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Research Article

The dosage of thiopental as pharmacological cerebral protection during non-shunt carotid endarterectomy: A retrospective study

[version 1; peer review: 1 approved with reservations]
PUBLISHED 11 Apr 2023
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Abstract

Background: Thiopental has been used as a pharmacological cerebral protection strategy during carotid endarterectomy surgeries. However, the optimal dosage required to induce burst suppression on the electroencephalogram (EEG) remains unknown. This retrospective study aimed to determine the optimal dosage of thiopental required to induce burst suppression during non-shunt carotid endarterectomy.
Methods: The Neurological Institute of Thailand Review Board approved the study. Data were collected from 2009 to 2019 for all non-shunt carotid endarterectomy patients who received thiopental for pharmacological cerebral protection and had intraoperative EEG monitoring. Demographic information, carotid stenosis severity, intraoperative EEG parameters, thiopental dosage, carotid clamp time, intraoperative events, and patient outcomes were abstracted.
Results: The study included 57 patients. Among them, 24 patients (42%) achieved EEG burst suppression pattern with a thiopental dosage of 26.3+10.1 mg/kg/hr. There were no significant differences in perioperative events between patients who achieved burst suppression and those who did not. After surgery, 33.3% of patients who achieved burst suppression were extubated and awakened. One patient in the non-burst suppression group experienced mild neurological deficits. No deaths occurred within one month postoperative.
Conclusions: The optimal dosage of thiopental required to achieve burst suppression on intraoperative EEG during non-shunt carotid endarterectomy was 26.3+10.1 mg/kg/hr.

Keywords

Carotid endarterectomy, barbiturate, thiopental, burst suppression, electroencephalogram

Introduction

Stroke is one of the leading causes of death and disability in Thailand,1 and carotid stenosis is one of the leading causes of stroke.2 The surgical treatment to prevent stroke is carotid endarterectomy (CEA). It is associated with periprocedural risks, including stroke (embolic or hemodynamic), myocardial infarction, and death. Therefore, strict selection criteria are applied for patients undergoing CEA. Current selection criteria support CEA for symptomatic low-risk surgical patients with 50% to 99% stenosis and asymptomatic patients with stenosis of 70% to 99%.3 However, the ability of the patient to tolerate the cross-clamp depends on the sufficiency of collateral flow through the circle of Willis. Inadequate collateral cerebral perfusion during the cross-clamp period increases the risk of perioperative stroke.4 Despite routine intraluminal shunt during the temporary occlusion of the ipsilateral internal carotid artery being controversial, intraoperative electrophysiological monitoring, such as electroencephalogram (EEG), is a valuable tool to detect cerebral hypoperfusion and determine selective shunting.5,6 When the neurosurgeon performed the non-shunt technique, adequate cerebral perfusion during carotid cross-clamping could be achieved using several methods to protect the brain.7 Spetzler et al.8 reported excellent non-shunt surgical outcomes using intra-operative barbiturate and microsurgical techniques. The clinical use of barbiturates is known for cerebral protection against the prevention of focal cerebral ischemia,9 especially when barbiturate was administered before the ischemic insult with doses large enough to produce burst-suppression activity on the EEG.10 However, no definite predetermined amount of barbiturate-induced burst-suppression activity on EEG; to reach the burst-suppression pattern, the optimal dosage, timing, and administration mode vary among studies.

The Neurological Institute of Thailand is one of the few medical centers with EEG for intraoperative surveillance. Thus the authors aimed to study the optimal dose of barbiturates as thiopental for inducing EEG burst-suppression patterns in anesthetized patients undergoing carotid endarterectomy with a non-shunt technique.

Methods

Study design and participants

The study was approved by The Research Ethics Committee of the Neurological Institute of Thailand (approval number IRB53068). Written informed consent was waived, as this study was a retrospective observational without patient interventions. Data were collected from all consecutive patients with carotid artery stenosis who underwent CEA at the Neurological Institute of Thailand, Bangkok, from January 2009 to December 2019. Patients scheduled for CEA with intraoperative EEG were included, while Patients undergoing CEA without thiopental as pharmacological cerebral protection were excluded.

Management of anesthesia and perioperative care

In our institution, neurosurgeons perform carotid endarterectomy under general anesthesia using a non-shunt technique with pharmacological cerebral protection strategies.11

Monitoring of burst-suppression patterns by EEG

In addition to standard anesthetic monitoring with an arterial line, all patients were monitored with the two-channel cortical EEG using the EEG pod of Infinity Delta Series (Drager Medical AG & Co. Lubeck, Germany). The EEG signal was obtained using silver-silver chloride electrodes located according to the international 10-20 systems. The differential montage was recorded: left and right frontal (FP1-C3, FP2-C4; channels 1 and 2), with a neutral electrode placed at the ear lobe. The impedance was recommended at < 5,000 ohms. Power Spectra analysis (Fast Fourier transform: FFT) was used to simplify the complex EEG to computer-processed EEG (CEEG) for an 8-second epoch. Trained anesthesiologists visually assessed the raw EEG and compressed spectral EEG parameters [Spectral Edge Frequency 95% (SEF95%), Median (MED), and Burst Suppression Ratio (BSR)]. Burst Suppression Ratio (BSR) was defined as the percentage of time the EEG waveform is flatlined over the last 60 seconds (when flatline EEG alternates with “bursts” of activity).

Anesthetic procedures

Anesthesia was induced with thiopental (Pentothal Sodium®) (3-5 mg/kg) or propofol (1-2 mg/kg), followed by fentanyl (1-2 mcg/kg), atracurium (0.5-0.6 mg/kg), or cis-atracurium (0.15 mg/kg) to facilitate tracheal intubation. The anesthesia was maintained with sevoflurane or desflurane (<1 MAC) and continuous infusion of a neuromuscular blocking agent (atracurium 0.3-0.5 mg/kg/hr or cis-atracurium 0.06-0.1 mg/kg/hr). An additional dose of fentanyl 25-50 mcg was titrated during the operation. Antihypertensive medications were administered for hypertension, and fluids or vasopressors were used to treat hypotension.

Before the temporary occlusion of the carotid artery, a single dose of heparin 5,000 units and thiopental (5 mg/kg) was given intravenously (IV) followed by continuous infusion of 10 mg/kg/hr with an additional 50 mg titrated intravenously to achieve burst suppression on EEG throughout the ischemic period. During the carotid clamp time, the blood pressure was raised 10% above the pre-operative level to induce collateral circulation. The inhalation agent was suspended during the thiopental infusion. At the end of the operation, the neuromuscular blockade was reversed with glycopyrrolate 0.2 mg for each 1.0 mg of neostigmine or atropine 0.02 mg/kg and neostigmine 0.02 to 0.07 mg/kg. The patient was extubated if the patient had adequate ventilation, eye-opening, and purposeful responses. All patients were transferred to the neurosurgical intensive care unit for postoperative care.

Data collection

Electronic database searches and manual data were abstracted, including demographic data, clinical courses, and outcomes. Patient characteristics were age, gender, American Society of Anesthesiologists Physical Status classification (ASA), Glasgow Coma Scale (GCS), and history of any comorbidities: cerebrovascular accident or transient ischemic attack (TIA), coronary artery disease (CAD), hypertension (HT), diabetes mellitus (DM), and dyslipidemia. Pre-operative investigation data such as the site and degree of stenosis measured by carotid duplex ultrasonography and magnetic resonance angiography (MRA) or conventional angiography were abstracted.

Intraoperative data including EEG parameters [Burst suppression ratio (BSR), Spectral edge frequency 95% (SEF95%), Median (MED)], thiopental dosage, carotid clamp time, intraoperative events (hypertension, hypotension, cardiac arrhythmias), duration of surgery, fluid administration, estimated blood loss, perioperative blood product transfusions (units), and successful extubation after surgery. Extubation time in the neurosurgical intensive care unit, Glasgow outcome scale (GOS) at discharge, and one-month postoperative were studied.

Outcome measures

The study's primary outcome was the amount of thiopental required to achieve burst suppression on EEG during cerebral protection. In addition, the study investigated several secondary outcomes related to the patient's recovery, including the percentage of successful extubations after surgery, the time to extubation in the neurosurgical intensive care unit, and the Glasgow Outcome Scale (GOS) at discharge and one month postoperatively. These measures were analyzed to assess the patient's recovery following the procedure.

Statistical analysis

Statistical analysis was performed using SPSS Statistical software, version 22 (IBM SPSS Inc., Chicago, IL). Descriptive statistics were presented as means±standard deviations, percentages, and numbers. The Chi-square test was used to compare categorical variables, while unpaired t-tests were employed for analyzing continuous variables. Paired t-tests were utilized to compare EEG data before and the average of EEG data during the carotid cross-clamp. A significance level of P-value≤0.05 was considered statistical significance.

Results

There were 69 carotid endarterectomies performed during the study period, with 12 cases excluded. Of the remaining 57 patients analyzed (Figure 1), only 24 achieved burst suppression on intraoperative EEG despite receiving continuous thiopental infusion with additional titration. These 24 patients were classified as the burst suppression group (BS) for the analysis. The demographic data and related details of both the BS and non-BS group are presented in Table 1. The group had a significantly higher average age of 72.8±9.1 years than the non-BS group, with an average age of 66.7±7.2 years (p-value=0.007). However, there were no significant differences in gender, body weight, ASA physical status, comorbidities, or pre-operative investigation data between the two groups. Hypertension was a common condition in both groups. The percentage of patients who received thiopental or propofol as induction agents and the dosages were not significantly different between the two groups (Table 2). Perioperative doses of fentanyl and end-tidal concentrations of sevoflurane or desflurane also showed no significant differences. The amount of thiopental required to achieve burst suppression on intraoperative EEG was significantly higher in the BS group compared to the non-BS group (26.3±10.1 mg/kg/hr vs. 18.7±8.8, p-value=0.004). Although the carotid clamp time was slightly shorter in the BS group, it did not reach statistical significance (73.2±23.7 min vs. 83.3±34.8, p-value=0.225).

24f218b4-77d5-4220-9c2e-336170cf8892_figure1.gif

Figure 1. Flow diagram of the study.

Table 1. Demographic data.

VariablesGroup BS (n=24)Group Non-BS (n=33)p-value
Age (year)72.8±9.166.7±7.20.007
Gender: Male7 (29.2)13 (39.4)0.424
ASA II/III21 (87.5)/3 (12.5)22 (66.7)/11 (33.3)0.071
Weight (kg)64.6±10.462.5±7.40.397
Glasgow Coma Score=1522 (91.7)31 (93.9)0.74
Comorbidities (n)
 Coronary Artery Disease3 (12.5)4 (12.1)0.966
 Hypertension18 (75)22 (66.7)0.497
 Diabetes Mellitus12 (50)16 (48.5)0.910
 Dyslipidemia6 (25)11 (33.3)0.497
Pre-operative investigation data
 Bilateral stenosis3 (12.5)5 (15.2)0.776
 Site of operation Right/Left15 (62.5)/9 (37.5)21 (63.6)/12 (36.4)0.930

Table 2. Perioperative data.

VariablesGroup BS (n=24)Group Non-BS (n=33)p-value
Induction:
 Thiopental/Propofol7 (29.2)/17 (70.8)14 (42.4)/19 (57.6)0.306
 Thiopental (mg/kg)3.9±0.34.7±0.70.087
 Propofol (mg/kg)1.5±0.41.3±1.20.547
During carotid clamp:
 Total thiopental (mg)1,951.8±741.41,411.7±439.80.001
 Total thiopental (mg/kg/hr)26.3±10.118.7±8.80.004
Fentanyl (mcg/kg/hr)0.9±0.31±0.30.838
Sevoflurane/Desflurane15 (62.5)/9 (37.5)24 (72.7)/9 (27.7)0.296
Sevoflurane/Desflurane (% end tidal)0.2±0.1/1.6±0.70.2±0.1/1.7±0.70.310/0.921
Carotid clamp time (min)73.2±23.783.3±34.80.225
Operative time (min)180.2±39.4193.8±47.10.254
Anesthetic time (min)243.8±43.6251.1±51.10.576
Crystalloid (mL)1,795.1±652.61,867.1±574.40.661
Estimated blood loss (mL)141.9±175.1172.6±187.70.533
Urine output (mL)909.2±503.71,123.3±589.60.156
Events
 Hypertension12 (50)21 (63.6)0.303
 Hypotension13 (54.2)17 (51.5)0.843
 Arrthymia4 (16.7)4 (12.1)0.626
 Vasopressor infusion4 (16.7)2 (6.1)0.198
Emergence
 Extubation after operation (n=24)8 (33.3)16 (48.5)0.253
Post-operative
 Extubation at ICU (n=33)16 (66.7)17 (51.5)0.253
 Time to extubation at ICU (min)872.4±593.3601.6±473.90.156

The spectral edge frequency 95% (SEF95%) of both the BS and non-BS groups tended to decrease after carotid clamping, as indicated in Table 3. However, the two groups had no significant difference regarding MED or SEF95% before and after the clamping. Similarly, neither group significantly differed between the left and right MED or SEF95%. After carotid clamping, the BS group had an average BSR of 36.0±20.4 (right) and 36.3±20.6 (left), but this difference was not statistically significant. In contrast, the non-BS group did not exhibit any burst suppression pattern.

Table 3. The EEG data before and the average of EEG data during the carotid clamp time.

VariablesGroup BS (n=24)Group Non-BS (n=33)
Phase of carotid clampBeforeDuringp-valueBeforeDuringp-value
MEDRight side1.8±0.51.8±0.60.3421.8±0.81.9±0.70.290
Left side1.8±0.61.8±0.50.8591.9±0.51.8±0.70.284
SEF95%Right side9.2±2.98.8±2.00.3119.5±4.29.3±2.80.585
Left side9.2±2.78.9±1.90.54110.2±4.39.3±2.80.207
BSRight side036.0±20.4-00-
Left side036.3±20.6-00-

The incidence of hypertension, hypotension, and arrhythmias did not show a statistically significant difference between the two groups. Following the operation, eight patients (33.3%) in the BS group and sixteen (48.5%) in the non-BS group were awake and extubated. Most patients in both groups were intubated and transferred to the neurosurgical intensive care unit. There was no significant difference in extubation time for patients who were initially unable to extubate between the two groups (BS group 872.4±593.3 min. vs. non-BS group 601.6±473.9 min). One patient experienced a mild neurological deficit. No deaths were reported one month after the operation (Table 4).

Table 4. Clinical outcomes.

VariablesGroup BS (n=24)Group Non-BS (n=33)p-value
Postoperative outcomes
 TIA1 (4.2)3 (9.1)0.472
 RIND1 (4.2)1 (3)0.818
 Mild neurological deficit0 (0)1 (3)0.39
Length of ICU stay (day)1.7±1.11.4±1.10.418
Length of hospital stay (day)12.5±13.114.5±11.00.54
GOS at discharge=522 (91.7)29 (87.9)0.645
GOS at 1 month=523 (95.8)28 (84.8)0.182

Discussion

This study aimed to determine the amount of thiopental required to induce burst suppression patterns on intraoperative EEG monitoring in patients undergoing carotid endarterectomy without a shunt and to evaluate patient outcomes. The main findings indicated that not all patients achieved burst suppression despite the intention to maximize cerebral protection through a continuous thiopental infusion and titrated intravenous administration. Patients who received significantly higher doses of thiopental (26.3±10.1 mg/kg/hr) were likelier to achieve burst suppression on EEG. However, no significant difference was observed in postoperative outcomes between the burst suppression (BS) and non-burst suppression (non-BS) groups. Currently, limited data is available on the efficacy and optimal dosage of thiopental for inducing pharmacological burst suppression to prevent perioperative stroke during selective shunting in CEA.

Barbiturates, such as thiopental, are commonly used to prevent cerebral ischemia during cerebrovascular surgery. Thiopental is a fast-acting, short-duration barbiturate anesthetic that may exert its neuroprotective effects through various mechanisms, including antioxidant activity, GABA-ergic activity, stimulation of protein synthesis, removal of free radicals, and modulation of excitatory synaptic neurotransmission via adenosine.12 Animal studies have shown that barbiturates can decrease brain oxygen demand and the size of cerebral infarction.1315 In cerebrovascular procedures that require temporary clips, such as extracranial-intracranial bypasses, carotid endarterectomies, and aneurysm clipping, barbiturates have been demonstrated to reduce the cerebral metabolic rate of oxygen and increase blood flow to ischemic regions.1618

The thiopental dose required for EEG burst suppression patterns during cerebrovascular surgery can vary depending on several factors, including variability in monitoring and assessing burst suppression levels among healthcare providers. Sreedhar and Gadhinglajkar19 have reviewed several dosing regimens of thiopental for cerebrovascular surgery, including a bolus dose (4 mg/kg), a low dose followed by IV infusion (1 to 3 mg/kg IV followed by 0.06 to 0.2 mg/kg/min), and a high dose followed by infusion (loading 25 to 50 mg/kg followed by 2 to 10 mg/kg/hr).

The initial bolus doses of thiopental used in our study did not result in EEG burst suppression for most patients, which differs from the findings of Ramesh VJ.20 According to Ramesh VJ, almost all patients who received a bolus dose of 3 to 5 mg/kg experienced EEG burst suppression with a BSR greater than 25%. The initial bolus doses of thiopental only resulted in temporary suppression durations, consistent with previous studies by Moffat et al.21 and Gelb et al.,22 which provided limited cerebral protection during the intraoperative period.

Our study used a continuous thiopental infusion to maintain EEG burst suppression during the carotid cross-clamp procedure. We administered a high dose of thiopental, similar to previous studies by McConkey PP et al.23 and Frawley JE et al.24 However, not all patients in our study achieved EEG burst suppression, unlike the abovementioned studies where incremental bolus doses of thiopental were titrated. Nonetheless, none of our patients experienced a significant period of ischemia, as defined by a decrease in SEF95% to 50% of the baseline.25

EEG-confirmed burst suppression is commonly accepted as the optimal endpoint for cerebral protection following barbiturate therapy during cerebrovascular surgery. Intraoperative monitoring of burst suppression is typically conducted using electroencephalography (EEG) or Bispectral Index (BIS).26,27 However, BIS-derived BSR may underestimate the duration of EEG suppression, potentially reducing sensitivity for detecting burst suppression.28 Our study opted for direct visualization of the EEG trace to achieve a more accurate and real-time comparison of raw EEG changes and BSR values between both sides of the brain. This EEG trace allowed us to detect potential cerebral ischemia and determine the level of cerebral protection.

The study found that older patients were more likely to achieve burst suppression on EEG with thiopental therapy, potentially due to age-related factors.29 Although not all patients achieved burst suppression, the BS and non-BS groups had favorable clinical outcomes without significant perioperative complications. The BS group did have a more extended postoperative intubation period. However, their Glasgow Outcome Scale was not significantly different from the non-BS group at discharge or one month after surgery. These outcomes could be attributed to barbiturate therapy, as research on rats suggests that EEG burst suppression may not be necessary for maximum cerebral protection.30,31 Barbiturates can offer sufficient brain protection at lower doses that do not require EEG burst suppression. Further research is needed to verify this concept in humans.

The dosage of thiopental that does not lead to EEG burst suppression may impact cerebral protection during carotid endarterectomy. However, thiopental-induced cerebral protection is only one of several strategies for cerebral protection. Other factors, such as the degree of stenosis, pre-existing medical conditions, and perioperative risks associated with carotid endarterectomy, influence patient outcomes.32

Limitations of this study include the fact that it only focused on the dosage of thiopental and its effects on intraoperative EEG monitoring as a direct tool for evaluating brain electrical activity during carotid endarterectomy. It is important to note that EEG only provides information on brain electrical activity and does not directly measure cerebral blood flow or cerebral oxygen saturation (SjVO2). Therefore, relying solely on EEG may not accurately reflect the actual level of cerebral protection. Multimodal intraoperative monitoring techniques, such as transcranial Doppler (TCD) ultrasound, somatosensory evoked potentials, and cerebral oxygen saturation monitoring, are recommended for a more comprehensive patient status assessment. Additionally, this study did not assess the thiopental serum levels for barbiturate coma treatment. The retrospective cohort design also limited the quality of data collection. Therefore, a prospective randomized study is recommended to investigate further the role of intraoperative monitoring and barbiturate therapy in optimizing cerebral protection during carotid endarterectomy.

In conclusion, thiopental at a dosage of 26.3+10.1 mg/kg/hr can induce burst suppression on intraoperative EEG during carotid endarterectomy, potentially providing cerebral protection. Further research is needed to understand thiopental's neuroprotective mechanisms and explore alternative monitoring techniques.

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Sookplung P, Suchartwatnachai P and Akavipat P. The dosage of thiopental as pharmacological cerebral protection during non-shunt carotid endarterectomy: A retrospective study [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:381 (https://doi.org/10.12688/f1000research.131838.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
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Reviewer Report 19 May 2023
Masahiko Kawaguchi, Department of Anesthesiology and Division of Intensive Care, Nara Medical University, Nara, Japan 
Approved with Reservations
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The authors retrospectively evaluated the optimal dosage of thiopental required to induce burst suppression during non-shunt carotid endarterectomy. As an analysis of 57 patients, the authors concluded the optimal dosage of thiopental required to achieve burst suppression on intraoperative EEG ... Continue reading
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Kawaguchi M. Reviewer Report For: The dosage of thiopental as pharmacological cerebral protection during non-shunt carotid endarterectomy: A retrospective study [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:381 (https://doi.org/10.5256/f1000research.144721.r169287)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 03 Jul 2023
    pimwan sookplung
    03 Jul 2023
    Author Response
    Dear Dr. Masahiko Kawaguchi.
    Thank you very much for taking the time to contribute to the opportunity to improve the research article. I hope our revised paper will be appreciated ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 03 Jul 2023
    pimwan sookplung
    03 Jul 2023
    Author Response
    Dear Dr. Masahiko Kawaguchi.
    Thank you very much for taking the time to contribute to the opportunity to improve the research article. I hope our revised paper will be appreciated ... Continue reading

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Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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