Effect of propofol versus sevoflurane on auditory and cognitive functions: A randomized controlled trial

doi:10.21203/rs.3.rs-2215165/v1

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Effect of propofol versus sevoflurane on auditory and cognitive functions: A randomized controlled trial

https://doi.org/10.21203/rs.3.rs-2215165/v1

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Background

Hearing loss and cognitive impairment are postoperative complications which need more awareness by anaesthesiologists. We aimed to study the possible deleterious effect of Propofol versus Sevoflurane on auditory function, attention and auditory memory.

Methods

This prospective randomized controlled trial was conducted on 80 patients who were candidate for elective laparoscopic cholecystectomy under general anesthesia; 40 patients received Propofol (propofol group ), and 40 patients received Sevoflurane (sevoflurane group). The included patients were assessed before and 1 week postoperative regarding the auditory functions by using the auditory brainstem response (ABR) and the attention and auditory memory by using the Paced Auditory Serial Addition Test (PASAT) and Paired Associate Learning test (PALT) scales.

Results

There was no statistically significant difference between both groups in either age (P-value = 0.537) or sex (P-value = 0.175). In Propofol group, the postoperative values of LT ABR-I and III were significantly higher than the preoperative ones (p value < 0.001, 0.003), all the postoperative RT ABR waves were significantly higher than the preoperative ones (P < 0.05). In Sevoflurane group, the postoperative values for LTABR- I, III, III-V were significantly higher than the preoperative ones with p value (0.012, 0.008 and 0.009) and the postoperative values for RTABR-III, V, I-III, and III-V were significantly higher than preoperative values ( p = 0.041, 0.029, 0.005 and < 0.001). There was no statistically significant differences between the Propofol and Sevoflurane groups in all waves of ABR in both sides ( P > 0.05). There was a significant worsening between pre and postoperative PASAT scores in Propofol and Sevoflurane groups respectively with p value (< 0.001) with no statistically significant difference between both groups (P-value = 0.906).Also, There was a significant worsening between pre and postoperative PALT scores in Propofol group only (p value = 0.01) with a statistically significant difference between both groups (P-value = 0.038).

Conclusion

There was a statistically significant postoperative impairment in auditory function, attention and auditory memory following anesthesia with both propofol and Sevoflurane with no significant difference between the two drugs.

The protocol of this study was registered in ClinicalTrials.gov. The identification number is NCT04874545.

Propofol

Sevoflurane

ABR

PALT

PASAT

Hearing loss is one of the postoperative complications, which occurs more frequently than most anaesthesiologists suspect. Perioperative hearing loss may be unilateral or bilateral, conductive or sensorineural, and temporary or permanent.^[1] Several reports suggested that some anesthetic agents such as propofol can cause hemodynamic instability with perioperative hypotension with transient vertebrobasilar hypoperfusion and subsequently reduce blood supply to the cochlea producing cochlear injury resulting in hearing loss ^[2]. Traumatic, mechanical causes, and CSF pressure fluctuations were also reported as contributing factors for perioperative hearing loss ^[1].

Perioperative hearing loss may be subclinical and may pass unobserved unless audiometry is performed ^[1]. The auditory brainstem response (ABR) can provide an evaluation of the shape of the behavioral audiogram and so, it is a very useful method for assessment of hearing sensitivity. It involves series of voltage peaks which occur within the first few milliseconds (ms) after the auditory stimulus and represent the progressive propagation of neural activity through the ascending auditory pathway ^[3]. The use of propofol was reported to cause a significant increases in the latencies of ABR waves III and V and the interpeak intervals I-V and III-V. ^[4]

Postoperative cognitive dysfunction (POCD) is a well-known complication of anesthetic drugs ^[5]. It characteristically manifests as subtle deficits in multiple neurocognitive domains, including attention, auditory memory, executive function, visuospatial abstraction and psychomotor speed. POCD can be mild and only diagnosed by psychometric assessment, but, sometimes, it may have serious consequences on the functional status and quality of life. ^[6]

In an international multicentre study [International Study of POCD (ISPOCD1)], the incidence of POCD was 25.8% at 1 week, 9.9% at 3 months^,[7] and 1% at 1 to 2 years in older adults after major non-cardiac surgery.^[8] Whilst post-operative cognitive dysfunction was reported to be transient and self-limiting, strong evidence indicated that elderly patients that are three times more likely to suffer from permanent cognitive impairment or dementia ^[9]

A large and growing body of evidence has implicated the roles of neuroinflammation and neurodegeneration in the pathogenesis of POCD, However, the data were not entirely conclusive because of the heterogeneities in animal models and human populations studied, as well as the variability in the clinical assessments tools. ^{[10, 11]}

Propofol and sevoflurane are commonly used general anesthetics in clinical practice. The incidence of POCD was reported to be significantly higher in patients undergoing major surgery under inhalational anesthesia with sevoflurane in comparison to those maintained on intravenous propofol. ^[12–13] The detrimental effects of both sevoflurane and propofol on neuronal cell integrity were addressed in multiple animal studies. Exposure of newborn rats brain to sevoflurane has been shown to induce apoptotic neurodegeneration. ^[14] Also, direct experimental evidence indicated that that the anesthetic dose of propofol induced neuronal cell death in the cortex and thalamus of the developing rat brain.^[15]

The aim of this work to study the probable harmful effect of Propofol versus Sevoflurane on auditory function, attention and auditory memory in patients undergoing laparoscopic cholecystectomy preoperative and 1 week after the operation .

Study design

This prospective randomized controlled trial was conducted on patients who were candidate for elective laparoscopic cholecystectomy under general anesthesia. Patients were randomly allocated into one of two groups; Propofol group or Sevoflurane group. Randomization was carried out using a closed opaque envelope technique. The included patients were recruited from the general surgery department, Beni-Suef university hospital, during the period of June 2021 to December 2021. Written informed consent was obtained from all the included patients. The study design followed the requirements of revised Helsiniki declaration of biomedical ethics. This study was accepted by the research ethical committee of faculty of medicine, Beni-Suef University (approval number: FMBSUREC/12062018). The protocol of this study was registered in ClinicalTrials.gov.in 5/5/2021. The identification number is NCT04874545.

Eligibility Criteria:

ASA I-II patients who were candidate for elective laparoscopic cholecystectomy from both genders, aged from 20 to 70 years. The following patients were excluded from our study: patients with a conductive or sensorineural hearing loss, patients using drugs known to be ototoxic or neurotoxic, patients with a history of ear trauma or ear infection, patients with traumatic injury or weakness which interfere with audiological assessment, patients exposed to intraoperative major hemodynamic fluctuations, patients with severe bleeding or postoperative shock, patients who are allergic to any drug used in the study, and patients with a history of neurodegenerative disease, associated medical or metabolic disorder known to affect cognition. Illiterate patients and pregnant females were also excluded from the study. A flow diagram was demonstrated in figure (1)

Measures

Patients were submitted to clinical assessment comprising the hemodynamics of the patients;, heart rate, mean arterial blood pressure ,SPO2, and endtidal CO2. A routine preoperative biochemical and hematological testing, along with electrocardiograms were performed for all the included patients. All included participants were subjected to cognitive and auditory evaluation preoperative and 1 week after the operation.

1) Cognitive assessment:

1. Paired Associate Learning test (PALT): It was used to evaluate auditory verbal memory by using the idea of semantic cueing. The inspector said ten associated pairs in front of the candidate. These pairs contain 6 well-matched semantically related pairs and 4 mismatched semantically unrelated pairs. After one minute, the candidate was given the first word of the pairs and was asked to recall the second word. The test was repeated three times. Each correct compatible pair took a score 0.5, while each correct incompatible pair took a score 1. The total score ranged from 0 to 21.^[16]

2. Paced Auditory Serial Addition Test (PASAT): It was used to evaluate attention and auditory working memory. A sequence of 61 single digit numbers were spoken on an audiotape at a rate of one every 3 seconds. The candidate was asked to add each number to the one immediately previous to it and not to give a running total and to report the sum orally. Total score is the summation of correct responses and it ranges from 0 to 60. ^[17]

2) Audiological Assessment:

Brainstem auditory evoked potentials (BAEPs) was performed using (Interacoustic Eclipse ''EP25''). The reference electrodes were located on the right(A2) and left (Al) mastoids, the active electrode was on the scalp at the vertex (Fz position of the 10–20 International System of EEG electrode placement) and the ground electrode was on the lower mid-frontal area (Fpz position). Ag/AgCl electrodes filled with conductive paste were attached to skin that was abraded with a skin prepping gel. Electrode impedances were less than 5 kΩ, and inter-electrode impedances were less than 2 kΩ. The candidate was in relaxed state. Click was obtained through TDH39 headphones. Click was presented at a rate of 21.1 stimuli per second in rarefaction polarity at intensity of 80 dBHL. Averaged potentials to 1200 clicks were obtained. Two recordings were obtained to ensure the replicability of the waveforms. The latencies of waves I, III, V and interpeak latencies I–V, I– III, III–V (IPLs) were calculated with BAEPs.

Anesthetic Technique

On reaching to the operating theatre, 18 G intravenous cannula was inserted and IV crystalloid fluids were infused. The monitor was connected to the patients to take the preoperative readings. Induction of anesthesia was done by injecting fentanyl 2 µg/kg, propofol1.5-2.5 mg/kg and atracurium 0.5 mg/kg for muscle relaxation. Laryngoscopy and endotracheal intubation were performed using oral cuffed tube lubricated with lidocaine jelly 2%. Maintenance of anesthesia was done using either propofol or sevoflurane. In Propofol group, maintenance of anesthesia was done using propofol total intravenous anesthesia (TIVA) 6–12 mg/ kg/h and mixture of O₂ and Air (70: 30). In Sevoflurane group, maintenance of anesthesia was done using sevoflorane1.5–2% and mixture of O₂ and Air (70: 30). The concentrations of propofol and sevoflorane was adjusted according to patient’s vital sign.

Ventilation in both groups was controlled artificially to maintain an end-tidal partial pressure of carbon dioxide of 35–45 mmHg. At the end of surgery, neuromuscular blockade was reversed with IV neostigmine 0.04mg/kg and atropine 0.02 mg/kg. The trachea was extubated when the patient responds to commands. The patients then received oxygen via face mask 3–4 L/min and were monitored.

Primary And Secondary Outcomes

The primary endpoint is the occurrence of a significant decline in auditory function, attention, and auditory memory in both Propofol and Sevoflurane groups one week following surgery.

The secondary endpoint is the occurrence of significant differences between Propofol and Sevoflurane groups in the postoperative decline in auditory function, attention, and auditory memory.

Sampling

We calculated the sample size based on the results of a pilot study we performed before starting our study. The sample size calculation was done using G*Power version 3.1.9.2 Software. The probability of type I error (α) was 5%, effect size = 0.65, noncentrality parameter λ = 2.842, critical t = 1.992, df = 74.394. A total number of forty participants in each group was required to reach a statistical power (1–β) 80%

Statistical analysis

IBM SPSS (Statistical Package of Social Science) Version 25 was used to analyze the data. Categorical variables were expressed as numbers and percentages. Quantitative variables were expressed as median and inter quartile range (IQR). Chi-squared test was used for comparison between groups in categorical data, whereas Mann-Whitney test was used for comparison between groups in quantitative data. Wilcoxon test was used for comparison between pre and post-operative quantitative data in each group. Mixed ANOVA test was used for comparing pre and post-operative quantitative data in the two groups. P-value ≤ 0.05 was considered statistically significant. All tests were two-tailed.

This prospective randomized controlled trial was conducted on 80 patients who were candidate for elective laparoscopic cholecystectomy under general anaesthesia; 40 patients received Propofol (Propofol group), and 40 patients received Sevoflurane (Sevoflurane group).

Regarding the demographics of the patients, There was no statistically significant difference between both groups in either age (P-value = 0.537) or sex (P-value = 0.175) (Table 1). As regards the intraoperative clinical data of the patients, There was no statistically significant difference between both groups regarding the median value of B/P (P-value = 0.558), HR (P-value = 0.456), SPO2 (P-value = 0.305), or ETCO2 (P-value = 0.559) (Table 2)

There was a significant difference between pre and postoperative PASAT scores in Propofol and Sevoflurane groups respectively with p value (< 0.001) with no statistically significant difference between both groups (P-value = 0.906). (Table 3)

There was a significant difference between pre and postoperative PALT scores in Propofol group (p value = 0.01), but there was no significant difference between pre and postoperative PALT scores in Sevoflurane group (p value = 0.488), moreover, there was a statistically significant difference between both groups (P-value = 0.038). (Table 3).

In Propofol group, there was a statistically significant difference between pre and postoperative RT ABR I, III, V, I-III, I-V, III-V with p value (0.011, 0.001, 0.004, 0.046, 0.007and 0.019 ) respectively. In Sevoflurane group, there was a statistically significant difference between pre and postoperative RT ABR III, V, I-III, III-V with p value (0.041, 0.029, 0.005 and < 0.001) respectively (Table 4).

In Propofol group, there was a statistically significant difference between pre and postoperative LT ABR I, III with p value (< 0.001, 0.003) respectively. In Sevoflurane group, there was a statistically significant difference between pre and postoperative LT ABR I, III, III-V with p value (0.012, 0.008 and 0.009) respectively. Finally, there was no statistically significant differences between the Propofol and Sevoflurane groups in all waves of ABR in both sides P value > 0.05).

This study was conducted to detect the possible deleterious effect of propofol versus sevoflurane on auditory function, attention and auditory memory. A total of 80 patients were enrolled in this study (n = 40 in each group). Our results revealed that there was a significant delay in the latency of most of the waves of postoperative ABR than preoperative assessment for both of propofol and sevoflurane groups separately with no significant difference between the two drugs regarding ABR parameters.

Similar findings were obtained by Mun and Cho who reported that Propofol can cause transient vertebrobasilar hypoperfusion producing cochlear injury resulting in hearing loss ^[2]. Propofol increases cerebral vascular resistance by 50% and decreases systolic blood pressure by 20–30%^[18]. It was also reported to change the evoked otoacoustic emissions (OAE) thresholds ^[19]. In contrast, Gungor et al reported that transient evoked otoacoustic emissions (TEOAE) were not significantly affected after propofol ^[20].

Sevoflurane exposure was reported to impair hearing in the mice offspring which was demonstrated by a decrease in ABR wave I amplitude, an indicator for ribbon-synapse functionality. Exposure to sevoflurane caused no apparent damage to hair cells, but cochlear ribbon synapses were decreased in postnatal day 15 offspring, and partially improved by postnatal day 30. That was explained by increased mitochondrial reactive-oxygen species stress and decreased autophagy in the cochlear explants ^[21].However, sevoflurane, described by other authors to be safe in terms of ototoxicity, They noticed that sevoflurane has a hypotensive effect without changing cochlear blood flow, while propofol, although having a similar effect on blood pressure to sevoflurane, has less of a protective effect on inner ear microcirculation ,transient evoked otoacoustic emissions (TEOAE) was not significantly affected after sevoflurane ^[22]. The decline of hearing function could also be explained by that anesthetic agents can cause the dysfunction of the eustachian tube cilia and resultant hearing dysfuction .Previous studies reported that ear volume and ear pressure increased on tympanography after the induction of general anaesthesia ^[1].

Changes of middle ear pressure (MEP) could affect auditory function measurments besides agents’ direct pharmacological effects on cochlear micromechanics and hemodynamics. Sevoflurane was reported to increase the middle ear pressure. So, propofol may be used in middle ear operations more safely than sevoflurane ^[23].

In the present study, there was a statistically significant postoperative impairment in attention (assessed by PASAT) following both propofol and Sevoflurane anesthesia with no significant difference between the two drugs. Whereas, the auditory memory (assessed by PALT) was significantly impaired following propofol but not sevoflurane anesthesia.

The choice of the general anesthetic drugs and their association with the occurence of POCD remains a controversial topic. Sun et al. reported that propofol had a more significant adverse effect on postoperative cognitive function than sevoflurane. ^[24] Similarly, Schoen et al. showed that sevoflurane-based anesthesia was associated with better short-term post-operative cognitive performance in comparison to propofol-based anesthesia. ^[25] On the other hand, Tang et al. declared that sevoflurane had a more severe impact on cognitive function than propofol. ^[26] Guo et al. reported that there was no significant difference in the incidence of POCD in elderly patients receiving sevoflurane-based versus propofol-based general anesthesia. ^[27]

Multiple human and animal studies were conducted to clarify the pathophysiological mechanisms undelying the cognitive dysfunction following propofol and sevoflurane anaesthesia. Prolonged exposure of developing rats to propofol and sevoflurane has been proven to cause neurodegeneration and apoptosis in their brain. ^[28] Erdem et al. reported that both sevoflurane and propofol based anesthesia were associated with elevation in the markers of neurodegeneration; S100β and neuron-specific enolase (NSE) indicating significant neuronal injury. ^[29]

Additionally, propofol and sevoflurane were known stimulate GABAA receptor and elevate the intracellular calcium, which leads to turbulences in mitochondrial membrane potential causing neuronal dysfunction and death, increasing the production of reactive oxygen species (ROS) which exacerbates ischemic brain damage. Avoidance of excessive hyperoxic ventilation or administration of antioxidants while under anaesthesia may protect against anesthetic neurotoxicity ^[30]. High concentrations of sevoflurane were found to induce serious cognitive dysfunction through changing the integrity of the BBB and increasing an intracerebral oxidative stress response. ^[31]

It has to be mentioned that POCD was reported by Terri et al. to occur in adult patients of all ages after non-cardiac surgery. The authors conducted their study on one thousand sixty-four patients aged 18 year or older, categorized as young (18–39 year), middle-aged (40–59 year), or elderly (60 year or older). The results revealed that at hospital discharge, POCD was present in 117 (36.6%) young, 112 (30.4%) middle-aged, and 138 (41.4%) elderly patients, but increasing age was an independent risk factors for POCD at 3 months after surgery. ^[32]

This study is considered the first work to investigate the effect of anesthesia with Propofol versus Sevoflurane on attention and auditory memory in addition to auditory functions. However, this study had some limitations. Firstly, the relatively small sample size and the short follow up period. Secondly, we didn’t perform assessment for the vestibular function. Thirdly, we focused only on assessment of attention and auditory memory and didn’t test the other cognitive domains.

There were a statistically significant postoperative impairment in auditory function, attention and auditory memory following both propofol and Sevoflurane anesthesia with no significant difference between the two drugs.

ABR : Auditory brain stem response ; TIVA : Total intravenous anesthesia ;POCD: postoperative cognitive dysfunction ; PASAT : Paced Auditory Serial Addition Test; PALT: Paired Associate Learning test ; ms: milliseconds ; BAEPs: Brainstem auditory evoked potentials ; SPSS :Statistical Package of Social Science ; (IQR): inter quartile range ; SNHL : sensorineural hearing losses ; CSF: cerebrospinal fluid pressure ; (TEOAE) : transient evoked otoacoustic emissions ; MEP : middle ear pressure ; (ROS): reactive oxygen species ; GABAA: gamma-Aminobutyric acid ; IV : intravenous

Ethics approval and consent to participate:

An informed written consent was taken from each patient. All data obtained from every patient were confidential and were not used outside the study. The patients have rights to withdraw from the study at any time without giving any reason. All the cost of the investigations was afforded by the researcher. Our study was approved by ethical committee of the Department of Anaesthesiology, faculty of medicine, Beni-Suef University (approval number FMBSUREC/12062018). The study design followed the requirements of revised Helsiniki declaration of biomedical ethics, Also the protocol of this study was registered in clinical trial registration: www.ClinicalTrials.gov, identifier: NCT04874545 in 5/5/2021

Consent for publication:

Not applicable.

Availability of data and material:

The datasets generated and/or analyzed during the current study are not publicly available due to the current Cairo University regulations and Egyptian legislation but are available from the corresponding author on reasonable request and after institutional approval.

Competing interests:

The authors declare that they have no conflict of interest.

Funding:

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors

Authors’ contributions:

WF: research idea, manuscript writing, MH: research idea, manuscript writing, RAK: data acquisition, data analysis and interpretation, HAA: data acquisition, data interpretation and manuscript writing and reviewing. HE: writing manuscript and editing, HE: Manuscript reviewing ; DAR: research idea, manuscript writing, all authors have read and approved the final manuscript.

Acknowledgement:

The authors acknowledge subjects for their participation and cooperation in this study

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Table (1): Demographics of the patients in Propofol and Sevoflurane groups

P-value	Sevoflurane group	Propofol group	Demographic data
0.537	36 (13.5)	37(8.75)	Age [Median (IQR)]
0.175	20(50%)	26(65%)	Males [N (%)]	Sex
0.175	20(50%)	14(35%)	Females [N (%)]	Sex

P-value > 0.05 (non-significant) ; IQR: inter quartile range

Table (2): Intraoperative clinical data of the patients in Propofol and Sevoflurane groups

P-value	Sevoflurane group	Propofol group	Intraoperative clinical data
0.558	86 (40)	85 (30)	Median BP [Median (IQR)]
0.456	80 (13)	82.5 (15)	HR [Median (IQR)]
0.305	100 (0)	100 (1)	SPO2 [Median (IQR)]
0.559	35 (0)	35 (0)	ET CO2 [Median (IQR)]

P value > 0.05 (non-significant) ; IQR: inter quartile range

Table (3): Pre and postoperative psychometric tests scores of the patients in Propofol and Sevoflurane groups.

Psychometric tests		Preoperative assessment [Median (IQR)]	Postoperative assessment [Median (IQR)]	P- value	P- value between groups
PASAT	Propofol group	44.5 (11.25)	43.5(27)	<0.001*	0.906
PASAT	Sevoflurane group	44 (11.5)	41(27)	<0.001*	0.906
PALT	Propofol group	17.5 (4.5)	17(11)	0.01*	0.038*
PALT	Sevoflurane group	18.5 (3.75)	19(10)	0.488	0.038*

*P value ≤ 0.05 (significant) ; PASAT : Paced Auditory Serial Addition Test; PALT : Paired Associate Learning test ; IQR: inter quartile range

Table (4): Pre and postoperative ABR of the patients in Propofol and Sevoflurane groups.

P- value between groups	P- value	Postoperative assessment [Median (IQR)]	Preoperative assessment [Median (IQR)]	ABR
0.582	0.011*	1.6(0.66)	1.515 (0.35)	Propofol group	I	RT ABR
0.582	0.058	1.565(0.78)	1.435 (0.47)	Sevoflurane group	I
0.358	0.001*	3.635(0.77)	3.53 (0.39)	Propofol group	III
0.358	0.041*	3.725(1.4)	3.6 (0.36)	Sevoflurane group	III
0.313	0.004*	5.73(1.47)	5.53 (0.33)	Propofol group	V
0.313	0.029*	5.685(0.82)	5.635 (0.38)	Sevoflurane group	V
0.161	0.046*	2.235(1.4)	2.13 (0.20)	Propofol group	I-III
0.161	0.005*	2.225(1.4)	2.1 (0.27)	Sevoflurane group	I-III
0.822	0.007*	4.215(1.8)	4 (0.38)	Propofol group	I-V
0.822	0.052	4.12(2.53)	4 (0.27)	Sevoflurane group	I-V
0.897	0.019*	2(1.4)	1.965 (0.24)	Propofol group	III-V
0.897	<0.001	2.13(2.6)	1.93 (0.24)	Sevoflurane group	III-V
0.395	<0.001	1.515(0.73)	1.4 (0.19)	Propofol group	I	LT ABR
0.395	0.012*	1.53(0.8)	1.47 (0.12)	Sevoflurane group	I
0.370	0.003*	3.67(2.13)	3.57 (0.18)	Propofol group	III
0.370	0.008*	3.645(2.3)	3.5 (0.25)	Sevoflurane group	III
0.532	0.052	5.6(0.93)	5.47 (0.35)	Propofol group	V
0.532	0.152	5.585(0.85)	5.5 (0.34)	Sevoflurane group	V
0.885	0.387	2.115(1.27)	2.2 (0.26)	Propofol group	I-III
0.885	0.132	2.13(1.53)	2.095 (0.18)	Sevoflurane group	I-III
0.597	0.554	4.115(1.14)	4.165 (0.44)	Propofol group	I-V
0.597	0.388	4(1.33)	3.915 (0.42)	Sevoflurane group	I-V
0.593	0.116	2.07(1)	1.87 (0.34)	Propofol group	III-V
0.593	0.009*	2.005(2.87)	1.9 (0.36)	Sevoflurane group	III-V

* P value ≤ 0.05 (significant); ABR: Auditory brain stem response; IQR: inter quartile range

No competing interests reported.

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Effect of propofol versus sevoflurane on auditory and cognitive functions: A randomized controlled trial

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2) Audiological Assessment:

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