Case Report as a prelude: After routine thoracic surgery, the patient was awake and was tracheally extubated. Shortly thereafter, laryngospasm developed and resident and attending anesthesiologist (co-author SL) were unable to ventilate. Soon thereafter, they administered succinylcholine and successfully ventilated. They noticed that the agent monitor displayed an expired desflurane concentration much higher than it had been when the patient had been extubated while awake. This led to exploring hypoventilation and reanesthetization after inhaled anesthesia.
During administration of a volatile anesthetic, the delivery of the drug is adjusted to maintain a set level of anesthetic to keep the patient anesthetized. The concentration of the vapor in the lungs (alveoli) that is needed to prevent movement (motor response) in 50% of subjects in response to surgical stimulus is known as minimum alveolar concentration (MAC). MAC is determined after equilibration between gases in the alveoli, the blood, and the brain. In the meantime, the anesthetic is also accumulating in the other tissues of the body, particularly muscle and fat. It is partial pressure or tension and not concentration that equalizes among compartments. We shall call this the “level” of anesthetic in various compartments.
When the delivery of volatile anesthetic is discontinued at the end of the surgical procedure, ventilation (VA) will lower the level of volatile anesthetic in the patient’s lungs, blood, and tissues. The patient will awaken when the level of the anesthetic in the brain has been lowered to a particular level termed MAC awake. However, if the other tissues have accumulated considerable amounts of the anesthetic, these depots of anesthetic may redistribute to the blood, alveoli, and then the brain.
Because there is minimal metabolism of modern volatile anesthetics, elimination of the volatile anesthetic depends almost entirely on VA. Thus, the elimination process will be interrupted by apnea or impeded by hypoventilation. Apnea or hypoventilation before tracheal extubation may be due to many causes, but most commonly it is the result of residual IV drugs such as propofol, benzodiazepines, opioids, and neuromuscular junction blockers. Apnea or hypoventilation after tracheal extubation may be caused by airway obstruction, laryngospasm or bronchospasm, or the effects of residual drugs.
Overall, inadequate VA may result in a reaccumulation of anesthetic in the blood, alveoli, and brain, resulting in what is called reanesthetization. We used the computer simulation Gas Man to examine the effect of hypoventilation after initial emergence from volatile anesthesia and to quantify the possibility and identify the sources of reanesthetization. Our hypothesis was that tissues, especially muscle, accumulate and achieve a high partial pressure of volatile anesthetic during anesthesia and then serve as the source of anesthetic that can cause reanesthetization if there is postanesthesia hypoventilation.
All simulations were performed using Gas Man version 3.1.9 and version 4.1.1 Gas Man is a commercially available1 physiologically based computer model of inhaled anesthetic uptake and distribution2 used for education.3,4 Gas Man can accurately predict expired anesthetic concentrations during induction and emergence from anesthesia.5 Gas Man assumes several things. Inhaled anesthetic kinetics may be described with a flow-limited 4-compartment mammillary model (alveolar gas [ALV], vessel-rich tissue group [VRG], muscle group [MUS], and fat group [FAT]) attached to another compartment, the breathing circuit (CKT). The partial pressure in each compartment equilibrates with the anesthetic brought to it so that both delivery rate and compartment volume determine the time course of compartment equilibration. Except for the concentration effect, the equilibration follows first-order kinetics. The model allows the user to fix the essential elements: anesthetic solubility in blood and tissue groups, gas flows, total blood flow and specific tissue group blood flows, and tissue volumes. It does not correct for intertissue diffusion of anesthetics,6 anesthetic metabolism, or VA/perfusion abnormalities. The particular (Euler) integration used stabilizes the behavior of the model under extreme conditions of fresh gas flow, VA, and cardiac output (CO). The model is able to faithfully reproduce the kinetic relationships described by Kety7 and explored by Eger8 and others, but it has not been extensively studied.
To study the time course of emergence and possible reanesthetization, 1-, 2-, 4-, and 6-hour periods of anesthesia at 0.75 MAC, 1 MAC, and 1.5 MAC with isoflurane, sevoflurane, and desflurane were simulated. In all simulations, the Gas Man default settings for alveolar ventilation (VA, 4 L/min), cardiac output (CO, 5 L/min), blood flow to VRG, MUS, and FAT (76%, 18%, and 6% of CO, respectively), and anesthetic solubility were used (Table 1). Using the default delivery concentration setting for each anesthetic drug and a semiclosed breathing circuit, a VRG concentration of 0.75, 1, and 1.5 MAC was rapidly achieved, and these target levels were maintained within tight limits for the remainder of the 1-, 2-, 4-, or 6-hour period of anesthesia by periodically making small decreases in the amount of drug delivered through adjustment of the vaporizer setting (Table 1).
At the end of the simulated period of anesthesia, the vaporizer setting was changed to 0 to stop the delivery of anesthetic, and the fresh gas flow (from the anesthesia machine) was set to 8 L/min to rapidly remove the anesthetic from CKT (Figs. 1 and 2). When the anesthetic concentration in the VRG reached a level of 0.33 MAC (MAC awake), the time was recorded and VA was adjusted to simulate hypoventilation after tracheal extubation at MAC awake (Figs. 3 and 4). VA settings of 0, 0.1, and 4 L/min were simulated for the range of inhaled drugs and periods of anesthesia. It is understood that VA of 0 and 0.1 L/min would become incompatible with life. These extremes of VA were simulated to demonstrate and explore the effect of severe hypoventilation on reanesthetization. Such low levels of VA could occur clinically during opioid overdose, laryngospasm, or bronchospasm. After this decrease in the VA, the VRG concentration was carefully analyzed. If VRG anesthetic tension reached 0.33 and/or 0.5 MAC during the simulated period of hypoventilation, the simulation was paused and the variables were recorded. If VRG tension reached 0.5 MAC, we called this severe reanesthetization; if it increased above 0.33 MAC but did not reach 0.5 MAC, we called this mild reanesthetization.
The lowest postextubation VA preventing an increase in the VRG concentration to 0.5 MAC was simulated and recorded using multiple bracketing simulations. The same technique was used to determine the lowest postextubation VA that prevented an increase in the VRG anesthetic tension above its extubation value of 0.33 MAC.
Table 2 shows the time to severe reanesthetization (VRG > 0.5 MAC) for simulated patients extubated at VRG anesthetic tension of 0.33 MAC after various durations of anesthesia. Figure 3 is an example simulation.
When the target was 0.75 MAC, severe reanesthetization did not occur with any drug after any simulated duration. Severe reanesthetization did not occur after a 1-hour or 2-hour 1 MAC administration of any of these drugs (Fig. 5). When the target was 1.0 MAC, severe reanesthetization (Table 2) occurred after a 4- or 6-hour administration of each of the 3 anesthetic drugs. When the target was 1.5 MAC, severe reanesthetization occurred after all durations of anesthesia with each drug simulated. After shorter duration of anesthesia, severe reanesthetization happened later.
Table 3 shows the minimum VA protective of reanesthetization after extubation at a VRG anesthetic tension of 0.33 MAC after anesthetics of 1-, 2-, 4-, and 6-hour duration. The left side of Table 3 shows the minimum postextubation VA protective of severe reanesthetization. At 0.75 MAC, severe reanesthetization did not occur. At 1 MAC, VA > 0.5 L/min was protective for all 3 drugs. At 1.5 MAC for 6 hours, VA > 0.6 L/min was protective for desflurane, VA > 0.7 L/min was protective for sevoflurane, and VA > 1.2 L/min was protective for isoflurane. At 1.5 MAC for 4 hours, VA > 0.50 L/min was protective for desflurane, VA > 0.55 L/min was protective for sevoflurane, and VA > 1.15 L/min was protective for isoflurane. The right side of Table 3 shows the minimum postextubation VA protective of mild reanesthetization.
The Muscle Compartment Is the Source of Anesthetic for Reanesthetization
We sought the source of anesthetic that causes reanesthetization. Gas Man includes a graphical representation of the anesthetic tension in the CKT, the ALV, the VRG, the MUS, and the FAT. Upon reaching the extubation point of 0.33 MAC in the VRG, the anesthetic tension of the CKT and ALV was slightly less than the VRG anesthetic tension. However, the anesthetic tension in the MUS, which had reached nearly 1 MAC (Table 4; Fig. 6) after 4 or 6 hours of anesthesia administered at 1 MAC, decreased much more slowly than the anesthetic tension in the CKT, ALV, FAT, and VRG once emergence was begun. Thus, muscle seems to be the source of volatile anesthetic-induced reanesthetization with postextubation hypoventilation. The fact that reanesthetization does not occur after 1 hour of anesthetic is consistent with the observation that muscle is the source of the anesthetic resulting in this phenomenon. For these 3 volatile anesthetic drugs, the anesthetic tension in muscle after 1 hour of anesthetic at 1 MAC does not approach 1 MAC and does not exceed MAC awake as it does after 4- or 6-hour administration at 1 MAC (Table 4). Additionally, the anesthetic tension in FAT is much lower than 0.33 MAC for all anesthetic drugs and durations simulated (Table 4).
Because postoperative hypoventilation after extubation sometimes results in reanesthetization, we were interested in using Gas Man to model various degrees of postextubation hypoventilation after a range of periods and depths of anesthesia. Our goal was to determine and demonstrate the source of volatile anesthetic that results in reanesthetization during postextubation hypoventilation after a long anesthetic. We observed that before the anesthetic was terminated, there was a high partial pressure (MAC fraction) of anesthetic in MUS and a very low level in FAT. We expected and wanted to demonstrate that normal ventilation after extubation expels this tissue reserve of volatile anesthetic while maintaining a low alveolar level of volatile anesthetic, which prevents an increase in the VRG anesthetic tension, thereby preventing reanesthetization. It followed that once the VA decreases below the minimum VA protective of reanesthetization, this elimination of anesthetic from the returning venous blood would be insufficient to prevent anesthetic level in arterial blood from increasing above MAC awake and causing a similar increase in VRG delayed by a few minutes.
We found that reanesthetization occurs after prolonged periods of anesthesia (4 or 6 hours, but not 1 and generally not 2 hours) and that it occurs more quickly after a 6-hour anesthetic compared with a 4-hour anesthetic. Both findings were consistent with our hypothesis since more anesthetic accumulates in the tissues the longer the period of anesthesia. The model showed that the severity of hypoventilation predicted both the likelihood and speed with which reanesthetization would occur. Thus, while reanesthetization could be simulated with all 3 drugs after a 4- or 6-hour anesthetic when the postextubation VA was 0 or 0.1 L/min, it did not occur with any of the anesthetic drugs when a postextubation VA of 1 L/min or more was simulated because the VA at 1 L/min is sufficient to prevent an increase in the VRG anesthetic tension, which would result in reanesthetization. Considering this same argument, it was not surprising that we also found reanesthetization occurred more quickly with a postextubation VA of 0 L/min compared with 0.1 L/min.
We were also interested in demonstrating that there is minimum VA protective of reanesthetization after anesthesia, and we found this VA. We expected this to be between 0.1 and 1.0 L/min (Table 3). The simulation showed that avoidance of reanesthetization after an anesthetic with isoflurane generally required twice the VA of sevoflurane or desflurane (Table 3).
Since an increase in the VRG anesthetic tension after extubation could signal inadequate VA, we were also interested in finding the minimum VA preventing an increase in the VRG anesthetic tension above 0.33 MAC (Table 3). These values are related to the blood solubility of each drug (Table 1) because a greater VA is required to eliminate more soluble anesthetic drugs. It is unclear why the simulated VRG anesthetic tension increases briefly after extubation after a 1-hour 1 MAC desflurane anesthetic while this did not occur after 1-hour 1 MAC administration of the other 2 anesthetic drugs (Fig. 5). It is likely this results from the high MUS anesthetic tension achieved due to desflurane’s low MUS solubility and the rapid decrease in arterial, alveolar, and VRG anesthetic tensions.
Apart from showing that postextubation hypoventilation could result in reanesthetization in Gas Man simulations, we were also interested in determining the source of the anesthetic that causes reanesthetization. As explained in the Results section, MUS and not FAT seem to be the tissue repository of anesthetic resulting in reanesthetization (Fig. 6). The low anesthetic tension in FAT, coupled with the low blood flow to FAT (default Gas Man settings are 18% of CO to MUS and 6% to FAT), keeps FAT from playing any role in the early period after anesthesia. The low blood flow to FAT is illustrated by the fact the anesthetic tension in FAT is virtually unchanged during emergence (Table 4). However, muscle is the tissue with a high enough anesthetic tension at the point of extubation to result in reanesthetization. Additionally, MUS has a high enough blood flow for the partial pressure gradient between MUS and the VRG to relatively quickly result in reanesthetization of the VRG with postextubation hypoventilation since the anesthetic tension in MUS at extubation is 0.8 to 0.9 MAC compared with 0.33 MAC in the VRG.
These simulations exemplify the fact that in the presence of good VA, inhaled anesthetic drugs are removed from the body effectively. They also remind us that impaired VA blocks the removal of these anesthetics from the body and allows retention in the body and the potential for reanesthetization.
It must be recognized that Gas Man, the simulation tool used here, does not consider all known physiologic and pharmacologic processes. It does suffice to demonstrate principles and subtleties of pharmacokinetics, and it has been used to describe the effects of changes in VA.9,10
In summary, these Gas Man simulations show that the combination of prolonged periods of anesthesia and postextubation hypoventilation can result in reanesthetization. The use of the more soluble anesthetic drug isoflurane increases the likelihood of reanesthetization since the minimum protective alveolar ventilation for isoflurane is approximately twice that for sevoflurane and desflurane. Muscle is the tissue repository of anesthetic that results in reanesthetization. While the VA resulting in reanesthetization is generally so low as to be clinically insignificant given that it required at least 10 minutes at these VAs to reach 0.5 MAC (Table 2), a postextubation VA of 0.5 L/min is the lowest that will prevent reanesthetization after a 6-hour 1 MAC anesthetic with isoflurane (Table 3) and a VA of at least 2.0 L/min is required to avoid any increase in the anesthetic tension of the VRG after a 6-hour 1 MAC isoflurane anesthetic (Table 3). Thus, when hypoventilation occurs after extubation, reanesthetization is most likely to occur when the hypoventilation episode was preceded by a prolonged isoflurane anesthetic. The fact that reanesthetization can occur with hypoventilation after extubation following a prolonged desflurane anesthetic was not unexpected. Indeed, it was this observation that led us to perform these simulations.
Name: Stanley Leeson, MB BCh, FRCA.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Stanley Leeson has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Russell S. Roberson, MD.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Russell S. Roberson has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: James H. Philip, MEE, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: James H. Philip has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Conflicts of Interest: James H. Philip received honoraria from Med Man Simulations, Inc., a non-profit charitable organization.
This manuscript was handled by: Tony Gin, MD, FRCA, FANZCA.
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