals, both in ordinate and abscissa axes. So, different moments are nothing more than data recorded at 5-minute intervals as from pre-infusion (13 moments). Well; this could lead to the question: then why figures do not start from "zero" at isoflurane PET? The answer is statistical: animals 1 and 6 had 0.07 and 0.13 isoflurane PET at pre-infusion. It is possible that such isoflurane trace was a consequence of the circuit being still contaminated by previous experiment, what has not been observed in remaining experiments.
Increased heart rate (Figure 14) was interpreted as response to increased isoflurane expired fraction. Dr. Squeff Nora has correctly observed that it could be a consequence of surgical stimulation. This is possible, however both heart rate and cardiac index suffer ascending inflexion for the described curve before laparotomy (15 minutes - 30 minutes, respectively).
Our study has tried to evaluate a new infusion method for a clinically well known drug. And again Dr. Squeff Nora is right and we agree that this might not necessarily mean pharmacologically well known. Nevertheless, it opens an interesting observation field, for example, by allowing potential elimination of vaporizers (but not of antipollution systems). On the other hand, although being administered by the Inhalational route for many years, their systemic and tissue effects still have to be further investigated if this infusion route proves to be of interest.
Finally, we agree that understanding the pharmacological and molecular profile of a substance makes its use safer and even more elegant, and emulsified inhalational anesthetics for intravenous infusion may find a new stage for their notorious anesthetic application.
If my colleague allows me to add to the Goose's deeds, excellent watchman qualifications are also attributed to this notorious bird, placing it close to a "watchdog".
We thank once more for the careful attention dedicated to our study. We hope to having consistently answered to Dr. Squeff Nora's relevant questions.
Ligia Andrade da Silva Telles Mathias, TSA, M.D.