Effects of General Anesthesia on Brain FC and Cognition in Children With Potential Neurological Damage

Postoperative Cognitive Dysfunction Clinical Trial

Official title:

Effects of General Anesthesia on Brain Functional Connectivity and Cognition in Children With Potential Neurological Damage

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05602311
• Other study ID #: XH-22-006
• Status: Recruiting
• Start date: August 15, 2022
• Est. completion date: February 15, 2023

Study information

• Verified date: November 2022
• Source: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
• Contact: yun wang, Bachelor
• Phone: 17821030239
• Email: 1575835421[@]qq.com
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Postoperative Cognitive Dysfunction(POCD)is a common postoperative complications, existing clinical research focused on the adult patients, ignoring that the developing human brain with underlying neurological impairments may be at higher risk for cognitive impairment, so we need a prospective study, observe this kind of "special groups" in the brain structure and function of before and after general anesthesia, To determine the susceptibility to neurotoxicity of general anesthesia drugs.

Description:

Cognitive disorder refers to the abnormal or hindering of people's cognition of learning, memory, thinking, spirit, emotion and psychology, etc. In severe cases, aphasia, agnosia and apraxia will occur. In general, any factors that cause functional and structural abnormalities of the cerebral cortex can lead to cognitive impairment, and surgical anesthesia is one of the factors. Postoperative Cognitive Dysfunction (POCD) broadly refers to the temporary deterioration of cognitive function related to surgery. The diagnosis requires preoperative (as baseline) and postoperative neuropsychological tests, and the degree of postoperative cognitive decline can be determined by comparing the results of preoperative and postoperative tests. Numerous studies have shown that elderly patients are at higher risk for POCD after surgery and anesthesia. Although the neurotoxic effects of narcotic drugs on young neuronal cells have also been extensively discussed in recent years, the current lack of studies on POCD in children is in sharp contrast to the large literature on POCD in adults. The potential impact of general anesthesia on POCD in these younger populations, especially preschool and school age children, is largely unknown due to insufficient clinical evidence. The effects of general anesthesia on cognitive function in children are complex and controversial. Although a considerable number of animal studies have shown a link between general anesthesia and short-term or long-term neurocognitive impairment in animals, extrapolation of the results to humans remains difficult. Children's central nervous system has not yet mature, general anesthetics on its neurotoxic effect is still not clear, the existing clinical research results differ: some studies have shown that experience a single brief general anesthesia on children and long-term neurological development has no obvious negative impact, some research said general anesthesia to impaired cognitive function in children, especially after the experience again and again, long time exposure to anesthesia. However, few clinical studies have investigated the effects of general anesthesia on cognitive function in children with underlying neurological impairment. Are the effects of general anesthesia drugs on brain function and brain network structure in this "special population" with neurofragility different from those in children without neurological damage risk? Whether general anesthesia can increase the risk of postoperative cognitive impairment or aggravate the existing cognitive dysfunction in this "special population" deserves further study. Obstructive sleep disordered breathing (SDB) in children is a spectrum of continuous nocturnal breathing disorders characterized by more than airway obstruction and varying degrees of abnormal gas exchange. The mildest of the SDB is Primary Snoring (PS), which is characterized by habitual snoring (often defined as snoring more than three times per week) but few respiratory events (<1 event/hour), decreased oxygen saturation, or slight awakening due to labored breathing; The most severe condition is Obstructive Sleep Apnea (OSA), which is characterized by recurrent episodes of complete or partial airway obstruction, resulting in decreased oxygen saturation at night and or sleep awakenings. Children with OSA often present with snoring, sleep structure disorder, frequent oxygen desaturation, daytime sleepiness, attention deficit disorder and other symptoms. Adenoid and tonsillar hypertrophy is considered to be the most common cause of SDB in children. A large number of studies have shown that SDB patients have decreased cognitive function and learning ability, including attention, executive function, language learning and memory function. In addition, it has been reported that SDB children have structural changes in different brain regions, especially the hippocampus and frontal cortex, in addition to cognitive impairment. Some scholars believe that SDB may be an independent risk factor for postoperative cognitive impairment. The human brain can be regarded as a network of interconnected structures and synchronized functions. With the change of the functional state of the brain, the brain network is in dynamic change. The use of neuroimaging techniques (such as functional nuclear magnetic resonance, functional near infrared spectroscopy, etc.) and electrophysiological techniques (such as electroencephalography) can reconstruct the human brain network, which is conducive to the further study of brain structure and function. Based on these techniques, a growing number of researchers have found resting-state or task-state brain network changes in children with neuropsychiatric disorders with different patterns of cognitive and behavioral disorders, such as autism, attention deficit hyperactivity disorder, and epilepsy. In addition to brain network changes occurring in pathological conditions, many drugs that directly act on the central nervous system can also cause brain network changes, and general anesthesia drugs are one of them. The brain network changes in adults and children under maintenance of general anesthesia, which may be a macroscopic reflection of the molecular mechanism of consciousness loss caused by general anesthesia. Previous studies have shown that the prefrontal and frontal functional connectivity of electroencephalogram in children under maintenance of general anesthesia increases, while the parieto-occipital functional connectivity decreases. Thus, cognitive impairment is often accompanied by the change of brain network, and general anesthesia on brain networks may also be affected, in view of some adult clinical study shows that preoperative neurocognitie dysfunction or potential risk of cognitive dysfunction in patients with postoperative cognitive function damage probability increases, we hypothesized that: Children with SDB who are still in brain development and have a high risk of neurological injury belong to the "special population" who are more susceptible to the neurotoxicity of general anesthesia drugs. It is hypothesized that the susceptibility to neurotoxicity of general anesthesia drugs in this population is due to the more obvious inhibitory effect of general anesthesia drugs on the existing brain network connectivity. In diseases and general anesthetics on brain network, under the "double whammy" of SDB in children with the normal development of children after general anesthesia operation may face a higher risk of POCD, need to be evaluate cognitive function before and after exposure to general anesthesia, in order to make clear the SDB patients with preoperative cognitive development situation and short-term changes in cognitive function after general anesthesia surgery, At the same time, the changes of brain network before and after anesthesia in children with SDB were observed, and whether the changes of brain network were correlated with the changes of cognitive function was analyzed, so as to try to explain the increased susceptibility to neurotoxicity of general anesthesia in children with neurological injury risk. Above all，POCD is a common postoperative complications, existing clinical research focused on the adult patients, ignoring that the developing human brain with underlying neurological impairments may be at higher risk for cognitive impairment, so we need a prospective study, observe this kind of "special groups" in the brain structure and function of before and after general anesthesia, To determine the susceptibility to neurotoxicity of general anesthesia drugs.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: February 15, 2023
• Est. primary completion date: January 1, 2023
• Gender: All
• Age group: 4 Years to 10 Years

Eligibility

Inclusion Criteria:

1. Age 4 to 10 years old, both sexes;

2. Apgar score =8 at birth;

3. ASA (American Society of Anesthesiologists Physical Condition Rating) ?-?;

4. to be treated with SDB under general anesthesia;

5. His legal guardian has signed the informed consent -

Exclusion Criteria:

1. Age < 4 years old; or age >10 years old;

2. suffering from serious heart, lung and brain diseases;

3. History of dystocia or perinatal cerebral ischemia and hypoxia;

4. Gestational age at birth =32 weeks;

5. Confirmed or suspected neurological retardation or hearing and vision abnormalities;

6. suffering from malignant tumor;

7. had received general anesthesia or deep sedation before enrollment

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Postoperative Cognitive Complications
• Postoperative Cognitive Dysfunction
• Trauma, Nervous System

Intervention

Drug:
• General anesthetic
Monitoring the changes of brain functional connectivity and assess cognition in two groups after general anesthesia

Locations

Country	Name	City	State
China	Department of Anesthesia, Shanghai Xinhua hospital	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine

Country where clinical trial is conducted

China, 

References & Publications (32)

Amrock LG, Starner ML, Murphy KL, Baxter MG. Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. Anesthesiology. 2015 Jan;122(1):87-95. doi: 10.1097/ALN.0000000000000477. — View Citation

Bourke R, Anderson V, Yang JS, Jackman AR, Killedar A, Nixon GM, Davey MJ, Walker AM, Trinder J, Horne RS. Cognitive and academic functions are impaired in children with all severities of sleep-disordered breathing. Sleep Med. 2011 May;12(5):489-96. doi: 10.1016/j.sleep.2010.11.010. Epub 2011 Apr 13. — View Citation

Buratti L, Viticchi G, Baldinelli S, Falsetti L, Luzzi S, Pulcini A, Petrelli C, Provinciali L, Silvestrini M. Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship. J Alzheimers Dis. 2017;60(3):1195-1203. doi: 10.3233/JAD-170445. — View Citation

Cha J, Zea-Hernandez JA, Sin S, Graw-Panzer K, Shifteh K, Isasi CR, Wagshul ME, Moran EE, Posner J, Zimmerman ME, Arens R. The Effects of Obstructive Sleep Apnea Syndrome on the Dentate Gyrus and Learning and Memory in Children. J Neurosci. 2017 Apr 19;37(16):4280-4288. doi: 10.1523/JNEUROSCI.3583-16.2017. Epub 2017 Mar 20. — View Citation

Daurat A, Sarhane M, Tiberge M. [Obstructive sleep apnea syndrome and cognition: A review]. Neurophysiol Clin. 2016 Jun;46(3):201-15. doi: 10.1016/j.neucli.2016.04.002. Epub 2016 Jun 16. Review. French. — View Citation

Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, Stargatt R, Bellinger DC, Schuster T, Arnup SJ, Hardy P, Hunt RW, Takagi MJ, Giribaldi G, Hartmann PL, Salvo I, Morton NS, von Ungern Sternberg BS, Locatelli BG, Wilton N, Lynn A, Thomas JJ, Polaner D, Bagshaw O, Szmuk P, Absalom AR, Frawley G, Berde C, Ormond GD, Marmor J, McCann ME; GAS consortium. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016 Jan 16;387(10015):239-50. doi: 10.1016/S0140-6736(15)00608-X. Epub 2015 Nov 4. Erratum in: Lancet. 2016 Jan 16;387(10015):228. — View Citation

Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J Anaesth. 2009 Dec;103 Suppl 1:i41-46. doi: 10.1093/bja/aep291. Review. — View Citation

Ehsani R, Djalali Motlagh S, Zaman B, Sehat Kashani S, Ghodraty MR. Effect of General Versus Spinal Anesthesia on Postoperative Delirium and Early Cognitive Dysfunction in Elderly Patients. Anesth Pain Med. 2020 Aug 8;10(4):e101815. doi: 10.5812/aapm.101815. eCollection 2020 Aug. — View Citation

Evered L, Scott DA, Silbert B, Maruff P. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic. Anesth Analg. 2011 May;112(5):1179-85. doi: 10.1213/ANE.0b013e318215217e. Epub 2011 Apr 7. — View Citation

Evered LA, Silbert BS. Postoperative Cognitive Dysfunction and Noncardiac Surgery. Anesth Analg. 2018 Aug;127(2):496-505. doi: 10.1213/ANE.0000000000003514. Review. — View Citation

Guo X, Duan X, Chen H, He C, Xiao J, Han S, Fan YS, Guo J, Chen H. Altered inter- and intrahemispheric functional connectivity dynamics in autistic children. Hum Brain Mapp. 2020 Feb 1;41(2):419-428. doi: 10.1002/hbm.24812. Epub 2019 Oct 10. — View Citation

Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999 Jan 1;283(5398):70-4. — View Citation

Ji C, Ni Q, Chen W, Yang Z, Ma D. General anesthetic neurotoxicity in the young: Mechanism and prevention. Neurosci Biobehav Rev. 2019 Dec;107:883-896. doi: 10.1016/j.neubiorev.2019.10.003. Epub 2019 Oct 10. Review. — View Citation

Katz ES, D'Ambrosio CM. Pathophysiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc. 2008 Feb 15;5(2):253-62. doi: 10.1513/pats.200707-111MG. Review. — View Citation

Kline RP, Pirraglia E, Cheng H, De Santi S, Li Y, Haile M, de Leon MJ, Bekker A; Alzheimer's Disease Neuroimaging Initiative. Surgery and brain atrophy in cognitively normal elderly subjects and subjects diagnosed with mild cognitive impairment. Anesthesiology. 2012 Mar;116(3):603-12. doi: 10.1097/ALN.0b013e318246ec0b. — View Citation

Kulason K, Nouchi R, Hoshikawa Y, Noda M, Okada Y, Kawashima R. Indication of Cognitive Change and Associated Risk Factor after Thoracic Surgery in the Elderly: A Pilot Study. Front Aging Neurosci. 2017 Dec 5;9:396. doi: 10.3389/fnagi.2017.00396. eCollection 2017. — View Citation

Li R, Wang L, Chen H, Guo X, Liao W, Tang YL, Chen H. Abnormal dynamics of functional connectivity density in children with benign epilepsy with centrotemporal spikes. Brain Imaging Behav. 2019 Aug;13(4):985-994. doi: 10.1007/s11682-018-9914-0. — View Citation

Lin H, Lin Q, Li H, Wang M, Chen H, Liang Y, Bu X, Wang W, Yi Y, Zhao Y, Zhang X, Xie Y, Du S, Yang C, Huang X. Functional Connectivity of Attention-Related Networks in Drug-Naïve Children With ADHD. J Atten Disord. 2021 Feb;25(3):377-388. doi: 10.1177/1087054718802017. Epub 2018 Sep 27. — View Citation

Lumeng JC, Chervin RD. Epidemiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc. 2008 Feb 15;5(2):242-52. doi: 10.1513/pats.200708-135MG. Review. — View Citation

Marcus CL, Brooks LJ, Draper KA, Gozal D, Halbower AC, Jones J, Schechter MS, Sheldon SH, Spruyt K, Ward SD, Lehmann C, Shiffman RN; American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012 Sep;130(3):576-84. doi: 10.1542/peds.2012-1671. Epub 2012 Aug 27. — View Citation

McCann ME, de Graaff JC, Dorris L, Disma N, Withington D, Bell G, Grobler A, Stargatt R, Hunt RW, Sheppard SJ, Marmor J, Giribaldi G, Bellinger DC, Hartmann PL, Hardy P, Frawley G, Izzo F, von Ungern Sternberg BS, Lynn A, Wilton N, Mueller M, Polaner DM, Absalom AR, Szmuk P, Morton N, Berde C, Soriano S, Davidson AJ; GAS Consortium. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019 Feb 16;393(10172):664-677. doi: 10.1016/S0140-6736(18)32485-1. Epub 2019 Feb 14. Erratum in: Lancet. 2019 Aug 24;394(10199):638. — View Citation

Puglia MP, Vlisides PE, Kaplan CM, Jewell ES, Therrian M, Mashour GA, Li D. Constrained Functional Connectivity Dynamics in Pediatric Surgical Patients Undergoing General Anesthesia. Anesthesiology. 2022 Jul 1;137(1):28-40. doi: 10.1097/ALN.0000000000004221. — View Citation

Shi Y, Dykhoff HJ, Guevara LRH, Sangaralingham LR, Schroeder DR, Flick RP, Zaccariello MJ, Warner DO. Moderators of the association between attention-deficit/hyperactivity disorder and exposure to anaesthesia and surgery in children. Br J Anaesth. 2021 Nov;127(5):722-728. doi: 10.1016/j.bja.2021.07.025. Epub 2021 Sep 6. — View Citation

Slim M, Westmacott R, Toutounji S, Singh J, Narang I, Weiss S, Krishnan P, Grbac E, Surmava AM, Andres K, MacGregor D, deVeber G, Moharir M, Dlamini N. Obstructive sleep apnea syndrome and neuropsychological function in pediatric stroke. Eur J Paediatr Neurol. 2020 Mar;25:82-89. doi: 10.1016/j.ejpn.2019.11.006. Epub 2019 Nov 21. — View Citation

Strutz P, Tzeng W, Arrington B, Kronzer V, McKinnon S, Ben Abdallah A, Haroutounian S, Avidan MS. Obstructive sleep apnea as an independent predictor of postoperative delirium and pain: protocol for an observational study of a surgical cohort. Version 2. F1000Res. 2018 Mar 15 [revised 2018 Jan 1];7:328. doi: 10.12688/f1000research.14061.2. eCollection 2018. — View Citation

Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, Maxwell LG, Youn A, McGowan FX. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA. 2016 Jun 7;315(21):2312-20. doi: 10.1001/jama.2016.6967. — View Citation

Tasbihgou SR, Absalom AR. Postoperative neurocognitive disorders. Korean J Anesthesiol. 2021 Feb;74(1):15-22. doi: 10.4097/kja.20294. Epub 2020 Jul 6. — View Citation

Uddin LQ, Dajani DR, Voorhies W, Bednarz H, Kana RK. Progress and roadblocks in the search for brain-based biomarkers of autism and attention-deficit/hyperactivity disorder. Transl Psychiatry. 2017 Aug 22;7(8):e1218. doi: 10.1038/tp.2017.164. Review. — View Citation

Warner DO, Zaccariello MJ, Katusic SK, Schroeder DR, Hanson AC, Schulte PJ, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Hu D, Voigt RG, Paule MG, Chelonis JJ, Flick RP. Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology. 2018 Jul;129(1):89-105. doi: 10.1097/ALN.0000000000002232. — View Citation

Zaccariello MJ, Frank RD, Lee M, Kirsch AC, Schroeder DR, Hanson AC, Schulte PJ, Wilder RT, Sprung J, Katusic SK, Flick RP, Warner DO. Patterns of neuropsychological changes after general anaesthesia in young children: secondary analysis of the Mayo Anesthesia Safety in Kids study. Br J Anaesth. 2019 May;122(5):671-681. doi: 10.1016/j.bja.2019.01.022. — View Citation

Zhang D, Ying J, Ma X, Gao Z, Chen H, Zhu S, Shi L, Lu X. Social Cognitive Dysfunction in Elderly Patients After Anesthesia and Surgery. Front Psychol. 2020 Sep 24;11:541161. doi: 10.3389/fpsyg.2020.541161. eCollection 2020. — View Citation

Zhao J, Han S, Zhang J, Wang G, Wang H, Xu Z, Tai J, Peng X, Guo Y, Liu H, Tian J, Jin X, Zheng L, Zhang J, Ni X. Association between mild or moderate obstructive sleep apnea-hypopnea syndrome and cognitive dysfunction in children. Sleep Med. 2018 Oct;50:132-136. doi: 10.1016/j.sleep.2018.04.009. Epub 2018 Jun 9. — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the scores of Wechsler intelligence scale	The scores of Wechsler intelligence scale before operation and 1 day after operation were compared between the two groups.	The 1 day before surgery;24 hours after surgery
Primary	The incidence of POCD	The incidence of POCD was calculated by Z-score method	up to 24 hours after surgery
Secondary	comparison of functional connectivity	The changes of brain functional connectivity were compared between the two groups under two states of consciousness (awake and anesthesia)	up to 5 minutes
Secondary	Correlation between fNIRS brain function connectivity and cognitive function changes	The correlation between cognitive function changes and brain functional connectivity, age and anesthesia time were evaluated	one day before surgery and 24 hours after surgery