Comparison of pattern of breathing with other measures of induction of anaesthesia, using propofol, methohexital, and sevoflurane{dagger}

T. L. Strickland and G. B. Drummond*

Department of Anaesthetics, Royal Infirmary, Edinburgh EH3 9YW, UK*Corresponding author

{dagger}Presented to the Anaesthetic Research Society, Aberdeen, 25th March 1999 (Br J Anaesth 1999; 83: P180–1).

Accepted for publication: January 9, 2001


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We assessed change of the pattern of breathing as a marker of induction of anaesthesia, using a method of maintaining spontaneous breathing throughout the induction period. We compared this index with a measure used clinically, the lash reflex, and measures used for drug investigations such as loss of grip of an object, cessation of finger tapping, and loss of arm tone. Ninety female patients (mean age 32 (17–63) yr, mean weight 63 (10) kg) were randomly allocated to induction of anaesthesia using propofol, methohexital, or sevoflurane. The i.v. agents were given by slow injection estimated to give an induction dose (for weight drop end point) in 90 s. Sevoflurane was given by progressively increasing the inhaled concentration to 8% so that induction should occur within 90–120 s. We measured time to change in breathing pattern, loss of voluntary finger tapping, loss of the lash reflex (tested at 15 s intervals), loss of postural tone in an outstretched arm, and loss of grip of a small metal cylinder held between finger and thumb. For methohexital and sevoflurane, the mean times for induction of anaesthesia occurred in the above order. With propofol, the lash reflex and tone were lost at the same time. The mean (SD) time to induction, by loss of arm tone was 64 (16) s for propofol, 83 (23) s for methohexital, and 94 (31) s for sevoflurane. The mean time to change in breathing pattern was 47 (20) s for propofol, 53 (14) s for methohexital, and 78 (29) s for sevoflurane. Although the time to achieve each end point was different, all the end points (except the lash reflex) appeared to provide similar measures of induction of anaesthesia. The pattern of breathing is an early sign of the onset of anaesthesia.

Br J Anaesth 2001; 86: 639–44

Keywords: ventilation, pattern; anaesthetics i.v.; anaesthesia, induction


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Clinical investigations of induction of anaesthesia use a variety of measures of loss of consciousness. These include loss of verbal contact, loss of volitional activity such as finger tapping, loss of reflexes, and loss of muscle tone.14 However, these tests may not be equivalent measures of anaesthesia. Dose–response curves for the separate tests may not be parallel for a given agent; for example the lash reflex may be lost before consciousness when propofol is used.5 The dose–response curves may also vary depending on the induction agent used thus they may not be parallel for differing agents.6

Propofol and barbiturates are two commonly used anaesthetic induction agents; and for day case surgery, inhalation induction with sevoflurane is becoming more common.7 However, some induction methods require considerable co-operation from the patient, such as vital capacity breaths or breath holding.8 Asking the patient to hold their breath helps to prevent apnoea after induction of anaesthesia, but can upset the continued uptake of the anaesthetic. Respiration can also be better maintained if re-breathing is allowed to offset the effects of hypocapnia.9 10 In our studies of this topic, we noted that breathing frequency and pattern changed noticeably and promptly to a different, regular pattern which could give an early and reliable index of loss of consciousness.

We designed the present study to compare the onset of regular breathing pattern with other frequently used end points of anaesthetic induction, both clinical and those used in investigations. We used three different induction agents—propofol, methohexitonal, and sevoflurane— which have possibly different patterns of action. We compared change in pattern of breathing with the more conventional estimates of induction of anaesthesia. We also considered the contention that conventional estimates of anaesthetic induction are not equivalent.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study was approved by the local ethics committee. We studied patients about to have surgery in the gynaecology day case unit, and asked healthy, English speaking women, aged more than 16 yr, to give written, informed consent. Patients were not recruited if they had received any form of sedation or analgesia.

We used a blocked, randomized, parallel design. Patients were allocated in blocks of 30 to receive either propofol, methohexitonal, or sevoflurane as an induction agent by sealed envelopes. Three were withdrawn for technical reasons after allocation. These choices were replaced.

As the rate of administration of i.v. agents would affect the time taken to administer an induction dose, and the rate of administration affects the induction dose required, we attempted to give each patient the appropriate dose in the same time. We estimated the induction dose of thiopental, using the regression equation of Avram,11 which takes age and weight into account:

Dose of thiopental (mg)=295+weight (kg)–age (yr)x1.86

The estimated induction dose (EID) of the i.v. agents was calculated using a relative potency for methohexital of 4.9312 and 0.53 for propofol (personal data). This dose was increased by 50%, made up to 30 ml using 0.9% saline, and given from a Graseby 3500 syringe driver set to run at 800 ml h–1, so that the EID would be given in about 90 s. The injection continued until all the end points had been reached or 150% of the EID had been given. The method of induction with sevoflurane did not require any change in the patient’s breathing. We added sevoflurane 0.5% to the fresh gas. After three breaths, this was doubled to 1%. The concentration was doubled after each three breaths until the maximum concentration of 8% was reached. This level was then maintained until all the end points had been reached.

The patients were monitored with ECG, non-invasive arterial pressure, and pulse oximetry. Arterial pressure readings were not taken during induction of anaesthesia. Before induction started, the patient breathed from a coaxial Mapleson D circuit supplied with oxygen 3 litre min–1 and fitted with a pneumotachograph and a sidestream carbon dioxide analyser (Datex Cardiocap II). A good mask seal was obtained, checked by movement of the reservoir bag and a carbon dioxide trace that showed a satisfactory expiratory plateau and a secondary peak during inspiration, indicating re-breathing. The pressure from the pneumotachograph was measured with a transducer (Furness) and recorded with a digital logging device (Dash IV). A second channel recorded a signal voltage used to mark the end points of induction. The device also gave a paper printout of the two signals at 20 mm s–1. After 45 s of regular breathing had been recorded, induction of anaesthesia was commenced.

Each patient lay supine on a horizontal table and a vein on the dorsum of the left hand was cannulated and connected to the infusion pump if appropriate. Before breathing from the mask was started, the right arm was held raised and straight, at 45% to the horizontal and away from the side of the body. The patient gripped a steel cylinder, 10 cm long, and 1.5 cm diameter, between the first finger and thumb of her right hand. She was asked to tap regularly with the index finger of the left hand, and to keep tapping, keep hold of the weight, and keep the arm up for as long as possible. The patient’s lash reflex was tested every 15 s. The signal voltage to the recorder was switched to indicate the time the lash reflex vanished, when the patient finally stopped tapping her index finger, when her right arm came down to become horizontal, (loss of muscle tone) and when the weight was dropped. When all the end points were reached and a change in breathing pattern had been noted, or after the entire i.v. dose had been given, the recording was stopped and anaesthesia continued as indicated clinically. If the entire dose of methohexital or propofol was given without all the end points having occurred, only those end points that had been reached were analysed.

A separate printout was made of the respiratory flow record and coded to conceal the agent and patient from a single observer who measured the time that the pattern of respiration changed (Fig. 1). If there was no clear changeover in breathing pattern, the end of the last recognizable ‘conscious’ breath and the start of the first recognizable ‘unconscious’ breath were chosen and the midpoint calculated. We measured the time from start of induction to the time to achieve the other end points from the recording of the events.



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Fig 1 A good example of the change in respiratory pattern during induction of anaesthesia. Inspiratory flow is down. Swallowing during expiration (marked S) occurs in two breaths preceding the onset of a sudden change in frequency and pattern of flow.

 
Statistical analysis
The data were displayed visually as cumulative effect against administration time, and described using statistics assuming a normal distribution. The coefficient of variation was taken as an index of the slope of the time–response curve. Responses were compared using ANOVA, and Minitab version 9. We compared the homogeneity of these coefficients with a method that allows comparisons of several variances.13 Using a common coefficient of variation, derived from a weighted sum of the coefficients of variation in each group, the test generates a value similar to the chi-squared statistic for three or more groups. No statistical package was used for this calculation, but it was aided with Excel 2000. Significance was set at P<0.05.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We asked 132 patients to take part in the study, and 93 patients agreed to do so. Data from 30 patients in each group are presented: three patients were withdrawn for technical reasons. Patient details are given in Table 1. There were no serious complications during induction of anaesthesia and oxygen saturation remained above 95% in all patients.


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Table 1 Physical characteristics of the patients studied
 
The change in breathing pattern was easily determined as a single time in 22, 20, and 15 of the patients who received propofol, sevoflurane, and methohexital, respectively. A good example of the transition is shown in Figure 1. Breathing frequency always increased, and the flow pattern changed recognizably in all except one subject. However, the change was gradual in about one-third of the patients and the time of transition had to be determined by interpolation. Apnoea (absent respiratory flow for more than 10 s) occurred during induction of anaesthesia in 6, 3, and 2 of the patients receiving propofol, sevoflurane, and methohexital, respectively. These differences in incidence were not statistically different between the groups (Fisher’s exact test). In all of these cases, the apnoea coincided with the change in pattern. The time of change could not be detected in one patient who received propofol.

One patient who received methohexital failed to drop the weight and this patient and five others (two propofol, three methohexital) still had a lash reflex after the entire i.v. dose had been given.

Propofol had a more rapid effect than the other agents. Apart from the lash reflex, the pattern of change in the end points was remarkably consistent (Figs. 2 and 3). Comparison of the agents using ANOVA showed that there were highly significant differences between the agents, using all the measures of induction. However, only with tapping, tone, and grip did the 95% CI for each distribution not overlap.



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Fig 2 Mean time with SD to end point for the three agents. Propofol, open column; methohexital, shaded column; sevoflurane, filled column.

 


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Fig 3 Cumulative response curves for the three agents. The responses shown in these panels are in sequence: open square symbols, breathing change; filled triangles, cessation of tapping; open diamonds, loss of arm tone; and filled circles, loss of grip. The loss of lash reflex overlaps some of these curves and is, therefore, shown as continuous lines. Six patients did not lose the lash reflex.

 
The effect of sevoflurane was delayed, presumably because of the progressive increase in the inhaled concentration, causing a delay before effective concentrations of the agent were being inhaled. The cumulative time curves appeared sigmoid (Fig. 3) and logit plots confirmed this. An example is shown in Figure 4.



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Fig 4 Cumulative response curves for the three agents, using a logit scale, for the loss of arm tone. Propofol, open circles; methohexital, closed triangles; and sevoflurane, open squares. The plots are straight, diverge, and do not overlap.

 
The response that differed from the others was the lash reflex. The original data are shown as a solid line in Figure 3 and the corresponding logit plot in Figure 5. Compared with the logit for tone, where the slope is less for the slower acting agent (sevoflurane), the slopes for propofol and sevoflurane are parallel and the slope for the methohexitone response is less. To test this possibility, we compared the coefficient of variation of the responses. We chose this measure for comparison between the tests because the mean time to achieve the responses differed considerably, and as time progressed the variation increased (see Figs 2 and 3). The coefficients of variation are given in Table 2. The only end point with a difference in variance between the agents was the lash reflex (P<0.01). The best estimate of the coefficient, based on pooled data, is greatest for this response.



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Fig 5 Cumulative response curves for the three agents, using a logit scale, for the loss of the lash reflex. Symbols as in Figure 4. The plots are straight, but do not diverge, and those for methohexital and propofol overlap.

 

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Table 2 Comparison of coefficients of variation (%) for the tests, between agents and between drugs. Significant difference between agents, *P<0.05; and between tests, **P<0.001
 
These observations are supported by sequence of loss of the responses in the individual subjects. The most likely sequence of response was breathing, tapping, tone, and grip; this sequence was found 53 times out of a possible 88. In contrast, the lash reflex was lost before arm tone in 9, 11, and 15 of the patients who received propofol, methohexital, and sevoflurane, respectively; that is only 35 times out of a potential 84.

For methohexital, but not for the other agents, there was a significant difference (P<0.01) in the coefficients of variance of each index. With this agent, the greatest coefficient of variation is for the lash reflex (Table 2).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We wished to relate the sign of automatic breathing to measures of induction, used in previous studies. Comparisons between studies are often impeded by the large variety of different measures used. These include loss of verbal contact,14 closing the eyes,15 loss of response to verbal command,3 16 17 stopping a task such as finger tapping,4 gripping a weight,9 18 19 20 loss of a reflex such as the lash reflex,21 22 or even combinations such as the lash reflex with finger tapping,4 23 or verbal contact.24 25 A recent large study of anaesthetic induction dose used a combination of verbal contact and response to physical contact.26 Respiratory changes at induction of anaesthesia have not been studied, perhaps because the loss of the conscious component of the drive to breathe often causes apnoea at this time. Usually, use of breathing circuits has been directed towards avoiding re-breathing,27 but hypocapnia is a frequent difficulty at induction.9 Reliable inhalation induction without apnoea is possible if fresh gas flows are reduced,10 and avoid the need to give patients instruction and practice.8 Perhaps the mildly greater PaCO2 values in the subjects in this study may have altered the kinetic factors affecting anaesthetic action, but current evidence for a large effect is limited,28 the pattern of responses is unlikely to be affected, and preliminary studies have not shown that mild re-breathing affects i.v.-induction (unpublished data).

For several reasons, we chose to compare times rather than doses in this study. First, the pattern of response loss was of more importance than the actual doses used. Second, one of the agents was inhaled, and estimating the ‘dose’ was not possible, particularly since as soon as the breathing pattern changed, the plateau pattern of exhaled gas composition was lost. However, it is likely that with induction occurring over this short period of time, the alveolar concentration of sevoflurane would still be increasing progressively.8 29 Third, the kinetics of induction are far from simple30 even though we chose drug infusion rates (typically about 160 mg kg–1 h–1) that would have reduced the influence of administration rate on time to induction, and to a lesser extent the effect of administration rate on dose requirement.26 The inter-relationship between kinetics and drug effect make acute studies, such as this one, uncertain grounds for speculation about drug effects. For example, propofol had a more rapid onset than we expected (i.e. appeared more potent), perhaps because the solution was diluted.26

Comparison of end points for a single drug are more valid, because the drug effect in this study will certainly have been progressively increasing. Previous studies have shown differences in slope of dose–response relationships for different end points, with the lash reflex generally having a greater variation in dose requirement.5 20 We were surprised to find that breathing was such a sensitive indicator of anaesthetic effect. This suggests that the change in respiration is a sign of withdrawal of conscious control, which occurs before loss of other cortical control such as finger tapping. Another volitional act, handgrip, was extremely resistant to depression. Our impression was that this function appeared in our patients to have become a component of muscle tone. Our results are at variance with those of a study where propofol was slowly infused in volunteers, when a weight was dropped while the subject was awake, and before the lash reflex was lost.20 Apart from the lash reflex, breathing change showed greater variation than the other tests, but this difference was not significant. A practical conclusion of this study is that breathing change is a sensitive index, but not very exact; and the most reliable and simple index is dropping of the outstretched arm, which is generally easily used clinically.

The response that is clearly different from the others is the lash reflex. Part of the greater variability of this measure might be caused by the intermittent measurements, but this could not explain the differences between agents. Anaesthesia is now not considered to be a single phenomenon.3133 In contrast to our other tests, which could be measures of a cortically mediated ‘obtunding’ effect, the lash reflex may indicate an ‘immobilizing’ effect that is less dependent on cortical effects,34 although other studies have found a close relationship between lash reflex and response to verbal command2 during propofol infusions. Further comparison between different agents with clinically relevant endpoints is justified.35


    Acknowledgement
 
Ms Strickland was supported by a Vacation Research Grant from the Anaesthetic Research Society, to carry out this project.


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 Introduction
 Methods
 Results
 Discussion
 References
 
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