1Service dAnesthésie Réanimation Pédiatrique, Hôpital Armand Trousseau, Paris, France. 2The Medical School, University of Birmingham, Birmingham B15 2TT, UK. 3INSERM E0107, Paris, France*Corresponding author: Service dAnesthésie, Hôpital denfants Armand Trousseau, 26 av. du Dr Arnold Netter, F-75571 Paris cedex 12, France
Accepted for publication: January 3, 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Sixteen non-pre-medicated pre-pubertal children undergoing middle-ear surgery, were studied. Data analysis was performed at three points: baseline, when the end-tidal concentration of nitrous oxide was stabilized at 50%, and after withdrawing nitrous oxide. Low (0.040.14 Hz) and high frequency (0.20.6 Hz) components of the spectral power of RRIV and SAPV, and SBR sensitivity were calculated using these 2-min data epochs.
Results. Our results show that brief exposure to 50% nitrous oxide in children results in: (1) absence of effect on mean AP and SAPV; (2) attenuation of the low frequency component of heart rate variability with a shift of the sympatheticparasympathetic cardiac balance toward a parasympathetic predominance; and (3) absence of alteration of spontaneous baroreflex sensibility.
Conclusions. Unlike the results demonstrated in adults, our findings show very few cardiovascular effects of nitrous oxide in children. Furthermore, whereas in adults nitrous oxide is associated with an excitatory cardiovascular profile, in children this agent seems to be associated with a depressant cardiovascular profile. The rapid return to baseline after discontinuation of administration and the absence of baroreflex changes are positive attributes for the use of nitrous oxide in children.
Br J Anaesth 2002; 88: 63743
Keywords: anaesthesia, paediatric; anaesthetics gases, nitrous oxide; arterial pressure, drug effects; parasympathetic nervous system; reflexes, baroreceptor; sympathetic nervous system
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The benefits and adverse effects of nitrous oxide have been reviewed recently.5 However, to our knowledge there are no data regarding the autonomic cardiovascular effects of nitrous oxide in children. Ebert and colleagues6 have demonstrated an increase in the peripheral sympathetic nerve activity associated with a moderate alteration of the cardiac baroreflex-mediated tachycardia in healthy adults breathing a mixture of 40% nitrous oxide and 60% oxygen. As pre-pubertal children show different autonomic cardiovascular profiles with a higher parasympathetic cardiac drive and lower sympathetic vascular tonus compared with adults,7 their haemodynamic response to nitrous oxide inhalation might differ from that of adult subjects. To investigate cardiovascular autonomic activity and the spontaneous baroreflex sensitivity in pre-pubertal children receiving nitrous oxide, we conducted a study based on non-invasive continuous recordings of RR-intervals and finger arterial pressure (AP). Vascular and cardiac sympathetic activities and cardiac parasympathetic activity were assessed using spectral analysis of systolic arterial pressure variability (SAPV) and RR-interval variability (RRIV). Data analysis was performed at three points: baseline, when the end-tidal concentration of nitrous oxide was stabilized at 50% and after withdrawing nitrous oxide. In addition, the baroreceptor-heart rate reflex was evaluated by calculating the spontaneous baroreflex slope using the beat sequences method8 as well as the cross-spectral analysis method.9
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Study procedure
Children were not pre-medicated and atropine was not given. Before nitrous oxide inhalation, a Finapres (model 2300, Ohmeda, Trappes, France) probe was placed on the middle phalanx of the third finger of the right hand, which was passively maintained at heart level during the study. This non-invasive device is widely used in adults and children in laboratory settings for physiological studies. In children, its reliability to assess non-invasively the main components of short-term systolic and diastolic AP variability has been demonstrated in intensive care10 and during the perioperative period.11 To ensure optimal AP measurement, we used appropriate cuff sizes (S or M) according to the manufacturers instructions.
The electrocardiogram was recorded using disposable electrodes attached to the thorax and placed to provide clear R-waves, and connected to a Datex cardiocap II monitor (Instrumentation Corp, Helsinski, Finland). RR-interval and AP were recorded continuously from baseline to the end of the recovery period. Expired gases and oxygen saturation were continuously recorded (Capnomac Ultima, Datex, Instrument Corporation Helsinki, Finland). This study took place in an anaesthetic area, nitrous oxide was delivered through an anaesthetic machine using an open circuit with a non-rebreathing valve. Nitrous oxide administration was standardized as follows: a comfortable-fitting face mask was applied and all subjects started to breathe air delivered at 6 litre min1 for a control period. Five minutes after application of the mask, when heart rate and AP were stable, a 2-min data sample was obtained (baseline). Then the subjects received nitrous oxide in oxygen to achieve a steady-state end-tidal concentration of 50%. When the expired concentration of nitrous oxide was stabilized at 50%, the second 2-min data sample was obtained (nitrous oxide inhalation). The i.v access was then obtained where the local anaesthetic cream (EMLA) had been applied. Nitrous oxide was then discontinued and the mixture of nitrous oxide and oxygen was replaced with air. The third 2-min data sample was obtained when the expired concentration of nitrous oxide returned to below 1%.
Data processing
Analysis of autonomic cardiovascular activity
The details of data sampling and analysis have already been described.12 The analogue outputs of the Datex monitor and of the Finapres device were connected to an analogue-to-digital converter to permit data acquisition, storage, and analysis using a microcomputer. AP and ECG signals were digitized (300 Hz) and processed by an algorithm based on feature extraction to detect and measure the characteristics of an AP cycle and a R-wave (Acqknowledge v3.25, Biopac Systems, Inc, Santa-Barbara, CA). Systolic AP was extracted from the AP signal, and RR-interval was calculated as time in milliseconds (ms), measured between successive R-waves. A re-sampling rate of 10 Hz was chosen without interpolation, that is systolic AP and RR-interval values were replicated every 0.1 s until a new AP cycle or R-wave occurred within a 0.1 s window. The evenly spaced sampling allowed direct spectral analysis using fast Fourier transformed algorithm on a 1024-point stationary time series. This corresponded to a period of 102.4 s at our sampling rate. Power of the RR-interval or systolic AP spectrum had units of (ms)2 or (mm Hg)2. The integration of the values of consecutive bands was computed to estimate the various components of the variability. The total area under the curve (AUC) was taken as the overall variability and was obtained by integration of all the spectral bands after exclusion of the first one. The low frequency component was obtained by integration of the values of consecutive bands from 0.049 to 0.147 Hz of systolic AP or RR-interval spectrum, in order to include the 10-s rhythm (0.1 Hz). The high frequency oscillation was obtained by integration of consecutive bands from 0.205 to 0.598 Hz in order to include those corresponding to the spontaneous breathing rate of all children. The normalized low and high frequency power (LFnu and HFnu), calculated as a percentage of the overall variability (AUC), were used for calculations and statistical analysis, as previously suggested.13
Assessment of spontaneous baroreflex
The technique of spontaneous baroreflex analysis was used to calculate sensitivity of the cardiac baroreflex during spontaneous fluctuations of AP and heart rate.14 The computer software examined each 2-min data set to select all sequences of three or more successive heart beats in which there were concordant increases or decreases in systolic AP and RR-interval. A linear regression was applied to each of the sequences, and an average regression slope was calculated for the sequences detected during each recording period. The slope of this regression (expressed as ms mm Hg1) represents the mean cardiac baroreflex sensitivity for that time period and has been shown to reflect values obtained at the resting AP using the vasoactive drug method.15
The baroreflex was also determined by the closed-loop spectral analysis method described by Pagani and colleagues.9 The cross-power spectral density was derived from the power spectra of RR-interval and systolic AP obtained as described previously. Following Pagani and colleagues9 only frequencies in which the squared coherence function of the cross spectrum of RR-interval and systolic AP was greater than 0.5 were used to calculate the gain of the baroreflex index. There were two regions where this level of squared coherence could be found that have been described as low (below 0.15 Hz) and high frequency (above 0.15 Hz). We calculated the baroreflex gain in these two spectral bands.
Statistical analysis
Data are expressed as mean (SD). Significant differences between anaesthesia and recovery were analysed by one way analysis of variance (ANOVA) for repeated measures, followed by paired t-test with Bonferronis correction to adjust for multiple comparisons.
Differences were considered to be statistically significant when the P value was <0.05.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Spontaneous baroreflex analysis
Data relating to the non-invasive assessment of the spontaneous baroreflex are summarized in Tables 2 and 3. The sensitivity of the spontaneous baroreflex, as assessed either by the sequences method or by the cross-correlation of the spectral components of heart rate and systolic AP was not affected by nitrous oxide inhalation. As expected, values of spontaneous baroreflex sensitivity assessed by the sequences method were highly correlated to those derived from the cross-spectral method both in the low frequency band (r=0.5, P<0.001) and the high frequency band (r=0.8, P<0.001).
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
These results differ noticeably from those reported in adult subjects. Earlier studies performed in adults, have provided indirect evidence that brief exposure to nitrous oxide enhances sympathetic nervous system activity.1618 Ebert and co-workers19 have provided direct evidence of sympathetic activation produced solely by nitrous oxide in healthy adults. They have shown that brief exposure to nitrous oxide results in augmentation of sympathetic outflow with increasing concentrations (2540%) of nitrous oxide. Indeed 1520 min of exposure to 40% nitrous oxide was associated with a 59% increase in efferent sympathetic traffic directed to vascular smooth muscle in skeletal muscle in adults.6 In the present study, we evaluated the efferent sympathetic activity using the low frequency component of SAPV. This low frequency component was calculated between 0.05 and 0.15 Hz, and therefore included the Mayer waves (0.1 Hz). The low frequency component calculated in this frequency band was increased in conditions associated with sympathetic activation such as the tilt test,20 the cold-pressor test,21 or mental stress.22 Moreover, Pagani and colleagues23 have demonstrated that the low frequency component of SAPV was positively correlated with the low frequency component of muscular sympathetic nerve activity (MSNA) variability. They have provided more direct support for the concept of using changes in the low frequency component of SAPV as a marker of changes in the sympathetic efferent activity to the peripheral vasculature. In our paediatric study, we failed to demonstrate any effect of nitrous oxide inhalation on the spectral power of SAPV. As reported previously, baseline MSNA correlates directly and vagal baroreflex gain correlates inversely with age.24 The lack of sympathetic excitation in children breathing nitrous oxide might be a result of lower peripheral sympathetic vasomotor tone, as has been suggested in young animals25 and pre-pubertal children.726 In accordance with this hypothesis, we have reported previously that healthy pre-pubertal children showed few 0.1 Hz oscillations of AP in the supine and standing positions, although standing is classically assumed to cause sympathetic nervous system excitation.
The power-spectral analysis of RRIV is routinely used as a non-invasive means of quantifying the cardiac autonomic input. The high frequency peak represents respiratory sinus arrhythmia and is a reliable indicator of parasympathetic efferent activity. The low frequency oscillations of the RR-interval seem to be subject to both sympathetic and parasympathetic influences.27 Despite its mixed origin, some studies indicate that the low frequency component, when measured in normalized units, may be an adequate reflection of sympathetic drive on the sinus node. Indeed Pagani and colleagues23 reported a very tight correlation between the low frequency component of RR and the low frequency component of MSNA variability. The concept of sympatho-vagal balance reflects the autonomic state resulting from the sympathetic and parasympathetic influences on the sinus node. The low to high frequency ratio was proposed to assess the fractional distribution of power when algorithms such as fast Fourier transformation were used. This new approach was tested with subtractive strategies28 and observational studies.29
We have demonstrated a decrease in the low frequency component of the RRIV without any significant changes in the high frequency component, leading to a decrease in the low to high frequency ratio in children breathing 50% nitrous oxide. These findings suggest that in children, inhalation of 50% nitrous oxide induces a decrease in sympathetic cardiac tone, leading to a shift of the sympatho-vagal balance towards the parasympathetic influence in accordance with the closed-loop conditions and the reciprocal relationship between low and high frequency components.30 Gallety and co-workers31 have shown a significant decrease in high frequency power leading to a rise in the low to high frequency ratio of heart rate variability in supine adults breathing 30% nitrous oxide; in addition, they showed that enhanced sympathetic dominance as a result of the standing position was blunted under nitrous oxide. The latter result suggests that nitrous oxide may exert a sympathetic inhibitor effect as we have demonstrated in children.
The healthy children we studied showed considerable baseline heart rate variability, which is more pronounced than that observed in adults. The respiratory contribution to RRIV in our subjects, taken at baseline, was higher than the low frequency contribution, in contrast to the findings described in adults. The data reflect a high vagal modulation of the RR-interval in children, as we have demonstrated previously.26 This specific RRIV profile might explain the different features observed in children breathing nitrous oxide compared with the results described in adults.
In our study, four out of 16 children vomited during exposure to nitrous oxide. It is well known that nitrous oxide may induce nausea and vomiting when administered as the sole anaesthetic drug in volunteers.32 An interesting finding in our study is the marked vagal predominance demonstrated in children who vomited compared with the others. This vagal predominance was observed not only under nitrous oxide, but also at baseline. We suggest that in children, nitrous oxide inhalation may induce an increase in parasympathetic system output associated with emesis in some predisposed children who have a high level of basal vagal tone. This effect might be related to interactions of nitrous oxide with opioïd receptors in the brain.33
The spontaneous baroreflex method was used to calculate the sensitivity of the cardiac baroreflex by measuring the chronotropic responses to arterial pressure fluctuations.34 This method has been shown to yield a reliable index of parasympathetic responsiveness of the baroreflex within its resting operating range.15 The baroreflex sensitivity is defined by the ratio of change in RR-interval to change in systolic AP. It has been established that these variations in RR-interval are brought about by changes in parasympathetic and sympathetic efferent influences on the heart. However, the relative roles of the two efferent pathways that control the RR-interval are not strictly simultaneous and reciprocal. In particular it has been shown that in supine resting conditions the parasympathetic pathway plays the major role in heart rate control, whereas the sympathetic system has a minor modifying influence.34 Thus, in our study, the baroreflex sensitivity was probably influenced primarily by the parasympathetic drive. Ebert, studying adult volunteers,6 found a decrease in baroreflex-mediated tachycardia induced by nitroprusside injection during brief exposure to 40% nitrous oxide in oxygen. Ostlund and co-workers,35 studying the whole range of baroreflex stimuli using neck pressure and suction, found no change in carotid cardiac chronotropic responses to hypertensive stimuli with 39% nitrous oxide but found, at the same time, that the sensitivity of tachycardic responses to hypotensive stimuli tended to be lower than when breathing air. However, in our study we failed to demonstrate any effect of nitrous oxide on cardiac baroreflex response in children, either using the sequences method that allows to separate the up and down sequences of RR-interval and AP, or using cross-spectral analysis that is based on concordant AP and RR-interval changes independent of their direction. These discrepancies may be explained either by the differences between the baroreflex assessment methods or by the autonomic physiological differences between children and adults discussed previously.
In our study a maximum of 50% nitrous oxide was chosen because it is the nitrous oxide concentration delivered with the EMONO system. Previous human studies suggest that sympathetic excitation is most prevalent during the first 1530 min of exposure to nitrous oxide. Our experimental procedure was kept brief to stimulate typical duration of exposure found in clinical practice. However, it is possible that some time-related factors in adult studies such as gastric distension and stimulation, have not been taken into account in our study.
In summary our non-invasive study documents autonomic cardiovascular changes induced by brief exposure to 50% nitrous oxide in children. Unlike the results demonstrated in adults, our findings show very few cardiovascular effects of nitrous oxide. In children, this agent seems more associated with depressant cardiovascular profiles than with excitatory profiles such as those demonstrated in adults. The rapid return to baseline after discontinuation of nitrous oxide and the absence of baroreflex alterations is reassuring if nitrous oxide is to be used in children.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox AJ. Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992; 327: 9937[Abstract]
3 Baskett PJ. The use of Entonox by nursing staff and physiotherapists. Nurs Mirror Midwives J 1972; 135: 3032[Medline]
4 Annequin D, Carbajal R, Chauvin P, Gall O, Tourniaire B, Murat I. Fixed 50% nitrous oxide oxygen mixture for painful procedures: a French survey. Pediatrics 2000; 105: E47[Medline]
5 Stenqvist O, Husum B, Dale O. Nitrous oxide: an ageing gentleman. Acta Anaesthesiol Scand 2001; 45: 1357[ISI][Medline]
6 Ebert TJ. Differential effects of nitrous oxide on baroreflex control of heart rate and peripheral sympathetic nerve activity in humans. Anesthesiology 1990; 72: 1622[ISI][Medline]
7 Yamagushi H, Tanaka H, Adachi K, Mino M. Beat to beat blood pressure and heart rate responses to active standing in Japanese children. Acta Paediatr 1997; 85: 57783[ISI]
8
Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G. Evaluation of baroreceptor reflex by blood pressure monitoring in unanesthetized cats. Am J Physiol 1988; 254: H37783
9 Pagani M, Somers V, Furlan R, et al. Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension 1988; 12: 60010[Abstract]
10 Triedman JK, Saul JP. Comparison of intraarterial with continuous noninvasive blood pressure measurement in postoperative pediatric patients. J Clin Monit 1994; 10: 1120[ISI][Medline]
11 Constant I, Laude D, Elghozi JL, Murat I. Assessment of short-term blood pressure variability in anesthetized children: a comparative study between intraarterial and finger blood pressure. J Clin Monit 1999; 15: 20514[ISI]
12 Constant I, Dubois MC, Piat V, Moutard ML, McCue M, Murat I. Changes in EEG and autonomic cardiovascular activity during induction of anesthesia with sevoflurane compared to halothane in children. Anesthesiology 1999; 91: 160415[ISI][Medline]
13 Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 1996; 17: 35481[ISI][Medline]
14 Parati G, Di Rienzo M, Bertinieri G, et al. Evaluation of the baroreceptorheart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans. Hypertension 1988; 12: 21422[Abstract]
15
Parlow J, Viale JP, Annat G, Hughson R, Quintin L. Spontaneous cardiac baroreflex in humans. Comparison with drug-induced responses. Hypertension 1995; 25: 105868
16 Eisele JH, Smith NT. Cardiovascular effects of 40 percent nitrous oxide in man. Anesth Analg 1972; 51: 95663[Medline]
17 Hill GE, English JE, Lunn J, et al. Cardiovascular responses to nitrous oxide during light, moderate, and deep halothane anesthesia in man. Anesth Analg 1978; 57: 8494[ISI][Medline]
18 Kawamura R, Stanley TH, English JB, Hill GE, Liu WS, Webster LR. Cardiovascular responses to nitrous oxide exposure for two hours in man. Anesth Analg 1980; 59: 939[Abstract]
19 Ebert TJ, Kampine JP. Nitrous oxide augments sympathetic outflow: direct evidence from human peroneal nerve recordings. Anesth Analg 1989; 69: 4449[Abstract]
20
Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KU, Eckberg DL. Human responses to upright tilt: a window on central autonomic integration. J Physiol 1999; 517: 61728
21 Weise F, Laude D, Girard A, Zitoun P, Siché JP, Elghozi JL. Effects of the cold pressor test on short term fluctuations of finger arterial blood pressure and heart rate in normal subjects. Clin Auton Res 1993; 5: 30310
22 Pagani M, Furtan R, Pizzinelli P, Crivellaro W, Cetti S, Malliani A. Spectral analysis of R-R and arterial pressure variabilities to assess sympatho-vagal interaction during mental stress in humans. J Hypertens 1989; 7: S14S15[ISI]
23
Pagani M, Montano N, Porta A, et al. Relationship between spectral components of cardiovascular variabilities and direct measures of sympathetic nerve activity in humans. Circulation 1997; 95: 14411448
24
Rudas L, Crossman AA, Morillo CA, et al. Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine. Am J Physiol 1999; 276: H16918
25 Magrini F. Haemodynamic determinants of the arterial blood pressure rise during growth in conscious puppies. Cardiovasc Res 1978; 12: 4228[ISI][Medline]
26 Constant I, Villain E, Laude D, Girard A, Murat I, Elghozi J.L. Heart rate control of blood pressure variability in children: a study in subjects with fixed ventricular rhythm. Clin Sci 1998, 95; 3342
27
Malliani A, Pagani M, Montano N, Mela GS. Sympathovagal balance: a reappraisal. Circulation 1998; 98: 26403
28
Rimoldi O, Pierini S, Ferrari A, Cerutti S, Pagani M, Malliani A. Analysis of short-term oscillations of R-R and arterial pressure in conscious dogs. Am J Physiol 1990; 258: H96776
29 Furlan R, Guzzetti S, Crivellaro W, et al. Continuous 24-hour assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects. Circulation 1990; 81: 53747[Abstract]
30 Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation 1991; 84: 48292[Abstract]
31 Galletly DC, Tobin PD, Robinson BJ, Corfiatis T. Effect of inhalation of 30% nitrous oxide on spectral components of heart rate variability in conscious man. Clin Sci 1993; 85: 38992[ISI][Medline]
32 Hornbein TF, Eger EI 2nd, Winter PM, Smith G, Wetstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg 1982; 61: 5536[Abstract]
33 Gillman MA. Nitrous oxide at analgesic concentrationsan opiate agonist: further evidence. Anesth Analg 1982; 61: 3945
34 Bertinieri G, di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G. A new approach to analysis of the arterial baroreflex. J Hypertens Suppl 1985; 3 (Suppl 3): S7981[Medline]
35 Robinson BF, Epstein SE, Beiser GD, Braunwald E. Control of heart rate by the autonomic nervous system. Studies in man on the interrelation between baroreceptor mechanisms and exercise. Circ Res 1966; 19: 40011[ISI][Medline]
36
Ostlund A, Linnarsson D. Slowing and attenuation of baroreflex heart rate control with nitrous oxide in exercising men. J Appl Physiol 1999; 87: 8304