Hemodynamic Responses to Nitrous Oxide during Inhalation Anesthesia in Pediatric Patients David J. Murray, MD, * Robert B. Forbes, MD,? David L. Dull, MD,* Larry T. Mahoney, MD+ Departments

of

Anesthesia and Pediatrics, University of Iowa College of Medicine,

Iowa City, IA.

*Assistant Anesthesia

Professor,

Department

of

tAssociate Anesthesia

Professor,

Department

of

$Associate Pediatrics

Professor,

Department

of

Address reprint requests to Dr. Murray at the Department of Anesthesia, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Supported by a starter grant from the Foundation for Anesthesia Education and Research (1988), Hartford, CT. Received for publication July 14, 1989; revised manuscript accepted for publication April 25, 1990. 0 1991 Butterworth-Heinemann

14

J. Clin. Anesth.,

Study Objective: To measure the hemodynamic changes produced by nitrous oxide (N,O) during halothane and isofurane anesthesia in infants and children. Design: A repeated measures design in two groups of infants and small children. Setting: Operating rooms at a university hospital. Patients: Nineteen healthy unmedicated infants and small children (mean age 12 months} who required elective surgery. Interventions: Prior to anesthesia induction, cardiovascular measurements were recorded using pulsed Doppler and two-dimensional echocardiography. Following anesthesia induction with halothane (n = 10) or isoflurane (n = 9) in oxygen (0,) and air, anesthetic measures were stabilized at I .O minimum alveolar concentration (MAC) and cardiovascular measures were repeated. After 30% N,O was added to the 1 .O MAC anesthetic concentrations, a third set of cardiovascular measurements was recorded. A final cardiovascular data set was measured 5 minutes following an increase in N,O concentration to 60%. Measurements and Main Results: Mean arterial pressure (MAP), cardiac index (CD, stroke volume (SV), and ejection fraction (EF) decreased similarly and signzficantly at 1 .OMAC halothane and isoflurane. Heart rate (HR) increased during isoflurane anesthesia but decreased during halothane anesthesia. The addition of N,O resulted in a decrease in HR, CI, and MAP when compared to 1 .O MAC levels of halothane or isoflurane; however, SV and EF were not significantly changed from levels measured during 1 .O MAC halothane or isoflurane. Conclusions: The addition of N,O to halothane and isoflurane anesthesia in infants and children decreased HR. This decrease led to a decrease in cardiac output (CO). Unlike with adults, N,O did not produce cardiovascular signs of sympathetic stimulation in infants and children.

Keywords: Anesthesia;

vol. 3, January/February

1991

pediatrics;

halothane;

isoflurane;

nitrous oxide.

N,O during anesthesia in pediatric patients: Murray et al.

Introduction In healthy adult volunteers, the addition of nitrous oxide (N,O) to halothane or isoflurane has been shown to produce less circulatory depression than equal anesthetic concentrations of halothane or isoflurane in oxygen (0,).1-5 In adults, the addition of N20 during halothane or isoflurane has been shown to produce signs of sympathetic stimulation.1-5 In infants and small children, no significant cardiovascular differences have been observed when the cardiovascular effects of halothane or isoflurane in 0, were compared to equal MAC levels of N,O combined with halothane or isoflurane.6 This finding suggests that N20 may have greater cardiovascular effects in infants and children than in adults. Following open heart surgery in infants, the substitution of N,O for nitrogen (N2) produced small but significant decreases in mean arterial pressure (MAP), heart rate (HR), and cardiac index (CI) but did not change stroke volume (SV), pulmonary vascular resistance (PVR), or systemic vascular resistance (SVR) in infants sedated with morphine.7 These two clinical studies suggest that N20 may have different cardiovascular effects in infants and small children than in adults. The purpose of this study was to define the cardiovascular changes that occur when increasing concentrations of N,O are added to a stable level of halothane and isoflurane anesthesia in healthy infants and small children.

Materials

and Methods

Nineteen ASA physical status I infants and small children who required elective surgery were studied after the protocol was approved by the University of Iowa Hospital’s Human Studies Committee. After informed parental consent was obtained, parents accompanied the patients to a presurgical care unit where two-dimensional echocardiographic and pulsed Doppler measures of left ventricular short axis area and left ventricular length, as well as pulmonary artery (PA) blood flow velocity, HR, and MAP,* were obtained prior to the induction of anesthesia in each child. The infants and small children were assigned to receive an inhalation induction with either halothane (n = 9) or isoflurane (n = 10) using a pediatric circle system with 4 liters per minute (L/min) of fresh gas f&v (2 Wmin air: 2 ‘L/min 0,). The anesthetic concentrations of halothane or isoflurane were adjusted to achieve and maintain 1.0 MAC anesthetic levels.g,10

Inspired and expired gas concentrations were measured using a Perkin-Elmer mass spectrometer (Perkin-Elmer Corp., Pomona, CA). Ventilation was controlled during the study period, and capnograms and expired and inspired anesthetic concentrations were recorded. After a constant end-expired halothane or isoflurane concentration had been maintained for 10 minutes, the cardiovascular data were measured over a P-minute period at the 1.O MAC endexpired concentration. The cardiovascular measurements were then repeated 5 minutes following the addition of 30% N20 to the 1.0 MAC halothane or isoflurane. A final measurement was made 5 minutes following an increase in end-expired N20 to 60%. All measurements were completed prior to endotracheal intubation and the start of elective surgery. The ultrasound studies were performed using an Ultra-Imager 2600 (Biosound, Inc., Indianapolis, IN) mechanical sector scanner with a 5 MHz single-element transducer combined with a 3.5 MHz Doppler interrogation frequency. Short-axis views, apical fourchamber views, and PA diameters were recorded at each measurement level. Mean PA blood flow velocity also was recorded at each measurement level.” Selected frozen images of electrocardiogram (EKG), two-dimensional echocardiography, and mean PA velocity were measured using a Microsonic CAD-886 image processing and video quantification system (Microsonics, Indianapolis, IN). The PA diameter and mean PA velocity were used to determine SV and cardiac output (CO). I’-‘* The two-dimensional recordings were used to calculate left ventricular enddiastolic volume.13-I7 Data were analyzed using a randomized block analysis of variance to compare the cardiovascular variables at different dosages and a two-factor repeated measures design to compare halothane and isoflurane.18 To maintain the overall error rate of p < 0.05, Bonferroni adjustment was used for the comparisons of the dosage levels. la Results are expressed as means + SEM.

Results The mean age (halothane 12.5 & 3.3 months; isoflurane 12.6 + 2.7 months), weight (halothane 9.4 a 0.7 kg; isoflurane 10.0 rt; 0.7 kg), and body surface area (halothane 0.50 + 0.01 m*, isoflurane 0.53 * 0.01 m2) of the two groups did not differ significantly. Inspired and expired gas concentrations were measured and recorded during controlled ventilation. The mean end-tidal carbon dioxide (CO,) during the J. Clin. Anesth., vol. 3, January/February

1991

15

Original Contribution.7

anesthesia study period was 3 1.7 ? 1.6 mmHg. The mean end-expired and inspired anesthetic levels re, corded for halothane were 1.06 + 0.04% and I .27 * 0.06%, and for isoflurane were 1.69 + 0.05% and 1.89 + 0.06%, respectively (Table 1). The measured end-expired N,O level was 30.2 ? 1.0% and 60.6 -+ 1.3%, respectively (Table 1). During 1.0 MAC halothane and isoflurane anesthesia, MAP, CI, ejection fraction (EF), and SV decreased significantly from levels measured prior to anesthesia induction (Table 2). Left ventricular enddiastolic volume (LVEDV) did not change from awake values. While HR increased significantly during 1.0 MAC isoflurane, HR decreased at 1 .O MAC halothane (Figure 1 and Table 2). Following the addition of 30% N,O to both halothane and isoflurane, HR decreased significantly (Figure I). The addition of 30% N,O resulted in significant decreases in CI in the halothane group but not in the isoflurane group (Figure2). SV, EF, and LVEDV were Table 1. Anesthetic

Concentrations

1 .O MAC

0 AWAKE

0

60

N,Ovol% -

HALOMANE

.__. ??___

-“NE

Figure 1. Heart rate (HR) changes during the study period. Results are expressed as means it SEM. (*p < 0.05 from awake; tp < 0.05 from 1.0 MAC measurement.) Measured

during

the Study

Expired (vol %) Inspired (vol %)

Period

Expired N,O (vol %)

1.0 MAC

1.07 -t 0.03

1.32 * 0.04

-

With 30% N,O With 60% N,O Isoflurane 1.0 MAC

1.06 * 0.04 1.06 +- 0.03 1.69 +- 0.03

1.27 2 0.03 1.24 * 0.03 1.89 ? 0.06

30.6 + 1.2 61.2 + 2.4 -

With 30% N,O With 60% N,O

1.68 ? 0.03 1.66 5 0.04

1.88 * 0.05 1.80 ? 0.06

29.8 + 0.X 60.4 + 1.6

Halothane

I 30

Note: Results are expressed as means ? SEM. alveolar concentration.

MAC = minimum

Table 2.

Cardiovascular

Measurements 1.0 MAC + Awake

Heart rate (beats/minute) Halothane Isoflurane Mean arterial pressure (mmHg) Halothane Isoflurane Stroke volume (ml/beat) Halothane Isoflurane Left ventricular end-diastolic volume Halothane Isoflurane Cardiac output (L/min) Halothane Isoflurane

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J. Clin.

Anesth.,

30% N,O

1.0 MAC + 60% N,O

130.3 + 6.8 132.4 -c 5.9

121.2 + 6.8* 139.8 * 7.0*

114.0 * 6.7*t 132.4 * 7.ot

1 11.9 -+ 6.7*t 126.2 ‘-’ 6.7l

72.0 ? 2.7 75.3 * 2.9

64.7 + 2.7* 65.1 + 3.6*

59.7 -i 2.6*t 58.4 ? 3.2*t

58.6 -+ 3.0*t 56.6 + 3.1*t

11.1 2 0.1 12.4 t 1.1

10.2 + 0.8* 10.3 Ifr 0.9*

9.7 * o.s* 11.0 f 0.8*

10.3 ? 0.08” 10.1 + 0.07”

12.3 t 1.4 13.3 * 1.2

12.7 ‘- 1.7 13.5 t 1.3

13.3 t 1.8 14.4 + 1.5

13.0 t 14.1 ?

1.40 5 0.10 1.58 ? 0.10

1.23 -t- O.lO* 1.40 2 0.10*

1.10 2 0.10*t 1.40 t 0.10*

1.03 ? o.oP?*t 1.27 * O.lO*t

(ml)

*p < 0.05 from awake. tp < 0.05 from 1.0 MAC. Note: Results are expressed MAC = minimum alveolar

1.0 MAC

as means k SEM. concentration.

vol. 3, January/February

1991

1.6 1.4

N,O during

B 8 AWAKE

0

30

anesthka

in pediatric

l.OMAC

0

60

AWAKE

0

-

HALOTHANE BOFUJRANE

30

Murray

et al.

I 60

N,Ovol%

N20voI%

-t-

patients:

--e-

HALOTHANE

-‘--.---

ISOFLURANE

Figure 2. Cardiac index (CI) changes during the study period. Results are expressed as means ? SEM. (*p < 0.05 from awake; tp < 0.05 from 1.0 MAC measurement.)

Figure 3. Percent (%) of awake ejection fraction. Results are expressed as means ? SEM. (*p < 0.05 from awake.)

unchanged from values measured during 1.0 MAC anesthesia. When compared to changes at 1.0 MAC, the addition of 60% N,O decreased HR, CI, and blood pressure (BP) similarly in the halothane and isoflurane groups (Figures 1,2, and?). SV, EF, and LVEDV were unchanged when compared with 1.0 MAC levels of halothane or isoflurane. HR decreased more in the infants who received halothane and N,O than in the infants who received isoflurane and N,O. The changes in CI, SV, LVEDV, and EF were similar during 60% N,O with 1.0 MAC halothane and 60% N,O with 1.0 MAC isoflurane.

of end-tidal gas measurements, cardiovascular changes that occurred following intubation may have altered the hemodynamic measurements.23 To improve the measurement of anesthetic concentrations, ventilation was controlled during the study period, and the capnograms were recorded. The mean end-tidal CO, measured during this study period was consistent with the use of controlled ventilation (31.7 rt 1.6 mm). If entrainment of inspired gas occurred during the study period, the end-tidal halothane and isoflurane levels measured would be overestimated. This action would result in an underestimate of the cardiovascular effects of halothane and isoflurane. While no direct measure of anesthetic levels in vessel-rich groups was made, the authors maintained constant end-tidal concentrations, and a stable expired-to-inspired anesthetic ratio (0.8) was present for 8 to 10 minutes prior to the cardiovascular measurements. Alveolar anesthetic levels reach equilibrium with central nervous system (CNS) levels more rapidly in infants than in adults during halothane anesthesia.22-24 The end-tidal to inspired anesthetic difference recorded during this study period and the duration of constant end-tidal levels were consistent with the premise that vessel-rich tissue group equilibrium was present for halothane during the study period.*2,z4 Isoflurane, a less soluble anesthetic, would be expected to result in vessel-rich tissue equilibrium more rapidly than would halothane. The addition of N20 accelerates the rate of rise of alveolar concentrations of volatile anesthetics.25s26 For

Discussion Anesthesia Measurements End-expired anesthetic measurements may include inspired gases when tidal volumes are small and respiratory rates rapid. rg-*’ The differences between expired and inspired gas concentrations are largest with CO,, and, therefore, the estimation of end-tidal CO, is most affected by entrainment of inspired gases. In infants maintained with halothane anesthesia, endtidal CO, measurements recorded from the proximal connector of an endotracheal tube approximate arterial CO, concentrations.*0-22 In this study, anesthetic measurements were made from an anesthetic mask. While intubation would have improved the accuracy

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Original Contributions

this reason, tissue levels of halothane and isoflurane following the addition of N,O may be greater than without N,0.25*26 To achieve constant end-expired levels, the inspired anesthetic concentration had to be adjusted following the addition of N,O.

Cardiovascular

Measurements

Noninvasive two-dimensional and pulsed Doppler echocardiography were used to assess left ventricular volume and PA blood flow velocity. This measurement method correlates with angiographic techniques,15-I7 but both technologies have limitations.“-” Two-dimensional imaging of the left ventricle volumes tends to underestimate left ventricular volumes. The angle of incidence of the Doppler signal with the pulmonary blood flow and measurement of the PA area by two-dimensional imaging can affect the accuracy of the CO measurements.1L-14 Using standardized echocardiographic measurements, the authors found correlation coefficients with invasive angiographic methods in infants and children to be greater than 0.9. In healthy adult volunteers, the addition of N,O to 1.0 MAC halothane anesthesia increased CO, SV, and right atria1 pressure without a change in HR.” In adults, sympathetic stimulation is believed to be the predominant cardiovascular effect when N,O is added to halothane anesthesia.‘-4 Similarly, when N,O was added to 1.0 MAC isoflurane, HR remained unchanged in adults but right atria1 pressure and MAP increased.5 In this study using pulsed Doppler echocardiography in infants and children, there was minimal evidence of sympathetic stimulation associated with the addition of N,O. When N, was substituted for N,O during controlled ventilation in intubated infants following surgical repair of congenital heart disease, Hickey et al.’ found small but significant decreases in HR and CI but no change in SVR or PVR in infants who had normal or increased PVR. The absence of changes in other measured values suggests that N,O has little or no sympathetic stimulating effect when administered in infants.’ In an earlier study of infants and small children that compared N,O with halothane or isoflurane to equivalent anesthetic concentrations of halothane or isoflurane in 02, N,O appeared to offer few cardiovascular benefits6 Based on the findings of this study, the cardiovascular effects of N,O in infants appear different from the sympathetic stimulation observed when N,O is added to halothane or isoflurane in adults. 18

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In the current study, the predominant cardiovascular change when N,O was added to 1.0 MAC halothane or isoflurane in healthy infants and children was a decrease in HR without changes in SV or EF. Unlike with adults, signs of sympathetic stimulation produced by the addition of N,O were not present in infants and children, but similar to adults, there was minimal clinical evidence of significant myocardial depression. The decrease in HR that occurs when N,O is added to volatile anesthesia may be of practical clinical importance, particularly when, as expected and observed in this study of infants and small children, the decreases in HR are accompanied by concomitant decreases in CO and MAP. The use of atropine and surgical stimulation should counter this predominant cardiovascular effect of N,O in infants and small children. In summary, the main cardiovascular change produced by adding 60% N,O to halothane and isoflurane in infants was a decrease in HR. While the decrease in HR following the addition of N,O is different from that in adults, N,O did not significantly alter other determinants of cardiovascular performance in healthy infants and children.

References 1 Eisele JH, Smith NT: Cardiovascular effects of 40 percent nitrous oxide in man. Anesth Analg 1972;51:95665. re2. Hill CE, English JE, Lunn J, et al: Cardiovascular sponses to nitrous oxide during light, moderate and deep halothane anesthesia in man. Anesth Analg 1978;57:84-94. 3. Bahlman SH, Eger EI II, Smith NT, et al: The cardiovascular effects of nitrous oxide-halothane anesthesia in man. Anesthesiology 1971;35:274-85. 4. Smith NT, Eger EI II, Stoelting RF, Whayne TF, Cullen DJ, Kadis LB: The cardiovascular and sympathomimetic responses to the addition of nitrous oxide to halothane in man. Anesthesiology 1970;32:4 10-2 1. 5. Dolan WM, Stevens WC, Eger EI II, et al: The cardiovascular and respiratory effects of isoflurane-nitrous oxide anaesthesia. Can Anaesth Sot J 1974;21:557-68. 6. Murray DJ, Forbes RB, Murphy K, Mahoney LT: Nitrous oxide: cardiovascular effects in infants and small children during halothane and isoflurane anesthesia. Anesth Analg 1988;67: 1059-64. M, Thompson JE, 7. Hickey PR, Hansen DD, Strafford Jonas RE, Mayer JE: Pulmonary and systemic hemodynamic effects of nitrous oxide in infants with normal and elevated pulmonary vascular resistance. Anesthesiology 1986;65:374-8. 8. Friesen RH, Lichtor JL: Indirect measurement of blood pressure in neonates and infants utilizing an automatic

N,O during anesthesia in pediatric patients: Murray et al.

9.

IO.

11.

12.

13.

14.

15.

16.

17.

noninvasive oscillometric monitor. Anesth An&g 1981;60:742-5. Gregory GA, Eger EI II, Munson ES: The relationship between age and halothane requirement in man. Anesthesiology 1969;30:488-91. Cameron CB, Robinson S, Gregory GA: The minimum anesthetic concentrations of isoflurane in children. Anesth Analg 1984;63:418-20. Murray DJ, Vandewalker G, Matherne GP, Mahoney LT: Pulsed Doppler and two-dimensional echocardiography: comparison of halothane and isoflurane on cardiac function in infants and small children. Anesthesiology 1987;67:211-7. Goldberg SJ, Sahn DJ, Allen HD, Valdes-Cruz LM, Hoenecke H, Carnahan Y: Evaluation of pulmonary and systemic blood flow by 2-dimensional echocardiography using fast Fourier transform spectral analysis. Am J Cardiol 1982;50:1392-1400, Mahoney LT, Coryell KG, Lauer RM: The newborn transitional circulation: a two-dimension Doppler echocardiographic study. J Am Co11Cardiol 1985;6:623-9. Disessa TG, Friedman WF: Echocardiographic evaluCardiol Clin 1983; 1:487ation of cardiac performance. 99. Schnittger 1, Gordon EP, Kritz-Gerald PJ, Pop RL: Standardized intracardiac measurements of two dimensional echocardiography. J Am Co11 Cardiol 1983; 2:934-8. Mercier JC, Disessa TG, Jarmakani JM, et al: Two dimensional echocardiographic assessment of left ventricular volumes and ejection fraction in children. Circulation 1982;65:962-9. Tortoledo FA, Quinones MA, Fernandez GC, Wag-

18.

19. 20.

2 1.

22.

23.

24.

25. 26.

goner AD, Winters WL: Quantification of left ventricular volumes by two dimensional echocardiography: a simplified and accurate approach. Circulation 1983; 67:579-84. Kirk RE: Experimental Design: Procedures for the Behavioral Sciences. 2d ed. Belmont, CA: Brooks/Cole Publishing Company, 1982: 106-9, 237-66. Sasse FJ: Can we trust end-tidal carbon dioxide measurements in infants? J Clin Monit 1985; 1: 147-8. Schieber RA, Naurourn A, Sugden A, Saville AL, Orr RA: Accuracy of expiratory carbon dioxide measurements using the coaxial and circle breathing circuits in small objects. J Clin Monit 1985; 1: 149-55. Badgwell JM, Heavner JE, May WS, Goldthorn JF, Lerman J: End-tidal PCO, monitoring in infants and children ventilated with either a partial rebreathing or a non-rebreathing circuit. Anesthesiology 1987;66:405-10. Brandom BW, Brandom RB, Cook DR: Uptake and distribution of halothane in infants: in vivo and computer simulations. Anesth Analg 1983;62:404-10. Tibbills J, Malbezin S: Cardiovascular changes during deep halothane anesthesia in infants and children. Anesth Intensiv Care 1988; 16:285-g 1. Eger EI II: Uptake of inhaled anesthetics: the alveolar to inspired anesthetic difference. In: Eger EI II, ed. Anesthetic Uptake and Action. Baltimore: Williams & Wilkins, 1974:77-96. Stoelting RK, Eger EI II: An additional explanation for the second gas effect. Anesthesiology 1969;30:273-7. Epstein RM, Rackow H, Salanitre E, Wolf CL: Influence of the concentration effect on the uptake of anesthetic mixtures: the second gas effect. Anesthesiology 1964;25:364-71.

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