Introduction. Cytokine and Chemokine Profiles in Acute Carbon Monoxide Poisoning: Marked Elevation of Interleukin-6 in Cerebrospinal Fluid

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1 Cytokine and Chemokine Profiles in Acute Carbon Monoxide Poisoning: Marked levation of Interleukin-6 in Cerebrospinal Fluid Toshimitsu Ide, Y Kamijo, A Ide, K Yoshimura, T ishikawa, K Soma, H Mochizuki Japan March 11 arthquake M9.0 Seismic center Kitasato University, School of Medicine, Sagamihara, Japan Kyoto Hiroshima Kobe Tokyo Disaster area Pacific Ocean 2011 Google Map Kanto region (the Metropolitan area) Introduction Sagamihara our hospital Tokyo Mt. Fuji Yokohama Pacific Ocean 2011 Google Map Image of ncephalopathy Severity and Prognosis of CO poisoning CO xposure ncephalopathy Mild Headache ausea Dizziness Recovery with o Complications Loss of Consciousness Lucid interval (several days to 6 weeks) asymptomatic Time (Day) europsychiatric symptoms Memory disorder Attention disorder Depression Rigidity, Bradykinesia Gait disturbance Ataxia Apallic syndrome etc. Death Cardiopulmonary arrest Moderate Unconsciousness Palsy Loss of vision Severe Coma Seizure Shock ncephalopathy Persistent Vegetative State

2 Background We already reported that early elevation of interleukin-6 concentration in the cerebrospinal fluid (CSF) may be a predictive marker of delayed encephalopathy (D) due to carbon monoxide (CO) poisoning. (Am J merg Med 2009;27: ACCT 2009, San Antonio) However, cytokines other than IL-6 had not been determined Objective To investigate the relationship between outcome of CO poisoning and profile of cytokine/chemokine level in serum and CSF, in order to find any prognostic markers for prediction of the outcome. We also investigated other clinical factors and laboratory findings. Patients Materials & Methods CO poisoned patients transferred by ambulance: 66 patients (Period:ov ~ 4 years) Admission Hyperbaric Oxygen Therapy (3 days) Mild symptoms :9 patients (they didn t have any consciousness loss) Cardiopulmonary arrest:15 patients died Informed Consent Couldn t get informed consent/ Couldn t follow up for 3 month: 3 patients Followed up for 3 months after poisoning 39 patients Samples and Analyses We measured 17 cytokines/chemokines in the CSF and serum of 39 patients who had consciousness loss in their history. CSF and serum were simultaneously obtained within 24 hours after the last exposure and immediately frozen at -80 C for later analysis. The cytokines/chemokines were determined by the microbeads assay method. (Bio-Plex cytokine assay system, Bio-Rad Laboratories.) Patients follow-up: Followed up for 3 months after poisoning 39 patients Group (ncephalopathy) 9 patients (Persistent vegetative state/ encephalopathy) Statistical analyses: The two groups were compared by the Mann-Whitney U test. Group 30 patients (They had o sequelae after acute phase of poisoning)

3 Results Group Group (n=9, median) (n=30, median) P Age S GCS S CO-Hb (%) S White Blood Cell (/mm 3 ) S HCO3 - (mmol/l) S Base xcess (mmol/l) S CPK (IU/L) S Lactic acid S S: not significant Serum group group Variables n=9 n=30 (pg/ml) median (IQR) median (IQR) P-value IL-1β S IL S IL S IL S IL (47-73) 4.0 (1.8-29) <0.01(0.002) IL (10-17) 8.6 (6-10) <0.05(0.04) IL S IL S IL S IL S IL S G-CSF 15.2 (12-40) 2.7 (0-16) <0.05(0.02) GM-CSF S IF-γ S MCP S MIP-1β S TF-α S IQR: interquartile range CSF group group Variables n=9 n=30 (pg/ml) median (IQR) median (IQR) P-value IL-1β 5.3 (2.4-13) 0.1 (0-1) <0.001 (0.0005) IL S IL (1-2.6) 0.3 ( ) <0.001 (0.0009) IL S IL ( ) 13.3 (6.5-37) <0.001 (0.0002) IL S IL ( ) 69.9(45-126) <0.01 (0.002) IL ( ) 3.3 (2-4.8) <0.01 (0.005) IL (4-6.1) 3.2 ( ) <0.05 (0.04) IL S IL S G-CSF (92-137) 10.3 (4-34) <0.01 (0.007) GM-CSF 46.8 (34-66) 16.6 (0-23) <0.01 (0.005) IF-γ (72-170) 0.8 (0-20) <0.001 (0.0007) MCP ( ) ( ) <0.01 (0.002) MIP-1β 32.3 (24-44) 21.2 (14-32) <0.05 (0.04) TF-α 35.0 (21-114) 4.7 (3-9) <0.001 (0.0005) IQR: interquartile range CSF IL-1β CSF IL-4 CSF IL-8 CSF IL-10 CSF IL-6 Serum IL-6 IL-6 in Serum Data plot Caution!! CSF G-CSF CSF IF-γ CSF MCP-1 CSF TF-α A few exceptional cases Complicated with Burn and/or Airway burn Crush syndrome Aspiration peumonia

4 IL-6 in CSF Data plot ROC curve of CSF IL-6 Cutoff point 380 pg/ml A few exceptional cases - Complicated with Hypothermia - Unknown Sensitivity: 100% Specificity: 90% Our present study shows Summary & Discussion CSF IL-6 could be the best predictive marker of encephalopathy after CO poisoning. ot only IL-6, but also several cytokines and chemokines are elevated in CSF than those of serum. Those cytokines/chemokines would reflect the hypoxic stress and the inflammation in the central nervous system and may have relation to later encephalopathy. Carbon Monoxide Hypoxic Stress Blood-Brain Barrier Inframmation in CS Microglia (activated) Astroglia (activated) Oligodendroglia Myelin sheath IL-6,-8 G-CSF IF-γ MCP-1 ncephalopathy Over clinical threshold Demyelination MBP leakage into CSF MBP modification Axon MBP Antigenicity MBP: myelin basic protein 1 st Cytokines elevation 2 nd MBP elevation Hypoxia and CSF cytokines Animal: TF-α, IL-1β, IL-6 (Brain tissue) Clinical: IL-6, IL-8 (Post CPA patients) Resuscitation 2009;80: MR spectroscopy/ Diffusion tensor image Cho/Cr ratio, FA value are useful to evaluate white matter damage in the subacute phase after CO poisoning euroradiology 2010;52:

5 CSF versus MRI CSF Merit: make early prediction of encephalopathy give us patient risk control Demerit: invasive technique (but it is easy and safe for neurologist ) MRI (controversial for early prediction) Merit: not invasive (but sometimes need i.v. sedation) Demerit: required high grade MRI (3.0Tesla) can t perform (magnetic metal in the body) artifact (artificial teeth/ motion artifact) Conclusion There are differences in cytokines/chemokines profiles of the two groups in CO poisoning. Cytokines/chemokines analysis of CSF is more useful than that of serum, and the most useful biomarker among these cytokines was CSF IL-6 for prediction of encephalopathy. Acknowledgement This study was supported by The Japanese Ministry of ducation, Culture, Sports, Science and Technology KAKHI :Grant-in-Aid for Young Scientists(B). Thank you for your attention