Efficacy and Safety of Propofol as a Sole Sedative for fMRI Sedation in Autism Spectrum Disorder Individuals with Low IQ

Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions characterized by deficits in social interaction and communication and the presence of restricted interests and repetitive behaviors (APA, 2013). The prevalence of ASD in the world is about 0.6% and varies by regions (Salari et al., 2022). Early detection and early intervention may improve outcomes of ASD (Franz et al., 2022), which can alleviate the burden on families and society (Marsack-Topolewski & Church, 2019). The main approach for diagnosing ASD is through standardized measures that focus on comprehensive behavioral evaluation and psychological assessment (Hirota & King, 2023). However, these measures are subjective to some extent. Functional magnetic resonance imaging (fMRI) produces images that capture the neuronal activity of the brain, offering unique and valuable insights for investigating ASD. The findings on ASD from fMRI encompassed significantly high regional homogeneity within multiple resting-state networks, such as the abnormal association between the networks of dorsal attention, subcortical, and default mode and restricted repetitive behaviors (Hiremath et al., 2021). Furthermore, it is feasible to establish a personalized diagnostic system for ASD utilizing fMRI data (Dekhil et al., 2018; Feng et al., 2022), and to establish an objective foundation for exploring whether the neural systems of ASD individuals respond to specific interventional treatments (Fathabadipour et al., 2022; Jin et al., 2023). Therefore, adequate attention should be given to fMRI assessment in early years for individuals with ASD.

fMRI requires subject’s cooperation for acquiring high-quality images; however, ASD individuals with low IQ often struggle to maintain a static posture in confined spaces and endure the loud noise of MRI equipment due to cognitive impairments, particularly during fMRI scans, which require more time than standard MRI examinations. Therefore, ASD individuals with low IQ often encounter challenges when undergoing conscious fMRI examinations. Consequently, previous fMRI studies on ASD have predominantly focused on patients with sufficient intellectual and adaptive function to actively participate in the examination, resulting in a dearth of research involving ASD individuals with low IQ. What’s more, assisting these individuals to complete fMRI scans is a practical problem that our team encountered.

Our study is a component of a large-scale clinical research project focusing on ASD individuals with low IQ for whom current treatments show limited efficacy. The researchers aspire to utilize fMRI to explore the brain functional mechanisms underlying their specific manifestations and determine the target of a non-invasive brain stimulation treatment based on the characteristics of their brain functional connectivity. However, most ASD individuals with low IQ fail to cooperate with the scanning process or only low-quality fMRI data are obtained when they are awake or under sedation with commonly used chloral hydrate. Therefore, it’s urgent to discover a safe and effective sedation method for these individuals to complete fMRI.

Sedation during fMRI scanning is commonly employed in clinical practice to alleviate those patients’ anxiety, mitigate discomfort, and uncontrolled involuntary body movements, enhance the quality of fMRI image acquisition, and optimize examination success rates to minimize the necessity for repeated assessments. Although some sedation protocols have been proposed in prior studies, there remains no consensus regarding the most suitable sedation scheme for fMRI examinations of ASD individuals with low IQ.

Propofol, known for its rapid onset and recovery time, is a suitable candidate for procedural sedation outside the operating room (Hinkelbein et al., 2020; Miller et al., 2019; Muller et al., 2020). It has been successfully utilized in pediatric MRI examination, offering the advantage of shorter recovery time compared to commonly used dexmedetomidine and ketamine (Balasubramanian et al., 2019; Gurcan et al., 2021). Previous studies have demonstrated that propofol can be safely administered to children with ASD undergoing brain MRI without an increased frequency of serious side effects compared to children without ASD (Kamat et al., 2018b). However, further research is still needed to explore the effectiveness and safety of different propofol sedation regimens due to limited information on administering sedation specifically for fMRI in ASD patients (Riva et al., 2011). The objective of this prospective study was to analyze and evaluate the efficacy and safety of a single intravenous propofol sedation protocol in ASD individuals with low IQ during fMRI examinations, aiming to provide a safe and feasible sedation scheme for people with ASD.

A total of 80 patients scheduled to undergo a non-invasive brain stimulation treatment were included for fMRI examination under propofol sedation. However, in one case involving a 13-year-old 45 kg weighing boy, the examination could not be completed due to recurrent interruptions resulting from body movement associated with coughing and hypoxia, which necessitated mask-assisted ventilation and sputum aspiration for correction. A further investigation of the medical history revealed that this patient had an untreated upper respiratory tract infection approximately two weeks prior. Additionally, two patients, one male aged 10 and one female aged 6, successfully completed the fMRI scan, and the obtained fMRI data indicated that the FD value did not exceed 0.2 mm (FD: 0.060 mm and 0.077 mm, respectively) and the tSNR both suggested high quality (tSNR: 89); however, during a re-evaluation of the patients' original records, it was found that their IQ scores (72 for the male and 100 for the female) exceeded the established criterion (IQ < 70), resulting in their exclusion from the final statistical analysis. The remaining 77 cases, comprising 66 males and 11 females aged between 4 and 23 years with body weights ranging from 19 to 87 kg, did not exhibit any specific diseases, except for one patient diagnosed with allergic purpura and another with generalized eczema. All participants successfully completed the fMRI examination and were subsequently incorporated into the final analysis (Table 3). The demographic information regarding the occupation, educational background, and annual family income of the parents of individuals with ASD is presented in Table 4. The induction time for propofol sedation ranged from 3 to 19 min (Table 5). The actual fMRI scanning time varied between 38 and 60 min (Table 5). The awakening time was recorded as being between 2 and 13 min (Table 5). During the period from the initiation of sedation to patient awakening, the lowest recorded S_PO2 value fell within the range of 92% to 99% (Table 5). Among these cases, body movement was recorded in a total of twelve instances (15.6%), including head movement noted in five cases (6.5%) during the scanning process (Table 6). Consequently, six cases (7.8%) necessitated re-scanning (Table 6). Only one case (1.3%) demonstrated an FD value exceeding 0.2 mm, while sixty-two fMRI results (80.5%) were classified as high-quality (Table 6). Three cases (3.9%) were identified with upper airway obstruction, necessitating the insertion of an oropharyngeal airway device to maintain airway patency (Table 6). A significant difference was observed in the dosage of propofol administered per unit of body weight for induction across different age groups (p < 0.05). The dosages were recorded as follows: 3.4 (2.9, 4.8) mg/kg for individuals under 10 years old, 3.0 ± 0.8 mg/kg for those aged between 10 and 12 years, and 2.6 ± 0.8 mg/kg for individuals over the age of 12 (see Table 7 and Fig. 1). Additionally, a significant difference in propofol dosage per unit of body weight for induction was noted across various BMI categories (p < 0.05), with dosages recorded as follows: 3.3 (2.8, 4.5) mg/kg for individuals with a BMI less than 18 kg/m², 3.0 ± 0.9 mg/kg for those with a BMI ranging from 18 to less than or equal to24 kg/m², and finally, at a dose of 2.2 ± 0.8 mg/kg for individuals with a BMI greater than 24 kg/m² (see Table 7 and Fig. 2). No significant differences were found in the maintenance dosage of propofol per unit of body weight across different age groups or varying BMIs (p > 0.05) (Table 7). Furthermore, no significant differences were observed in propofol dosing—comprising both induction and maintenance per unit of body weight—between male and female ASD patients, nor among different IQ groups (p > 0.05) (Table 7). No significant differences were observed in body movement and head movement across gender, age groups, BMI categories, and IQ classifications (p > 0.05) (Table 8). Aside from the three aforementioned cases of upper airway obstruction, which were effectively managed through the insertion of an oropharyngeal airway device by the anesthesiologist during sedation, no additional significant adverse events—such as oxygen desaturation, hypotension, PONV, or hospitalization—were observed.

Although considerable research has been undertaken to mitigate the challenges associated with head motion during fMRI data acquisition (Davydov et al., 2022; Frew et al., 2022; Goto et al., 2016), effectively managing subject head motion remains a critical issue. This study addresses the practical challenges encountered by ASD individuals with low IQ who struggle to cooperate during fMRI examinations, aiming to investigate a safe and effective sedation protocol for this population. By reviewing pertinent literature and leveraging clinical experience in sedation, an innovative approach utilizing a continuous basal infusion of propofol combined with manually administered incremental doses was implemented for fMRI sedation in this study. The results demonstrated the successful attainment of safe and effective sedation in 77 ASD individuals with low IQ, thereby facilitating high-quality fMRI image data acquisition without any uncontrollable adverse reactions.

The sedation method employed in this study demonstrates its effectiveness across two key dimensions. Firstly, with respect to sedation efficacy, all ASD individuals with low IQ who underwent sedation using this method were able to rapidly attain an appropriate level of sedation for fMRI examinations and recovered promptly following the procedure. Secondly, in terms of fMRI data analysis, the high-quality fMRI data collected indicated that unusable fMRI data constituted only 1.3% of the cases. Compared to subjects typically sedated with oral chloral hydrate at a concentration of 10%, the propofol sedation regimen proved more suitable for ASD individuals with higher body weight, because of shorter induction times, faster awakening durations, reduced incidences of head motion, and lower FD values (Bai et al., 2023).

The administration of various anesthetics and sedative agents for procedural sedation necessitates careful consideration of their potential impact on fMRI results, as these substances may influence functional connectivity both within and between brain networks to some extent (Wei et al., 2013). While it is currently impractical to ascertain the specific effects of propofol on brain function due to a lack of established norms for relevant populations, it is evident that the influence of a single agent on brain function is relatively straightforward. From this perspective, utilizing a sole propofol sedation regimen undoubtedly exerts a less complex effect on brain function compared to other combined sedation protocols.

From a safety perspective, propofol offers several advantages, including rapid recovery, adjustable depth of anesthesia or sedation, and a reduction in postoperative complications. Several studies have demonstrated that it can be utilized safely and effectively for the sedation of individuals with ASD during MRI examinations (Abulebda et al., 2018; Kamat et al., 2018a; Lai et al., 2011). The lack of any reported occurrences of improper sedation in the present study further substantiates that propofol can be safely administered for fMRI sedation in individuals diagnosed with ASD. Nevertheless, while propofol has been demonstrated to be a safe agent for sedating individuals with ASD during MRI scans, the continuous presence of a skilled anesthesiologist throughout the procedure offers an enhanced level of vigilance that surpasses reliance on monitoring equipment alone. This ensures a timely response to any potential adverse events and provides reassurance to both ASD patients and their families.

This study offers several insights that may benefit researchers engaged in MRI sedation studies pertaining to individuals with ASD. Firstly, it is crucial to identify respiratory depression promptly and implement appropriate interventions as early as possible. The incidence of respiratory depression associated with propofol overdose may result in hypoxia and carbon dioxide accumulation, which can be assessed using two objective indicators: SpO2 and end-tidal carbon dioxide pressure (PetCO2). However, SpO2 readings may lag behind the actual onset of hypoxia, and currently available devices capable of monitoring PetCO2 in magnetic fields may not be accessible. Consequently, during fMRI procedures, anesthesiologists must meticulously monitor the magnitude and frequency of thoracic or abdominal wall respiratory movements in ASD patients, as these are the most direct indicators of potential respiratory depression. Signs indicative of respiratory depression—such as absent respiratory movement, a breathing rate below 10 breaths per minute, or an abrupt increase in heart rate—should prompt consideration of this risk. It is important to highlight that hypoxia can induce a normal physiological reflex coughing, potentially compromising the usability of fMRI data. Additionally, the necessity for re-scanning not only prolongs the actual scanning duration but also escalates associated medical costs and risks. Different strategies for managing respiratory depression must be employed at various stages. During the sedation induction phase, any signs of respiratory depression should initially be addressed through face mask ventilation; once scanning commences, corrective measures are restricted to either reducing the propofol infusion rate or discontinuing propofol administration while simultaneously increasing nasal oxygen flow and enhancing input oxygen pressure. In our study, we implemented a technique involving manual compression of an oxygen bag to augment both the flow and pressure of supplemental oxygen, which effectively rectified hypoxemia and alleviated the coughing associated with hypoxia.

Secondly, effective preventive measures and interventions can mitigate the risk of upper airway obstruction during propofol sedation, which may arise from the relaxation of oropharyngeal and hypoglossal muscles as well as posterior displacement of the tongue. Alleviating upper airway obstruction is essential not only for maintaining normal S_PO2 levels and preventing carbon dioxide accumulation but also for minimizing head movement resulting from such obstructions. Our experience indicates that signs of upper airway obstruction during sedation can be assessed by observing indicators such as deep breathing, increased respiratory rate, snoring, or even the presence of three depressions (obvious depressions in the suprasternal fossa, supraclavicular fossa, and intercostal fossa) in the patient's spontaneous breathing pattern. Upon confirming upper airway obstruction post-sedation with propofol, the initial intervention involves elevating the patient's shoulder and neck using a cotton roll while maintaining a slight posterior tilt of the head. If this maneuver successfully resolves upper airway obstruction, fMRI scanning may commence. Should these measures prove ineffective in alleviating upper airway obstruction, insertion of an oropharyngeal airway device is warranted to restore patency. While reducing sedation depth may alleviate or eliminate obstructive events, it simultaneously poses risks associated with insufficient sedation depth leading to body movements that could compromise scan integrity. Our guiding principle is to ensure an adequate level of sedation while preserving spontaneous respiration, and to mitigate the risk of upper airway obstruction through the aforementioned appropriate preventive strategies and interventions. Notably, although our experience suggests that the propofol sedation technique utilizing an infusion pump in conjunction with manual syringe administration used in this study did not result in significant fluctuations in plasma drug concentrations, there was one case in which upper airway obstruction was absent prior to sedation but manifested during the scanning process. Managing this situation requires the anesthesiologist to exercise clinical judgment based on the specific circumstances: if it is assessed that the patient is excessively sedated, the propofol infusion rate may be decreased, and the oxygen bag can be pressurized to optimize both the concentration and flow of supplemental oxygen. This strategy provides additional time for recovery of oropharyngeal muscle tone and alleviation of posterior tongue displacement, thereby resolving upper airway obstruction without provoking cough due to hypoxia. If this method is implemented during scanning and upper airway obstruction persists, it is essential to promptly terminate the scan and insert an oropharyngeal airway device prior to the initiation of the revised fMRI scan.

Thirdly, it is imperative to identify the factors contributing to body movement and address them prior to resuming the fMRI scan. The most substantial challenge encountered during fMRI scanning is body movement, particularly head movement, which renders the ongoing scan sequence ineffective and necessitates a re-scan. In addition to previously mentioned upper airway obstruction and hypoxia, inadequate sedation depth is often considered a primary contributor to body movement. Insufficient sedation depth can easily occur when relying solely on weight-based calculations for maintenance dosing without utilizing a sedation depth monitor. When the UMSS score drops to 2 or below, machine noise may disturb the patient and lead to body movement. Furthermore, it is crucial to note that seizures or seizure-like phenomena (SLP) may arise following propofol administration, potentially resulting in body movement due to propofol itself (Li et al., 2023). However, it should be emphasized that SLP predominantly manifests during the induction and emergence phases of propofol anesthesia or sedation, with no reported instances observed during the phase of maintenance (Hickey et al., 2005). The underlying causes of body movement should be addressed prior to initiating a re-scanning procedure, as failure to resolve them may result in recurring body movement.

Ultimately, the adoption of individualized propofol administration is strongly advised due to potential complications such as respiratory depression and the risk of upper airway obstruction at elevated dosages (Bhardwaj et al., 2024). The dose-weight method is initially utilized to calculate the range of propofol dosages, which is subsequently adjusted based on individual responses during the induction phase. This approach aims to identify an optimal sedation point that effectively reduces body movement induced by noise stimulation while preserving a favorable respiratory state. Dosing propofol solely based on body weight may introduce bias. The relationship between propofol dosage and body weight during the induction period, as observed in this study—where older participants received a lower dosage of propofol per unit of body weight compared to their younger counterparts, while individuals with low BMI required higher doses (mg/kg) than those with high BMI—slightly diverges from findings reported in another study (Johnson et al., 2021). Although this study did not reveal significant differences in maintenance dosing across various gender, age, and BMI categories, the consideration of individualized dosing remains warranted.

Prior to the adoption of propofol for sedation in individuals with ASD undergoing fMRI, chloral hydrate was extensively utilized as a sedative for many children diagnosed with ASD via oral or rectal administration. However, this sedation method demonstrated reduced efficacy when utilized for pediatric ASD patients with higher body weight and adult individuals with ASD, leading to suboptimal fMRI outcomes within this demographic, thereby highlighting the urgent need for a safe and effective sedation strategy appropriate for more individuals with ASD. Currently, several challenges may impede the implementation of propofol sedation for fMRI in individuals with ASD. These challenges include the inability to utilize target-controlled infusion models of propofol that maintain more stable blood concentrations in children with ASD, a lack of suitable depth-of-sedation monitoring equipment for use in magnetic field environments, and unresolved safety concerns regarding the administration of propofol in patients with difficult-to-manage respiratory conditions such as obstructive sleep apnea.

From a humanistic perspective, this study offers hope to ASD individuals with low IQ who may be unable to undergo comprehensive brain function analysis under a sedation-free protocol or chloral hydrate sedation. It potentially enables them to benefit from transcranial interventions or brain function assessments related to fMRI. This advantage extends not only to the patients themselves but also to their families and society.

One limitation of the study is that it is constrained by ethical issues, resulting in a deficiency of age- and gender-matched fMRI data under sedation with normally developing individuals as controls. This limitation raises concerns that the selected propofol sedation may potentially interfere with the final analysis of the fMRI results (Craig et al., 2021). Future research should concentrate on formulating strategies to mitigate the effects of sedative agents on the outcomes of brain function analysis. Another limitation of this study is that, due to the absence of a control group consisting solely of patients diagnosed with intellectual disabilities, it did not clarify whether the propofol sedation protocol differed between ASD individuals with low IQ and those exclusively diagnosed with intellectual disabilities. Multi-center collaborations should be initiated to conduct comparative analyses between individuals diagnosed exclusively with intellectual disabilities and those who both have ASD and intellectual disabilities, in order to enhance our understanding of the differences in propofol sedation protocols utilized during fMRI examinations for these two patient populations. The third limitation pertains to our inability to collect data regarding the level of cooperation demonstrated by these patients during the establishment of intravenous access prior to sedation, as such access is essential for administering propofol sedation and should be incorporated into the sedation protocol. The inadequate collection of cooperation levels among ASD patients during this process hindered an investigation into whether their cooperation was related to IQ, previous interventions, or parental demographic characteristics, thereby limiting our capacity to provide a more comprehensive dataset for fMRI sedation in ASD patients. The fourth limitation lies in the fact that no sedation depth monitoring device capable of withstanding the effects of magnetic fields was accessible in this study. As a result, the depth of sedation was not monitored in these ASD patients. Ultimately, the dose of propofol employed was more reliant on the clinical experience of the anesthesiologist, which implies that the dose of propofol utilized might not have been the most appropriate one.

The observation that no difficult-to-manage adverse events occurred and that all ASD participants, with the exception of one case, successfully completed the planned fMRI scans yielding high-quality data suggests that propofol, when utilized as a sole sedative, is both safe and effective for fMRI in ASD individuals with low IQ, provided appropriate protocols are adhered to. It is essential to consider incorporating additional cases for observation to explore the potential correlation between older age and higher BMI with reduced dosage requirements per unit body weight in the propofol sedation protocol for fMRI. Furthermore, future studies involving larger sample sizes should be conducted to establish an optimal sedation protocol that maximizes safety while minimizing any potential impact on fMRI results.