Observational study of behavioral disturbance in children with developmental disorder under general anesthesia

doi:10.21203/rs.3.rs-3316402/v1

Objective

Anxiety and fear due to the unknown, and separation from parents are common emotions that children experience when faced with the need for dental treatment. In children with developmental disorders (DD), we hypothesized that a more anxious state, resulting in poor cooperation, might be associated with negative behavioral changes after general anesthesia. In this study, we assessed the perioperative behaviors of children with and without DD.

Methods

Patients (1–6 yrs) undergoing elective dental treatment were divided into two groups: children with DD and those without DD using inhalational anesthetics such as sevoflurane or isoflurane. The following data were collected prospectively: the modified Yale Preoperative Anxiety Scale (m-YPAS) 1 at the preoperative consultation, m-YPAS 2 at induction of anesthesia, the occurrence of emergence agitation (EA), and the Pediatric Anesthesia Emergence Delirium (PAED).

Results

The m-YPAS 1 and 2 scores of children with DD were significantly higher than those of children without DD (p<0.05). The occurrence of EA after isoflurane anesthesia in children with and without DD was significantly lower than that after sevoflurane anesthesia (P<0.01). However, after sevoflurane anesthesia, children with DD showed no significant difference in EA compared with children without DD (p=0.13). After isoflurane anesthesia, children with and without DD showed no significant differences (p= 1.00). For both inhalational anesthetics, PAED also showed no significant difference between children with and without DD after sevoflurane anesthesia (p=0.50) and isoflurane anesthesia (p=0.47).

Conclusion

Isoflurane suppressed EA more effectively than sevoflurane in children. After general anesthesia, however, no significant differences were observed between children, although children with DD showed significant behavioral disturbances.

Clinical relevance

We provided it was important to pay special attention to children with DD during preoperative and induction of anesthesia. Isoflurane suppressed emergence agitation more effectively.

Trial registration

This prospective observational study was approved by the Ethics Committee of Kyushu University Hospital (#24034) and registered with the UMIN Clinical Trials Registry (UMIN000034094).

agitation

developmental disorder

anesthesia

pediatric

Anxiety and fear are common emotions experienced by children when faced with the need to undergo dental treatment. [1, 2] Additionally, general anesthesia is a distressing experience for children, which may lead to adverse behavioral changes. [3–6] High perioperative anxiety has been associated with postoperative pain and maladaptive behavioral changes in children. [7–9]

Unlike delirium, emergence agitation (EA) after general anesthesia is a state of mild restlessness and mental distress. [10–12] Many studies have reported that inhalational anesthetics such as sevoflurane and desflurane are associated with increased rates of EA (10–66%). [13–16]

Children with developmental disorders (DD), such as attention deficit hyperactivity disorder (ADHD), are characterized by inattention, impulsivity, and hyperactivity. [17] The population with DD comprises approximately 2–20% of all children. [18, 19] Children with DD may need sedation or general anesthesia for dental treatment, as they often exhibit anxiety and fear during dental treatment. [1, 2, 20] Otherwise, their cognitive impairment may prevent them from cooperating with dentists. Children with DD may be perioperative problems for anesthesiologists when children with DD receive general anesthesia. However, the combination of psychological factors and events that lead to the development of preoperative anxiety remains insufficiently investigated. [3, 19] Moreover, the results of the incidence of perioperative behavior disturbance and EA among various anesthetic agents are quite contradictory.

We focused on the perioperative behavioral changes in children with DD. This study aimed to compare changes in a perioperative behavioral disturbance before and after dental treatment under general anesthesia between children with and without DD. We hypothesized that children with DD would be less cooperative during the perioperative period than those without DD.

This prospective observational study was approved by the Ethics Committee of Kyushu University Hospital (#24034) and registered with the UMIN Clinical Trials Registry (UMIN000034094). Written informed consent was obtained from parents or guardians with child assent, as appropriate, undergoing elective dental treatment, American Society of Anesthesiologists physical status I or II, mask induction of general anesthesia, and between 1–6 years of age. Patients with uncontrolled seizures, emergency surgery, intravenous induction, cardiac disease, or predicted difficult airways were excluded from the study. The patients were randomly assigned to receive either sevoflurane (sevoflurane group: children with and without DD) or isoflurane (isoflurane group: children with and without DD).

Trained research assistants recorded the preoperative cooperative behaviors and observations. The patient did not receive any premedication. The parents accompanied the patient to the operating room for general anesthesia. Anesthesia was induced by inhalation of sevoflurane in oxygen and/or nitrous oxide (N₂O) after the start of noninvasive monitoring of oxygen saturation (SpO₂). During anesthesia induction, the patient and parents were not separated while the patient awakened. After the loss of consciousness, an electrocardiogram (ECG), blood pressure (BP), and heart rate (HR) were monitored. Fentanyl, remifentanil, atropine, and rocuronium were administered via peripheral intravenous access. After intubation, anesthesia was maintained with sevoflurane or isoflurane in oxygen and air. Furthermore, fentanyl and/or remifentanil were administered for analgesia, and acetaminophen was administered before the end of dental treatment for postoperative analgesia in all cases. After the dental procedures, all anesthetics were turned off using the last stimulus technique, such as the removal of the gastric tube and suction into the trachea. Then, the fresh gas inflow rate was changed to 6 L/min of oxygen and minute volume 6–10 ml/kg. No further stimulation was permitted until spontaneous ventilation occurred. Ventilation was discontinued when the patient regained a spontaneous respiratory effort. After spontaneous regular respiration and upper airway patency were observed, the patient was extubated smoothly. Their respiratory and hemodynamic conditions were stable, and they were discharged to the patient's room. Trained research assistants assessed emergence and postoperative behavior.

The following data were collected: sex, age, height, weight and anesthetic records. Additionally, to the following data, the modified Yale Preoperative Anxiety Scale (m-YPAS) was administered twice prospectively: on the preoperative anesthetic consultant and at the induction of anesthesia. On emergence EA for 1 min. The Pediatric Anesthesia Emergence Delirium (PAED) scale score for 10 min was also collected.

Statistics

An a priori power analysis was performed using data based on clinical experiences resulting from our preliminary study. The sample size of 20 patients was calculated based on assuming α = 0.05, 1.4 standard deviation (SD), and 80% power using JMP® 15 (SAS Institute Inc., Cary, NC, USA). Factoring in an estimated dropout rate of approximately 10%, the total sample size for this study was 100 patients.

Nonparametric analytical methods were used, including Fisher's exact test for distribution comparison, which was used to analyze the differences in patient backgrounds and anesthetic records between the two inhalational analgesia groups were used to compare the groups for nonparametric data using MATLAB (version 2015a; MathWorks, Inc., Natick, MA). Some data are expressed as mean ± SD or the number (n), some as median values, and others in percentages. Statistical significance was set at P-value < 0.05.

This study included 100 children. A flowchart of the study design is shown in Fig. 1. Clinical characteristics did not differ significantly (Table.1, 2).

The m-YPAS 1 and 2 levels in children with DD were significantly higher than those in children without DD (p < 0.05) (Table.3). In both groups, m-YPAS 2 was significantly higher than m-YPAS 1 (p < 0.05).

No significant differences were observed in the occurrence of EA between the children with and without DD (Table.4). However, the occurrence of EA after isoflurane anesthesia was significantly lower than that after sevoflurane anesthesia (P < 0.05). Furthermore, children with DD using sevoflurane were not significantly different in EA compared with children without DD (p = 0.13), and children with DD using isoflurane were the same and not significantly different in EA compared with children without DD using isoflurane (Table.4).

PAED was not significantly different between the sevoflurane group (p = 0.50) and the isoflurane group (p = 0.47) (Table.5). Additionally, no significant differences were observed between the children with and without DD (p = 1.00, p = 1.00).

This study showed that children with DD were more uncooperative with preoperative consultants and induction of anesthesia and were more likely to exhibit exaggerated maladaptive behavioral changes on EA with the use of sevoflurane.

Perioperative pediatric anxiety is common and can have a negative psychological impact on children undergoing anesthesia, because exposure to unfamiliar environments may cause children to display fear and high levels of distress. [2, 21, 22] Reasons for pediatric anxiety include fear of the uncertainty of anesthesia, loss of control, potential pain, and separation from parents. [19, 23, 24] Many risk factors such as child age, lack of knowledge about anesthetic practice, gas induction via face mask, have been investigated. [2, 20] Particularly, children with DD were more likely to be uncooperative. According to previous reports, children with DD undergoing procedures have significantly lower cortisol levels than children without DD and are harder to manage clinically. [19, 20] An agitated child is distressing for the caregiver to control and can result in life-threatening events like self-harm, disrupting intravenous lines, and surgical dressings, which result in bleeding and falling accidents.

We used the m-YPAS as an objective indicator of preoperative anxiety in infants undergoing general anesthesia. [3, 5, 6, 25, 26] The m-YPAS is an observational measure of children's preoperative anxiety divided into 5 categories: Activity, Vocalizations, Emotional Expressivity, State of Arousal, and Use of Parent. All m-YPAS categories have been demonstrated to have good to excellent inter- and intraobserver reliability. [3, 4] Eleven scores range from 23.3 (no anxiety) to 100 (very intense anxiety), with higher scores indicating greater anxiety levels. This measure was developed and validated in previous investigations and has been used in multiple experimental protocols. [3, 5, 8, 26]

In this study, children with DD were significantly more anxious and less cooperative than those without DD during the preoperative consultation. Moreover, although anesthesia was induced in the presence of parents, behavioral disturbances during anesthesia induction were significantly greater in children with DD. As it may be natural to feel anxious on the day of surgery, the m-YPAS 2 was significantly higher than the m-YPAS 1 in both groups.

By contrast, EA is the most commonly encountered uncooperative and restless behavior in pediatric patients recovering from general anesthesia. [12–14] EA is defined as a disturbance in a child’s awareness of and attention to his or her environment with disorientation and perceptual alterations. [13, 23, 24] They respond differently to stress and have impaired coping skills, fear of being separated from their parents, and a loss of control or autonomy. Indeed, children with low adaptability are more likely to show EA and exhibit negative postoperative behaviors. [22] They could manifest as a refusal to separate from their parents, crying, thrashing, or verbal resistance. The reported incidence of EA varies depending on the definition and measurement tools used. [6, 23] In this study, 1 min after emergence from inhalational anesthetics was designed as the evaluation point of EA. In our results, no significant difference was observed in the occurrence of EA between the groups, although children with DD were more uncooperative on preoperative consultation and induction of anesthesia than children without DD.

Sevoflurane is the preferred anesthetic agent for the induction and maintenance of pediatric anesthesia because it has less odor and other irritants. [4, 11] Moreover, the blood/gas and tissue/blood partition coefficients of sevoflurane were lower than those of isoflurane. [15] This character is significant for quick and smooth induction and early emergence from anesthesia. [13] However, concerns have been raised regarding its propensity to result in significant excitatory emergence in the immediate recovery phase. EA has been hypothesized to result from differences in the clearance of inhalational agents from the central nervous system, leading to varying recovery rates at different sites of brain function after general anesthesia [14]. Most anesthesiologists agree that sevoflurane causes a high incidence of EA. [15]

In the case of isoflurane, the blood/gas and tissue/blood partition coefficients of inhalational anesthetics are higher than those of sevoflurane. [12, 23, 27, 28] The use of isoflurane may reduce the use of several anesthetic drugs to prevent EA from general anesthesia in the operating room. [12, 23]

PAED is a dissociated state of consciousness that occurs in the immediate post-anesthesia period and is characterized by nonpurposeful movement, restlessness, and inconsolable crying. [21, 22] Both fentanyl and NSAIDs have been shown to reduce the incidence of PAED as they reduce postoperative pain. [6, 12, 16] The incidence of PAED in our study showed no significant difference between children with and without DD and between sevoflurane anesthesia and isoflurane anesthesia. Children may not suffer much from postoperative pain, which is known to be associated with behavioral disturbances, as dental surgery is less invasive. Furthermore, 10 min was defined as the evaluation point of PAED. Although it is a self-limiting phenomenon that lasts 5–25 min, no differences were observed in cooperation between the two groups. [21]

Multiple studies have demonstrated that anxiolytic premedication facilitates anesthesia induction. Several anesthetic drugs, such as non-opioid analgesics, opioids, and benzodiazepines, prevent EA from general anesthesia in the operating room. [6, 14] A sedative medication injection may be needed, particularly for uncooperative patients. [15] However, we do not recommend preoperative premedication because of the possible side effects, additional costs, and workload. Several drug- and non-drug-related procedures have been designed to reduce anxiety and agitation in children. [7] Additionally, immersive virtual reality tours of the operating room and a favorite toy blanket could help reduce preoperative anxiety. [8, 25, 26] Some techniques are also being used more regularly to help distract patients and alleviate their negative emotions. [15]

Our results demonstrated that both groups showed more uncooperative behavior and were more likely to exhibit exaggerated maladaptive behavioral changes in EA with the use of sevoflurane than isoflurane; however, no significant differences were observed in PAED between sevoflurane and isoflurane. These findings are significant for the clinical management of these patients.

Our study had a few limitations. First, the sample size was small due to the minimal number of pediatric patients, particularly children with DD. Finally, this study excluded desflurane, an inhalational anesthetic. In the future, a bigger sample size using desflurane may be necessary.

Children with DD undergoing dental treatment showed significantly more preoperative behavioral disturbances than those without DD before anesthesia. However, no significant differences were observed in EA and PAED between children with and without DD. Therefore, we may not need special attention to children with DD after anesthesia. Contrarily, isoflurane suppressed EA more effectively than sevoflurane. Therefore, isoflurane may be preferred for pediatric anesthesia.

Contributions

R. Nishimura contributed to data acquisition, interpretation and revised the manuscript.

M. Tsukamoto contributed to the conception, design, data acquisition, drafted and critically revised the manuscript.

M. Goto contributed to data acquisition, interpretation and revised the manuscript.

K. Matsuo contribute to performe the statistical analyses.

T. Yokoyama contributed to the conception, interpretation and revised the manuscript.

All authors gave their final approval and agreed to be accountable for all aspects of the work. All authors have read and approved the final manuscript.

Ethics approval: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent to participate: Informed consent was obtained from all the patients.

Conflicts of interest: The authors have no conflicts of interest to declare.

Funding: None.

Janthasila N, Keeratisiroj O, Music therapy and aromatherapy on dental anxiety and fear: A randomized controlled trial, J Dent Sci, 2023;18(1):203–210.
Delivet H, Beauvais D, Mialot A, Vacher T, Marsac L, Brasher C, Michelet D, Dahmani S, Description of typical personality factors and events that lead to anxiety at induction of anesthesia in French children, Paediatr Anaesth, 2018;28(11):987–998.
Berghmans JM, Poley M, Weber F Van De Velde M, Adriaenssens P, Klein J, Himpe D, Utens E, Does the Child Behavior Checklist predict levels of preoperative anxiety at anesthetic induction and postoperative emergence delirium? A prospective cohort study, Minerva Anestesiol, 2015;81(2):145–56.
Kain ZN, Caldwell-Andrews AA, Weinberg ME, Mayes LC, Wang SM, Gaal D, Saadat H, Maranets I, Sevoflurane versus halothane: postoperative maladaptive behavioral changes: a randomized, controlled trial, Anesthesiology, 2005;102(4):720–6.
Beringer RM, Greenwood R, Kilpatrick N, Development and validation of the Pediatric Anesthesia Behavior score–an objective measure of behavior during induction of anesthesia, Paediatr Anaesth, 2014;24(2):196–200.
Beringer RM, Segar P, Pearson A, Greamspet M, Kilpatrick N, Observational study of perioperative behavior changes in children having teeth extracted under general anesthesia, Paediatr Anaesth, 2014;24(5):499–504.
Jenkins BN, Fortier MA, Kaplan SH, Mayes LC, Kain ZN, Development of a short version of the modified Yale Preoperative Anxiety Scale, Anesth Analg, 2014;119(3):643–650.
Ryu JH, Oh AY, Yoo HJ, Kim JH, Park JW, Han SH, The effect of an immersive virtual reality tour of the operating theater on emergence delirium in children undergoing general anesthesia: A randomized controlled trial, Paediatr Anaesth, 2019;29(1):98–105.
Kain ZN, Caldwell-Andrews AA, Maranets I, McClain B, Gaal D, Mayes LC, Feng R, Zhang H, Preoperative anxiety and emergence delirium and postoperative maladaptive behaviors, Anesth Analg, 2004;99(6):1648–1654.
Zou Y, Liu SH, Xue FS, Emergence agitation or delirium in children, J Anesth, 2022;36(1):156.
Cohen IT, Finkel JC, Hannallah RS, Hummer KA, Patel KM, The effect of fentanyl on the emergence characteristics after desflurane or sevoflurane anesthesia in children, Anesth Analg, 2002;94(5):1178–81,
Singh R, Kharbanda M, Sood N, Mahajan V, Chatterji C, Comparative evaluation of incidence of emergence agitation and post-operative recovery profile in paediatric patients after isoflurane, sevoflurane and desflurane anaesthesia, Indian J Anaesth, 2012;56(2):156–61.
Cravero J, Surgenor S, Whalen K, Emergence agitation in paediatric patients after sevoflurane anaesthesia and no surgery: a comparison with halothane, Paediatr Anaesth, 2000;10(4):419–24.
Kanaya A, Emergence agitation in children: risk factors, prevention, and treatment, J Anesth, 2016;30(2):261–7.
Kuratani N, Oi Y, Greater incidence of emergence agitation in children after sevoflurane anesthesia as compared with halothane: a meta-analysis of randomized controlled trials, Anesthesiology, 2008;109(2):225–32.
Na HS, Song IA, Hwang JW, Do SH, Oh AY, Emergence agitation in children undergoing adenotonsillectomy: a comparison of sevoflurane vs. sevoflurane-remifentanil administration, Acta Anaesthesiol Scand, 2013;57(1):100–5.
Xu L, Hu Y, Huang L, Liu Y, Wang B, Xie L, Hu Z, The association between attention deficit hyperactivity disorder and general anaesthesia - a narrative review, Anaesthesia, 2019;74(1):57–63.
Forsyth I, Bergesio R, Chambers NA, Attention-deficit hyperactivity disorder and anesthesia, Paediatr Anaesth, 2006;16(4):371–3.
Tait AR, Voepel-Lewis T, Burke C, Doherty T, Anesthesia induction, emergence, and postoperative behaviors in children with attention-deficit/hyperactivity disorders, Paediatr Anaesth, 2010;20(4):323–9.
Reddy SK, Deutsch N, Behavioral and Emotional Disorders in Children and Their Anesthetic Implications, Children (Basel), 2020;25;7(12):253.
Locatelli BG, Ingelmo PM, Emre S, Meroni V, Minardi C, Frawley G, Benigni A, Di Marco S, Spotti A, Busi I, Sonzogni V, Emergence delirium in children: a comparison of sevoflurane and desflurane anesthesia using the Paediatric Anesthesia Emergence Delirium scale, Paediatr Anaesth, 2013;23(4):301–8.
Mason KP, Paediatric emergence delirium: a comprehensive review and interpretation of the literature, Br J Anaesth, 2017;118(3):335–343.
Vlajkovic GP, Sindjelic RP, Emergence delirium in children: many questions, few answers, Anesth Analg, 2007;104(1):84–91.
Zhong Q, Qu X, Xu C, Effect of preoperative visiting operation room on emergence agitation in preschool children under sevoflurane anesthesia, Int J Pediatr Otorhinolaryngol, 2018;104:32–35.
Jung MJ, Libaw JS, Ma K, Whitlock EL, Feiner JR, Sinskey JL, Pediatric Distraction on Induction of Anesthesia With Virtual Reality and Perioperative Anxiolysis: A Randomized Controlled Trial, Anesth Analg, 2021;132(3):798–806.
Kim H, Jung SM, Yu H, Park SJ, Video Distraction and Parental Presence for the Management of Preoperative Anxiety and Postoperative Behavioral Disturbance in Children: A Randomized Controlled Trial, Anesth Analg, 2015;121(3):778–784.
Tsukamoto M, Hitosugi T, Yokoyama T, Comparison of recovery in pediatric patients: a retrospective study, Clin Oral Investig, 2019;23(9):3653–3656.
Tsukamoto M, Yamanaka H, Yokoyama T, Age-related differences in recovery from inhalational anesthesia: a retrospective study, Aging Clin Exp Res, 2018;30(12):1523–1527.

Table.1 Demographic data

	Sevoflurane group (n=50)		Isoflurane group (n=50)
	Children without DD n=25	Children with DD n=25	Children without DD n=25	Children with DD n=25
Gender (M/F)	12/13	19/6	12/13	20/5
Age (yrs)	4.1 ± 1.1	5.0 ± 0.8	4.2 ± 1.2	5.4 ± 1.4
Height (cm)	102.1 ±9.3	106.6 ± 8.7	102.7 ± 10.0	109.6 ± 9.9
Weight (kg)	7.2 ± 3.2	15.5 ± 1.2	16.2± 3.6	18.9 ± 4.7

Developmental disorder; DD

Values are means ± standard deviation or number.

Table.2 Demographic data and baseline scores

	Sevoflurane group (n=50)		P value	Isoflurane group (n=50)		P value
	Children without DD n=25	Children with DD n=25		Children without DD n=25	Children with DD n=25
Operative time (min)	187.0 ± 81.9	215.2 ± 83.4	0.23	230.7 ± 90.4	191.8 ± 72.4	0.60
Anesthesia time (min)	249.8 ± 82.1	279.2 ± 80.4	0.20	261.9 ± 88.9	254.2 ± 70.9	0.73
Temperature at the end of dental treatment (°)	37.1 ± 0.5	37.1 ± 0.5	0.84	37.1 ± 0.5	37.0 ± 0.5	0.86
End-tidal concentration at emergence (%)	0.4 ± 0.1	0.3 ± 0.1	0.26	0.2 ± 0.1	0.3 ± 0.1	0.44
Fentanyl (μg)	64.0 ± 27.3	74.6 ± 26.5	0.17	69.2 ± 26.2	69.6 ± 30.3	0.96
Remifentanil (μg)	550.5 ± 279.7	712.1 ± 234.4	0.07	754.5 ± 372.3	756.1 ± 336.2	0.98
Acetaminophen (mg)	214.0 ± 70.8	234.0 ± 83.6	0.36	189.6 ± 64.1	227.2 ± 58.5	0.35

Fisher's exact test between groups, Values are means ± standard deviation.

A P-value <0.05 is considered significant.

Table.3 mYPAS 1 at preoperative consultation and 2 at induction of general anesthesia between children with or without developmental disorder (DD)

	Children without DD n=50	Children with DD n=50	P value
mYPAS1	30.6 ± 4.9	35.8 ± 5.7	<0.05
mYPAS2	51.8 ± 11.3	70.7 ± 12.9	<0.05
P value	<0.05	<0.05

Values are means ± standard deviation, Fisher's exact test between groups.

A P-value <0.05 is considered significant.

Table.4 Incidence of emergence agitation.

Sevoflurane group

(n=50)

P value

Isoflurane group

(n=50)

Children without DD n=25

Children with DD n=25

Children without DD n=25

Children with DD n=25

Emergence agitation (n)

18

23

p=0.13

1

Fisher's exact test between groups, Values are number.

A P-value <0.05 is considered significant.

Table.5 PAED using sevoflurane or isoflurane between children with or without developmental disorder (DD)

Sevoflurane group

(n=50)

P value

Isoflurane group

(n=50)

P value

Children without DD n=25

DD

n=25

Children without DD n=25

DD

n=25

PAED

11.0 ± 2.6

11.4 ± 1.5

p=0.50

11.1 ± 2.6

10.6 ± 2.0

p=0.47

Values are means ± standard deviation, Fisher's exact test between groups. A P-value <0.05 is considered significant.

No competing interests reported.

Observational study of behavioral disturbance in children with developmental disorder under general anesthesia

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1