Severe Carbon Monoxide Poisoning Research Articles

長期的な高圧酸素療法が社会復帰に奏効したと思われる間歇型一酸化炭素中毒の1例(A case of delayed encephalopathy after recovery from acute carbon monoxide poisoning through repetitive hyperbaric oxygen therapy)

間歇型一酸化炭素（carbon monoxide: CO）中毒は遅発性脳症（delayed encephalopathy: DE）とも呼ばれ，治療法は確立されておらず，重度の後遺症を残す症例も多い。DEに対し，長期的な高圧酸素療法（hyperbaric oxygen therapy: HBOT）を施行し，社会復帰を得た症例を経験したので報告する。症例は30歳の女性。家族が自宅ガレージに駐車後エンジンを停止するのを忘れており，翌日上階室内で意識消失しているところを発見された。来院時，GCS 8の意識障害を認め，CO–Hb 32%で急性CO中毒と診断した。気管挿管を実施し，100%平圧酸素投与と48時間の脳低温療法を施行した。CTで淡蒼球の低吸収化，MRIで前頭葉大脳白質に高信号を認めた。その後第19病日までに意識は元の状態まで回復したが，第32病日に突然，無表情となり不隠行動と失禁がみられ，第35病日に立位や嚥下が困難となり，意思疎通も不能となった。DEを発症したと考え，2.0気圧，60分間でHBOTを開始した。3か月間で計60回行ったところ，徐々に神経所見が改善し，大きな後遺症を残すことなく退院となり社会復帰した。DEに対するHBOTの有効性を示す大規模研究はないが，本症例では長期的なHBOTが著効した印象が強く，重度のDEにおいて症状が進行しても長期治療すべき症例があると考えられた。 Delayed encephalopathy (DE) after acute carbon monoxide (CO) poisoning is a disease with a poor prognosis. There is no established treatment for DE, and no evidence that hyperbaric oxygen therapy (HBOT) is beneficial in DE. A 30–year–old female presented with severe CO poisoning. She was found unconscious and her carboxyhemoglobin level on admission was 32%. She was admitted to the intensive care unit, and immediately treated with mechanical ventilation with normobaric oxygen and brain hypothermia therapy. She regained consciousness 19 days later, and returned to her normal activities. However, 13 days later she became restless and developed incontinence. Her neurologic state began to deteriorate rapidly, progressing to akinetic mutism over the next week and finally she became less communicative. She was diagnosed with DE after CO intoxication. HBOT was conducted every day at 2.0 absolute atmosphere (ATA), each session lasting 60min, and gradual and progressive clinical improvement was observed. Her condition gradually improved over the next three months and she regained independence in her activities of daily living. She also showed significant improvement in neurocognitive function. HBOT appears useful in treating DE patients. 倫理規定に関する事項は次の通りである。 ①倫理委員会が審査・承認すべき事項には該当しない。 ②個人情報保護に基づき，匿名化している。 ③患者および家族より論文の掲載に関して同意を得ている。 急性一酸化炭素（carbon monoxide: CO）中毒の経過において，数日から数週間後に見当識障害，認知機能障害，運動失調，無言無動などの特徴的な神経症状が出現する症例があり，間歇型CO中毒，あるいは遅発性脳症（delayed encephalopathy: DE）と呼ばれる。急性CO中毒の10～30%に発症すると報告 1されているが，明確な治療方法は確立されておらず，重度の後遺症を残す症例も多い。また，DEの発生は遅発性のため，急性期施設である救命救急センターにおいて救急医が経験する機会は少ない。 今回，救命救急センター入院中にDEを発症し，長期的な高圧酸素療法（hyperbaric oxygen therapy: HBOT）を施行し，完全に社会復帰した症例を経験したので報告する。 患 者：30歳の女性。対人恐怖症があり，自宅2階で十数年間ひきこもり生活をしていた。その他既往歴なし。7月某日，自室の直下にある1階ガレージでシャッターを閉めたまま家族が車のエンジンを停止し忘れた。24時間後に自室のソファ上で意識がない状態で発見されて救急搬送となった。 来院時現症：意識レベルJCS II–30，GCS 8（E2V2M4），心拍数138/分，血圧133/90mmHg，呼吸数22/分，SpO2 97%（リザーバーマスク酸素10L/min投与下）。嘔吐痕と失禁を認めた。搬入時の動脈血ガス分析はCO–Hb 32%であり急性CO中毒と診断した。高乳酸血症（乳酸値10.3mmol/L）を伴う代謝性アシドーシスを合併していた。血液検査所見は白血球数高値のほか，高アミラーゼ血症，高CPK血症を認めた（Table 1）。 来院後経過（Fig. 1）：意識障害と誤嚥による呼吸不全のため気管挿管を実施し，頭部CT検査を行ったところ脳腫脹を認めたため，ICU入室後に48時間の脳低温療法（35℃）を施行した。急性期CO中毒に対して，乳酸値が正常化するまで，100%酸素を約40時間投与した。誤嚥性肺炎は抗菌薬投与と人工呼吸管理で改善した。従命反応可能なレベル（GCS：E4VtM6）まで意識が改善したため，第12病日に気管チューブを抜去したが仮性球麻痺を認め，第13病日に誤嚥防止のため気管切開術を施行した。第19病日に意識清明となり，第30病日には仮性球麻痺も改善し，気管切開チューブを抜去した。その後リハビリテーションを継続していたが，第32病日に突然，失禁，無表情，不隠行動，不随意運動が出現した。その後症状は悪化し，立位困難，嚥下障害，無言無動を呈し，意思疎通ができなくなった。症状からDEを発症したと考え，第35病日よりHBOTとステロイドパルス療法を開始した。HBOTは2気圧（ATA）60分間を1日1回平日に施行した。ステロイドパルス療法はmethylprednisolone 1gを3日間投与した。嚥下障害に対して胃瘻造設を施行し経腸栄養を行った。その後HBOT施行20回目に従命反応が出現し，22回目には発語を認めた。27回目で意識清明となり，経口摂取が可能となった。29回目で排尿が自立し，43回目で歩行が可能となった。症状の改善効果が固定したと判断するまで，HBOTは合計60回，3か月間実施した。退院前の高次脳機能検査ではmini–mental status examination（MMSE）＝25，Wechsler adult intelligence scale（WAIS）–III＝（全検査IQ69，言語性IQ85，動作性IQ59）と若干の低下は認めたが，入院から4か月後に独歩退院となった。 Clinical course from admission to discharge. ＜経過中の検査所見＞ 頭部CT：第4病日に来院時にはなかった両側淡蒼球の濃度低下が出現し，その所見は退院まで変化が認められなかった（Fig. 2）。 Brain CT series, brain MRI series and brain SPECT series. 頭部MRI（FLAIR，DWI）：第7病日に撮像された頭部MRIでは両側の淡蒼球と前頭葉の深部白質に高信号を呈した。DE発症直前の第29病日ではさらに白質病変が拡大したが，第92病日のMR–FLAIR画像では前頭葉の軽度萎縮を認める一方，深部白質の高信号病変は縮小した（Fig. 2）。 SPECT（123I–IMP脳血流シンチグラム)：初回（第36病日）のSPECTでは全般的な脳血流低下を認めたが，第62病日の両前頭葉の局在的な血流低下を経て，第92病日には左前頭葉と左側頭葉内側領域に明らかな血流改善を認めた（Fig. 2）。 脳波検査：第62病日の脳波では全般性の持続性低振幅徐波が認められ，重度のびまん性脳症を示唆した。第92病日の脳波における前頭部の律動性δ波と第121病日の脳波における持続性不規則徐波は前頭葉の脳機能低下を示唆したが，同時にα帯域の後頭部優位律動が徐々に回復しており，SPECTの変化にも一致した（Fig. 3）。 Electroencephalogram series. DEはCO暴露数日から数週間の意識清明期（lucid interval）後に，異常行動，人格変化，高次脳機能障害などの精神神経症状や歩行障害，パーキンソニズムなどの運動機能障害を来すことにより診断される。病理学的には大脳白質のミエリンやオリゴデンドログリアの損傷による脱髄性白質脳症といわれており 2，機序は酸素欠乏後の酸素再供給に伴う活性酸素発生や免疫系の関与を指摘されている 3。 DEは急性CO中毒の10～30%に発症するとされており，発症予測因子の研究では，Pepeら 4は初期の意識レベルGCS 8以下（オッズ比7.15）と搬入時白血球数10,000/µL以上（オッズ比3.31）の症例で有意に発症率が増加していたと報告しており，Parkinsonら 5のMRIを使用した研究においては，DE発症には大脳白質病変が必発であると報告している。一方で淡蒼球病変の有無はDE発症に関与しないとされている。本症例では初期の意識レベルGCS 8以下，搬入時白血球数10,000/µL以上，MRIの大脳白質病変すべての発症予測因子を満たしていた。本症例でDE発症の可能性が高かったことを考えると，発症を念頭に置いた経過観察が必要であったが，一方で発症時期については数日から数週間と幅があり，どの程度の経過観察期間が必要かに関して明確な基準はない。近年のDEに対してHBOTを施行した症例の検討で，予後良好群は，若年，意識清明期が長い，肺炎の合併がない，最も状態が悪化したときのADLが悪くないことを報告しているが，予後良好群の平均間歇期間は25.9±6.5日であった 6。いつまで急性期病院で経過観察すべきかの議論は別として，発症予測因子がある場合には1か月程度はDEを発症する可能性を考えた経過観察が必要であろう。 DE発症予防に対する急性期治療の効果についても明確ではない。CO中毒に対する急性期のHBOTは，DEを予防するという報告 7がある一方，平圧療法と比較して1か月後の社会復帰率やDEの予防効果に差はないとする報告 8もあり，議論の分かれるところである。当施設では人工呼吸管理中の患者は安全を考慮して急性期のHBOTは施行せず，平圧高濃度酸素療法を行っている。また，Kamijoら 9は急性CO中毒に脳低温療法を施行した症例報告により脳低温療法はDEを予防する可能性があることを示唆しているが，本症例では脳低温療法を施行したものの，DEを発症した。DE予防のための急性期脳低温療法に関しては今後の検討が必要と考えられる。 DE発症後のHBOTの有効性に関しては，RCTを含めた大規模研究は施行されておらず，未だ定説は得られていないが，長期間施行することで有効とする報告 10もある。DE自体は自然回復するのか不明であるが，我々の経験した症例ではHBOT 20回目から神経学的な回復がみられ，画像所見も改善を認めたため，HBOTが非常に効果的であった印象がある。本症例のようにADLや認知機能が著しく低下しても，諦めずに長期間のHBOTを試みる価値があると考えられる。HBOTの実施期間に関しては明確な基準はないが，本症例を経験して，土居らの報告 11のように症状が固定したと判断するまで長期的に続けるべきという意見に賛同する。HBOTのDEに対する機序は，大脳灰白質にある神経細胞が残存しているうちに，白質にある髄鞘の再生を促進するとともに，神経細胞自体に保護的作用を発揮すると推測される。本症例では20回ごとに治療効果判定と継続判断を行った。ステロイドパルス療法もDEの改善に効果的な可能性が示唆されており 12，oligodendrocyteの保護あるいは分化を促進することで髄鞘の再生を促す機序，あるいはステロイドの各種抗炎症作用によるといわれているが，本症例での有効性については不明であった。また早期のリハビリテーションも重要である。 本症例では経時的に画像検査を施行することができ，HBOTの治療効果を視覚的に確認し得た。CT所見はHBOT後の変化はみられなかったが，MRI所見は若干の改善傾向を認めた。SPECTでDE発症時に前頭葉の血流低下が認められることが報告 13されているが，本症例では頻回のHBOT後に著明な血流改善所見を認めた。SPECTでの脳血流の変化から脳細胞代謝や脳細胞機能低下は不可逆的ではなく，HBOTにより改善しうることが示唆された。本症例でHBOTによりMRI，SPECT，および脳波所見の改善を認めたため，HBOT継続判断には臨床症状にこれらの検査所見も加えて，検査所見の改善傾向を認めるうちは治療を継続すべきと考える。 重度のDEにおいても神経学的な回復を見込める症例も存在するため，複数回のHBOTの適応を積極的に検討すべきである。その適応や継続の判断には神経生理学的検査や脳画像診断は有用である。搬入時昏睡の重症例やDE発症リスクをもつ患者に対しては危険性を十分に説明し厳重な経過観察をすべきである。 本論文に関連して開示すべき利益相反はない。

Severe pulmonary edema following hyperbaric oxygen therapy for acute carbon monoxide poisoning: a case report and clinical experience

Pulmonary edema following hyperbaric oxygen (HBO₂) therapy is a rare clinical phenomenon. This case report describes such a patient - a 56-year-old woman who suffered from severe pulmonary edema after HBO₂ therapy for carbon monoxide (CO) poisoning. Patient experienced ecphysesis and dyspnea suddenly after HBO₂ therapy (100% oxygen at 0.25 MPa, for 60 minutes with a five-minute air break and decompression at 0.01 MPa/minute). Post therapy her heart rate (HR), blood pressure (BP), respiratory rate (RR) and oxygen saturation (SO₂) were 140 bpm, 60/40 mmHg, 38 bpm and 84%, respectively. Diagnoses of acute pulmonary edema and shock were made. Various treatments including antishock, tracheal intubation, mechanical ventilation for respiratory support, a diuretic, dexamethasone, asthma relief, and acidosis correction were administered. Pulmonary computed tomography (CT) indicated significant pulmonary edema. Due to active treatment, the patient showed gradual improvement. Pulmonary CT re-examination showed pulmonary edema markedly improved. At the two-year follow-up, the patient reported no abnormal mental or neurological symptoms. Acute pulmonary edema is rare but can lead to serious side effects of HBO₂ therapy in patients with severe acute CO poisoning. This complication must be must considered when administering HBO₂ therapy to patients with severe CO poisoning.

Value of early-stage cerebral oxygen utilization coefficient in predicting delayed encephalopathy after acute carbon monoxide poisoning

Objective: To investigate the dynamic change in cerebral oxygen utilization coefficient (O(2)UCc) in the early stage of acute severe carbon monoxide poisoning (ASCMP) and its value in predicting delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) . Methods: A prospective observational study was conducted for patients with ASCMP who were admitted to our hospital from November 2013 to March 2016, and their baseline features and physiological parameters were recorded. Observation ended at two months after acute poisoning; according to the presence or absence of DEACMP, the patients were divided into DEACMP group with 21 patients and non-DEACMP group with 64 patients. The change in O(2)UCc was monitored on admission and at 6, 24, 48, and 72 hours. Spearman correlation was used to investigate the correlation between O(2)UCc and Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and the receiver operating characteristic (ROC) curve was used to evaluate the accuracy of O(2)UCc in predicting DEACMP. Results: Both groups had a significant increase in O(2)UCc on admission, and the DEACMP group had a significantly greater increase than the non-DEACMP group (52.57%±9.30% vs 41.46±%6.37%, P<0.05) . Then both groups tended to have a reduction in O(2)UCc, and the DEACMP group had a significantly higher O(2)UCc than the non-DEACMP group at 6, 24, and 48 hours (47.40%±7.92%, 39.38%±8.01%, and 32.29%±6.31% vs 34.51%±7.89%, 28.79%±5.4%, and 27.72%±5.46%, P<0.05) . On admission and at 6, 24, and 48 hours, O2UCc was positively correlated with APACHE II score (r=0.304, 0.398, 0.426, and 0.300, P=0.005, 0.000, 0.000, and 0.005) . The ROC curve showed that O(2)UCc had a value in predicting DEACMP on admission and at 6, 24, and 48 hours, and 6-hour O2UCc had the highest predictive value with an area under the ROC curve of 0.870 (95% confidence interval 0.794-0.947, P<0.05) . Conclusion: The dynamic change in O(2)UCc has a reference value in early identification of DEACMP, and O(2)UCc can be used as an important reference index for predicting DEACMP.

PROSPECTIVE METHODS FOR CORRECTION OF NEUROTOXIC IMPAIRMENTS CAUSED BY SEVERE CARBON MONOXIDE POISONING (REVIEW)

The review sets forth perspective directions of correction of neurotoxic disorders in case of carbon monoxide damage. It was shown that carbon monoxide intoxication, in addition to the development of hemic hypoxia, leads to indirect lesions in the structures of the central nervous system that develop both in the early and delayed periods of poisoning. Those lesions can be caused by the development of oxidative stress, activation of programmed cell death, impact on the intercellular signaling system etc. There is evidence that oxygen monotherapy does not lead to a complete recovery of cognitive functions in a delayed period of severe carbon monoxide poisoning. It was found out that to correct central nervous system functions disorders in case of acute damage by carbon monoxide, it is necessary to use agents possessing neuroprotective mechanisms of action. The review reports data on the effectiveness of hydrogenated solution, methane solution, allopurinol, erythropoietin, granulocyte colonystimulating factor, remifentanil, mesenchymal stem cells, cerebrolysin for correction of the central nervous system disorders in this type of pathology.

Correlation between clinical severity and different non-invasive measurements of carbon monoxide concentration: A population study.

ObjectivesCarbon monoxide (CO) poisoning is a major concern in industrialized countries. Each year, thousands of victims, resulting in approximately 100 fatalities, are encountered in France. The diagnosis of CO poisoning is challenging; while carboxyhemoglobin (COHb) may be useful, it is a weak indicator of the severity of CO poisoning. This weak indicator may be a result of the delay between poisoning occurrence and the blood assay. Two apparatuses, CO oximeters and exhaled CO analyzers, now permit COHb to be determined outside hospitals. Our hypothesis is that these instruments allow the early measurement of COHb concentrations, which are more correlated with the severity of poisoning, expressed using the poisoning severity score (PSS).DesignIn an observational and retrospective cohort study, the distribution of COHb measurements obtained by CO oximetry or by exhaled CO analyzers was compared between groups of severity expressed using the PSS.SettingData were collected in the Paris area from January 2006 to December 2010 by the French Surveillance System of CO poisoning.ParticipantsAll patients with CO poisoning reported to the French Surveillance System of CO poisoning.ResultsThere was a significant difference in the COHb values obtained by CO oximetry between groups stratified according to PSS (p<0.0001). A significant difference in the values of exhaled CO was also observed between PSS groups (p = 0.006), although the relationship was not linear.ConclusionsThe COHb concentrations measured using CO oximetry, but not those measured using exhaled CO analyzers, were well correlated with the severity of CO poisoning.

N-Butylphthalide Improves Cognitive Function in Rats after Carbon Monoxide Poisoning.

Cognitive impairment is the most common neurologic sequelae after carbon monoxide (CO) poisoning, and the previous investigations have demonstrated that N-Butylphthalide (NBP) could exert a broad spectrum of neuroprotective properties. The current study aimed to investigate the effect of NBP on cognitive dysfunction in rats after acute severe CO poisoning. Rats were randomly divided into a normal control group, a CO poisoning group and a CO+NBP group. The animal model of CO poisoning was established by exposure to CO in a chamber, and then all rats received hyperbaric oxygen therapy once daily, while rats in CO+NBP group were administered orally NBP (6 mg/ 100g) by gavage twice a day additionally. The results indicated that CO poisoning could induce cognitive impairment. The ultrastructure of hippocampus was seriously damaged under transmission electron microscopy, and the expressions of calpain 1 and CaMK II proteins were significantly elevated after CO exposure according to the analysis of immunofluorescence staining and western blot. NBP treatment could evidently improve cognitive function, and maintain ultrastructure integrity of hippocampus. The expression levels of both calpain 1 and CaMK II proteins in CO+NBP group were considerably lower than that of CO poisoning group (P < 0.05). Taken together, this study highlights the molecular mechanism of cognitive dysfunction in rats after CO exposure via the upregulation of both calpain 1 and CaMK II proteins. The administration of NBP could balance the expressions of calpain 1 and CaMK II proteins and improve cognitive function through maintaining ultrastructural integrity of hippocampus, and thus may play a neuroprotective role in brain tissue in rats with CO poisoning.

Treatment of acute carbon monoxide poisoning with induced hypothermia.

ObjectiveThe effect of induced hypothermia on severe acute carbon monoxide (CO) poisoning remains to be addressed further. We investigated the effect of induced hypothermia on severe acute CO poisoning.MethodsRetrospective chart review was conducted for patients who diagnosed as severe acute CO poisoning in emergency department and underwent induced hypothermia from May 2013 to May 2014. Hospital courses with critical medication and major laboratory results were investigated through the chart review.ResultsAmong total 227 patients with acute CO poisoning during the period of study, patients with severe acute CO poisoning were 15. All patients underwent induced hypothermia with a temperature goal 33°C. Initial and follow-up levels of S100B protein after induced hypothermia were 0.47 μg/L (interquartile range, 0.11 to 0.71) and 0.10 μg/L (interquartile range, 0.06 to 0.37), respectively (P = 0.01). The mean Glasgow Coma Scales at emergency department admission was 6.87 ± 3.36. Except 1 patient who expired after cardiopulmonary resuscitation, Glasgow Coma Scales at 30-day of hospital discharge were 15 in 10 patients (71.4%), 14 in 1 patient (7.1%), 13 in 1 patient (7.1%), and 6 in 2 patients (14.2%). Seven patients (46.7%) developed delayed neurologic sequelae. Four patients showed mild types of delayed neurologic sequelae and 3 showed moderate to severe types of delayed neurologic sequelae.ConclusionMost of patients underwent induced hypothermia had a good recovery from severe acute CO poisoning. Therefore, induced hypothermia may be considered as a possible treatment in severe acute CO poisoning.

Assessment of Functional Disturbances in the Central Nervous System Caused by Severe Carbon Monoxide Poisoning in Rats.

An experimental model was developed for assessment of disturbances in CNS functions of laboratory animals caused by severe carbon monoxide poisoning. Normalization of the state of experimental rats after acute poisoning was accompanied by the development of cognitive abnormalities. Disturbances in the long-term memory were observed on days 1 and 14 after CO poisoning, while abnormalities in the short-term memory developed on days 1, 7, and 14. Learning impairment were recorded on day 8, while the training course began on day 7.

Acute carbon monoxide poisoning in a regional hospital in Hong Kong: historical cohort study

This study aimed to describe the clinical profiles of all patients with carbon monoxide poisoning admitted to a regional hospital in order to enhance the vigilance of health care professionals for delayed neurological sequelae associated with carbon monoxide poisoning and to identify the prognostic factors associated with their development. This study also aimed to assess the impact of hyperbaric oxygen therapy on the development of delayed neurological sequelae in these patients. This was a historical cohort study in which all patients with a diagnosis of carbon monoxide poisoning managed in a regional hospital in Hong Kong from 12 February 2003 to 8 November 2013 were recruited. Main outcome measures included delayed neurological sequelae. Of the clinical profiles of 93 patients analysed, 24 patients received hyperbaric oxygen therapy and did not develop delayed neurological sequelae. Seven patients who did not receive hyperbaric oxygen therapy developed delayed neurological sequelae. Comparison of groups with and without delayed neurological sequelae (excluding hyperbaric oxygen therapy-treated patients) revealed that loss of consciousness (P=0.038), Glasgow Coma Scale score of 3 (P=0.012), elevated troponin level (P<0.001), higher creatine kinase level (P=0.008), and intubation requirement (P=0.007) were possible prognostic factors for the development of delayed neurological sequelae. Although not statistically significant, this study showed a 100% protective effect of hyperbaric oxygen therapy against development of severe delayed neurological sequelae in patients with severe carbon monoxide poisoning. Further study with better study design is warranted. Loss of consciousness, low Glasgow Coma Scale score, intubation requirement, elevated troponin and higher creatine kinase levels were possible prognostic factors for development of delayed neurological sequelae in patients with severe carbon monoxide poisoning. A well-defined treatment protocol, appropriate follow-up duration and neuropsychiatric tests together with a hospital-based hyperbaric chamber are recommended for management of patients with severe carbon monoxide poisoning.

Neuroprotective effects of exogenous methane in a rat model of acute carbon monoxide poisoning

ObjectiveDelayed neuropsychological sequelae (DNS) are the most common and serious effects of severe carbon monoxide (CO) poisoning, occurring in approximately half of all CO poisoning cases. Growing evidence suggests that oxidative stress and secondary reactions in delayed brain injury are crucial to CO toxicity, similar to ischaemia–reperfusion injury. Exogenous methane plays a protective role in ischaemia–reperfusion injury by affecting key events through anti-oxidant, anti-inflammatory, and anti-apoptosis actions. Our study aimed to explore the potential of exogenous methane to relieve the severity of DNS. MethodsThirty-six male Sprague–Dawley (SD) rats were divided into three groups of normal-, CO- and CO plus methane-treated rats. The rats in the latter two groups were exposed to 1000ppm CO for 40min and then to 3000ppm CO for another 20min. Following CO exposure, saline or methane saline (10ml/kg) was intraperitoneally administered to rats in the CO group or the CO plus methane group, respectively. On the ninth day after CO exposure, Morris water maze testing, histological analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) and immunohistochemical labelling were performed on 6 rats in each group. The remaining 6 rats in each group were used to detect oxidative damage markers, inflammatory cytokines and apoptosis proteins. ResultsMethane significantly improved CO-impaired pathological characteristics as well as learning and memory performance. In addition, methane significantly increased the superoxide dismutase (SOD) activity, lowered the CO-increased level of malondialdehyde (MDA) 3-nitrotyrosine (3-NT) and 8-hydroxy-2-deoxyguanosine (8-OHdG), inhibited levels of tumour necrosis factor-α (TNF-α), interleukin 1-β (IL1-β) and caspase-3 in the rat cerebral cortex and hippocampus but had no effect on IL-6 levels. ConclusionThe hippocampus was the main target of CO-induced alterations in the rat brain compared to the cerebral cortex. Methane treatment protected the rat brain from the harmful effects induced by CO exposure and improved the outcome of DNS through anti-oxidant, anti-inflammatory and anti-apoptosis activities.

G-CSF administration attenuates brain injury in rats following carbon monoxide poisoning via different mechanisms.

Acute severe carbon monoxide (CO) poisoning induces hypoxia that leads to cardiovascular and nervous systems disturbances. Different complex mechanisms lead to CO neurotoxicity including lipid peroxidation, inflammatory and immune-mediated reactions, myelin degeneration and finally neuronal apoptosis and necrosis. Granulocyte colony-stimulating factor (G-CSF) is considered to be a novel neuroprotective agent. In this study, we evaluated the efficacy of G-CSF therapy on CO neurotoxicity in rats with acute CO poisoning. Rats were exposed to 3000 ppm CO in air (0.3%) for 1 h, and then different doses (50,100, and 150 µg/kg) of G-CSF or normal saline were administrated intraperitoneally. Water content of brain as an indicator for total edema and blood brain barrier integrity (Evans blue extravasation) were evaluated. Malondialydehyde was determined in order to evaluate the effect of G-CSF on CO-induced lipid peroxidation in brain tissues. Also, the effect of G-CSF on myeloperoxidase activity in the brain tissue was evaluated. The effect of G-CSF administration on induced apoptosis in the brain was measured using TUNEL method. To evaluate the level of MBP, STAT3 and pSTAT3 and HO-1 proteins and the effect of G-CSF on these proteins Western blotting was carried out. G-CSF reduced water content of the edematous poisoned brains (100 µg/kg) and BBB permeability (100 and 150 µg/kg) (P < 0.05). G-CSF (150 µg/kg) reduced the MDA level in the brain tissues (P < 0.05 as compared to CO poisoned animals). G-CSF did not decrease the MPO activity after CO poisoning in any doses. G-CSF significantly reduced the number of apoptotic neurons and Caspase 3 protein levels in the brain. Western blotting results showed that G-CSF treatment enhanced expression of HO-1 and MBP, STAT3 and pSTAT3 proteins in the brain tissues. Based on our results, a single dose of G-CSF immediately after CO poisoning significantly attenuates CO neurotoxicity via different mechanisms. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 37-47, 2017.

Prognostic Value of Plasma Visfatin Level for Chinese Patients with Severe Carbon Monoxide Poisoning.

This prospective observatory study was designed to investigate whether plasma visfatin might serve as a marker of prognosis in patients with severe carbon monoxide (CO) poisoning. A total of 52 consecutive patients with severe CO poisoning and 52 gender- and age- matched healthy subjects were enrolled in the study, and their plasma visfatin levels were determined using an enzyme-linked immunosorbent assay. The clinical outcomes, including in-hospital mortality, 6-month mortality, and poor outcome (Glasgow Outcome Scale score of 1 - 3), were recorded. Plasma visfatin levels were statistically significantly higher in patients than in healthy controls (97.4 ± 28.0 ng/mL vs. 12.1 ± 3.7 ng/mL; p < 0.001). Multivariate logistic regression analysis showed that plasma visfatin level was an independent prognostic predictor of in-hospital mortality [odds ratio (OR), 1.214; 95% confidence interval (CI), 1.103 - 1.425; p < 0.001], 6-month mortality (OR, 1.269; 95% CI, 1.085 - 1.534; p < 0.001), and 6-month poor outcome (OR, 1.302; 95% CI, 1.023 - 1.520; p < 0.001). Moreover, receiver operating characteristic curves showed that plasma visfatin level had high predictive value for in-hospital mortality [area under curve (AUC), 0.931; 95% CI, 0.832 - 1.000], 6-month mortality (AUC, 0.894; 95% CI, 0.801 - 0.987), and 6-month poor outcome (AUC, 0.886; 95% CI, 0.796 - 0.977). Plasma visfatin levels are significantly higher in patients with severe CO poisoning and could be a useful biomarker to predict short- and long-term clinical outcome after severe CO poisoning.

Edaravone attenuates brain damage in rats after acute CO poisoning through inhibiting apoptosis and oxidative stress

Acute carbon monoxide (CO) poisoning is the most common cause of death from poisoning all over the world and may result in neuropathologic and neurophysiologic changes. Acute brain damage and delayed encephalopathy are the most serious complication, yet their pathogenesis is poorly understood. The present study aimed to evaluate the neuroprotective effects of Edaravone against apoptosis and oxidative stress after acute CO poisoning. The rat model of CO poisoning was established in a hyperbaric oxygen chamber by exposed to CO. Ultrastructure changes were observed by transmission electron microscopy (TEM). TUNEL stain was used to assess apoptosis. Immunohistochemistry and immunofluorescence double stain were used to evaluate the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) protein and their relationship. By dynamically monitored the carboxyhemoglobin (HbCO) level in blood, we successfully established rat model of severe CO poisoning. Ultrastructure changes, including chromatin condensation, cytoplasm dissolution, vacuoles formation, nucleus membrane and cell organelles decomposition, could be observed after CO poisoning. Edaravone could improve the ultrastructure damage. CO poisoning could induce apoptosis. Apoptotic cells were widely distributed in cortex, striatum and hippocampus. Edaravone treatment attenuated neuronal apoptosis as compared with the poisoning group (P < 0.01). Basal expressions of HO-1 and Nrf-2 proteins were found in normal brain tissue. CO poisoning could activate HO-1/Nrf-2 pathway, start oxidative stress response. After the administration of Edaravone, the expression of HO-1 and Nrf-2 significantly increased (P < 0.01). These findings suggest that Edaravone may inhibit apoptosis, activate the Keapl-Nrf/ARE pathway, and thus improve the ultrastructure damage and neurophysiologic changes following acute CO poisoning.

Predicting duration of mechanical ventilation in patients with carbon monoxide poisoning: A retrospective study

PurposePatients with severe carbon monoxide (CO) poisoning may develop acute respiratory failure, which needs endotracheal intubation and mechanical ventilation (MV). The objective of this study was to identify the predictors for duration of MV in patients with severe CO poisoning and acute respiratory failure. Materials and methodsThis is a retrospective observational study of 796 consecutive patients diagnosed with acute CO poisoning that presented to the emergency department. Patients who received MV were divided into 2 groups: the early extubation (EE) consisting of patients who were on MV for less than 72 hours and the nonearly extubation (NEE) consisting of patients who were on MV for more than 72 hours. Demographic and clinical data of the two groups were extracted for analysis. ResultsThe intubation rate of all CO-poisoned patients was 23.4%. A total of 168 patients were enrolled in this study. The main source of CO exposure was intentional CO poisoning by charcoal burning (137 patients). Positive toxicology screening result was found in 104 patients (61.9%). The EE group had 105 patients (62.5%). On arriving at the emergency department, high incidence of hypotension; high white blood cell count; and elevation of blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, creatine kinase, and troponin-I levels were statistically significant in the NEE group (P < .05). Positive toxicology screening result was statistically significant in the EE group (P < .05). In a multivariate analysis, elevation of troponin-I level was an independent factor for NEE (odds ratio, 1.305; 95% confidence interval, 1.024-1.663; P = .032). Positive toxicology screening result was an independent factor for EE (odds ratio, 0.222; 95% confidence interval, 0.101-0.489; P = .001). ConclusionsA positive toxin screen predicts extubation within the first 72 hours for patients with severe CO poisoning and acute respiratory failure. On the other hand, elevation of initial troponin-I level is a predictor for a longer duration of MV.

Carbon Monoxide Toxicity after Lighting Coals at a Hookah Bar

Unintentional non-fire-related (UNFR) carbon monoxide (CO) poisonings continue to account for a significant health and economic burden in the United States. While most of these poisonings are related to faulty central heating or water heaters in private dwellings, less common sources should also be considered when a patient presents with any signs or symptoms suggestive of CO toxicity. The authors present a case where a patient was found to have severe CO poisoning, a COHgb level of 33.8%, after lighting coals for a water pipe called a hookah. The patient was initially unconscious and was found to have electrocardiogram (ECG) changes consistent with cardiac ischemia that resolved following treatment with hyperbaric oxygen therapy. In recent years, hookah bars have gained in popularity, especially in urban areas and around college campuses. This was the first case to identify the potential occupational exposure of employees working at hookah bars to CO. Furthermore, the patient's COHb level of 33.8% was higher than any previously reported in the literature with exposure via hookah pipe. The practitioner should consider CO poisoning in patients who smoke tobacco via a hookah and consider early hyperbaric oxygen therapy in those experiencing significant symptoms.

The relationship between lactate clearance rate and delayed encephalopathy after acute carbon monoxide poisoning

To study the relationship between lactate clearance rate (LCR) and prognosis after acute carbon monoxide poisoning in patients with delayed encephalopathy (DEACMP). Data from 354 patients with acute severe carbon monoxide poisoning (ASCOP) were retrospectively analyzed. The patients were divided into hyperlactacidemia group (arterial lactic acid > 2 mmol/L, n=263) and low lactic acidosis group (arterial lactate ≤2 mmol/L, n=91) according to the blood lactic acid level at admission. Arterial blood (1 mL) was collected from all patients before and 6, 24, 72 hours after treatment at ambient air, and arterial blood lactic acid was determined, and LCR was calculated. The initial level of blood lactic acid and LCR at 6, 24, 72 hours were compared between two groups. At the same time, the patients with hyperlactacidemia were divided into high LCR group (LCR more than 10%, n=101) and low LCR group (LCR less than or equal to 10%, n=162) according to 6-hour LCR, and the incidence of DEACMP was compared between two groups. The relationship between LCR and the incidence of DEACMP was analyzed with Spearman linear correlation analysis. The risk factors associated with DEACMP were analyzed with logistic regression analysis. The initial level of blood lactic acid (2.73±0.57 mmol/L vs. 1.69±0.20 mmol/L, t=5.327, P=0.001) and LCR at 6, 24, 72 hours [6 hours: (9.0±2.4)% vs. (1.2±0.6)%, t=9.468, P=0.001; 24 hours: (8.6±3.7)% vs. (1.2±0.4)%, t=4.889, P=0.001; 72 hours: (14.0±3.9)% vs. (1.7±1.0)%, t=5.211, P=0.001] in hyperlactacidemia group were significantly higher than those in low lactic acidosis group. The initial level of blood lactic acid in high LCR group was significantly lower than that in low LCR group (2.41±0.23 mmol/L vs. 2.92±0.63 mmol/L, t=2.429, P=0.023), and LCR at 6 hours and 24 hours were significantly higher than those in low LCR group [6 hours: (11.0±1.2)% vs. (8.0±2.1)%, t=4.487, P=0.001; 24 hours: (12.2±3.0)% vs. (6.3±1.8)%, t=6.264, P=0.001]. But there was no difference in 72-hour LCR between high LCR group and low LCR group [(14.1±3.6)% vs. (13.9±4.1)%, t=0.182, P=0.857]. The incidence of DEACMP in high LCR group was significantly lower than that in low LCR group [15.8% (16/101) vs. 61.1% (99/162), χ(2)=51.814, P=0.001]. The blood LCR at early period (6, 24, 72 hours) in ASCOP patients with hyperlactacidemia was negatively correlated with the incidence of DEACMP (r1=-0.493, P1=0.011; r2=-0.408, P2=0.038; r3=-0.428, P3=0.029). Logistic regression analysis showed that LRC at 6 hours and 24 hours [odds ratio (OR) was 2.701, 1.070, P value was 0.035, 0.001], long-time coma (OR=1.537, P=0.068), contact carbon monoxide (CO) long time (OR=2.686, P=0.014), age (OR=1.464, P=0.017), acute carbon monoxide complications (OR=1.363, P=0.072) patients with ASCOP had an increased risk of DEACMP. LCR is helpful for the assess of DEACMP patients severity, for the treatment guide and for prognosis judgement.

The Correlation of Lactate and Carboxyhemoglobin Levels in Carbon Monoxide Poisonings

Carbon monoxide (CO) poisoning is the most common, and perhaps the most serious toxicological emergency in the United States today. Current recommendations suggest that CO levels greater than 25 should be treated with hyperbaric oxygen therapy (HBOT). Lactic acid is produced during periods of tissue hypoxia/ischemia, and has been shown to serve as an independent indicator of disease severity in a number of critical illnesses. The objective of this study is to determine if serum lactate levels on emergency department (ED) presentation have utility as a markers of severity of carbon monoxide poisoning.

Therapeutic red cell exchange for severe carbon monoxide poisoning

Carbon monoxide (CO) is the most common cause of fatal poisoning worldwide. Therapeutic red cell exchange (TREX) has been used in the treatment of many different diseases. Therefore, we aimed to evaluate the efficacy of TREX on the clinical status, outcome, and discharge of patients with severe CO poisoning. Demographic data, clinical status, and outcomes of 12 patients that were treated with TREX for severe CO poisoning after referral to the Emergency and Hematology Departments of Gaziantep University between November 2011 and April 2012 were evaluated. Mean carboxyhemoglobin level decreased from (59.7 ± 12.7)% (38-79%) to (17 ± 9.4)% (8-43%), and mean Glasgow Coma Scale score increased from 4 ± 1.6 (3-8) to 9.4 ± 3.5 (3-14) after TREX therapy. Five patients were admitted to the intensive care unit. Rhabdomyolysis developed in one case. Of the 12 patients, 11 were discharged alive, and one patient died. TREX may be an alternative treatment method for reducing mortality and morbidity in cases of severe CO poisoning.

Comments on ‘oxidative stress increases in carbon monoxide poisoning’

We read with great interest the article by Kavakli et al. in which the total oxidant and the antioxidant status were investigated in patients with carbon monoxide (CO) poisoning. Although lipid peroxidation has been linked to CO-induced neuropathology for more than two decades, serum levels of oxidative stress markers have not been investigated before. In this study, they measured, in patients with CO poisoning (n 1⁄4 88) and control subjects (n 1⁄4 37), serum levels of total oxidant and antioxidant status and calculated oxidative stress index (1⁄4 total oxidant status/total antioxidant status). They found that total oxidant status and oxidative stress index, but not total antioxidant status significantly increased in patients with CO poisoning when compared with controls. Additionally, they found that carboxyhemoglobin (COHb), total oxidant status and oxidative stress index were significantly reduced after 6 h of treatment. We applaud their efforts to gain insight into the pathophysiology of CO poisoning, which is a frequent cause of morbidity and mortality in Turkey. In the discussion, they conclude that ‘ . . . oxidative stress index may be a useful guide in planning treatment of CO poisoned patients’ and ‘ . . . in decision of hyperbaric oxygen therapy application, oxidative stress index levels should be taken into consideration’. We think that the data presented in this article is not sufficient to support their conclusion that oxidative stress index is a marker of severity and can be used in the selection of patients for hyperbaric oxygen therapy. Oxygen is first-line therapy in CO poisoning. Severely poisoned patients are referred to hyperbaric oxygen therapy. In order to argue that oxidative stress index can discriminate severely poisoned patients, they should have compared oxidative stress index levels in mild, moderate and severely poisoned patients. They could also analyze whether there is a correlation between COHb and oxidative stress markers. If the data is available, the authors could also analyze the correlation between oxidative stress markers and the number of clinical manifestations. Interestingly, in a recent study Garrabou et al. measured serum levels of lipid peroxidation (oxidative stress) in patients with CO poisoning and analyzed its correlation with clinical findings. Although, serum levels of lipid peroxidation were similar in patients with moderate and severe CO poisoning, pretreatment lipid peroxidation level was strongly correlated with the total number of symptoms along the 3 months follow-up. In addition, pretreatment lipid peroxidation was significantly higher in patients who developed late neurological sequel (LNS) compared with those without LNS. Since COHb poorly correlates with severity of CO poisoning, new serum markers are needed to evaluate severity and outcome of patients with CO poisoning. Further studies are needed to elucidate the value of oxidative stress markers in the management of CO poisoning.

Optimization of Treatment Policy for Acute Carbon Monoxide Poisoning

Objective: to evaluate the efficiency of combination use of hyperbaric oxygenation, succinate-containing solutions, and anti-edematous agents in patients with acute carbon monoxide poisoning. Subjects and methods. The results of treatment were analyzed in 32 patients admitted in 2009—2011 for severe acute carbon monoxide poisoning and a Glasgow coma score of 6—8. The patients were divided into 2 groups: 1) patients whose combination therapy involved hyperbaric oxygenation, Succinasol infusions, and L-lysine-aescinate injections; 2) those who received traditional therapy. All the patients underwent complex clinical, laboratory, and neurophysiologic examinations. Results. Just 24 hours after the combination use of Succinasol and L-lysine-aescinate, Group I patients were observed to have substantially reduced lactate, the content of the latter approached the normal value following 48 hours, which was much below the values in the control group. The similar pattern was observed when endogenous intoxication parameters were examined. During the performed therapy, the level of consciousness and that of intellect according to the MMSE and FAB scales were restored more rapidly in the study group patients than in Group 2. Conclusion. The combination use of hyperbaric oxygenation, the succinate-containing solution Succinasol, and the anti-edematous agent L-lysine-aescinate considerably enhances the efficiency of intensive therapy for acute carbon monoxide poisoning. Key words: carbon monoxide, toxic hypoxic encephalopathy, combination therapy, hyperbaric oxygenation, succinic acid, L-lysine-aescinate.