Letter to the Editor. Ketamine sedation for the suppression of spreading depolarizations

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  • University of Cincinnati, Cincinnati, OH
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TO THE EDITOR: We wish to congratulate Carlson et al.1 on their important study demonstrating the effect of ketamine sedation to suppress injurious spreading depolarizations (SDs) during intensive care after severe brain injury (Carlson AP, Abbas M, Alunday RL, et al: Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial. J Neurosurg [epub ahead of print May 25, 2018; DOI: 10.3171/2017.12.JNS171665]). SDs have been intensively studied as a causative mechanism of lesion development and excitotoxicity in animal models,6 and translational studies have demonstrated even greater relevance to human brain injury.3,5 A hurdle to broader application—and patient benefit—has been identification of effective approaches to prevent SDs through pharmacology or amelioration of tissue conditions that trigger them. The multicenter study of Hertle et al.8 showed a strong effect of ketamine on decreasing SD incidence, yet the study suffered from having a retrospective and nonrandomized design in which case mix, factors leading to sedation choice, and natural SD time course4,7 were possibly confounding. Carlson et al. addressed these concerns with a randomized, multiple-crossover design in which ketamine, dosed to the patient’s sedative needs, was alternated with dexmedetomidine and either propofol or midazolam every 6 hours. Thus, the effects of injury type/severity and SD timing were balanced between the alternating regimes. The authors found that periods with no or low-dose ketamine (< 1.5 mg/kg/hr) had increased risk of SD compared to periods of ketamine dosage > 1.5 mg/kg/hr, with an impressive odds ratio of 13.8.

We noted that effects in this trial were not significant in a per-subject analysis and suspect this was due to a relatively low overall rate of SDs when patients were off ketamine. Toward this point, we wish to communicate a case of severe brain trauma with a high baseline rate of SDs that were strikingly suppressed with a 1.5-mg/kg ketamine bolus (see Fig. 1 for details). From the start of electrocorticography after emergency neurosurgery, SDs (n = 55) recurred continuously in the injured hemisphere at regular intervals of 20 ± 6 minutes for 18 hours. After the ketamine bolus was given, the next expected SD did not occur, and SDs remained suppressed for 2 hours. Subsequently, they resumed at regular intervals of 23 ± 6 minutes, totaling 50 SDs in the following 19 hours. The potency of this effect was particularly noteworthy given the injury severity and the refractory rise of intracranial pressure (ICP). Ketamine was not continued due to a family decision to withdraw care. It is provocative to wonder whether the patient’s course might have been different had he received sustained ketamine sedation from the start.

FIG. 1.
FIG. 1.

Ketamine bolus suppresses SDs in a case of severe brain trauma. A 49-year-old man fell 30 feet from a ladder. Upon arrival to our Level I trauma center, he was withdrawing his upper extremities. Head CT scan (left) showed a large subdural hematoma, and the patient was taken emergently to the operating room for hemicraniectomy and hematoma evacuation. A subdural electrode strip was placed on the left inferior frontal gyrus, ICP and tissue oxygen (PtiO2) probes were placed through a bolt in the contralateral hemisphere, and scalp electroencephalography (EEG) monitoring was performed. In the 1st day of postoperative neurointensive care, ICP became progressively refractory to standard treatment, while SDs occurred continuously at electrodes 4–6 of the subdural strip. In order to maximize sedation while preserving arterial pressure, a 1.5-mg/kg intravenous bolus of racemic ketamine was given. The traces (right) show a 9-hour period around this time. Upper trace: Recordings from electrode 5 of the subdural strip show SDs evidenced by the negative deflections (asterisks) in the direct-current electrocorticography (ECoG) study and simultaneous depressions of spontaneous ECoG activity (0.5–50 Hz; second trace). Center trace: EEG study from the C3–P3 channel shows amplitude fluctuations reflecting the depression periods of SD. Similar fluctuations were present in other ipsilateral EEG channels. Note that both ECoG and EEG studies show a dramatic recovery of spontaneous brain activity after ketamine administration, which persists continuously for 2 hours until SDs resume. ICP increased progressively from 55 to 75 mm Hg over the period shown, and mean arterial pressure was maintained at 100–110 mm Hg. Due to the patient’s poor neurological examination results and lack of improvement, the family elected to withdraw care, and the patient died the next day.

There has been resistance to ketamine use for sedation in brain-injured patients due to historical fears that it may cause ICP elevation. However, these views have been refuted in randomized studies, and in some centers ketamine is now routinely used in conjunction with other anesthetics for sedation when patients are mechanically ventilated.2 The randomized study by Carlson et al. has now provided a conclusive demonstration that sedative doses of racemic ketamine are not only safe regarding ICP effects, but also effective in suppressing SDs. We agree that multicenter trials of ketamine for neuroprotection are now warranted and note that SD monitoring in such a trial would allow a novel precision medicine approach through selective patient inclusion and mechanistic targeting.7

Acknowledgments

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Defense Medical Research and Development Program under Award No. W81XWH-16-2-0020. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.

Disclosures

The authors report no conflicts of interest.

References

  • 1

    Carlson AP, Abbas M, Alunday RL, Qeadan F, Shuttleworth CW: Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized multiple crossover trial. J Neurosurg [epub ahead of print May 25, 2018; DOI: 10.3171/2017.12.JNS171665]

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  • 2

    Chang LC, Raty SR, Ortiz J, Bailard NS, Mathew SJ: The emerging use of ketamine for anesthesia and sedation in traumatic brain injuries. CNS Neurosci Ther 19:390395, 2013

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  • 3

    Dreier JP, Fabricius M, Ayata C, Sakowitz OW, Shuttleworth CW, Dohmen C, : Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: review and recommendations of the COSBID research group. J Cereb Blood Flow Metab 37:15951625, 2017

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  • 4

    Dreier JP, Major S, Pannek HW, Woitzik J, Scheel M, Wiesenthal D, : Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain 135:259275, 2012

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  • 5

    Hartings JA: Spreading depolarization monitoring in neurocritical care of acute brain injury. Curr Opin Crit Care 23:94102, 2017

  • 6

    Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, : The continuum of spreading depolarizations in acute cortical lesion development: Examining Leao’s legacy. J Cereb Blood Flow Metab 37:15711594, 2017

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  • 7

    Hartings JA, Strong AJ, Okonkwo DO, Bullock MR: Spreading depolarisations and traumatic brain injury: time course and mechanisms—authors’ reply. Lancet Neurol 11:389390, 2012

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  • 8

    Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, : Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain 135:23902398, 2012

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  • University of New Mexico School of Medicine, Albuquerque, NM
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Response

We appreciate the comments from this very experienced and pioneering group regarding the role of SDs in brain injury. The case presented provides a very dramatic illustration of the “on/off” effect of ketamine on SDs, and we thank authors for sharing this very interesting case. We agree that this example strengthens our data regarding an effect that can be quite dramatic in some patients.

We also appreciate the comments regarding ketamine and ICP, which we agree add to the large body of literature supporting the safety from an ICP perspective. Finally, we strongly agree that the observational, retrospective, and now prospective pilot data that have been amassed regarding the potential benefits of monitoring for SDs and administering targeted therapy (such as ketamine) are adequate to warrant prospective multicenter trials.

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Contributor Notes

Correspondence Jed A. Hartings: jed.hartings@uc.edu.

INCLUDE WHEN CITING Published online August 3, 2018; DOI: 10.3171/2018.6.JNS18235.

Disclosures The authors report no conflicts of interest.

  • View in gallery

    Ketamine bolus suppresses SDs in a case of severe brain trauma. A 49-year-old man fell 30 feet from a ladder. Upon arrival to our Level I trauma center, he was withdrawing his upper extremities. Head CT scan (left) showed a large subdural hematoma, and the patient was taken emergently to the operating room for hemicraniectomy and hematoma evacuation. A subdural electrode strip was placed on the left inferior frontal gyrus, ICP and tissue oxygen (PtiO2) probes were placed through a bolt in the contralateral hemisphere, and scalp electroencephalography (EEG) monitoring was performed. In the 1st day of postoperative neurointensive care, ICP became progressively refractory to standard treatment, while SDs occurred continuously at electrodes 4–6 of the subdural strip. In order to maximize sedation while preserving arterial pressure, a 1.5-mg/kg intravenous bolus of racemic ketamine was given. The traces (right) show a 9-hour period around this time. Upper trace: Recordings from electrode 5 of the subdural strip show SDs evidenced by the negative deflections (asterisks) in the direct-current electrocorticography (ECoG) study and simultaneous depressions of spontaneous ECoG activity (0.5–50 Hz; second trace). Center trace: EEG study from the C3–P3 channel shows amplitude fluctuations reflecting the depression periods of SD. Similar fluctuations were present in other ipsilateral EEG channels. Note that both ECoG and EEG studies show a dramatic recovery of spontaneous brain activity after ketamine administration, which persists continuously for 2 hours until SDs resume. ICP increased progressively from 55 to 75 mm Hg over the period shown, and mean arterial pressure was maintained at 100–110 mm Hg. Due to the patient’s poor neurological examination results and lack of improvement, the family elected to withdraw care, and the patient died the next day.

  • 1

    Carlson AP, Abbas M, Alunday RL, Qeadan F, Shuttleworth CW: Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized multiple crossover trial. J Neurosurg [epub ahead of print May 25, 2018; DOI: 10.3171/2017.12.JNS171665]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Chang LC, Raty SR, Ortiz J, Bailard NS, Mathew SJ: The emerging use of ketamine for anesthesia and sedation in traumatic brain injuries. CNS Neurosci Ther 19:390395, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Dreier JP, Fabricius M, Ayata C, Sakowitz OW, Shuttleworth CW, Dohmen C, : Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: review and recommendations of the COSBID research group. J Cereb Blood Flow Metab 37:15951625, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Dreier JP, Major S, Pannek HW, Woitzik J, Scheel M, Wiesenthal D, : Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain 135:259275, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Hartings JA: Spreading depolarization monitoring in neurocritical care of acute brain injury. Curr Opin Crit Care 23:94102, 2017

  • 6

    Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, : The continuum of spreading depolarizations in acute cortical lesion development: Examining Leao’s legacy. J Cereb Blood Flow Metab 37:15711594, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Hartings JA, Strong AJ, Okonkwo DO, Bullock MR: Spreading depolarisations and traumatic brain injury: time course and mechanisms—authors’ reply. Lancet Neurol 11:389390, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, : Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain 135:23902398, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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