Status Epilepticus–Induced Hyperemia and Brain Tissue Hypoxia After Cardiac Arrest

OBSERVATION Status Epilepticus–Induced Hyperemia and Brain Tissue Hypoxia After Cardiac Arrest

Sang-Bae Ko, MD, PhD; Santiago Ortega-Gutierrez, MD; H. Alex Choi, MD; Jan Claassen, MD, PhD; Mary Presciutti, RN; J. Michael Schmidt, PhD; Neeraj Badjatia, MD, MS; Kiwon Lee, MD; Stephan A. Mayer, MD

Objective: To report changes of cerebral blood flow and Results: Repetitive electrographic seizure activity de- metabolism associated with status epilepticus after car- tected at the start of monitoring was associated with dra- diac arrest. matic reductions in brain tissue oxygen tension and striking surges in cerebral blood flow and brain temperature. Design: Case report. Intravenous lorazepam and levetiracetam administration resulted in immediate cessation of the seizures and Setting: Neurological intensive care unit in a univer- these associated derangements. The lactate to pyruvate sity hospital. ratio was initially elevated and trended down after administration of anticonvulsants. Patient: An 85-year-old man resuscitated from out-of- hospital cardiac arrest underwent brain multimodality moni- Conclusion: Brain multimodality monitoring is a fea- toring and treatment with therapeutic hypothermia. sible method for evaluating secondary brain injury associated with seizure activity after cardiac arrest. Main Outcome Measures: Changes of cerebral blood flow and metabolism. Arch Neurol. 2011;68(10):1323-1326

EUROVASCULAR COU- (PbtO2), and regional CBF, and microdi- pling is the phenom- alysis provides hourly measurements of ex- enon of tight regulatory tracellular metabolites such as glucose, lac- balance between local ce- tate, and pyruvate. Although, MMM has rebral blood flow (CBF) been used mostly in comatose patients with andN oxygen supply to neural activity.1,2 severe traumatic brain injury, subarach- Experimental studies have shown that dur- noid hemorrhage, and intracerebral hem- ing periods of increased metabolic de- orrhage, its use is currently expanding to mand, brief periods of inadequate perfu- include patients with cardiac arrest and sta- sion can occur.3-5 One report, using optical tus epilepticus (SE).8 recordings of intrinsic signals, showed that In 2008, we expanded the use of MMM brain tissue oxygenation decreased 20 sec- to cardiac arrest patients treated with thera- onds before the onset of electrical seizure peutic hypothermia. We herein describe activity in a patient with repetitive sei- changes in PbtO2, CBF, brain tempera- zures.6 However, optical recording of in- ture, and microdialysis measurements that trinsic signals methods only measure sur- occurred in a patient with uncontrolled rogates for brain oxygenation or cerebral electrographic SE. blood volume by quantifying reflectance of specific light wavelength. In addition, it requires an open-skull window for sig- REPORT OF A CASE nal detection, which limits its clinical applicability. An 85-year-old man with a history of con- Real-time continuous measurement of gestive heart failure was found unrespon- brain physiological parameters is cur- sive by his neighbors. Cardiopulmonary rently possible through multimodality resuscitation was initiated by emergency Author Affiliations: 7 Neurological Intensive Care monitoring (MMM). Continuous record- medical services within 10 minutes. Ini- Unit, Columbia University ing of cerebral physiology includes intra- tial rhythm showed pulseless electrical ac- College of Physicians and cortical electroencephalography (ICE), tivity; after 2 rounds of epinephrine and Surgeons, New York, New York. partial brain tissue oxygen tension atropine administration, spontaneous cir-

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 MAP 150 250 22 700 40 100 260 45 100 34.5 50 CPP 100 240 20 20 80 200 50 ICP 34 40 220 600 50 0 40 60 18 ICP, mm Hg Brain oxygen tension, mm Hg Lactate level, mmol/L Pyruvate level, µmol/L Glucose level, mmol/L 0 CPP, mm Hg 33.5 Brain temperature, °C Cerebral blood flow, mL/100 g/min Total power, AU Lactate to pyruvate ratio 150 200 Brain 35 temperature 0 40 16 33 30 180 500 100 30 PbtO2 20 160 32.5 14

140 0 50 20 400 32 12 25 120 CBF 31.5 0 10 10 100 300 20 MAP, mm Hg MAP, Total power EEG 31 80 LPR 8 15 0 60 30.5 6 200 Lactate 40 level 30 10 20 4 Pyruvate 100 level 29.5 0 2 5

29 0 0 Glucose 0 level 28.5

4 AM 6 AM 8 AM 10 AM 12 PM 2 PM 4 PM 6 PM Time

Figure 1. Real-time relationship of patient’s physiological parameters. As electroencephalography (EEG) monitoring was initiated, high power in electrical activity was observed suggesting seizure. For the entire duration of the ictal periods, sudden surges in cerebral blood flow (CBF) and drops in partial brain tissue oxygen tension (PbtO2) were repeated. Microdialysis data showed a high ratio of lactate to pyruvate levels, suggesting metabolic disturbance. As lorazepam and levetiracetam were administered (arrow), the ictal activity disappeared. The gray bar indicates the more detailed time frame shown in Figure 2. AU indicates arbitrary units; CPP, cerebral perfusion pressure; ICP, intracranial pressure; and MAP, mean arterial pressure.

culation returned 25 minutes after the initial arrest. On recording was performed using an 8-contact, 1.32-mm- admission to the neurointensive care unit in the ab- wide ICE electrode (Ad-Tech, Racine, Wisconsin). At 4:30 sence of vasopressor support, blood pressure was 134/80 AM, at the start of monitoring, the initial PbtO2 was low mm Hg; heart rate was 74 beats/min; and respiratory rate at 7 mm Hg (normal, Ͼ20 mm Hg) and CBF was 38 mL/ was 16 breaths/min. Hypothermia was immediately ini- 100 g/min. The initial lactate to pyruvate ratio was 52 (nor- tiated using an intravascular cooling catheter (Alsius Icy mal, Ͻ20), and the brain glucose level was reduced at 1.2 Catheter; Zoll Circulation, Chelmsford, Massachusetts) mmol/L (normal, Ͼ2.0 mmol/L). and bladder temperature reached 33°C within 2 hours. Over the next 11 hours, a striking pattern of surging On neurological examination, the patient was unrespon- CBF associated with parallel reductions in PbtO2 was re- sive to verbal or painful stimuli and pupils were 2 mm corded (Figure 1). During CBF surges, concurrent in- and bilaterally reactive with intact corneal reflexes. Oc- creases in ICP (10 mm Hg) and brain temperature (0.2°C) casional mild facial twitching was observed. Oculoce- were noted. At 11:45 AM, recording of surface and ICE phalic reflexes were absent. Limbs were flaccid with no EEG was started and showed repetitive electrographic sei- grimace or withdrawal to pain. zures. Compressed spectral array analysis of digital EEG After obtaining informed consent, MMM probes were showed that the abnormal rhythmicity index and spec- placed in the right frontal lobe. Brain tissue oxygen was trogram perfectly overlapped with increases in total power measured using a Clark-type probe (Licox system; Inte- of EEG, suggesting that total power was a surrogate for gra NeuroSciences, Plainsboro, New Jersey), intracranial electrical SE. Discrete electrographic seizures were con- pressure (ICP) was measured using a parenchymal moni- sistently preceded (30 seconds) by reductions in PbtO2 tor (Camino; Integra NeuroSciences), cerebral metabo- (Figure 2). During interictal periods, PbtO2 returned lism was monitored with a microdialysis catheter with to 22 to 25 mm Hg, which is a noncritical level, accom- 10-mm membrane length (CMA Microdialysis, Solna, Swe- panied by a cessation of abnormal surges of CBF, ICP, den), and CBF was assessed using a thermal diffusion mi- and brain temperature. croprobe (QFlow 400; Hemedex Inc, Cambridge, Massa- After analysis of EEG and MMM data, 1000 mg of le- chusetts). Intracranial electroencephalography (EEG) vetiracetam and 4 mg of lorazepam were administered

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 120 60 MAP 40 100 150 34.5 250 CPP 100 50 100 20 50 34 ICP, mm Hg PbtO2, mm Hg CPP, mm Hg Brain temperature, °C 80 200 CBF, mL/100 g/min EEG power, AU ICP 0 50 60 0 40 Brain temperature 33.5 150 0 40 PbtO2 33 100 30 20

0 50 CBF 32.5 20

0 MAP, mm Hg MAP, EEG power 32 10

31.5 0 Rhythmicity index

30.5

Spectrogram 30

12 PM 12:30 PM 1 PM 1:30 PM 2 PM 2:30 PM 3 PM 3:30 PM 4 PM Time

Figure 2. Relationship of physiological variables with quantitative electroencephalography (EEG) parameters during ictal events. During the repetitive seizure events, partial brain tissue oxygen tension (PbtO2) consistently decreased followed by a surge in intracranial pressure, brain temperature, and cerebral blood flow (CBF). In addition, total power on the EEG is well synchronized with the rhythmicity index and the existence of high-frequency waves in the spectrogram, suggesting an ictal rhythm. AU indicates arbitrary units; CPP, cerebral perfusion pressure; ICP, intracranial pressure; and MAP, mean arterial pressure.

intravenously at 3:52 PM (Figure 1, arrow) and the sei- riod of relative tissue oxygen hypoxia. During normal zures were terminated. After cessation of the seizures, the brain activation, this is characterized by a brief “initial lactate to pyruvate ratio decreased from levels higher than dip” in brain tissue oxygenation that rapidly normalizes 60 to levels of 40 to 45, and the brain glucose level in- as CBF increases to meet metabolic requirements.10 In creased from between 1.2 to 2.2 mmol/L to more than 3 pathological states such as SE, our findings confirm that mmol/L. Subsequently, EEG showed intermittent orga- critical brain tissue hypoxia can persist for periods as long nized bursts of synchronized delta activity without defi- as 2 hours, despite demand-related increases in CBF.2,5,11 nite ictal discharges. After 24 hours of hypothermia treat- Interestingly, our time-locked data show that PbtO2 ment, the patient was slowly rewarmed, which provoked began to drop about 30 seconds prior to the onset of elec- episodes of increased ICP (Ͼ20 mm Hg) treated with man- trographic seizure activity (Figure 2), which is similar nitol. On day 2, the patient was declared clinically brain to the reported time difference (20 seconds) using opti- dead. cal recording of intrinsic signals in a patient with repetitive partial seizures.6 The reason for this is unclear, but COMMENT a few potential physiologic explanations should be con- templated. First, the initial surge in electrical activity suf- To the best of our knowledge, this is the first descrip- ficient to induce increased cerebral oxygen metabolism tion of dynamic PbtO2 and CBF changes in a human pa- might not be robust enough for detection by ICE.6 Al- tient with SE. Using intracortical EEG, we were able to though ICE is superior to scalp EEG for detecting elec- identify ongoing SE. Dramatic reductions in PbtO2 and trographic seizures,12 it might not be sensitive for de- surges in CBF, compatible with increased metabolic detecting less synchronized focal dendritic activity of a small mand out of proportion to CBF increase, were seen dur- number of neurons. Second, brain hypoxia might be a ing SE. This phenomenon between brain metabolism and prerequisite for the compensatory CBF surge. In animal CBF has been observed in animal models of SE.2-6,9 Our studies, CBF does not change until PbtO2 drops below data confirm that neurovascular coupling was pre- a certain level, which triggers CBF to increase with a cer- served in our patient and was triggered by an initial pe- tain time gap, similar to our data.13 Third, but less likely,

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 the time gap might be caused by the small difference in versity College of Physicians and Surgeons, Milstein Hos- probe location. The measured distance between the Clark- pital Bldg 8 Center, 177 Fort Washington Ave, New York, type probe and the thermal diffusion probe was 22.7 mm, NY 10032 ([email protected]). and the ICE was located directly adjacent to the CBF Author Contributions: Study concept and design: Ko, probe. If seizures started near the Clark-type probe and Claassen, and Mayer. Acquisition of data: Ko, Choi, propagated toward the thermal diffusion probe, the time Presciutti, Schmidt, Badjatia, Lee, and Mayer. Analysis lag may be explained by the distance between the probes. and interpretation of data: Ko, Ortega-Gutierrez, Claassen, However, considering the distance and the time lag be- and Mayer. Drafting of the manuscript: Ko, Choi, Claassen, tween the 2 probes (about 30 seconds), the calculated Presciutti, Schmidt, Badjatia, and Lee. Critical revision of propagation velocity is too slow to be considered sei- the manuscript for important intellectual content: Ortega- zure activity (44 mm/min). Gutierrez, Choi, Claassen, Schmidt, Badjatia, Lee, and Complementary to the hemodynamic data, hourly mi- Mayer. Administrative, technical, and material support: crodialysis measurements show additional evidence for Schmidt. Study supervision: Claassen, Badjatia, Lee, and metabolic distress as a consequence of seizures. Sustained Mayer. elevation and resolution of an increased lactate to pyru- Financial Disclosure: Dr Mayer has received speaking vate ratio after the ictal period has been reported after SE.14 honoraria from Zoll Circulation (Alsius Cooling Generally, an increased lactate level is an indicator of is- System). chemia, and a decreased pyruvate level is regarded as a sign of perturbed metabolic activity, indicating an impaired gly- colytic pathway.15 Although it is not clear which is more REFERENCES important in a patient with SE, both an increase of lactate level and a decrease of pyruvate level might be equally mean- 1. Roy CS, Sherrington CS. On the regulation of the blood-supply of the brain. ingful in this patient. In addition, brain temperature also J Physiol. 1890;11(1-2):85-158, 17. increased with the elevation of CBF, although the abso- 2. Schwartz TH. Neurovascular coupling and epilepsy: hemodynamic markers for lute degree of change was small (0.2°C). 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