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Issues in Pulmonary Anesthesiology
The Effect of Isoflurane, Halothane, Sevoflurane, and Thiopental/Nitrous Oxide on Respiratory System Resistance after Trachial Intubation
1Rooke, GA, Choi, JH, Bishop, MJ The Effect of Isoflurane, Halothane, Sevoflurane, and Thiopental/Nitrous Oxide on Respiratory System Resistance after Trachial Intubation, Anesthesiology 1997 June; 86(6) 1294-1299 (c) 1997 American Society of Anesthesiology
1Background: In the background section of this paper there is the assertion that following tracheal intubation, lung resistance or more generally respiratory system resistance abbreviated Rrs increases. Furthermore volatile anesthetics are usually viewed as bronchodilators. The study compares the bronchodilating ability of four anesthetic maintenance protocols: 1.1 MAC end-tidal sevoflurane, isoflurane or halothane and thiopental/nitrous oxide.
An important but relatively rare complication of anesthesia is bronchospasm.
Wheezing, at least detectable wheezing, is an unusual event with an overall likelihood of occurring of about 0.17% with general anesthetics.
Bronchospasm is typically managed effectively when it does occur, possibly because of the use of potent inhalational agents which help manage bronchospasm-perhaps often preventing it in the first place.
Sometimes halothane is recommended as the most appropriate inhalational agents for this application; however, probably other volatile agents are similarly effective. For example, sevoflurane appears comparable to halothane in this regard and is less noxious.
Because bronchospasm is a relatively rare occurrence, it becomes an experimental challenge to actually evaluate relative efficacy of volatile agents in management.
One experimental approach would deal with the capability of volatile anesthetics to block intubation-induced bronchospasm.
Tracheal intubation is likely to cause some bronchoconstriction in most patients; furthermore, in a study involving volunteers given topical anesthesia, tracheal intubation resulted in a 40% increase in airway resistance.
Indirect evidence for endotracheal-intubation induced bronchoconstriction is derived from post-intubation measurements.
Furthermore, respiratory resistance noted following tracheal intubation is reduced by bronchodilator administration.
The extent of post-intubation resistance appears to vary depending on which induction agent is used.
Taking all these observations together, tracheal intubation may serve as a stimulus that would increase lung resistance thus allowing comparison between various anesthetics with respect to reversing this increase.
This study involved 66 middle age adults with "mild to moderate" lung disease. Exclusion criteria included: if patients were being treated with:
(1) a β2-adrenergic receptor agonist inhaler
(2) Anticholinergic inhaler
(3) Corticosteroids
(4) Theophylline.
With the participants awake and in a sitting position, baseline lung function was determined by measuring peak expiratory flow (PEF).
Then, anesthesia was induced in the supine participants using 2 μg/kg fentanyl, 5 mg/kg and thiopental and 1 mg/kg succinylcholine.
Tracheal intubation preceded using a cuffed endotracheal tube with an inner diameter of 7.5-8 mm.
Following intubation (not waiting for succinylcholine effects to subside), 0.1 mg/kg vecuronium or pancuronium was administered ensuring paralysis for the remainder of the study.
The choice of vecuronium or pancuronium was dependent on the probable duration of the case.
Controlled ventilation was set at 8/min. using a tidal volume of 10 ml/kg, and expiratory flow rate of 36 L/min. with an inspiratory: expiratory ratio of 1:3 typically.
Fresh gas flow was 3 L/min.
Respiratory system resistance, Rrs, was initiated by two minutes following intubation, when mechanical ventilation had been established as described above.
Following Rrs measurement completion, which took typically less than 30 seconds, one of 4 anesthetic maintenance protocols, chosen by random drawing, was initiated.
These protocols were: (1) and thiopental infusion and 0.25 mg/kg/min. + 50% nitrous oxide in oxygen; (2) 1.4% isoflurane in oxygen; (3) 0 25% halothane in oxygen; or (4) 2.3% sevoflurane in oxygen.
The volatile anesthetic concentrations were selected to approximate 1.1 MAC.
About 20 mcg/ml thiopental plasma concentration is necessary for 0.6 MAC of thiopental alone; plasma levels were probably asked that level during the study.
Over-pressure helped achieve end-tidal anesthetic concentrations quickly. Following this "bolus" administration, fresh gas concentration was adjusted in order to maintain a relatively constant end-tidal concentration for the remaining time in the study. The Rrswas measured 5 minutes and 10 minutes after anesthesia maintenance period had begun. In case the patient became hypotensive, IV administration of 50-100 μg phenylephrine was used.
Rrs was measured in centimeters of H2O/second using the "isovolume method" following correction for endotracheal tube resistance. This technique is based on measuring airway pressure and flow at identical volumes during inspiration and expiration. Furthermore, this technique has been applied in assessing mechanically ventilated patients.
A device called a pneumotachograph was calibrated in air for volume using a syringe.
Following volume measurements, corrections were made to take into account the presence of 50% nitrous oxide.
Using this pneumotachograph device interface with a personal computer, ventilatory flow and pressure occurs were sampled at 10 millisecond intervals with volume curve determined by integration of flow curves. The technique was developed to take into account pressure effects induced by the endotracheal tube itself allowing a proper calculation to be made. Corrected pressures using calculating Rrs use following parameters Pi = inspiratory pressure, Pe = expiratory pressure,C = compliance, Fi = expiratory flow, Fe = expiratory flow, and V = lung volume above functional residual capacity (FRC)
1Respiratory system resistance, Rrs, is calculated using the following 2 equations:
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The authors note that with the "isovolume" method, inspiratory and expiratory resistances contribute to Rrs measurement.
In the article, continuous variables were typically described as means +/- standard deviation, although in the figures standard error of the mean was used.
Comparisons within and between treatment groups utilized analysis of variance and the Student-Newman-Keuls post hoc past four multiple comparisons.
Comparisons between categorical variables utilized the chi-square statistical approach. Rrs5 and 10 minutes measurements were referenced our analysts obtained immediately after intubation and were expressed in terms of a percentage of this initial Rrs value. Statistical significance was set at 0.05.
The authors report no difference between groups relative to sex, age, height, weight, ASA classification, percentage of smokers and smoking history, and peak expiratory flow presented as a percentage of expected peak flow. (see Authors Table 1 below
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Following the first 30 individual studied, the authors noted that the response to thiopental was significantly, clearly different from the response to the inhalational agents. Accordingly, only seven patients were included in the thiopental group. Following this point in the study, patients were randomized among the inhalational agents. Following intubation, but prior to initiation of maintenance anesthesia, Rrs was not significantly different between the four study groups. At the five-and 10-minute times of maintenance anesthesia, Rrsdecreased significantly for the three volatile agent groups but not for the group in which patients receive thiopental + nitrous oxide.
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As shown above, the Rrs was decreased most for sevoflurane and was statistically different from isoflurane and halothane.
The difference between halothane and isoflurane was described as exhibiting a P value of 0.26, thus not meeting of the study's criteria for significance.
Most of the decrease in Rrs was observed at the five-minute time point (86 percent of the difference).
Additional change was apparently significant for the halothane and isoflurane groups, but not for the sevoflurane group
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Examining individual responses for the treatment groups indicated significant variation; moreover, one individual in the halothane group showed an actual increase in RRS, the only individual exhibiting that type of change.
If this particular data point (value) was not included in the analysis, the magnitude of the halothane response increases to 66% +/- 17% at the 10 min point, thus eliminating any difference between the halothane and sevoflurane groups.
Before we consider the discussion in detail, consider the authors conclusions:
that in middle aged adults with mild-to-moderate chronic lung disease, 1.1 MAC end-tidal concentrations for sevoflurane, halothane, and isoflurane reduced Rrs present after induction and intubation.
By contrast, no change was noted if anesthesia was maintained using thiopental infusion plus nitrous oxide. The authors conclude that sevoflurane may be reasonable alternative to the nominal choice of halothane as an adjunct to prevent or management intraoperative bronchospasm.
The authors indicated that the most surprising result was that sevoflurane decreased Rrs more than isoflurane and performed at least as well as halothane during this 10-minute exposure to the 1.1 MAC end-tidal anesthetic level. In general, sevoflurane has been associated with the least amount of airway irritation.
These results concerning sevoflurane and RRS was not noted in studies on dogs.
Reduced solubility associated with sevoflurane would promote more rapid tissue equilibration, compared other volatile anesthetics
This advantage was minimized in the study by using relatively high inspiratory concentrations thus making it more likely that end-tidal gas (arterial) concentrations would remain at 1.1 MAC for all the anesthetics.
Ultimately what would have happened with prolonged exposure achieving and-organ equilibration remains to be determined; nevertheless, significant responses were noted at the five-minute point, with sevoflurane performing as well are better than halothane or isoflurane.
The authors commented that "clinical
tradition" promotes the idea that halothane is better for reversing
clinical bronchospasm than isoflurane.
At least at the time this paper was written, there appears no scientific basis for this conclusions in humans; furthermore, even animal studies only suggest mixed support for halothane's use over the sevoflurane.
The present study indicated that halothane was not significantly better in reducing are as compared to isoflurane.
The authors, however, note that the inability to demonstrate a statistically significant difference may be related to the study's power suggesting that greater than 60 participants per group would be required to achieve statistical significance taking the observed means and standard deviations for halothane and isoflurane.
In conclusions drawn from the study is also important to note factors that could prevent broad generalizations.
In this regard the results could have been influenced by the choice of 1.1 MAC for the end-tidal concentration and by the mechanism used to stimulate bronchoconstriction. This point was emphasized in the discussion by the authors.
The significance of the end-tidal concentration with respect to this particular endpoint is noted in dogs studies in which halothane was a more effective bronchodilator compared isoflurane at 0.6 MAC but not at 1.7 MAC. Using anaphylaxis to Ascaris, the bronchoconstriction in that case was not more sensitive to sevoflurane compared to isoflurane.
The rationale for the 1.1 MAC choice in the study was that it was a dose that would be tolerated by most patients and the stimulus of endotracheal intubation to promote bronchospasm was selected because it is a common mechanism by which bronchospasm may be induced during anesthesia.
The authors also note that pancuronium was used in a few
patients and that pancuronium might promote bronchospasm through
potentiating vagal mechanisms.
The authors conclude that the basic conclusion that sevoflurane is at least as effective a bronchodilator compared to halothane would not have been influenced by pancuronium.
The authors also note that the anesthetic effect on
functional residual capacity (FRC) could influence the studies results.
A decrease in FRC with anesthesia induction reduces airway caliber increasing airway resistance.
This is the mechanism proposed to explain increases in airway resistance following isoflurane-mediated induction.
In the study all individuals have identical inductions such that any possible changes in FRC before maintenance anesthesia should been similar; all groups have similar Rrs values after intubation but before maintenance anesthesia began.
The absence of reports that volatile agents themselves increase FRC, in conjunction with the above information, indicates that decreases in respiratory resistance can be reasonably interpreted in terms of a bronchodilator characteristic of the volatile agents.
This does not rule out that differences in resistance between volatile agents could occur as a result of agent-specific effects on FRC but, as the authors note, paralyzing agents used in the study would presumably minimize these possible differences.
The patient population used in the study had a high
incidence of lung disease most likely because of smoking.
This conclusion is supported by the fact that only 18 out of the 66 study participants had a peak expiratory flow equal to or greater than the expected value.
Patients did not have clinical asthma, did not exhibit respiratory distress before surgery and did not develop bronchospasm that was clinically apparent.
Chronic bronchodilator treatment was allowed in the patient groups, for ethical reasons, and therefore this therapy may mitigate bronchospasm risk.
In other words, there could be a group of patients at higher risk than those used in the study, higher risk for bronchospasm during anesthesia.
The authors are careful to point out that the response to volatile agents noted in the current study group may not be automatically extended to higher risk patient groups or in patients who develop more severe bronchoconstriction than those exhibited in the study
It is important that the authors themselves outlined these limitations and the care required before extrapolating results of the current study to more broad applications.
It is the responsibility of all authors to indicate the reasonable limitations of the work, not relying on the reader to judge those limitations without guidance.
The authors know the work best with respect to the limitations of methodology and interpretation and have the obligation to go out of their way to illustrate the particular limitations and degrees of certitude that can be applied to results reported.
With respect to the measurement itself, Rrs using the isovolume technique takes into account airway resistance, chest wall resistance, and tissue viscosity.
Chest wall resistance should have been constant and changes in Rrs should represent lung resistance changes because the patients were paralyzed.
The underlying relationship between RRS and lung resistance has been analyzed in anesthetized paralyzed animals and validated in that system as well.
Changes in tissue viscosity and Rrs are not readily separated from airway resistance changes in the study.
Other work is suggested that both sources might contribute about equally to changes in long resistance caused by airway stimuli.2
Rrs represents an overall resistance to gas flow that must be overcome either by the patient when the mechanical ventilator.
1Rooke, GA, Choi, JH, Bishop, MJ The Effect of Isoflurane, Halothane, Sevoflurane, and Thiopental/Nitrous Oxide on Respiratory System Resistance after Trachial Intubation, Anesthesiology 1997 June; 86(6) 1294-1299 (c) 1997 American Society of Anesthesiology--reference 2 below second sourced from reference 1.
2Warner, DO, Vettermann, J, Brichant J-F, Rehder, K: Direct and neurally mediated effects of halothane on pulmonary resistance in vivo. Anesthesiology 1990; 72: 1057-1063.
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