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Because the MNI standard space was constructed by affine registration of a number of subjects to a common standard coordinate system, it was reasonable to use only affine transformation to achieve a suitable alignment between these two spaces. The optimal-normalized tissue segments of each individual had an identical voxel size of 1.

All normalized, segmented, and modulated MNI standard-space images were smoothed with an 8-mm Gaussian kernel prior to tissue volume calculation and voxel-wise group comparisons.

The Diagnosis and Treatment of Carbon Monoxide Poisoning ()

Overall tissue volumes i. The total intracranial volume TIV was determined as the sum of the three volumes. The demographic and clinical characteristics of those in the patient and control groups were compared by analysis of variance ANOVA for age and education. Nonstationary correction part of the VBM toolbox for correcting non-isotropic smoothness of the data was used to investigate group differences [ 31 ]. The differences in GM volume were compared between the following groups: 1 all patients vs.

DE group. Because of the exploratory design of this study, strict criteria were used to obtain the findings. Anatomic structures of the coordinates representing significant clusters were identified based on the Talairach and Tournoux atlas [ 33 ]. Partial correlation analysis adjusted for age, sex, education, and TIV was performed to assess the correlation between NP test scores and areas with smaller volumes in all CO intoxicated patients compared to those in the control group. Three patients presented a coexistence of globus pallidus and white matter change.

The TIV was Compared individually in the post-hoc analysis to those in the control group, those in the non-DE group showed a lower performance level in percent conceptual level response, digit symbol, and symbol search tests, whereas patients in the DE group showed a lower performance level in only the digit symbol and symbol search tests.

A novel effective chemical hemin for the treatment of acute carbon monoxide poisoning in mice

Lower gray matter volumes GMVs in chronic CO-intoxicated patients vs normal subjects, with highlighted significant areas. A Compared to healthy controls, all chronic CO-intoxicated patients showed significantly lower GMV in the bilateral basal ganglia, left claustrum, right amygdala, left hippocampus, bilateral parietal, and left frontal lobes.

B Only one significant difference in GMV was observed in the left post-central gyrus between the healthy control and the non-DE groups. C The DE group showed significantly lower GMV in the left hippocampus, left mammillary body, left claustrum, right amygdala, right anterior cingulate, right caudate body, and left frontal and bilateral parietal lobes.

By using a p value of 0. Gray matter volume difference between DE and non-DE group. The poor picture completion score correlated with a low GMV in the left lateral globus pallidus, left post-central gyrus, and left hypothalamus. The low digit symbol score correlated with a low GMV in the left hypothalamus, whereas a low symbol search score correlated with a low GMV in the right putamen. To date, the relationship between structural changes and altered cognitive function in DE and non-DE patients has not been fully studied.

In this first VBM study which compares these two groups, morphological differences were found between DE and non-DE patients, and many of the structural deficits of DE patients correlated with their lower level of cognition. Carbon monoxide poisoning-related cognitive impairment includes impaired memory and executive function [ 36 ], reduced mental processing speed, and decreased intellectual function [ 14 ], which are consistent with the NP results in this study.

However, the memory function has not been assessed in this study that may be seen as a limitation. The results of this study further support previous findings indicating that delayed CO encephalopathy might impair the frontal executive function and persist even after the recovery of other neurological deficits [ 37 ].

Increased structural alterations in DE patients corroborate the NP sequelae in patients with chronic status after CO intoxication. Long-term follow-up for this particular group is required. Consistent with the hypothesis posed in this study, structural differences between the DE and non-DE groups were found.

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In contrast, structural abnormalities in the DE group included lower volume of the left claustrum, right amygdala, right caudate body, left hippocampus, right inferior parietal lobule, left superior frontal gyrus, left medial frontal gyrus, right anterior cingulate, left post-central gyrus, and left mammillary body. Previous studies report generalized brain atrophy occurring in chronic CO intoxicated patients, with volume reductions in the fornix [ 12 ], hippocampus [ 14 ], corpus callosum [ 13 ], basal ganglia, and cerebral and cerebellar cortex.

However, detailed lobar location of cortical involvement has never been studied [ 38 ]. This VBM study provides a highly objective method for clarifying significant brain atrophy in the DE group, compared to the non-DE counterpart. The pathogenesis of DE after CO intoxication is likely multifactorial, involving mitochondrial damage combined with hypoxemia and hypoperfusion during the acute stage [ 39 — 41 ], as well as glutamatergic excitation [ 42 ] and lipid peroxidation after return to CO-free air [ 43 ].

Although the exact mechanism in the development of DE is unclear, a COHb concentration level that is higher in the DE group than in the non-DE group in this study might increase the occurrence of delayed symptoms and suggest a more obvious effect on the brain [ 5 — 7 ].

1. Introduction

The pathologic hallmark is extensive demyelination, and current theories for the pathogenic mechanism include direct toxicity effects of CO, cerebral blood vessel damage, cerebral edema, and a hypersensitive reaction [ 44 ]. Individual self-protective factors like tolerance to hypoxia and hypoperfusion or resistance to CO cytotoxic action in WM [ 4 , 8 , 10 ], may be responsible for the presence and variable duration of clear periods in DE.

Both are a part of the brain limbic system. Past neuroimaging research suggests the anterior cingulate cortex to be part of the circuit involved in a type of attention [ 45 ] that regulates both cognitive and emotional processing [ 46 ]. The affective subdivision of the anterior cingulate connects to the amygdala [ 47 ], and modulation of the amygdala-anterior cingulate connections seems to be a key substrate of emotional attention bias [ 48 , 49 ].

Lesions involving the anterior cingulate and amygdala is believed to disrupt and cause affective biases [ 50 ]. In this study, the DE group presented lower levels of performance in digit symbol and symbol search, indicating a slower processing speed, which is thought to be connected with a poor attention function [ 51 ].

This result is consistent with previous concept, even though there is no significant correlation between the cluster volume in the left anterior cingulate, right amygdala, and the reported NP tests. Although this study offers valuable insights into the cortical involvement in CO intoxication issues, it nevertheless has some limitations. First, our sample size is too small for definite conclusion of DE and non-DE. Patients without DE were difficult to contact and often rejected invitations to join the non-invasive research because they have little concern about following-up results in the chronic stage.

Second, varying treatments for CO-intoxicated patients exist, such as whether they receive hyperbaric oxygen therapy or not. Moreover, the initial laboratory data were not thoroughly collected for every subject in the emergency room. Therefore, initial disease severity could not be compared to long-term outcomes to define a clearer relationship.


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In conclusion, cognitive impairment and morphologic deficits were found to be present in patients with CO intoxication even after long-term follow-up. Patients in the DE group accomplished with more imaging abnormalities and higher COHb level will express worse neuropsychiatric outcome. In addition to WM injury, the GM microstructure damage also has clinical implication and additional psychiatric research in CO intoxication should prove quite beneficial.

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Hum Brain Mapp. Ashburner J: A fast diffeomorphic image registration algorithm. Psychiatry Res. Talairach J, Tournoux P: Co-planar stereotaxic atlas of the human brain : 3-dimensional proportional system: an approach to cerebral imaging. Gale SD, Hopkins RO: Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. Clin Neurol Neurosurg. Behav Cogn Neurosci Rev. Ann N Y Acad Sci. Ginsberg MD: Carbon monoxide intoxication: clinical features, neuropathology and mechanisms of injury. J Toxicol Clin Toxicol.

Penney DG: Acute carbon monoxide poisoning: animal models: a review. Biochem Biophys Res Commun. Thom SR: Carbon monoxide-mediated brain lipid peroxidation in the rat. J Appl Physiol. Arch Phys Med Rehabil. Trends Cogn Sci.

The Diagnosis and Treatment of Carbon Monoxide Poisoning

In the control group, there were no marked changes to the neurons in any region of the hippocampus in either side of the brain Fig. Compared with the CO-poisoning group, the swelling of neurons in the hippocampus of mice in the hemin-treated and hemin-pretreated groups was less evident; there were fewer necrotic cells and the cell arrangements were more orderly Fig. In addition, the morphology of cells was irregular with unclear boundaries accompanied by nuclei undergoing karyopyknosis Fig.

Hyperbaric Chamber- Carbon Monoxide Detox

In the control group, there were no evident pathological changes in the nerve cells, which indicated that no swelling or necrosis had occurred Fig. Compared with the CO-poisoning group, the cell arrangements in the hemin-treated and hemin-pretreated groups were more regular, the number of Nissl bodies markedly decreased and fewer necrotic cells were observed Fig. Representative images of Nissl staining of the hippocampus in the mice. The degeneration or disarrangement of cells is indicated by the arrows. In clinical settings, the initial management of patients with CO poisoning consists of removing the patient from exposure to the toxic atmosphere and supplying pure oxygen to accelerate the elimination of CO and improve tissue oxygenation The exposure to acute CO poisoning is primarily by inhalation.

Therefore, CO poisoning animal models were previously established by inhalation, which may be classified as either dynamic or static exposure Dynamic exposure, which is similar to routine human inhalation, may negate the interference of other non-toxic factors such as asphyxia. However, due to the high cost of requirements and higher demand of hermeticity, the extensive use of this approach is not convenient. Conversely, static exposure is simple, but it is difficult to prevent hypoxia induced by CO 2 and other interferential factors.

Therefore, the results may not be accurate. Previous research has demonstrated that the establishment of an acute CO poisoning model by intraperitoneal injection is a convenient and effective animal model Compared with inhalation exposure, intraperitoneal injection of CO results in a more precise CO exposure dose which is more suitable for scientific research. Additionally, a single intraperitoneal injection of CO exhibits the same poisoning mechanism and symptoms as those in the clinical settings 27 , even though its exposure route is different from clinical acute CO poisoning.

In the present study, a modified Spearman-Karber method was used to determine a single intraperitoneal injection lethal dose that was the lower limit of the median lethal dose LD50 In the present study, following a single intraperitoneal injection of CO, significant CO poisoning manifestations were observed in mice.

Furthermore, the binding ability of haemoglobin to oxygen was significantly reduced resulting in tissue hypoxia and lipid peroxidation, and blood MDA levels increased rapidly and pathological changes in the hippocampal cells were observed. In conclusion, the mouse model of the present study was established via a single intraperitoneal injection of CO that successfully simulated the pathogenic process of CO poisoning as observed in clinical settings.

Hemin, as a synthetic heme chloride with a high absorption rate, is recognized as a good source of iron to prevent iron deficiency in anemia Hemin that has the property to combine with oxygen is able to improve the oxygen carrying capacity of blood Furthermore, hemin is also an activator of neuroglobin 29 , the oxygen carrier that participates in transportation and storage of oxygen in neurons and subsequently increases the oxygen concentration within neurons. Therefore, hemin may be a potential therapeutic agent to relieve hypoxia following CO exposure.

The present study demonstrated that both pretreatment and treatment with hemin to mice with CO poisoning was able to significantly reduce their mortality rate. Furthermore, it is able to reduce toxic injury in mice, which was demonstrated by the prolonged onset of symptoms in mice and a significant decrease in the blood HbCO level.

In CO poisoning, hypoxia has a proportional association with the HbCO level 30 , and therefore, the present results indicated that the degree of poisoning in the pretreatment and treatment groups has been reduced compared with that in the CO-poisoning group. According to these results, the protective mechanism of hemin against CO poisoning may be due to a reduction in the blood HbCO level, which prevents oxygen transfer.

Furthermore, it may be because hemin replaces HbCO into oxyhaemoglobin to expel CO and thus, oxygen may be transported to the tissues by oxyhaemoglobin. Hemin may also combine with free CO in the bloodstream and thus relieve tissue injury. In addition, a previous animal study provided evidence that hemin is able to induce heme oxygenase-1 HO-1 activity leading to neuroprotection against acute CO poisoning It is believed that HO-1 exhibits protective effects against exogenous CO toxicity 31 through degradation of heme into biliverdin and free iron that show potential biological effects 32 , By combining the above evidence with the results of the present study, it is suggested that it is another possible mechanism that involves the production of HO-1 induced by hemin 34 following acute CO exposure.

However, further studies could be performed in this field to investigate the underlying molecular mechanisms. The present study also demonstrated that MDA, the blood oxidative stress indicator, decreased significantly in both the hemin-pretreated and hemin-treated groups compared with in the CO-poisoning model group. It is believed that oxidative stress is essential in CO-induced neuronal damage Furthermore, MDA is a common product of lipid peroxidation, which is able to reflect the systemic lipid peroxidation level and therefore indirectly reflects the degree of free radical attack and cell injury extent Therefore, it is possible to measure oxygen radicals and lipid peroxidation level in the brain tissue via serum MDA content.

The observations of the present study were consistent with the hypothesis that reactive oxygen species ROS may be associated with the acute toxic effects of CO on the central nervous system 8. The decrease in MDA indicated that the protective effect of hemin for acute CO poisoning injury may be associated with the inhibition of lipid peroxidation, reducing ROS in the brain. Furthermore, in clinical settings, oxygen therapy following CO-induced tissue hypoxia may be followed by ischemic-reperfusion injury in the CNS 37 , leading to increased production of ROS such as nitric oxide Therefore, it may be hypothesized that hemin may also be an alternative therapy to prevent secondary injury and thus protect the brain.

Histopathological examinations demonstrated that both hemin pretreatment and the hemin treatment in early stages could not only reduce hippocampus oedema and necrosis, but also the number of abnormal cells and neuronal damage. Since the hippocampal area is important in memory, learning and emotional activities, it is highly sensitive to hypoxia, asphyxia and ischemia because of its high metabolic rate Furthermore, white and gray matter in the brain are sensitive to hypoxic damage due to the anatomic structure of poor vasculature Therefore, the hippocampal area is able to show evident pathological changes in acute CO poisoning.

Furthermore, the improvement in pathological changes in the hippocampal area revealed that CO-induced impairment was significantly alleviated in mice pretreated or treated with hemin. In conclusion, the present study found that hemin has protective effects of decreasing mortality and relieving hippocampus oedema in mice with acute CO poisoning. Furthermore, the potential protective mechanisms may include a decrease in the level of HbCO, inhibition of lipid peroxidation and reduction of oxygen free radicals in brain cells.

Meanwhile, the present study could provide reliable evidence of animal experiments for the treatment of acute CO poisoning. Finally, applications of hemin for acute CO poisoning may provide a reliable basis for future clinical treatment to gain rescue time and further decrease the mortality rate. The present study was funded by the Natural Science Foundation of China grant no. S , and the Science and Technology Program of Guangzhou grant no.

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Prog Neuropsychopharmacol Biol Psychiatry. Annals Emergency Med. View Article : Google Scholar. Cuadrado A and Rojo AI: Heme oxygenase-1 as a therapeutic target in neurodegenerative diseases and brain infections. Curr Pharm Des. Hear Res. Bruce RD: An up-and-down procedure for acute toxicity testing. Fundam Appl Toxicol. Environmental Sci Technol. Ramieri A Jr, Jatlow P and Seligson D: New method for rapid determination of carboxyhemoglobin by use of double-wavelength spectrophotometry. Clin Chem. Anal Biochem. Comparative Clinical Pathol.

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Exp Ther Med. Kurauchi Y, Hisatsune A, Isohama Y and Katsuki H: Nitric oxide-cyclic GMP signaling pathway limits inflammatory degeneration of midbrain dopaminergic neurons: Cell type-specific regulation of heme oxygenase-1 expression.


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