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. Author manuscript; available in PMC: 2023 Apr 1.
Published in final edited form as: Neurocrit Care. 2021 Oct 1;36(2):612–620. doi: 10.1007/s12028-021-01350-w

The effect of Glibenclamide on somatosensory evoked potentials after cardiac arrest in rats

Brittany Bolduc Lachance 1, Zhuoran Wang 2, Neeraj Badjatia 1, Xiaofeng Jia 2,3,4,5,6
PMCID: PMC8967780  NIHMSID: NIHMS1739474  PMID: 34599418

Abstract

Background/Objective:

Science continues to search for a neuroprotective drug therapy to improve outcomes after cardiac arrest (CA). Glibenclamide (GBC) has shown promise in preclinical studies, but its effects on neuroprognostication tools are not well understood. We aim to investigate the effect of GBC on somatosensory evoked potential (SSEP) waveform recovery post-CA and how this relates to early prediction of functional outcome, with close attention to arousal and somatosensory recovery, in a rodent model of CA.

Methods:

16 male Wistar rats were subjected to 8-minute asphyxia CA and assigned to GBC (n=8) or control (n=8) groups. GBC was administered as a loading dose of 10ug/kg intraperitoneally 10 minutes after the return of spontaneous circulation, followed by a maintenance dose of 1.6ug/kg every 8 hours for 24 hours. SSEPs were recorded from baseline until 150 minutes following CA. Coma recovery, arousal, and brainstem function, measured by subsets of the neurological deficit score (NDS), were compared between both groups. SSEP N10 amplitudes were compared between the two groups at 30, 60, 90, and 120 minutes post-CA.

Results:

Rats treated with GBC had higher sub-NDS scores post-CA, with improved arousal and brainstem function recovery (p=0.007). Both groups showed a gradual improvement of SSEP N10 amplitude over time, from 30 minutes to 120 minutes post-CA. Rats treated with GBC showed significantly better SSEP recovery at every time point (p<0.001 for 30, 60, 90 min; p=0.003 for 120 min). In the GBC group, the N10 amplitude recovered to baseline by 120 minutes post-CA. Quantified Cresyl violet staining revealed a significantly greater percentage of damage in the control group compared with the GBC treatment group (P = 0.004).

Conclusions:

Glibenclamide improves coma recovery, arousal, and brainstem function after cardiac arrest with decreased number of ischemic neurons in a rat model. GBC improves SSEP recovery post-CA, with N10 amplitude reaching baseline by 120 minutes, suggesting early electrophysiologic recovery with this treatment. This medication warrants further exploration as potential drug therapy to improve functional outcomes in post-CA patients.

Keywords: cardiac arrest, somatosensory evoked potentials, glibenclamide, coma, N10

Introduction

Despite advances in medical science, cardiac arrest (CA) continues to hold high morbidity and mortality. There are approximately 356,000 out of hospital cardiac arrests (OHCA) in the United States each year, and despite advances in cardiopulmonary resuscitation (CPR) and pre-hospital emergency services, only 29% survive to the hospital (1). Of those who arrive at the hospital, most remain comatose after the return of spontaneous circulation (ROSC)(1), and only 9–10% survive to hospital discharge (1). Those survivors often go on to suffer long-term cognitive and psychiatric deficits affecting the quality of life (2). Neuronal ischemic/reperfusion injury is comprised of a complex, multisystem cascade of inflammation, loss of blood-brain barrier integrity, and eventual necrosis and apoptosis (3). For nearly two decades, targeted temperature management has been the only neuroprotective intervention to improve neurological outcome in comatose post-CA patients (4–6). Pharmacological advances for neuroprotection and prevention of cerebral ischemic injury post-CA remain in the pre-clinical phase of study.

Glibenclamide (GBC) is a second-generation sulfonylurea typically used to treat type 2 diabetes mellitus, which works via inhibition of sulfonylurea (SUR-1) receptors. SUR-1 channels open in response to ATP depletion, as occurs in CA, leading to sodium influx into cells, cerebral edema, and cell death (7–9). GBC has been shown to reduce infarct volume in stroke (10) and improve cerebral edema secondary to traumatic brain injury (TBI) (11). In CA, GBC has been shown to reduce diffusion-weighted imaging (DWI) abnormalities (12) and improve survival (13) in rats. However, the effect of this drug specifically on arousal recovery after CA was not addressed in these studies. For patients and families, the ability to regain consciousness provides more meaning than improved survival alone, and the first aim of this study is to assess whether this intervention can improve arousal recovery, consciousness, or somatosensory recovery after CA.

Given its novelty in post-CA management, the effects of GBC on standard neuro-prognostic tools are not well understood. Somatosensory evoked potential (SSEP) has recently risen to the forefront of neuro-prognostication and is believed to represent the afferent integrity of the thalamocortical system (14, 15). To date, the effect of GBC on this widely used neuro-prognostic tool has not been reported. Given the incorporation of SSEP analysis in standard post-CA prognostication protocols, it is critical to understand how GBC therapy can impact SSEP waveform recovery after CA.

In this study, we analyzed the effects of GBC on SSEP recovery post-CA, hypothesizing that GBC may improve SSEP amplitude and may lead to faster recovery of SSEP waveforms post-CA. We then investigated the association of early SSEP amplitude and GBC treatment on functional outcomes, with particular attention to arousal and somatosensory recovery.

Materials and Methods

Experimental protocols were approved by the University of Maryland Baltimore Institutional Animal Care and Use Committee. Sixteen male Wistar rats (300–325g, Charles River, Wilmington, MA) were randomly divided into the GBC treatment group (n=8) and control group (n=8). They were housed in a 12-hour dark/light cycle with free access to food and water.

Asphyxial cardiac arrest model

This asphyxial cardiac arrest and cardiopulmonary resuscitation (CPR) mirrored our previously published model (16–21). Rats were anesthetized with 4.5% isoflurane and maintained with 1.5% isoflurane after endotracheal intubation. Rats were ventilated (RWD-R415, RWD Life Science, San Diego, CA) with tidal volume 8mg/kg and respiratory rate of 55 bpm. Ventilator gas consisted of 50% N2 and 50% O2. The femoral artery was cannulated and arterial blood pressure (including mean arterial pressure (MAP), body temperature, heart rate, and ECG) were monitored continuously. Isoflurane washout was performed for five minutes, after which 5 minutes of baseline SSEP was obtained. The muscle relaxant vecuronium (2mg/mL) was then injected at a dose of 2mL/kg (22). Global asphyxia was induced by clamping the endotracheal tube and discontinuing the ventilator. Asphyxia was maintained for 8 minutes and CA was defined as pulse pressure <10mmHg. After 8 minutes of CA, ventilation with 100% oxygen was resumed and standard chest compressions (200 bpm) were initiated. Intravenous injection of epinephrine and sodium bicarbonate was administered through the femoral vein to aid resuscitation and correct metabolic acidemia. ROSC was defined as MAP>60 mmHg. Arterial blood gas analysis was obtained at baseline and 20 min after ROSC. All sedation was discontinued. After extubation and decannulation, rats gradually recovered. Temperature after ROSC was maintained at 36.5–37.5°C for all rats with the use of a warming light or fan as needed and was monitored via rectal probe. Rats were directly observed through extubation and for one additional hour during which they received 100% oxygen via mask. All rats were then maintained inside a neonatal incubator (Isolette Infant Incubator, Air Shields Inc., Hatboro, PA) for 24 hours post-ROSC. Rats unable to eat or drink were given sodium chloride and dextrose. Table 1 summarizes physiologic data of rats at baseline and after CA, with no significant differences between control and GBC groups. MAP data is compared to 30 minutes post-ROSC due to decannulation of rats between 60–90 minutes post-ROSC. Heart rate data was followed throughout SSEP monitoring.

Table 1:

Physiologic data control vs. GBC group

Group Mean Baseline HR (bpm) Mean 30min HR (bpm) Mean 60min HR (bpm) Mean 90min HR (bpm) Mean 120min HR (bpm) Mean Baseline MAP (mmHg) Mean 30min MAP (mmHg)
Control 377 433 386 403 407 81 78
GBC 424 459 356 369 399 92 80
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No difference in average heart rate at any time point, p=0.83. No difference in baseline MAP, p=0.34. No difference in 30min MAP between groups, p=0.90. HR: heart rate; MAP: mean arterial pressure

Glibenclamide Treatment

GBC (#G2539; Sigma, St. Louis, MO) was dissolved in dimethyl sulfoxide (DMSO) and diluted in saline (23). Treatment was administered intraperitoneally (IP) at a loading dose of 10 ug/kg 10 minutes after ROSC. This was followed by a maintenance dosage of 1.6 μg/kg every 8 h for 24 h post ROSC. Dosage selection has not resulted in hypoglycemia in previously published works (12).

Neurological Recovery Evaluation

Neurological recovery was assessed using subsets A and B of the neurological deficit score (NDS), which reflect coma recovery, arousal, and brainstem function. Specifically, subset A assessed consciousness (normal, stuporous, comatose), arousal (eye-opening), and respiration, with a total score of 19. Subset B assessed brainstem functions including olfaction, vision, pupillary reflex, corneal reflex, startle reflex, whisker stimulation, and swallowing, with a total score of 21. The composite NDS, which also includes scoring of motor strength, sensory response to pain, gait, balance, behavior (righting reflex, visual placing, turning alley), and seizures, has been previously well validated (16–18, 24), and was evaluated at 6, 24, 48, and 72h post-ROSC in all rats, including those rats that died prior to 72 hours, by a blinded assessor. The primary functional outcome was defined as the aggregate subset A and B scores in treatment versus control groups. To our knowledge, our study is the first to use the NDS subsets specifically assessing arousal and brainstem recovery after CA as a primary outcome, with the aim to assess the most basic functions necessary for regaining consciousness, as well as components thought necessary for intact transmission of cortical somatosensory potentials. The secondary outcome was cumulative survival at 72 hours.

SSEP Recording and Data Analysis

One day prior to the CA experiment, rats were implanted with five epidural screw electrodes (P1 Technologies Inc., Roanoke, VA) to record bipolar SSEPs from bilateral hemispheres. Two screw electrodes were placed in each hemisphere along the somatosensory cortex corresponding with forelimbs and hindlimbs. The fifth grounding electrode was placed over the parasagittal right frontal lobe. Extreme caution was used to avoid puncturing the dura mater or encountering brain tissue.

During the CA experiment, bipolar SSEPs were recorded using the TDT System data acquisition program (Tucker Davis Technologies, Alachua, FL). Median nerve was stimulated using subdermal needle electrodes with a direct current stimulation of 6mA in 200-microsecond pulses. Animals were their own sham in this study design, as has been done in prior publication (25). SSEPs were recorded for 15 minutes at baseline, prior to CA but after anesthesia and intubation, allowing the collection of naïve animal data while minimizing animal usage. After ROSC, recordings were obtained every 15 minutes for 150 minutes. One rat in the GBC group and one rat in the control group was performed without SSEP data.

The SSEP N10 amplitude, which is the first negative deflection at 10ms after the stimulus, was measured as the peak to peak difference from the N10 to P15 peaks (25). This was manually measured, and the average of 30 sweeps was mean-corrected and calculated at baseline, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. These values were compared between treatment and control groups and between baseline and time from ROSC.

Cresyl violet staining

We used cresyl violet staining to evaluate the viability of neurons by observing nuclear and cell body structures. Cresyl violet staining is more reliable and consistent for the evaluation of cytoplasmic and nuclear morphology, and thus was chosen over other histological techniques, such as H&E staining, to identify nuclear and nucleolar structures (17). Cortical neurons were studied given the importance of cortical integrity for consciousness and arousal recovery and the association of the SSEP cortical waveform with consciousness recovery, thus linking our electrophysiologic marker (N10 waveform) and our functional outcome assessment (subsets A and B of the NDS, assessing consciousness and arousal). Neurons were identified as ischemic neurons under ×400 magnification in a bright field of the Leica DMi8 microscope (Leica Microsystems, Wetzlar, Germany) when one of the following characteristics, including pyknosis, karyorrhexis, karyolysis, and cytoplasmic changes in form and color, was observed 72 hours after ROSC (17). The ratio of ischemic injured neurons to total neurons in random regions of cortex were output as histopathological damage scoring (HDS). The mean HDS was obtained from three random cortex regions near the hippocampus in the 400X magnification microscopic bright field. Three rats in each group were included for comparison of mean HDS.

Statistical Methods

Parametric data (SSEP, HDS) were shown as mean ± S.E.M. and non-parametric data (NDS) were presented as median and 25–75 interquartile range. One-way ANOVA was used to analyze SSEP and HDS. Repeated measurement was used to analyze sub-NDS. Crosstabs was used to calculate the sensitivity, specificity, positive predictive value, and negative predictive value at different SSEP levels. Differences were considered significant at p <0.05. All statistical analyses were performed using SPSS (Version 22, IBM SPSS Statistics, Armonk, NY). All experimental animals were used in statistical analysis with no exclusions.

Results

NDS Analysis, Functional Recovery, Survival

The GBC treatment group had higher aggregate NDS subset A+B scores (median [25–75th] interquartile range (IQR)) (37 [31–37]) compared to the control group (34 [0–34]) (p=0.007), as shown in Figure 1. Rats treated with GBC had longer survival and greater overall 72-hour survival (n=6, 75%) compared to control rats (n=4, 50%), though p>0.05. (Figure 2) There were no notable confounding variables between groups, including no differences in anesthesia time, baseline arterial blood gas (ABG) data, or 20-minute post-ROSC ABG data between groups. (Table 2) Cause of death for all premature mortalities was cardiopulmonary failure.

Figure 1: Aggregate NDS subset A+B scores control group versus GBC group.

Figure 1:

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Aggregate NDS subset A + B scores, representing arousal and brainstem functions, were significantly higher (p=0.007) in the GBC treatment group (25–75th IQR 31–37) compared to the control group (25–75th IQR 0–34). **p<0.01. GBC = glibenclamide, NDS = neurological deficit score

Figure 2: Cumulative 72-hour survival GBC versus Control group.

Figure 2:

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GBC group shows longer survival and greater overall 72-hour survival compared to the control group (75% versus 50%), p=0.615. GBC = glibenclamide

Table 2:

Anesthesia and Arterial Blood Gas Data (Median (SEM))

Anesthesia Time (min) Baseline pH 20min pH Baseline pCO2 20min pCO2 Baseline pO2 20min pO2 Baseline HCO3 20min HCO3
Control 63 (4) 7.36 (0.04) 7.33 (0.06) 41.30 (2.45) 37.30 (12.27) 172 (53) 342 (45) 23.2 (1.2) 19.7 (3.0)
GBC 60 (12) 7.28 (0.04) 7.36 (1.35) 37.90 (5.03) 37.70 (6.46) 393 (44) 293 (90) 23.8 (1.4) 22.6 (2.3)
p-value 0.36 0.67 1.0 0.92 0.53 0.14 1.0 0.83 0.30
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Quantitative SSEP Analysis

Bilaterally absent N20 (N10 in animals) cortical peaks has been regarded as a reliable, early predictor of poor outcome post-CA, even with concurrent TTM or sedation (26, 27). Baseline SSEP N10 amplitude was not significantly different between control and GBC groups. After cardiac arrest, aggregate analysis showed that SSEP N10 amplitude was significantly higher in the GBC group than the control group (p<0.001).

SSEP N10 amplitude was significantly higher in the GBC group at all individual time points (30min control 0.0675 ± 0.0241] vs. GBC 0.4985 ± SE 0.0181, p<0.001; 60min control 0.2150 ± 0.0399 vs. GBC 0.7105 ± 0.0186, p<0.001; 90min control 0.4290 ± 0.0521 vs. GBC 0.8565 ± 0.0172, p<0.001; 120min control 0.6260 ± SE 0.0681 vs. GBC 0.9505 ± 0.0085, p=0.003), shown in Figure 3.

Figure 3: Mean SSEP Amplitude GBC vs. Control Group.

Figure 3:

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Baseline SSEP N10 amplitudes were not significantly different between groups (p>0.05). SSEP N10 amplitude was significantly higher in GBC group at all post-ROSC time points. **p<0.01, ***p<0.001. GBC = glibenclamide, ROSC = return of spontaneous circulation, SSEP = somatosensory evoked potential

SSEP N10 amplitude in the GBC group returned to baseline at 120 minutes post-ROSC (p=0.231). Conversely, SSEP N10 amplitude in the control group remained significantly lower than baseline at 120 minutes post-CA (p=0.011), (Figure 4A). Figure 4B depicts the raw SSEP waveforms.

Figure 4. SSEPs before and after CA in two groups.

Figure 4

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A: SSEP N10 Amplitude Baseline vs. 120 Minutes Post-ROSC. SSEP N10 amplitude returned to baseline at 120 minutes post-ROSC in the GBC treatment group (p>0.05). SSEP N10 amplitude remained significantly lower than baseline at 120 minutes post-ROSC in the control group (p=0.011). B: Raw SSEP Waveforms Baseline vs. 120 Minutes Post-ROSC. Raw SSEP waveform at baseline and 120 minutes for a single control rat vs. a single GBC rat. ROSC = return of spontaneous circulation, SSEP = somatosensory evoked potential

Predictive Value of SSEP N10 Amplitude

Per AAN guidelines, bilateral absence of SSEP N20 response is the most reliable electrophysiologic marker for poor outcome or mortality after cardiac arrest, with a positive predictive value of 93–100% (28–31). The animal SSEP N10 waveform has been validated as the rodent cortical representation corresponding to the human N20 response (14, 25, 32, 33). Rather than this dichotomized evaluation, we assessed the predictive value of N10 amplitude for outcome and mortality after experimental cardiac arrest. Sensitivity was defined as the proportion of rats with poor functional outcome (NDS<60 at 72h) classified correctly, and specificity was defined as the proportion of rats with good functional outcome classified correctly using SSEP N10 amplitude as the criteria (14). A cutoff value for SSEP amplitude was chosen using the ROC curve to balance and optimize both sensitivity and specificity, as previously published (16). The sensitivity of SSEP amplitude <60% of baseline for predicting poor functional outcome was 78% (95% CI 43–100%) and the specificity was 80% ((95% CI 24–100%). The positive predictive value was 88% ((95% CI 58–100%), and the negative predictive value was 66% ((95% CI 12–100%) Table 3.

Table 3.

Predictive value of SSEP N10

Sensitivity (%) Specificity (%) PPV (%) NPV (%)
NDS <60 78 80 88 66
Mortality 83 50 56 80
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Predictive value of SSEP N10 amplitude <60% of baseline in predicting poor functional outcome defined as NDS <60 at 72h or mortality at 72h. PPV = positive predictive value; NPV = negative predictive value; NDS = neurological deficit score

Using the average SSEP N10 amplitude <60% of baseline to predict mortality at 72 hours, the sensitivity was 83% ((95% CI 41–100%) and the specificity was 50% ((95% CI 5–95%). The positive predictive value was 56% ((95% CI 15–96%), and the negative predictive value was 80% ((95% CI 24–100%).

Cresyl Violet Staining

Cresyl violet staining within the cortex revealed greater number of ischemic neurons in the control group compared to the GBC treatment group (Figure 5A). Quantification using histopathologic damage scoring (HDS) (17) revealed a significantly greater percentage of damage in the control group compared to the GBC treatment group (p=0.004) (Figure 5B).

Figure 5. Histopathologic evaluation of Control vs. GBC Groups using Cresyl Violet Staining within Cortex.

Figure 5

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A: Representative Cresyl violet staining of cortex displays an increased number of ischemic injured neurons in the control group compared to the treatment group. Red arrows highlight ischemic injured neurons. B: Quantification of ischemic injury defined by Histopathologic Damage Score (HDS) shows greater damage in the control group compared to the GBC treatment group (p=0.004). **p<0.01. GBC = glibenclamide

Discussion

This preclinical study highlights the potential prognostic value of SSEP N10 amplitude very early (within 2 hours) after cardiac arrest resuscitation, presenting the possibility of a rapid assessment tool for identifying severe neurological injury after CA and early identification of the potential to regain consciousness. We have demonstrated early electrophysiologic recovery and improved functional recovery with GBC treatment after resuscitation in a rodent model, lending additional preclinical support for GBC as potential drug therapy to improve outcome after global cerebral anoxia related to CA.

Recently, SSEP amplitude, rather than the standard dichotomization of present versus absent, has been reported as a prediction tool for prognostication after CA, with smaller amplitudes associated with poor outcome (34, 35). Similarly, our study demonstrates smaller SSEP N10 amplitudes at all time points after cardiac arrest in the control group, with poorer functional outcomes and survival. Conversely, we discovered higher SSEP N10 amplitudes with GBC treatment, with improved arousal and somatosensory recovery and improved survival. Most impressive, SSEP N10 amplitudes returned to baseline within 120 minutes from cardiac arrest in the treatment group. This provides preclinical evidence for the early use of this prognostic test in the setting of GBC treatment after cardiac arrest, allowing for earlier prognostication and, if further validated in future clinical studies, the potential for improved allocation of critical care resources. While this small animal study is not sufficient to suggest a direct change in practice toward utilization of SSEP amplitude in prognostication, it provides animal model data to influence further clinical study and does add support to the body of literature investigating the utility of amplitude in prognosis after CA and suggests potential further study continue to investigate this new application of a commonly used prognostic tool. Our study further supports these findings by showing that the administration of GBC after cardiac arrest improved arousal and brainstem reflex recovery, as well as overall 72-hour survival. These functional findings correlated well with histopathological analysis of neuronal ischemic injury.

GBC has been used to treat type 2 diabetes mellitus and has shown great promise as an intervention to improve functional outcomes after multiple neurological injuries (36). The brain remains particularly sensitive to the oxygen deprivation and ischemic-reperfusion injury incurred from cardiac arrest. Preclinical studies show the promise of GBC as a drug therapy to reduce neurological injury and improve functional recovery after cardiac arrest (11–13, 37). The mechanism of this drug is believed to result from attenuation of sodium and water diffusion, leading to a reduction of cerebral edema (9, 38). Thus far, published studies have not focused on the effect of this drug on arousal recovery specifically. Given that somatosensory evoked potentials represent thalamocortical integrity and contribute to arousal and coma, our study design and functional outcome assessment, subsets A and B of the NDS, advances this field by specifically demonstrating improved recovery of consciousness when treated with GBC after CA (14, 15). With the clinical implications of this drug therapy, these subsets of the NDS represent basic aspects of neural function, and abnormalities in these subset scores would be indicative of severe brain injury. We demonstrate that in the setting of GBC treatment, SSEP can provide rapid, early information about which animals have suffered severe injury and which animals may have potential for arousal recovery. These preclinical electrophysiological findings warrant further investigation and validation, as they may provide a window into improved informed decision making about prognostication and continuation of care.

The currently accepted dichotomized assessment of present versus absent cortical SSEP responses has 98–100% specificity for predicting poor outcome after cardiac arrest (29–31), with a positive predictive value between 93–100% (28–31). While a direct comparison of this clinical data with our animal study cannot be made, it is notable that our preclinical study demonstrated a specificity of 80% for accurately predicting good functional outcome and a positive predictive value of 88%. With consideration of our small sample size, these predictive values are strong indicators of the validity of this tool in early prognostication after drug therapy with GBC. In contrast, dichotomized present versus absent SSEP N20 (N10) potential lacks specificity for prediction of good functional outcome after CA (27, 28).

This study did not combine GBC therapy with current standards of care in post-cardiac arrest management, namely targeted temperature management, which may impact the effects of this drug on electrophysiologic recovery and outcome. Future study should consider the additive value of these therapies and SSEP recovery, particularly in the early phase of post-cardiac arrest care. This study also uses continuous SSEP monitoring post-CA, which is not pragmatic in clinical translation. Future application of this model would necessitate trending of SSEP amplitudes rather than the current practice of a single test in the post-arrest period. This small pilot study also included only male rats. Gender differences in CA recovery have been described (39, 40), and thus a more diverse study group including females should be investigated in the future. This study included baseline SSEP data for comparison, but did not include sham animals for histologic evaluation or functional outcomes, and this could strengthen future investigations. Future study should also consider longer-term outcome measures, as the current investigation followed outcomes only to 72h post-arrest. While the pathophysiology of GBC’s effects in the post-arrest period has been described within the literature (9, 11–13, 36, 37, 41), this particular study did not further investigate the mechanistic effects of this drug on brain tissue. Future studies may include further evaluation of brain edema and cell injury beyond our histological investigations. Our study suggests a very rapid onset of drug effect, given administration post-arrest and therapeutic effects as early as 30 minutes after ROSC. Clinically, IV administration of glibenclamide has been used in phase 2 trials investigating this drug in acute ischemic stroke and TBI and has been shown to produce rapid peak levels and stable maintenance (41). Future studies may consider monitoring plasma concentration levels to better understand the pharmacokinetics at play.

As the pre-clinical literature base supporting the beneficial role of GBC in outcome after cardiac arrest grows, this drug therapy comes closer to clinical translation. Clinical trials are under way investigating the effects of this drug on outcome after ischemic stroke (NCT01794182) and traumatic brain injury (NCT01454154), and we would advocate for advancing this clinical investigation to the level of comatose patients post-cardiac arrest. The present study further highlights the potential utility of amplitude of the cortical SSEP peak and the utility of trending amplitude over time for early prognostication after CA. It is important to stress that this is a small, preclinical, pilot study of this new application of SSEP data, requiring further validation before clinical translation or adoption. However, these early findings provide exciting potential for a prognostic test that may provide real-time, evolving information about cortical recovery after anoxic brain injury.

Conclusion

In conclusion, our findings suggest that GBC’s neuroprotective effects after cardiac arrest lead to preserved thalamocortical integrity, reflected as higher SSEP N10 amplitudes and improved SSEP recovery, returning to baseline within 120 minutes from ROSC. These effects resulted in improved coma recovery, arousal, brainstem function, and decreased ischemic neurons in a rodent model of CA.

Acknowledgments

The work was supported by R01HL118084 and R01NS110387 from the United States National Institutes of Health (both to XJ). XJ was partially supported by NIH RO1 NS117102 (to XJ).

Footnotes

Details

This manuscript complies with all instructions to authors.

All authors made substantial contributions to the concept, design, acquisition of data, interpretation of data, drafting and revision of the article. All authors approved the final version of the manuscript for submission.

This manuscript has not been submitted or published elsewhere. These findings were partly presented as a poster presentation during professor rounds at the Neurocritical Care Society meeting 2020.

Experimental protocols were approved by the University of Maryland Baltimore Institutional Animal Care and Use Committee.

Brittany Bolduc Lachance has nothing to disclose. Zhuoran Wang has nothing to disclose. Neeraj Badjatia has nothing to disclose. Xiaofeng Jia reports grants from NIH during the conduct of this study.

The ARRIVE guidelines checklist was used for this animal study.

Conflicts of interest

The authors declare no conflict of interest.

Reference

  • 1.Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, et al. : Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation 2019; 139(10):e56–e528 [DOI] [PubMed] [Google Scholar]
  • 2.Green CR, Botha JA, Tiruvoipati R: Cognitive function, quality of life and mental health in survivors of our-of-hospital cardiac arrest: a review. Anaesth Intensive Care 2015; 43(5):568–576 [DOI] [PubMed] [Google Scholar]
  • 3.Perman SM, Goyal M, Neumar RW, Topjian AA, et al. : Clinical applications of targeted temperature management. Chest 2014; 145(2):386–393 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Bernard SA, Gray TW, Buist MD, Jones BM, et al. : Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346(8):557–563 [DOI] [PubMed] [Google Scholar]
  • 5.Hypothermia after Cardiac Arrest Study G: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346(8):549–556 [DOI] [PubMed] [Google Scholar]
  • 6.Taccone FS, Picetti E, Vincent JL: High Quality Targeted Temperature Management (TTM) After Cardiac Arrest. Crit Care 2020; 24(1):6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Caffes N, Kurland DB, Gerzanich V, Simard JM: Glibenclamide for the treatment of ischemic and hemorrhagic stroke. Int J Mol Sci 2015; 16(3):4973–4984 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mehta RI, Tosun C, Ivanova S, Tsymbalyuk N, et al. : Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts. J Neuropathol Exp Neurol 2015; 74(8):835–849 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V: Sulfonylurea receptor 1 in central nervous system injury: a focused review. J Cereb Blood Flow Metab 2012; 32(9):1699–1717 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Simard JM, Sheth KN, Kimberly WT, Stern BJ, et al. : Glibenclamide in cerebral ischemia and stroke. Neurocrit Care 2014; 20(2):319–333 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Zweckberger K, Hackenberg K, Jung CS, Hertle DN, et al. : Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. Neuroscience 2014; 272:199–206 [DOI] [PubMed] [Google Scholar]
  • 12.Huang K, Wang Z, Gu Y, Ji Z, et al. : Glibenclamide Prevents Water Diffusion Abnormality in the Brain After Cardiac Arrest in Rats. Neurocrit Care 2018; 29(1):128–135 [DOI] [PubMed] [Google Scholar]
  • 13.Huang K, Gu Y, Hu Y, Ji Z, et al. : Glibenclamide Improves Survival and Neurologic Outcome After Cardiac Arrest in Rats. Crit Care Med 2015; 43(9):e341–349 [DOI] [PubMed] [Google Scholar]
  • 14.Madhok J, Maybhate A, Xiong W, Koenig MA, et al. : Quantitative assessment of somatosensory-evoked potentials after cardiac arrest in rats: prognostication of functional outcomes. Crit Care Med 2010; 38(8):1709–1717 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Xiong W, Koenig MA, Madhok J, Jia X, et al. : Evolution of Somatosensory Evoked Potentials after Cardiac Arrest induced hypoxic-ischemic injury. Resuscitation 2010; 81(7):893–897 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Jia X, Koenig MA, Nickl R, Zhen G, et al. : Early electrophysiologic markers predict functional outcome associated with temperature manipulation after cardiac arrest in rats. Crit Care Med 2008; 36(6):1909–1916 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Jia X, Koenig MA, Shin HC, Zhen G, et al. : Improving neurological outcomes post-cardiac arrest in a rat model: immediate hypothermia and quantitative EEG monitoring. Resuscitation 2008; 76(3):431–442 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Jia X, Koenig MA, Shin HC, Zhen G, et al. : Quantitative EEG and neurological recovery with therapeutic hypothermia after asphyxial cardiac arrest in rats. Brain Res 2006; 1111(1):166–175 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Wang Z, Du J, Lachance BB, Mascarenhas C, et al. : Intracerebroventricular Administration of hNSCs Improves Neurological Recovery after Cardiac Arrest in Rats. Stem Cell Rev Rep 2020 [DOI] [PMC free article] [PubMed]
  • 20.He J, Lu H, Young L, Deng R, et al. : Real-time quantitative monitoring of cerebral blood flow by laser speckle contrast imaging after cardiac arrest with targeted temperature management. J Cereb Blood Flow Metab 2019; 39(6):1161–1171 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Deng R, Koenig MA, Young LM, Jia X: Early Quantitative Gamma-Band EEG Marker is Associated with Outcomes After Cardiac Arrest and Targeted Temperature Management. Neurocritical care 2015; 23(2):262–273 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Deng R, Young LM, Jia X: Quantitative EEG markers in severe post-resuscitation brain injury with therapeutic hypothermia. Conf Proc IEEE Eng Med Biol Soc 2015; 2015:6598–6601 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Simard JM, Woo SK, Tsymbalyuk N, Voloshyn O, et al. : Glibenclamide-10-h Treatment Window in a Clinically Relevant Model of Stroke. Transl Stroke Res 2012; 3(2):286–295 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Shin HC, Tong S, Yamashita S, Jia X, et al. : Quantitative EEG and effect of hypothermia on brain recovery after cardiac arrest. IEEE Trans Biomed Eng 2006; 53(6):1016–1023 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Madhok J, Wu D, Xiong W, Geocadin RG, et al. : Hypothermia amplifies somatosensory-evoked potentials in uninjured rats. J Neurosurg Anesthesiol 2012; 24(3):197–202 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Dragancea I, Horn J, Kuiper M, Friberg H, et al. : Neurological prognostication after cardiac arrest and targeted temperature management 33 degrees C versus 36 degrees C: Results from a randomised controlled clinical trial. Resuscitation 2015; 93:164–170 [DOI] [PubMed] [Google Scholar]
  • 27.Sandroni C, Cavallaro F, Callaway CW, D’Arrigo S, et al. : Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 2: Patients treated with therapeutic hypothermia. Resuscitation 2013; 84(10):1324–1338 [DOI] [PubMed] [Google Scholar]
  • 28.Bouwes A, Binnekade JM, Kuiper MA, Bosch FH, et al. : Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol 2012; 71(2):206–212 [DOI] [PubMed] [Google Scholar]
  • 29.Bouwes A, Binnekade JM, Verbaan BW, Zandbergen EG, et al. : Predictive value of neurological examination for early cortical responses to somatosensory evoked potentials in patients with postanoxic coma. J Neurol 2012; 259(3):537–541 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Rossetti AO, Rabinstein AA, Oddo M: Neurological prognostication of outcome in patients in coma after cardiac arrest. Lancet Neurol 2016; 15(6):597–609 [DOI] [PubMed] [Google Scholar]
  • 31.Maciel CB, Morawo AO, Tsao CY, Youn TS, et al. : SSEP in Therapeutic Hypothermia Era. J Clin Neurophysiol 2017; 34(5):469–475 [DOI] [PubMed] [Google Scholar]
  • 32.Lachance B, Wang Z, Badjatia N, Jia X: Somatosensory Evoked Potentials and Neuroprognostication After Cardiac Arrest. Neurocrit Care 2020 [DOI] [PMC free article] [PubMed]
  • 33.Young LM CRJX: Multimodel Quantitative Analysis of Somatosensory Evoked Potentials After Cardiac Arrest with Graded Hypothermia. Conf Proc IEEE Eng Med Biol Soc 2017:1846–1849 [DOI] [PMC free article] [PubMed]
  • 34.Glimmerveen A KH, Ruijter B, Tjepkema-Cloostermans M, van Putten M, Hofmeijer J: Relevance of Somatosensory Evoked Potential Amplitude After Cardiac Arrest. Front Neurol 2020(11):335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Oh SH, Park KN, Choi SP, Oh JS, et al. : Beyond dichotomy: patterns and amplitudes of SSEPs and neurological outcomes after cardiac arrest. Crit Care 2019; 23(1):224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kurland DB: Glibenclamide for the treatment of acute CNS injury. Pharmaceuticals 2013; 6(10):1287–1303 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Huang K, Wang Z, Gu Y, Hu Y, et al. : Glibenclamide Is Comparable to Target Temperature Management in Improving Survival and Neurological Outcome After Asphyxial Cardiac Arrest in Rats. J Am Heart Assoc 2016; 5(7) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Simard JM: Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic injury. Nat Med 2006; 12(4):433–440 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Nakano T, Hurn PD, Herson PS, Traystman RJ: Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse. Brain Res 2010; 1357:124–130 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Oh SH, Park KN, Lim J, Choi SP, et al. : The impact of sex and age on neurological outcomes in out-of-hospital cardiac arrest patients with targeted temperature management. Crit Care 2017; 21(1):272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Pergakis M, Badjatia N, Chaturvedi S, Cronin CA, et al. : BIIB093 (IV glibenclamide): an investigational compound for the prevention and treatment of severe cerebral edema. Expert Opin Investig Drugs 2019; 28(12):1031–1040 [DOI] [PMC free article] [PubMed] [Google Scholar]

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