Preoperative anxiety is a major risk factor for delirium on recovery and for the occurrence of postoperative behavioral disturbance in children. Because the prevalence of significant preoperative anxiety has been reported to be as high as 50% of children undergoing elective surgery, systematic premedication has been advocated to reduce anxiety and improve cooperation before anesthesia.1,2 Worldwide, midazolam is the most commonly used premedication drug in pediatric anesthesia because it can be delivered by all routes of administration, it has a rapid onset and a short half-life compared with other benzodiazepines.
Many diagnostic procedures are performed in remote areas by nonanesthesiologists in children who are often heavily premedicated by midazolam without adequate monitoring. Large doses of midazolam have been associated with a frequent incidence of hypoxemia in children that can lead to a critical event, especially in children with co-morbidities.3 Studies in adults have reported alteration in functional residual capacity (FRC) and other variables of ventilation with benzodiazepines because of their muscle relaxant properties.4,5 To our knowledge, there are no studies investigating the extent of changes caused by midazolam on FRC, ventilation homogeneity, and respiratory mechanics in children after a 0.3 mg/kg dose, which is commonly administered as a premedication. Therefore, we aimed to investigate the effect of midazolam on respiratory function in spontaneously breathing children before and after premedication with midazolam and tested the hypothesis that premedication with midazolam will decrease FRC 20 min after oral administration.
After approval by our Institutional Ethics Committee and after obtaining parental written informed consent, 21 children (3–8 yr) without cardiorespiratory disease (including upper or lower respiratory tract infections within the last 4 wk) or thoracic malformation undergoing elective surgery were recruited into the study.
After the preanesthetic assessment, baseline measurements of FRC, lung clearance index (LCI), and respiratory mechanics were assessed before administering midazolam orally at a dose of 0.3 mg/kg. Twenty minutes after premedication,6 the level of sedation was evaluated using the University of Michigan Sedation Scale (UMSS). The UMSS is a simple observational tool that assesses the level of alertness on a 5-point scale ranging from 1 (wide awake) to 5 (unarousable with deep stimulation).7 Respiratory function was then assessed for the second time. After the administration of midazolam, all patients were monitored using pulse oximetry.
FRC and LCI were measured during tidal breathing with the child wearing a nose clip and breathing via a mouthpiece connected to an ultrasonic transit-time airflow meter (Exhalyzer D with ICU insert, Eco Medics, Duernten, Switzerland), using the sulfur hexafluoride (SF6, molecular mass 146 g/mol) multibreath washout technique. The technical setup of the measurement equipment has been described previously.8 Briefly, this airflow meter combines accurate flow measurements with instantaneous determination of the molecular mass in the mainstream using a single sensor. FRC was calculated by measuring the cumulative expired tracer gas volume, which was then divided by the initial tracer gas concentration before the washout. The LCI is commonly used to measure the degree of ventilation distribution and is a sensitive indicator of peripheral airway collapse.9–13 The LCI is calculated as the cumulative expired volume needed to decrease the end-tidal tracer gas (SF6) concentration to 1/40 of the starting concentration divided by the FRC, i.e., the number of lung volume turnovers needed to clear the lungs of the marker gas.12,13 The number of volume turnovers is calculated using the cumulative expired alveolar volume.10,11 FRC and LCI calculations were performed by a blinded observer using Spiroware software (Version 1.5.2, ndd Medizintechnik AG, Zurich, Switzerland).
Respiratory mechanics were assessed using the forced oscillation technique (FOT). The assessment of respiratory system impedance (Zrs) in children is a well-established procedure in spontaneously breathing children.14,15 The FOT measures input impedance of the respiratory system (Zrs) by determining the mechanical response of the respiratory system to an external signal or “forced oscillation.”
The frequencies of FOT signals to measure Zrs included components from 8 to 26 Hz. The oscillatory signal was superimposed over the tidal breathing of the patient; therefore, testing required the patient to wear a nose clip and breathe quietly through a mouthpiece containing a 0.1 μm bacterial filter. To minimize the motion of the upper airway wall, which results in shunting and phase distortion of the lower Zrs, a technician supported the subject’s cheeks and mouth floor. Measurements were excluded on the basis of leak, cough, swallowing, glottis closure, or any other physical factors that may have altered readings. Rrs and Xrs were calculated from the mean of four technically acceptable measurements; the acceptance criteria were based on the reproducibility of Zrs data at all frequencies, expressed as a range of 10% in the coefficient of variation. Each single measurement was recorded over 16 s. The Zrs data were fitted by a simple model of the respiratory system, yielding the value of the mean resistance in the 8-to-26 Hz range (R), elastance (E) and inertance (I). Equipment impedance distal to the P2 measurement point was subtracted from Zrs, and the resulting small and physiologically unimportant I values are not reported.
At each assessment, FRC and LCI measurements were preformed in duplicate and FOT measurements in quadruplicates and the average values were used for all calculations.
Sample size calculations were performed using the nQuery Advisor 4.0 software (Statistical Solutions, Boston, MA). Based on separate pilot data, a sample size of 18 children was required in order to detect an FRC difference in means of 2 mL/kg (change from 25 to 23 mL/kg), assuming that the common standard deviation is 2.4 mL/kg using a paired t-test with an α error of 0.05 and a β error of 0.1.
Normal distribution of the data was confirmed with a Shapiro-Wilk test; accordingly, data are expressed as mean (sd). Paired t-tests were used to compare parameters between the repeated measurements. A P value of <0.05 was considered statistically significant. Results were analyzed using SigmaStat for Windows (Version 3.11 Systat Software, San Jose, CA).
Twenty-one patients were successfully recruited. Three patients had to be excluded due to lack of cooperation during the measurements performed before premedication. Two of them refused to breathe through the mouthpiece for a sufficient time and one could not get an appropriate seal around the mouthpiece to produce valid measurements. The 18 patients included (8 male, 10 female) had a median (range) age of 78.5 (36–107) mo, a median weight of 23.4 (12.6–38.75) kg, and a median length of 118 (98–132) cm.
Oral midazolam at 0.3 mg/kg led to a UMSS score of 1 (1–2) (median [range]). All measurements were successfully achieved in the children in the sitting position with no significant intraindividual difference (FRC CV 2.1 ± 1.4). Premedication with midazolam led to a statistically significant decrease in FRC of 6.5%, mean (sd), from 25 (1.4) mL/kg to 23.4 (1.9) mL/kg and a statistically significant increase in LCI, R and E of 7.8%, 7.4% and 9.2%, respectively (Table 1, Fig. 1).
There was a significant correlation between the percentage changes before and after premedication between the FRC and LCI (r2 = 0.85, P < 0.001), FRC and R (r2 = 0.63, P < 0.001) and FRC and E (r2 = 0.58, P < 0.001) (Figs. 2 A–C).
None of the patients showed any desaturation below 95% after the administration of midazolam. The average time of study in each subject was 15 min per assessment.
Premedication is often administered in pediatric anesthesia to reduce anxiety and improve cooperation. This study examined the effects of premedication with midazolam (0.3 mg/kg) on FRC, ventilation homogeneity and respiratory mechanics. Premedication with midazolam led to a small but statistically significant decrease in FRC and ventilation homogeneity. Moreover, midazolam impaired respiratory mechanics with mild increases in both resistance and elastance of the respiratory system. The changes in respiratory function were significantly correlated between the parameters measured.
In the present study, premedication resulted in anxiolysis rather than sedation. Sedation can be caused by higher doses of premedication, which might cause sleepiness and insufficient active cooperation by drowsiness. However, all children in this study were only minimally sedated and were fully cooperative while performing the lung function measurements which only included quiet normal tidal breathing through a mouthpiece and no specific maneuvers. Apart from one child, there were no problems with regard to leakage around the mouthpiece as reflected by the stable inspiratory and expiratory tidal volume difference before and after premedication which could be a sign of insufficient cooperation. The small but statistically significant decrease in minute ventilation seen after premedication (Table 1) might be attributed to a reduction in anxiety rather than to sedation. Moreover, lung volume measurements and respiratory mechanical variables obtained in the present study were similar to those obtained previously in healthy children,14 and the intraindividual variability was negligible, suggesting high consistency in the data obtained with these techniques. The lack of a placebo control is a limitation of the present study. However, randomization was not possible in the preoperative setting because premedication with placebo in an anxious child before surgery was considered unethical.1,2
Although the level of sedation is correlated to the midazolam dose, we observed a statistically significant impairment in respiratory function with 0.3 mg/kg, a routinely used dose in clinical practice in many institutions. However, higher doses of midazolam are commonly used for sedation, and greater changes in respiratory function might be expected.
In the present study, the second assessment of FRC was made 20 min after the premedication with midazolam, a time when approximately two-thirds of the children showed satisfactory anxiolysis.6,16 This time span between the measurements and the premedication was chosen to ensure optimal anxiolysis at induction of anesthesia. To minimize impact and stress for the child, lung function measurements were performed on the ward. However, studies have demonstrated that the maximal clinical effect of midazolam may occur after 30 min6,16 thus indicating that the differences measured between the awake state and after premedication might potentially be under-estimated because of the shorter time span in the present study.
Effect on Lung Volume
FRC is determined by the balance between the chest wall compliance, elastic lung recoil, active tension in the muscles of respiration,17 and the respiratory rate and tidal volume of the individual. During relaxed expiration, there is normally sufficient expiratory time to allow for emptying of the lungs to the elastic equilibrium volume (EEV) of the respiratory system. Any factor that alters these forces will lead to an alteration in the resting lung volume. Children, especially young children, frequently have a dynamic elevation of FRC above EEV due to a more rapid respiratory rate limiting expiratory time and active “breaking” of expiratory flow by postinspiratory activation of inspiratory muscles and/or glottic breaking. If a child is anxious, this dynamic elevation of FRC may be expected to be increased. Preanesthetic medications have both anxiolytic and muscle relaxant properties4,5,18 and either action may result to a decrease in FRC, such as that seen in the present study.
Although premedication with midazolam resulted in small but statistically significant reduction in tidal volume and minute ventilation, respiratory rate and expiratory times did not change (Table 1), suggesting that the changes in FRC and LCI are unlikely to be explained simply by a reduction in the dynamic elevation of FRC above EEV. Our finding is also in agreement with a previous investigation with diazepam in which sedation led to a decrease in FRC and tidal volume and changes in regional ventilation.4
Premedication with midazolam was associated with an impairment in respiratory mechanics with mild but statistically significant increases in R and E. The increases in R might be attributed to a decrease in mean lung volume and to the potential effect of benzodiazepines on upper airway muscle tone.19,20 Loss in lung volume can lead to an increase in lung stiffness if lung volume decreases below EEV. Benzodiazepines can also alter airway muscle tone,19,20 and decreased airway support in combination with a reduction in lung volume can result in an increase in airway resistance. A reduction in electromyographic respiratory muscle activity has been shown in adults after sedation with benzodiazepines compared with the awake state.21
Although the small changes in respiratory mechanics observed in the present study were within variability of measurements of oscillation mechanics,14,15 the homogenous changes toward an increase in airway resistance suggest a real effect induced by the premedication. The changes in respiratory mechanics were closely correlated to those observed in lung volume giving further evidence for the loss in lung volume as the primary cause for the changes observed in respiratory mechanics. Nevertheless, there was a large interindividual variability with a maximal increase in airway resistance of 24%, suggesting that in children with normal lungs impairment of respiratory mechanics was only mild. However, these changes must be seen in the context of anesthesia, where FRC is also altered by many other factors (position, muscle relaxants, anesthetic drugs), which can be additive during the perioperative period.8,22–25 Furthermore, we argue that the extent of the changes in lung volume and in respiratory mechanics are likely to be greater in children with known risk factors for respiratory complications from anesthesia, especially established lung disease and/or obesity.
Summary and Conclusion
We demonstrated in the present study that premedication with midazolam led to a statistically significant decrease in FRC, an increase in ventilation homogeneity and alteration in respiratory mechanics. Although the changes observed in the present study with a relatively small dose of midazolam and shortly after its administration were mild, these children had normal lungs. However, the anesthesiologist should be aware that using midazolam in children at high risk of respiratory complications under anesthesia might lead to a significant decrease in respiratory function.
The authors thank all children and their families who participated in this study.
1. Kain ZN, Mayes LC, O’Connor TZ, Cicchetti DV. Preoperative anxiety in children: predictors and outcomes. Arch Pediatr Adolesc Med 1996;150:1238–45
2. Kain ZN, Mayes LC, Caldwell-Andrews AA, Karas DE, McClain BC. Preoperative anxiety, postoperative pain, and behavioral recovery in young children undergping surgery. Pediatrics 2006;118:651–8
3. Cote CJ, Notterman DA, Karl HW, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: a critical incident analysis of contributing factors. Pediatrics 2000;105:805–14
4. Prato FS, Knill RL. Diazepam sedation reduces functional residual capacity and alters the distribution of ventilation in man. Can Anaesth Soc J 1983;30:493–500
5. Jolly E, Aguirre L, Jorge E, Luna C. Efecto agudo del lorazepam sobre los musculos respiratorios en los pacientes con epoc estable. Medicina (Buenos Aires) 1996;56:472–8
6. Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet 1998;35:37–47
7. Malviya S, Voepel-Lewis T, Tait AR, Merkel S, Tremper K, Naughton N. Depth of sedation in children undergoing computed tomography: validity and reliability of the University of Michigan Sedation Scale (UMSS). Br J Anaesth 2002;88:241–5
8. von Ungern-Sternberg BS, Frei FJ, Hammer J, Schibler A, Doerig R, Erb TO. Impact of depth of propofol anaesthesia on the functional residual capacity and ventilation distribution in healthy preschool children. Br J Anaesth 2007 98:503–8
9. East TD, Andriano KP, Pace NL. Automated measurement of functional residual capacity by sulfur hexafluoride washout. J Clin Monit 1987;3:14–21
10. Schibler A, Hall GL, Businger F, Reinmann B, Wildhaber JH, Cernelc M, Frey U. Measurement of lung volume and ventilation distribution with an ultrasonic flow meter in healthy infants. Eur Respir J 2002;20:912–18
11. Larsson A, Linnarsson D, Jonmarker C, Jonson B, Larsson H, Werner O. Measurement of lung volume by sulfur hexafluoride washout during spontaneous and controlled ventilation: further development of a method. Anesthesiology 1987;67:543–50
12. Gustafsson PM, Kallman S, Ljungberg H, Lindblad A. Method for assessment of volume of trapped gas in infants during multiple-breath inert gas washout. Pediatr Pulmonol 2003;35: 42–9
13. Gustafsson PM, Aurora P, Lindblad A. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur Respir J 2003;22:972–9
14. Oostveen E, MacLeod D, Lorino H, Farré R, Hantos Z, Desager K, Marchal F. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003;22:1026–41
15. Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora P, Bisgaard H, Davis GM, Ducharme FM, Eigen H, Gappa M, Gaultier C, Gustafsson PM, Hall GL, Hantos Z, Healy MJ, Jones MH, Klug B, Lodrup Carlsen KC, McKenzie SA, Marchal F, Mayer OH, Merkus PJ, Morris MG, Oostveen E, Pillow JJ, Seddon PC, Silverman M, Sly PD, Stocks J, Tepper RS, Vilozni D, Wilson NM. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med 2007;175:1304–45
16. Marshall J, Rodarte A, Blumer J, Khoo KC, Akbari B, Kearns G. Pediatric pharmacodynamics of midazolam oral syrup. Pediatric Pharmacology Research Unit Network. J Clin Pharmacol 2000;40:578–89
17. Macklem PT, Murphy B. The forces applied to the lung in health and disease. Am J Med 1974;57:371–7
18. Dretchen K, Ghoneim MM, Long JP. The interaction of diazepam with myoneural blocking agents. Anesthesiology 1971;34: 463–8
19. Leiter JC, Knuth SL, Krol RC, Bartlett DJ. The effect of diazepam on genioglossal activity in normal human subjects. Am Rev Respir Dis 1985;132:216–19
20. Montravers P, Dureuil B, Desmonts JM. Effects of i.v. midazolam on upper airway resistance. Br J Anaesth 1992;68:27–31
21. Drummond GB. Comparison of sedation with midazolam and ketamine: effects on airway muscle activity. Br J Anaesth 1996;76:663–7
22. von Ungern-Sternberg BS, Hammer J, Schibler A, Frei FJ, Erb TO. Decrease of functional residual capacity and ventilation homogeneity following neuromuscular blockade in anesthetized young infants and preschool children. Anesthesiology 2006;105:670–5
23. von Ungern-Sternberg BS, Saudan S, Regli A, Schaub E, Erb TO, Habre W. Should the modified Jackson Rees Ayres-T piece breathing system be abandoned in preschool children? Paed Anaesth 2007;17:654–60
24. Nunn JF. Effects of anaesthesia on respiration. Br J Anaesth 1990;65:54–62
© 2009 International Anesthesia Research Society
25. von Ungern-Sternberg BS, Regli A, Schibler A, Hammer J, Frei FJ, Erb TO. Impact of positive end-expiratory pressure on functional residual capacity and ventilation homogeneity impairment in anesthetized children exposed to high levels of inspired oxygen. Anesth Analg 2006;104:1364–8