Analysis of long-term prognosis of neurological sequelae in children with carbon monoxide poisoning

doi:10.21203/rs.3.rs-4287444/v1

Background

Carbon monoxide poisoning is a common gas poisoning in emergency rooms during winter, but there are very few reports on carbon monoxide poisoning in children and long-term follow-ups. Epidemiological studies have shown that in China, infants (0-4 years old) and elderly people (70 years old and above) have a higher risk of DALYs (disability-adjusted life years), while young people (15-24 years old) have a higher risk of CO poisoning¹. For carbon monoxide poisoning in children, long-term cognitive impairment, if it occurs, will have a detrimental effect on children's neurodevelopment and long-term healthy growth.

Method:

This study retrospectively analyzed children admitted to the Fourth Affiliated Hospital of Guangxi Medical University for carbon monoxide poisoning from January 2018 to December 2022, and followed up on their neurological sequelae for a long period of time. The study was approved by the Ethics Committees of the Fourth Affiliated Hospital of Guangxi Medical University (the identification code was KY2023131) and informed consent was obtained from all participants and/or their legal guardians. The study complied with the Declaration of Helsinki. Through GDS scores, we further compared the differences between children with and without cognitive impairment，and identified some risk factors for long-term cognitive impairment in children after carbon monoxide poisoning.

Result

A total of 113 children were included in the study, with an average follow-up of 3.6 years (3.6±1.5 years). Among them, 13 children (11.5%, 13/113) had cognitive abnormalities. The use of gas water heaters in enclosed bathrooms (101 cases, 89.4%) was the most common cause of poisoning in children in this study, followed by heating with fire (11 cases, 9.7%). In addition, one child was forgotten by his father in a running car, resulting in poisoning. The clinical manifestations of children with cognitive abnormalities were mainly consciousness disorders (67 cases, 59.3%), dizziness or headache (37 cases, 32.7%), and other manifestations including irritability, crying, vomiting, limb weakness, and limb twitching, a total of 9 cases. The duration of consciousness disorders in children with cognitive abnormalities was mostly more than 1 day, with a median of 5 days, and the hospitalization time was longer. Children with cognitive abnormalities had higher CRP levels, higher D-dimer levels, and higher liver enzyme levels. The most common imaging change after carbon monoxide poisoning in children was cerebral edema, with two cases of subarachnoid hemorrhage observed and one case of demyelinating changes observed. For children with coma time less than 1 hour, there were few abnormal changes in cranial imaging. Children with cognitive abnormalities were more likely to develop epilepsy (38.5%, 5/13) and other system damage (53.8%, 7/13) during hospitalization, including pulmonary infection (3 cases), stressful gastrointestinal bleeding (2 cases), electrolyte imbalance (2 cases), liver and kidney or myocardial dysfunction (3 cases), and some children had multiple system damage at the same time.

There were statistical differences in the admission carbon monoxide hemoglobin level, fibrinogen, D-dimer, high-sensitivity C-reactive protein, neuron enolase, ALT/AST, lactate dehydrogenase, length of hospital stay, discharge and admission GCS scores, seizure frequency, duration of consciousness disorders exceeding 1 day, cranial imaging changes, use of ventilators, presence of other system damage, number of HBOT treatments, and whether the patient was transferred to another hospital between the two groups of children. Multivariate logistic regression analysis showed that the need to transfer to a higher-level hospital for treatment due to the severity of the condition and longer duration of coma were independent risk factors for cognitive impairment after long-term follow-up.

Conclusion

For children with an unconsciousness of more than 1 hour, it is recommended to consider performing a head imaging examination as soon as possible within 3 days after CO exposure to guide the treatment of the acute phase. For children who are transferred from lower-level hospitals to higher-level hospitals for treatment after poisoning, with an unconsciousness of more than 1 day or 5 days and more, long-term follow-up should be conducted to determine whether delayed encephalopathy or long-term cognitive impairment occurs, and timely and long-term intervention measures should be formulated.

Biological sciences/Neuroscience

Health sciences/Health occupations

Health sciences/Medical research

carbon monoxide poisoning

prognosis

children

neurological sequelae

Carbon monoxide poisoning is the most common gas poisoning in emergency rooms during winter. Although public health departments have made great efforts to promote the prevention of carbon monoxide poisoning, emergency rooms still receive many patients with carbon monoxide poisoning whenever the weather becomes cold. According to our retrospective study statistics, the most common causes of hospital admissions in our hospital were using gas water heater in a closed bathroom (89.4%) and using charcoal fire for heating (9.7%), which is also consistent with previous studies². The most common symptoms of mild poisoning are dizziness/headache, brief loss of consciousness (not exceeding 60 minutes), and the main symptom of severe poisoning is prolonged loss of consciousness and possible neurological sequelae. Although the global age-standardized mortality rate caused by unintentional carbon monoxide poisoning decreased by nearly 50% during the 20-year period studied, the improvement in various regions was uneven³, so we still need to continue to work hard in preventing and treating carbon monoxide poisoning.

Carbon monoxide has an affinity for hemoglobin that is 210 times greater than that of oxygen, which can hinder the delivery and utilization of oxygen. Carbon monoxide can cause cellular hypoxia, followed by oxidative stress and inflammation, and may cause neurological, cerebrovascular, or cardiovascular diseases, including encephalopathy, ischemia, and peripheral nerve injury. Through direct cellular damage and downstream signaling cascades, reactive oxygen species (ROS) produced during acute carbon monoxide poisoning can lead to long-term neurological and cardiac sequelae. ROS-mediated damage is particularly severe in brain cells, where lipid oxidation products bind to myelin basic protein to form adducts, activating microglia and promoting further immune responses, leading to neurodegeneration⁴.

Currently, there are few studies focused on pediatric CO poisoning patients. We conducted a retrospective study with an average follow-up of 3.6 years to analyze pediatric patients with CO exposure in medical centers and analyzed the risk factors associated with long-term cognitive impairment after CO poisoning.

2.1 Study Design

We retrospectively analyzed the data of children hospitalized with carbon monoxide poisoning in Liuzhou Workers' Hospital from January 2018 to December 2022. The study was approved by the Ethics Committees of the Fourth Affiliated Hospital of Guangxi Medical University (the identification code was KY2023131) and informed consent was obtained from all participants and/or their legal guardians. The study complied with the Declaration of Helsinki. The privacy information of all patients was protected, and we did not disclose any patient's private information.

The inclusion criteria for this study were: all hospitalized children (aged ≤ 18 years) diagnosed with acute carbon monoxide poisoning between January 2018 and December 2022 based on medical history and COHb levels > 5%. Information on the first hospitalization of the children due to carbon monoxide poisoning was collected. The exclusion criteria for this study were: 1) children who were still under 2 years old at the time of follow-up; 2) history of neurocognitive dysfunction before carbon monoxide poisoning, including genetic diseases, neonatal hypoxic encephalopathy, etc.; 3) previous history of CO poisoning, and this poisoning was not the first time of carbon monoxide poisoning; 4) cardiac arrest before or during emergency room arrival; 5) lost to follow-up or uncooperative children or uncooperative family members during follow-up.

Based on the child's medical history and COHb level of > 5%, the diagnosis of acute carbon monoxide poisoning was made. Some patients with carbon monoxide poisoning had received 100% high-flow oxygen therapy through a mask before coming to the emergency department, at which point the diagnosis of carbon monoxide poisoning could be made without relying on COHb levels. In addition, patients with any neurocognitive symptoms and signs, cardiovascular dysfunction, severe acidosis, or COHb levels of ≥ 25% can receive hyperbaric oxygen therapy. If the child's condition is unstable, it is considered dangerous to use hyperbaric oxygen therapy, so only 100% high-flow oxygen therapy was performed.

2.2 Research methods

Through the hospitalization system, collect clinical information such as blood biochemical and blood gas testing information at the time of admission, length of hospitalization, source of CO poisoning, clinical manifestation, GCS scores at admission and discharge, cranial imaging data, and clinical treatment information such as whether to use hyperbaric oxygen therapy, the number of hyperbaric oxygen therapy sessions, and the time between the first hyperbaric oxygen therapy session and the time of poisoning. Determine the cognitive status of the child during follow-up by following up with the child or the child's family. Follow-up is conducted using the GDS(global deterioration scale, GDS), with the range of cognitive impairment ranging from none (GDS score, 1 point) to present (GDS score, 2–7 points), which is objectively confirmed through detailed interviews with experienced pediatric rehabilitation physicians. According to the inclusion and exclusion criteria, based on the GDS scoring results, children are divided into normal group and cognitive abnormality group. The normal group has a GDS score of 1 point, indicating no cognitive impairment, with a total of 100 cases included; the GDS score ≥ 2 points for the cognitive abnormality group, with a total of 13 cases included. Compare the differences in various aspects of data between the two groups of children using statistical methods.

2.3 Statistical analysis

The general characteristics, laboratory results, and clinical manifestations of the participants were presented as the mean ± standard deviation or median (interquartile range) of continuous variables and the frequency (percentage) of variables. The two-sample independent Mann-Whitney U test for continuous variables and the chi-square test or Fisher's exact probability method for categorical variables were used to evaluate the differences between the two groups. For variables with differences, binary logistic regression analysis was performed to determine the association between cognitive impairment and CO poisoning-related clinical information. All statistical analyses were performed using SPSS version 22, with a significance level set at 0.05.

Retrieving the hospitalization system, from January 2018 to December 2022, a total of 515 patients were admitted to the hospital for carbon monoxide poisoning in Liuzhou Workers' Hospital. Through age screening, a total of 179 cases were obtained in the pediatric group. According to the inclusion and exclusion criteria, 41 cases were further eliminated, and finally a total of 154 cases were included. Through follow-up, a total of 25 patients were lost to follow-up, and finally 113 patients met the study criteria. According to the GDS classification of follow-up, 100 cases were divided into normal cognitive group and 13 cases were divided into abnormal cognitive group. The clinical characteristics of these children are shown in Tables 1, 2, and 3.

Compared with the normal group, the cognitive abnormality group had a longer hospitalization time, lower admission GCS scores, lower discharge GCS scores, more common seizures, longer periods of consciousness impairment, more common abnormal changes in cranial imaging, higher probability of using ventilators, more common occurrence of other system damage, and more children from lower-level hospitals were referred to the abnormal group. At the same time, children in the abnormal group also received more high-pressure oxygen therapy, including the number of high-pressure oxygen therapy for the first hospitalization and the total number of high-pressure oxygen therapy thereafter.

Laboratory data indicate that there are differences in fibrinogen, D-dimer, CRP, neuron enolase, ALT/AST, and lactate dehydrogenase, with higher levels in the abnormal group, while COHb levels are lower in the cognitive abnormality group than in the normal group.

Multivariate logistic regression analysis showed that the need to be transferred from a lower-level hospital to our hospital for treatment due to illness, longer coma duration, and long-term cognitive impairment were independently associated. The clinical data of the children studied are shown in Tables 1 to 4 below.

Table1 The blood biochemical results of two groups. There were statistically significant differences in COHb, fibrinogen, D dimer, CRP, NSE, CK-MB/CK ratio, ALT/AST, and lactate dehydrogenase between the two groups.

variable	Total (n=113)	Cognitive abnormality group (n=13)	Normal group (n=100)	P (U test)
blood gas pH	7.375, 7.417 (7.391)	7.38, 7.53 (7.43)	7.37, 7.41 (7.39)	0.090
Blood gas lactate	1.30, 2.55 (1.60)	1.1, 2.7 (1.3)	1.4, 2.5 (1.6)	0.255
COHb	1.9, 19.5 (8.8)	0.95, 9.65 (1.30)	3.5, 21.3 (9.6)	0.020
Blood gas K+	3.06, 3.68 (3.40)	3.04, 3.68 (3.42)	3.02, 3.68 (3.40)	0.927
WBC	8.65, 14.04 (11.12)	7.50, 22.26 (12.08)	8.73, 13.55 (10.94)	0.495
neutrophil granulocyte	5.49, 11.78 (7.94)	5.49, 19.58 (8.59)	5.49, 10.53 (7.94)	0.407
Leukocyte/neutrophil ratio	1.17, 1.54 (1.34)	1.13, 1.47 (1.32)	1.18, 1.61 (1.34)	0.496
lymphocyte	1.20, 2.63 (1.64)	1.12, 1.91 (1.49)	1.20, 2.76 (1.76)	0.280
Platelet count	246.5,378.5 (333.0)	310.0, 374.0 (336.0)	233.5, 384.5 (303.5)	0.437
fibrinogen	2.24, 3.04 (2.46)	2.60, 3.44 (3.03)	2.19, 2.81 (2.38)	0.018
partial thromboplastin time	22.1, 30.2 (25.8)	22.5, 33.0 (29.0)	21.9, 28.9 (24.6)	0.267
D-Dimer	0.175, 0.730 (0.390)	0.405, 3.150 (0.910)	0.155, 0.550 (0.315)	0.017
CRP	0.165, 3.810 (0.810)	1.700, 7.800 (4.440)	0.130, 1.423 (0.385)	0.001
NSE	20.76, 35.13 (24.98)	29.3,168.9 (40.7)	20.2, 29.8 (24.2)	0.003
CK-MB/CK ratio	0.10, 0.21 (0.15)	0.05, 0.26 (0.155)	0.10, 0.20 (0.15)	0.972
creatine kinase isoenzyme	17.0, 29.2 (20.0)	18,57 (36.50)	17,28 (20.0)	0.086
Alanine aminotransferase	9.0, 16.5 (11.0)	15.5, 35.5 (22.0)	9,14 (10.5)	0.000
Aspartate aminotransferase	18.0, 31.5 (24.0)	23.0, 84.5 (44.0)	17,30 (23.0)	0.005
lactate dehydrogenase	186.0, 264.8 (217.0)	232.0,596.0 (315.0)	183.0,242.5 (205.0)	0.003
Blood urea	3.175, 4.725 (3.700)	3.05, 4.20 (3.40)	3.20, 4.85 (3.70)	0.371
creatinine	33.75, 55.0 (45.0)	32,53.5 (42)	34,56 (45)	0.476
Cystatin C	0.50, 0.70 (0.56)	0.4475, 0.7275 (0.5050)	0.5175, 0.7025 (0.6200)	0.512

Table 2 The hospitalization days (P<0.05), admission GCS score(P<0.05), discharge GCS score (P<0.05), number of seizures (P<0.05), duration of CO exposure, duration of consciousness impairment (P<0.05), follow-up duration, GDS grading, and HBOT treatment (P<0.05) of two groups of patients

variable	Total (n=113)	Cognitive abnormality group (n=13)	Normal group (n=100)	P(U test)
Age	9.81±4.7	9.08±4.21	9.91±4.81	0.555
Hospitalization days	2.0, 7.0 (4.0)	3.5, 18.0 (7.0)	2.0, 6.0 (4.0)	0.006
First GCS	15, 15 (15)	5.5,15 (13.0)	15, 15 (15)	0.002
Discharge GCS	15, 15 (15)	10, 15 (15)	15, 15 (15)	0.000
GCS of out-in	0.0,0.0 (0.0)	0.0,5.5 (0.0)	0.0,0.0 (0.0)	0.087
Epilepsy frequency	0.0,0.0 (0.0)	0.0,1.0 (0.0)	0.0,0.0 (0.0)	0.024
Exposure time to CO/min	25,40 (30)	25,55 (30.0)	25.0, 39.5 (30.0)	0.821
Coma time /h	0.00, 0.75 (0.17)	0.085,216.0 (120.0)	0.00, 0.56 (0.17)	0.004
Follow up period/y	2.1, 5.0 (3.5)	2.9, 5.6 (4.5)	2.0, 5.0 (3.3)	0.193
GDS classification	1.0, 1.0 (1.0)	2.0, 3.0 (3.0)	1.0, 1.0 (1.0)	0.000
Time of first HBOT after poisoning	12.0, 29.0 (24.0)	9.0, 53.0 (24.0)	12.0, 27.0 (24.0)	0.714
HBOT times for the first hospitalization	2,11 (6)	6.5, 23.5 (12.0)	2,10 (5)	0.001
HBOT total times	3,12 (8)	10.5,162.5 (17.0)	2,12 (6)	0.001

Table 3 There were statistically significant differences between the two groups in terms of consciousness disturbance for more than one day, cranial imaging changes, whether they were referred patients, seizure frequency, whether they used ventilator, and combined with other system damage.

variable	Total (n=113)	Cognitive abnormality group (n=13)	Normal group (n=100)	P (chi square)
consciousness disorder for more than 1 day				0.00
Y	9 (8.0)	7 (53.8)	2 (2.0)
N	104 (92.0)	6 (46.2)	98 (98.0)
Gender				0.555
M(male)	46 (40.7)	4 (30.8)	42 (42.0)
F(female)	67 (59.3)	9 (69.2)	58 (58.0)
Head imaging changes [number of cases, (%)]				0.000
normal	50 (44.2%)	5 (38.5)	45 (45.0)
abnormal	12 (10.6%)	8 (61.5)	4 (4.0)
No image	51 (45.1%)	0 (0.0)	51 (51.0)
Referral Cases [number of cases, (%)]				0.000
Y	34 (30.1)	10 (76.9)	24 (24.0)
N	79 (69.9)	3 (3)	76 (76.0)
Symptoms [number of cases, (%)]				0.424
Consciousness disorders	67 (59.3)	10 (76.9)	57 (57.0)
Dizziness/headache	37 (32.7)	3 (23.1)	34 (34.0)
others	9 (8.0)	0 (0.0)	9 (9.0)
CO source [number of cases, (%)]				1.000
Take a bath with gas water heater	101 (89.4)	12 (92.3)	89 (89.0)
Barbecue heating	11 (9.7)	1 (7.7)	10 (10.0)
Other sources	1 (0.9)	0 (0.00)	1 (1.0)
Seizures [number of cases, (%)]				0.019
N	97 (85.8)	8 (61.5)	89 (89.0)
Y	16 (14.2)	5 (38.5)	11 (11.0)
The consciousness status when CO poisoning was found [number of cases, (%)]				0.238
sober	45 (39.8)	3 (23.1)	42 (42.0)
Consciousness disorders	68 (60.2)	10 (76.9)	58 (58.0)
Recurrent consciousness disorders after waking up [number of cases, (%)]				0.065
N	109 (96.5)	11 (84.6)	98 (98.0)
Y	4 (3.5)	2 (15.4)	2 (2.0)
Use ventilator [number of cases, (%)]				0.035
N	110 (88.5)	11 (84.6)	99 (99.0)
Y	3 (11.5)	2 (15.4)	1 (1.0)
Other systems damage [number of cases, (%)]				0.002
N	92 (81.4)	6 (46.2)	86 (86.0)
Y	21 (18.6)	7 (53.8)	14 (14.0)

This study comprehensively analyzed the factors that may be related to long-term cognitive impairment after carbon monoxide poisoning in children and analyzed the possible independent risk factors for long-term cognitive impairment through logistic regression analysis, providing a reference for short-term treatment, long-term follow-up, and subsequent continuous intervention after carbon monoxide poisoning in children.

Carbon monoxide binds to heme proteins, causing hypoxia injury and inflammation. After aggressive treatment of early injury, some patients still develop delayed encephalopathy, which places a burden on their lives and society. Children are in a stage of growth and development, and long-term cognitive impairment will have a long-term impact on their subsequent development. There are very few reports on cognitive impairment in children after carbon monoxide poisoning. Using gas water heater in a closed bathroom to take a bath leads to CO poisoning, which is the most common cause of CO poisoning in this study, which is also consistent with previous research findings⁵.

4.1 COHb level:

COHb level is a reliable laboratory indicator for diagnosing acute CO poisoning. In previous studies, COHb as a biochemical indicator had a relatively weak correlation with the severity or prognosis of patient poisoning^6-8. The clinical detection of COHb level is affected by various factors^8,9. Under indoor air conditions¹⁰, the half-life of COHb is 320 minutes, while under 100% normal pressure oxygen conditions¹¹, the half-life is shortened to approximately 74 minutes. Therefore, using COHb alone to evaluate the prognosis of CO poisoning patients has certain limitations. In this study, the median COHb level was 8.8%. The COHb level in the cognitive abnormality group was lower than that in the normal group overall. Clinically, COHb level is often used to classify carbon monoxide poisoning into mild, moderate, and severe categories. However, considering that most children with cognitive impairment come from lower-level hospitals for referral, the COHb level may have significantly decreased by the time they arrive at our hospital. This also suggests that COHb level alone cannot be used to judge the severity of poisoning. A forensic study on low COHb levels of carbon monoxide poisoning in Shanghai, China¹² showed that acute carbon monoxide poisoning with low COHb (less than 30%) still resulted in patient death, accounting for 18.9% (58/307) of the total cases studied. A retrospective study conducted by the Portuguese National Institute of Legal Medicine and Forensic Science showed that there was one case of blood and internal organs with cherry red color, but the detected COHb level was only 3%¹³. Therefore, some studies have suggested using TBCO (total blood carbon monoxide) as a surrogate biomarker for COHb⁹. Because for TBCO, its concentration is relatively stable during observation regardless of temperature, time, and HS volume parameters; while for COHb, its concentration changes significantly during storage.

4.2 The severity of carbon monoxide poisoning:

Previous studies have shown that PSS (Poisoning Severity Score) is a good indicator for predicting the prognosis of CO poisoning^14,15, but they mainly predict short-term adverse outcomes. Therefore, there are limitations in predicting the long-term outcome of patients. A retrospective study of 331 children showed that Glasgow Coma Scale score, white blood cell count, and troponin T level are factors associated with the severity of CO poisoning in children, which may help predict the clinical outcome of children with CO poisoning¹⁶. This study defined severe poisoning as the use of positive inotropic drugs, mechanical ventilation therapy, or multiorgan failure, but did not follow up on the long-term prognosis of children. It only analyzed factors that may be related to severe poisoning. A study of CO poisoning in patients aged 16 or older¹⁷ showed that the main endpoint outcome was neurocognitive sequelae in the subsequent 4 weeks, with GDS scores ranging from good (1-3 points) to poor (4-7 points). The results showed that age greater than 50 years (1 point), Glasgow Coma Scale score less than or equal to 12 points (1 point), shock (1 point), serum creatine kinase level greater than 320 U/L at emergency department visit (1 point), and no use of hyperbaric oxygen therapy (1 point) were still significantly associated with poor outcomes, and the scoring system was named COGAS. The area under the receiver operating characteristic curve for the COGAS score was 0.862 (95% CI, 0.828-0.895) for the derivation cohort and 0.870 (95% CI, 0.779-0.961) for the validation cohort. This study had a longer follow-up period (3.6±1.5 years), and divided the patients into cognitive impairment group (11.5%, 13/113) and normal group (88.5%, 100/113) based on long-term GDS scores. The GDS scores of the 13 cases in the cognitive impairment group are shown in the table below.

Table 4 The gender, age, coma duration, GDS grade, admission GCS score and cranial imaging characteristics of children in the cognitive abnormality group.

No.	G	Age	GDS	Follow-up /y	Coma duration/h	GCS	Imaging Results
1	M	4	7	3.64	144	7	CT: SAH, brain swelling; patchy low-density shadow in the right basal ganglia region
2	F	4	3	5.89	120	6	CT: Large areas of low-density shadow with unclear edges can be seen in various brain lobes
3	M	12	3	5.92	192	5	MRI: abnormal signal changes in bilateral cerebral cortex and bilateral white matter regions near the posterior horn of lateral ventricles
4	F	8	3	4.77	1	15	MRI: symmetrical abnormal signals in the white matter surrounding the posterior horn of bilateral ventricles, which may be due to old lesions
5	F	15	3	5.85	720	6	MRI: Patchy and small patchy T1 slightly low, T2 slightly high and FLAIR high signal were observed in bilateral basal ganglia, right hippocampus, left temporal lobe, and bilateral cerebellar hemispheres. Patchy T1 low and T2 high signal were observed in the right occipital lobe. Symmetric patchy T1 slightly low and T2 high signal were observed in the posterior horn of bilateral lateral ventricles, considered to be demyelinating changes
6	F	12	2	2.92	0.3	15	MRI (-)
7	F	10	2	2.83	0.3	15	MRI (-)
8	F	15	2	5.26	0.33	15	CT (-)
9	F	5	2	4.88	192	3	CT: Abnormal signal foci in the left radiating corona, bilateral basal ganglia, hippocampus, and cerebellar hemisphere
10	F	4	2	4.49	360	3	CT: Decreased density in bilateral cerebellar hemispheres, bilateral temporal lobes, and part of the frontal lobe, with unclear gray-white matter demarcation, particularly in the cerebellum; brain swelling; suspected subarachnoid hemorrhage
11	F	7	3	2.48	240	13	MRI: changes of acute CO toxic encephalopathy
12	M	14	3	3.53	0.17	15	MRI (-)
13	M	8	2	1.90	0.3	15	MRI (-)

4.3 About the sequelae of nervous system:

A retrospective study from Taiwan on children showed that acute seizures, severe metabolic acidosis, significantly low blood pressure, prolonged unconsciousness, and longer hospitalization time were associated with delayed neurological sequelae (DNS)⁵. A total of 30 children were included in the study, and only 5 (16.7%) children developed delayed neurological sequelae, but all recovered completely within 2 months. Due to the small number of cases, no further analysis of risk factors was conducted. Another study on delayed neurological sequelae (DNS) or permanent neurological sequelae (PNS) in children after carbon monoxide poisoning showed that treatment in intensive care unit due to prolonged loss of consciousness was the only independent risk factor for patients with DNS². The use of ventilators was the only independent risk factor for patients with PNS. A total of 81 children were included in the study, and patients with PNS were followed up for more than 1 year, similar to our follow-up duration. Although the study concluded that prolonged loss of consciousness was the only independent risk factor for the occurrence of DNS, it did not analyze the impact of specific duration of consciousness loss on the long-term neurological prognosis of children. A systematic review included 2328 patients¹⁸, and the results showed that low initial GCS scores in patients with carbon monoxide poisoning were associated with the occurrence of delayed neurological sequelae, and the incidence of delayed neurological sequelae in GCS < 9 group was significantly higher than that in the control group (OR 2.80, 95% CI 1.91–4.12, I²= 34%). This study showed through univariate analysis that children with consciousness disorders for more than 1 day were associated with long-term neurological sequelae, and multivariate analysis showed that duration of consciousness disorders was an independent risk factor for long-term neurological sequelae, and most of the coma duration in cognitive impairment group was more than 1 day, with a median of 5 days (120 hours). Among the 13 children with long-term neurological sequelae, only 2 were treated with ventilators during hospitalization, and one of them had a GCS score of only 3 points upon discharge. However, we did not find a correlation between the use of ventilators and PNS, which may be related to insufficient case numbers.

4.4 Explanation of inspection indicators:

Although some test results between the two groups showed statistical differences in univariate analysis, due to the lack of some test results, the test results were not included in the regression analysis, which is one of the limitations of this study. However, through univariate analysis of some test results, it was shown that children with cognitive impairment had higher levels of inflammation, higher liver enzyme indicators, higher neurotransmitter enolase indicators, and higher D-dimer and fibrinogen indicators. A previous study reported that the levels of NSE (neuron-specific enolase, NSE) and S100B proteins increased after traumatic brain injury in children¹⁹. A study in children showed that the level of NSE increased in children with hypoxic brain injury related to carbon monoxide poisoning²⁰, which may indicate that NSE may be a meaningful indicator for detecting cerebral ischemia and anoxia injury after CO poisoning. In a study of adults (aged 53.48±19.29 years)²¹, the incidence of DNS(delayed neuropsychological sequelae) was 29.2% (84/288). This study showed that NLR (neutrophil-to-lymphocyte ratio) was an important independent predictor of DNS in COP(carbon monoxide poisoning) patients, which also reflected from the side that COP patients with higher inflammatory indicators may be more prone to later neurological damage. Therefore, the significance of test results for long-term neurological prognosis needs further research.

4.5 Significance of cranial imaging:

Cranial imaging changes are another characteristic of COP-induced hypoxic ischemic encephalopathy, and such changes may have certain value in predicting COP-related delayed encephalopathy. Magnetic resonance imaging (MRI) can be used to sensitively identify COP-related cytotoxic edema within 72 hours after CO exposure²². The globus pallidus is the most common location of abnormal MRI signals in patients with acute COP, with abnormal signals observed in 19.9% of COP patients. Most lesions were located in the cortex, hippocampus white matter, and basal ganglia (including the globus pallidus), while lesions in the brain stem and thalamus are rare²³. Among the 13 children with cognitive impairment in this study, 8 (61.5%, 8/13) had cranial imaging changes, while 4 (4%, 4/100) had cranial imaging changes in the normal group. Univariate analysis showed that there was a statistically significant difference in cranial imaging changes between the two groups (P<0.05). The most common imaging change is brain edema, with SAH observed in 2 cases and demyelinating changes observed in 1 case. Among the 13 cases, no abnormal changes were observed in the cranial imaging of children with coma time less than 1 hour. In the normal group, there were 4 cases with abnormal cranial imaging, with coma times of 120 hours, 20 hours, 3 hours, and 0.33 hours. These data may suggest a positive correlation between coma time exceeding 1 hour and brain hypoxic changes, that is, it is easier to observe brain injury on imaging, which is closely related to patient prognosis. Among the imaging techniques for detecting acute ischemic changes in the brain, MRI has higher sensitivity than CT in identifying lesions²⁴. Therefore, for children with coma time exceeding one hour, cranial imaging should be considered, preferably cranial MRI. The examination time should be within 72 hours after CO exposure²⁵, to determine whether there are brain injury changes, which has certain guiding significance for the later treatment of children.

4.6 Hyperbaric oxygen therapy:

Hyperbaric oxygen therapy (HBOT) can accelerate the clearance of carbon monoxide in the body by increasing oxygen partial pressure and ventilation, and is a recognized treatment method for acute carbon monoxide poisoning, with many research results and theoretical support²⁶. In terms of drugs, drugs that can alleviate downstream pathophysiological damage caused by acute CO poisoning include steroids, anti-inflammatory drugs, and mitochondrial electron transfer chain substrates²⁷. There is very little research on the relationship between the use of hyperbaric oxygen and prognosis in children with carbon monoxide poisoning. An earlier study showed that HBOT should be carried out within 6 hours after poisoning, which is related to the significant reduction of DNS incidence rate²⁸. A study from Taiwan suggests that the acceptable HBOT time is within 22.5 hours after CO poisoning. If HBOT is performed more than 48 hours after CO poisoning, it is not beneficial for preventing DNS. The overall trend of evidence is that for patients who have been assessed to require HBOT, implementing hyperbaric oxygen therapy as soon as possible under possible conditions may have greater benefits. Our center launched hyperbaric oxygen therapy earlier, with 86.7% (98/113) of all enrolled children receiving hyperbaric oxygen therapy. The median number of HBOT hospitalizations for the first time was 8, and most of them could start HBOT within 1 day after poisoning. For severely poisoned children, we will urgently arrange HBOT to expel carbon monoxide from the body as soon as possible. Continue HBOT after the acute phase to exert its potential neuroprotective effect, as studies have shown that high affinity hemoglobin for carbon monoxide may continue to slowly release CO within hours to days after COHb returns to normal levels, continuing to cause damage to the nervous system²⁹. However, there is no good evidence to support the number of HBOT sessions that should be implemented to prevent long-term neurological sequelae, and clinical judgment can only be based on actual conditions or experience.

In our study, children who did not receive hyperbaric oxygen therapy had a shorter length of hospitalization and mild symptoms. Through Spearman rank correlation analysis, the duration of consciousness impairment, length of hospitalization, and presence of other systemic complications were positively correlated with the number of HBOT sessions during the first hospitalization. Univariate analysis also showed a statistically significant difference in the number of HBOT sessions between the two groups of children, with a median of 12 sessions for children in the cognitive abnormality group during their first hospitalization, compared to 5 sessions for children in the normal group. This also suggests that our center tends to perform multiple sessions of HBOT for children with more severe conditions.

For children with an unconsciousness of more than 1 hour, it is recommended to consider performing a head imaging examination as soon as possible within 3 days after CO exposure to guide the treatment of the acute phase. For children who are transferred from lower-level hospitals to higher-level hospitals for treatment after CO poisoning, with an unconsciousness of more than 1 day or 5 days and more, long-term follow-up should be conducted to determine whether delayed encephalopathy or long-term cognitive impairment occurs, and timely and long-term intervention measures should be formulated.

This study has certain limitations. We focused primarily on assessing the cognitive and learning abilities of the pediatric patients and did not follow up on the impact of carbon monoxide poisoning on other systems. Firstly, the age range of the included patients was quite broad, and children's learning abilities and cognitive levels are constantly developing. Therefore, there are significant differences in these abilities among children of different age groups. To facilitate data analysis and statistical analysis, we uniformly adopted the GDS grading system, which may not provide an accurate assessment of the patients' cognitive and learning abilities. During the follow-up assessment of GDS scores, we primarily compared the patients with their peers of the same age to ensure the detection of any differences in cognitive and learning abilities compared to most children of the same age. Secondly, the impairment of cognitive and learning abilities in these patients was mostly mild, making it difficult to strictly distinguish between different severity levels. Therefore, this study did not further conduct subgroup analysis and instead included all patients with cognitive abnormalities into a unified group. Additionally, since this study was retrospective, some patients' blood biochemical tests were not comprehensive. We only conducted univariate analysis to identify some significant test items and did not include them in the multivariate binary regression analysis. This is another aspect where the study could be improved. Future considerations could include conducting a multicenter prospective study to more comprehensively analyze relevant risk factors.

Funding:

Self-funded scientific research project of the health and Health Commission of the Guangxi Autonomous Region, Grant ID: Z-B20231454

Author Contribution

TY.W. and JH.L. designed the study and performed the data analysis. YL.W, WJ.L and TY.W. performed the medical record system data collection and follow-up. TY.W wrote the main part of the paper. TY.W. and JH.L performed the database search and drafted the manuscript. All authors have read, revised, and approved the final manuscript.

Data Availability

The datasets generated and/or analyzed during the current study are not publicly available due to protect patient privacy information, but are available from the corresponding author on reasonable request.

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No competing interests reported.

Analysis of long-term prognosis of neurological sequelae in children with carbon monoxide poisoning

Status:

Version 1

Abstract

1. Introduction

2. Method

2.1 Study Design

2.2 Research methods

2.3 Statistical analysis

3. Result

4. Discussion

5. Conclusion

6. Limitations

Declarations

Funding:

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1