Carbon monoxide (CO) poisoning causes brain injury by hypoxia and inflammatory mechanisms. Hypoxic conditions result in increased serum phosphate concentration due to loss of polarity of the cell membrane, changes in membrane fluidity, and consequent destruction of phospholipids in the cell membrane. This study aimed to evaluate whether serum phosphate measured in the emergency department (ED) can serve as an early predictor of neurocognitive sequelae 1 month after acute CO poisoning.
We included patients ≥16 years with acute CO poisoning from a cohort who were treated at a single tertiary academic hospital in Wonju, Korea, between January 2006 and May 2021. Neurocognitive outcome was assessed using the Global Deterioration Scale score; patients were classified into favorable (1–3 points) or poor (4–7 points) neurocognitive outcome groups based on this score. These two groups were compared before and after propensity score matching.
Data from 888 patients were analyzed. Seven hundred seventy-one patients (86.8%) were assigned to the favorable outcome group and 117 patients (13.2%) to the poor outcome group. Patients with a poor outcome had a higher mean serum phosphate level than those with a favorable outcome (3.9 mg/dL vs. 3.5 mg/dL, P=0.001). Propensity score matching yielded 85 matched patient pairs. After matching, serum phosphate level in the ED was not significantly different between the favorable and poor outcome groups (3.9 vs. 3.7 mg/dL, P=0.349).
Serum phosphate level measured in the ED did not predict poor neurocognitive outcomes 1 month after CO poisoning.
Carbon monoxide poisoning causes tissue hypoxia due to its affinity for hemoglobin, and direct inflammatory damage to tissues through various mechanisms. Hypoxic conditions result in increased serum phosphate concentrations due to loss of polarity of the cell membrane, changes in membrane fluidity, and consequent destruction of phospholipids in the cell membrane.
Serum phosphate level in blood evaluated in the emergency department did not predict poor neurocognitive outcomes at 1 month after carbon monoxide poisoning.
Carbon monoxide (CO) poisoning causes tissue hypoxia due to its affinity for hemoglobin, in addition to direct inflammatory damage to tissues through various mechanisms [
Patients with neurocognitive sequelae caused by CO poisoning may present with symptoms such as mental deterioration, cognitive dysfunction, amnesia, gait disturbance, mutism, urinary or fecal incontinence, psychosis, depression, and Parkinsonism [
Various biomarkers for neurocognitive prognosis in CO poisoning patients have been explored, including serum S100ß protein [
Phospholipids, a major element of cell membranes and nucleic acids, contain phosphate groups, and phosphate-containing compounds play essential roles in multiple physiological processes including cellular signal transduction, mineral metabolism, and energy exchange [
We hypothesized that higher serum phosphate levels assessed in the ED would correlate with worse neurocognitive outcomes in patients with CO poisoning. No previous studies have investigated the clinical usefulness of serum phosphate as an early predictor of poor neurocognitive outcomes in patients with acute CO poisoning. Therefore, the aim of this study was to evaluate the ability of serum phosphate measured in the ED to serve as a biomarker for early prediction of neurocognitive sequelae 1 month after acute CO poisoning.
The data used in our study were derived from a cohort treated at a single tertiary academic hospital in Wonju, Korea. In January 2006, a CO poisoning registry was opened to prospectively collect patient data in our hospital. Data from January 2006 to July 2020 were obtained from this registry, and data after August 2020 were collected prospectively with informed consent for the CARE CO cohort (ClinicalTrials.gov identifier: NCT04490317). We analyzed data collected between January 2006 and May 2021. The study was approved by the Institutional Review Board of Wonju Severance Christian Hospital (No. CR319133) and complied with the ethical guidelines of the Declaration of Helsinki. We anonymized patient data before the analyses.
The following criteria were used for exclusion: (1) less than 16 years old, (2) previous CO poisoning history, (3) a history of previous neurocognitive dysfunction such as stroke, dementia, or Parkinson’s disease before acute CO poisoning, (4) specific additive treatment such as therapeutic hypothermia or steroids, (5) serious illness such as advanced cancer, (6) insufficient data for important variables including serum phosphate, (7) preexisting parathyroid disease, as this could influence phosphate levels, (8) failure to follow-up neurocognitive status after discharge, and (9) fire as the CO source.
In our institution, acute CO poisoning is diagnosed based on the patient’s medical history and carboxyhemoglobin (COHb) >5% (for smokers, >10%). We treated patients with CO poisoning with 100% oxygen therapy through a face mask with a reservoir bag. Patients with any interval of loss of consciousness, neurocognitive symptoms or signs, cardiovascular dysfunction, elevated cardiac enzymes, ischemic electrocardiogram changes, severe acidosis, or COHb ≥25% were treated with HBO2 [
We evaluated the following clinical variables in CO poisoning patients: age, sex, intentionality of poisoning, source of CO (charcoal, oil, or gas), drug coingestion, maximal CO exposure time, initial Glasgow Coma Scale (GCS) at the site of rescue or ED arrival, comorbidities (diabetes mellitus, hypertension, cardiovascular diseases, and psychiatric diseases), alcohol coingestion, current smoker, symptoms and signs (loss of consciousness, shock, and seizure), and use of HBO2. Shock was defined as use of a vasopressor and lactate level greater than 2 mmol/L [
Laboratory parameters collected were serum COHb, bicarbonate, lactate, creatinine kinase, troponin I, and phosphate measured within 1 hour of ED arrival. Other electrolytes (sodium, potassium, calcium, and chloride) and variables that could affect phosphate levels (creatinine and albumin) were also measured [
Neurocognitive outcome was assessed using the Global Deterioration Scale (GDS) [
Summary statistics are reported as mean±standard deviation for numerical variables and as number (%) for categorical variables. Continuous data were compared using independent t-tests or Mann-Whitney U-tests, while categorical data were compared using Pearson chi-square tests or Fisher exact tests. The Shapiro-Wilks test was used to determine whether continuous variables were normally distributed.
To reduce the effect of selection bias and potential confounders, we used propensity score matching (PSM) to adjust for significantly different variables combined with clinically important variables related to the severity of CO poisoning (age, CO exposure time, GCS, diabetes mellitus, hypertension, loss of consciousness, shock, seizure, bicarbonate, lactate, creatinine, creatine kinase, and troponin I levels) [
All reported P-values are two-sided, and P-values <0.05 were considered statistically significant. SAS ver. 9.4 (SAS Institute Inc., Cary, NC, USA), and R ver. 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) were used for statistical analyses.
Among the 1,790 patients with acute CO poisoning, 888 patients were finally included in this study (
Baseline characteristics of included patients according to outcome are shown in
We investigated whether the 1-month GDS score changed after 1 year (86 patients were lost to follow-up at 1 year). The GDS score of 674 patients of 802 patients (84.0%) remained unchanged. Eighteen patients (2.3%) had an improved GDS score while 20 patients (13.7%) had a worse GDS score.
After performing 1:1 PSM with 13 covariates for the entire population, we obtained 85 matched patient pairs. The balance of covariates between the groups was checked (
We performed additional analysis to evaluate the ability of serum phosphate level to predict neurocognitive sequelae at an early stage after CO poisoning. In multivariable logistic regression models, serum phosphate was not a significant predictor of a poor prognosis (
In this study, serum phosphate level was significantly higher in those patients with a poor outcome before PSM. However, serum phosphate level did not show a significant association with a poor outcome after PSM for factors related to the severity of CO poisoning. In addition, serum phosphate was not a significant predictor of poor outcome in multivariable logistic regression models. This means that serum phosphate level alone cannot predict a poor outcome 1 month after acute CO poisoning. A few studies have reported increased serum phosphate levels in various hypoxia-related diseases. In cardiac arrest patients, serum phosphate is known to be related to prognosis [
We attribute the fact that serum phosphate was not useful for predicting the prognosis of acute CO poisoning patients to the following factors. First, serum phosphate is known to be elevated according to the degree of hypoxia. However, the hypoxic insult of acute CO poisoning may not be as severe as that of cardiac arrest in which severe ischemia occurs due to complete blockage of oxygen supply. That is, the hypoxia of CO may not be severe enough to cause a significant change in serum phosphate level. In general, serum lactate is known to reflect tissue hypoxia [
The study had several limitations. First, it was an observational, nonrandomized study. Hidden bias may therefore be present due to the effects of unmeasured confounders. Second, although a few randomized control trials have conducted multiple neurocognitive tests (approximately six tests usually equivalent to CO screening batteries) [
In conclusion, serum phosphate level evaluated at the ED did not predict poor neurocognitive outcomes 1 month after CO poisoning.
Global Deterioration Scale
Global Deterioration Scale
Subgroup analysis
Density plot of propensity scores according to presence of poor neurological outcome. (A) Before and (B) after propensity score matching.
Prognostic power for poor neurocognitive outcome by area under the receiver operator characteristic curve.
Supplementary materials are available at
No potential conflict of interest relevant to this article was reported.
This work was supported by the National Research Foundation (NRF) grant funded by the Korean government (the Ministry of Science and ICT) (No. NRF-2021R1A2C2004922).
Study flow diagram. CO, carbon monoxide.
Comparison of serum phosphate levels at 1 month (A) before and (B) after propensity score matching.
Linear trends in serum phosphate levels according to changes in Global Deterioration Scale (GDS) scores at 1 month (A) before and (B) after propensity score matching.
Smoothing restricted cubic splines plot of the odds ratio of a poor neurocognitive outcome based on logistic regression (A) before and (B) after propensity score matching. CI, confidence interval.
Baseline characteristics of the propensity score matched and unmatched cohorts
Characteristic | Unmatched |
Matched |
|||||
---|---|---|---|---|---|---|---|
Favorable outcome (n = 771) | Poor outcome (n = 117) | P-value | Favorable outcome (n = 85) | Poor outcome (n = 85) | P-value | ||
Age (yr) | 47.4 ± 16.0 | 57.9 ± 17.0 | < 0.001 | 54.9 ± 16.4 | 55.8 ± 17.6 | 0.725 | |
Male sex | 493 (63.9) | 66 (56.4) | 0.116 | 60 (70.6) | 49 (57.7) | 0.110 | |
Intentionality | 320 (41.5) | 54 (46.2) | 0.343 | 36 (42.4) | 43 (50.6) | 0.282 | |
Source | 0.018 | 0.599 | |||||
Charcoal | 647 (83.9) | 108 (92.3) | 76 (89.4) | 78 (91.8) | |||
Gas | 124 (16.1) | 9 (7.7) | 9 (10.6) | 7 (8.2) | |||
Drug coingestion | 60 (7.8) | 12 (10.3) | 0.361 | 11 (12.9) | 9 (10.6) | 0.634 | |
CO exposure time (hr) | 5.3 ± 4.5 | 9.1 ± 4.8 | < 0.001 | 8.0 ± 4.3 | 8.1 ± 4.7 | 0.849 | |
GCS score | 13.1 ± 2.9 | 9.1 ± 3.6 | < 0.001 | 9.7 ± 3.8 | 10.0 ± 3.4 | 0.549 | |
Comorbidity | |||||||
Diabetes mellitus | 77 (10.0) | 19 (16.2) | 0.042 | 10 (11.8) | 11 (12.9) | 0.816 | |
Hypertension | 136 (17.6) | 36 (30.8) | 0.001 | 23 (27.1) | 26 (30.6) | 0.612 | |
Cardiovascular disease | 30 (3.9) | 5 (4.3) | 0.843 | 5 (5.9) | 3 (3.5) | 0.469 | |
Psychiatric disease | 98 (12.7) | 19 (16.2) | 0.293 | 18 (21.2) | 15 (17.7) | 0.561 | |
Alcohol | 303 (39.3) | 34 (29.1) | 0.033 | 36 (42.4) | 28 (32.9) | 0.205 | |
Current smoker | 317 (41.1) | 33 (28.2) | 0.008 | 34 (40.0) | 27 (31.8) | 0.263 | |
Time from rescue to ED arrival (hr) | 3.5 ± 3.1 | 3.8 ± 3.1 | 0.375 | 3.7 ± 3.2 | 3.8 ± 3.0 | 0.815 | |
Symptoms and signs in the ED | |||||||
Loss of consciousness | 441 (57.2) | 107 (91.5) | < 0.001 | 74 (87.1) | 75 (88.2) | 0.816 | |
Shock | 22 (2.9) | 14 (12.0) | < 0.001 | 9 (10.6) | 8 (9.4) | 0.798 | |
Seizure | 9 (1.2) | 8 (6.8) | < 0.001 | 5 (5.9) | 5 (5.9) | 1.000 | |
Use of HBO2 | 709 (92.0) | 100 (85.47) | 0.022 | 72 (84.7) | 75 (88.2) | 0.501 | |
Laboratory findings | |||||||
COHb (%) | 22.1 ± 14.4 | 23.8 ± 15.3 | 0.248 | 27.3 ± 16.6 | 23.8 ± 14.6 | 0.141 | |
Phosphate (mg/dL) | 3.5 ± 1.1 | 3.9 ± 1.3 | 0.001 | 3.9 ± 1.7 | 3.7 ± 1.3 | 0.349 | |
Bicarbonate (mmol/L) | 20.7 ± 3.7 | 18.5 ± 4.2 | < 0.001 | 18.5 ± 4.0 | 18.7 ± 4.3 | 0.739 | |
Lactate (mmol/L) | 2.9 ± 2.4 | 3.8 ± 3.2 | < 0.001 | 3.8 ± 3.0 | 3.9 ± 3.4 | 0.828 | |
Creatinine (mg/dL) | 0.9 ± 0.3 | 1.2 ± 0.7 | < 0.001 | 1.08 ± 0.46 | 1.09 ± 0.49 | 0.886 | |
Creatine kinase (U/L) | 987.5 ± 3,281.7 | 4,422.9 ± 5,323.2 | < 0.001 | 3,036.3 ± 6,094.2 | 3,648.6 ± 5,078.7 | 0.478 | |
Troponin I (ng/mL) | 1.0 ± 3.7 | 4.8 ± 8.1 | < 0.001 | 4.4 ± 8.5 | 3.6 ± 6.1 | 0.511 | |
Albumin (g/dL) | 4.4 ± 0.4 | 4.2 ± 0.4 | < 0.001 | 4.2 ± 0.4 | 4.2 ± 0.5 | 0.629 | |
Sodium (mmol/L) | 140.0 ± 3.1 | 140.8 ± 3.5 | 0.007 | 140.0 ± 3.9 | 141.0 ± 3.5 | 0.104 | |
Potassium (mmol/L) | 4.1 ± 0.5 | 4.3 ± 0.6 | 0.001 | 4.2 ± 0.6 | 4.2 ± 0.6 | 0.688 | |
Calcium (mg/dL) | 8.9 ± 0.5 | 8.8 ± 0.6 | 0.014 | 8.8 ± 0.6 | 8.8 ± 0.6 | 0.732 | |
Chloride (mmol/L) | 105.9 ± 3.9 | 106.7 ± 4.3 | 0.058 | 106.6 ± 4.8 | 107.0 ± 4.6 | 0.646 |
Values are presented as mean±standard deviation or number.
CO, carbon monoxide; GCS, Glasgow Coma Scale; ED, emergency department; HBO2, hyperbaric oxygen therapy; COHb, carboxyhemoglobin.
Multivariable logistic regression analysis to evaluate predictors of a poor neurocognitive prognosis
Variable | Univariable |
Model 1 |
Model 2 |
||||
---|---|---|---|---|---|---|---|
OR (95% CI) | P-value | OR (95% CI) | P-value | OR (95% CI) | P-value | ||
Age (yr) | 1.04 (1.03–1.05) | < 0.001 | 1.05 (1.03–1.06) | < 0.001 | 1.04 (1.02–1.06) | < 0.001 | |
Male sex | 0.73 (0.49–1.08) | 0.117 | - | - | - | - | |
Intentionality | 1.21 (0.82–1.79) | 0.343 | - | - | - | - | |
Source | |||||||
Charcoal | Reference | Reference | Reference | ||||
Gas | 0.44 (0.22–0.88) | 0.021 | - | - | 0.50 (0.20–1.25) | 0.137 | |
Drug coingestion | 1.36 (0.71–2.60) | 0.362 | - | - | - | - | |
CO exposure time (hr) | 1.17 (1.13–1.22) | < 0.001 | 1.13 (1.07–1.19) | < 0.001 | 1.12 (1.06–1.19) | < 0.001 | |
GCS score | 0.74 (0.7–0.78) | < 0.001 | 0.79 (0.73–0.86) | < 0.001 | 0.80 (0.73–0.87) | < 0.001 | |
Comorbidities | |||||||
Diabetes mellitus | 1.75 (1.01–3.01) | 0.045 | 0.88 (0.44–1.80) | 0.732 | 0.91 (0.43–1.89) | 0.790 | |
Hypertension | 2.08 (1.34–3.20) | 0.001 | 1.11 (0.61–2.00) | 0.739 | 1.01 (0.55–1.84) | 0.980 | |
Cardiovascular disease | 1.10 (0.42–2.90) | 0.843 | - | - | - | - | |
Psychiatric disease | 1.33 (0.78–2.27) | 0.294 | - | - | - | - | |
Alcohol | 0.63 (0.41–0.97) | 0.035 | - | - | 0.95 (0.51–1.76) | 0.860 | |
Current smoker | 0.56 (0.37–0.86) | 0.008 | - | - | 0.74 (0.39–1.37) | 0.332 | |
Time from rescue to ED arrival (hr) | 1.03 (0.97–1.09) | 0.375 | - | - | - | - | |
Symptoms and signs at the ED | |||||||
Loss of consciousness | 8.01 (4.12–15.55) | < 0.001 | 2.27 (1.00–5.16) | 0.052 | 2.13 (0.93–4.89) | 0.074 | |
Shock | 4.63 (2.30–9.33) | < 0.001 | 1.05 (0.43–2.57) | 0.918 | 1.28 (0.49–3.35) | 0.609 | |
Seizure | 6.21 (2.35–16.45) | 0.000 | 1.36 (0.40–4.64) | 0.621 | 1.32 (0.38–4.63) | 0.663 | |
Use of HBO2 | 0.51 (0.29–0.92) | 0.024 | - | - | 0.71 (0.32–1.58) | 0.404 | |
Laboratory findings | |||||||
COHb (%) | 1.01 (1.00–1.02) | 0.248 | - | - | - | - | |
Bicarbonate (mmol/L) | 0.88 (0.84–0.92) | < 0.001 | 0.98 (0.9–1.07) | 0.636 | 1.00 (0.92–1.10) | 0.946 | |
Lactate (mmol/L) | 1.12 (1.05–1.19) | 0.001 | 0.95 (0.84–1.07) | 0.387 | 0.98 (0.86–1.12) | 0.765 | |
Creatinine (mg/dL) | 4.67 (2.97–7.33) | < 0.001 | 2.22 (1.19–4.15) | 0.012 | 2.49 (1.29–4.82) | 0.007 | |
Creatine kinase (U/L) | 1.00 (1.00–1.00) | < 0.001 | 1.00 (1.00–1.00) | 0.005 | 1.00 (1.00–1.00) | 0.010 | |
Troponin I (ng/mL) | 1.11 (1.08–1.15) | < 0.001 | 1.02 (0.98–1.06) | 0.369 | 1.01 (0.97–1.05) | 0.628 | |
Phosphate (mg/dL) | 1.29 (1.12–1.48) | 0.001 | 0.84 (0.68–1.04) | 0.113 | 0.81 (0.65–1.02) | 0.068 | |
Albumin (g/dL) | 0.36 (0.22–0.59) | < 0.001 | - | - | 0.64 (0.29–1.40) | 0.263 | |
Sodium (mmol/L) | 1.09 (1.03–1.17) | 0.007 | - | - | 1.07 (0.99–1.16) | 0.088 | |
Potassium (mmol/L) | 2.08 (1.47–2.96) | < 0.001 | - | - | 1.14 (0.69–1.87) | 0.605 | |
Calcium (mg/dL) | 0.60 (0.42–0.86) | 0.005 | - | - | 1.23 (0.70–2.17) | 0.472 | |
Chloride (mmol/L) | 1.05 (1.00–1.10) | 0.058 | - | - | - | - |
Model 1 was adjusted for statistically significant and clinically important variable not including electrolytes variables. Model 2 was adjusted for significant variables from all variables.
OR, odds ratio; CI, confidence interval; CO, carbon monoxide; GCS, Glasgow Coma Scale; ED, emergency department; HBO2, hyperbaric oxygen therapy; COHb, carboxyhemoglobin.
Baseline characteristics of cohorts by the propensity score matching without laboratory variables
Characteristic | Favorable (n = 85) | Poor outcome (n = 85) | P-value |
---|---|---|---|
Age (yr) | 54.9 ± 16.4 | 55.8 ± 17.6 | 0.725 |
Male sex | 60 (70.6) | 49 (57.7) | 0.079 |
Intentionality | 36 (42.4) | 43 (50.6) | 0.282 |
Source | 0.599 | ||
Charcoal | 76 (89.4) | 78 (91.0) | |
Gas | 9 (10.6) | 7 (8.2) | |
Drug coingestion | 11 (12.9) | 9 (10.6) | 0.634 |
CO exposure time (hr) | 8.0 ± 4.3 | 8.1 ± 4.7 | 0.849 |
GCS score | 9.7 ± 3.8 | 10.0 ± 3.4 | 0.549 |
Comorbidity | |||
Diabetes mellitus | 10 (11.8) | 11 (12.9) | 0.816 |
Hypertension | 23 (27.1) | 26 (30.6) | 0.612 |
Cardiovascular disease | 5 (5.9) | 3 (3.5) | 0.469 |
Psychiatric disease | 18 (21.2) | 15 (17.7) | 0.561 |
Alcohol | 36 (42.4) | 28 (32.9) | 0.205 |
Current smoker | 34 (40.0) | 27 (31.8) | 0.263 |
Time from rescue to ED arrival (hr) | 3.7 ± 3.2 | 3.8 ± 3.0 | 0.815 |
Symptoms and sign at the ED | |||
Loss of consciousness | 74 (87.1) | 75 (88.2) | 0.816 |
Shock | 9 (10.6) | 8 (9.4) | 0.798 |
Seizure | 5 (5.9) | 5 (5.9) | 1.000 |
Use of HBO2 | 72 (84.7) | 75 (88.2) | 0.501 |
Laboratory findings | |||
COHb (%) | 27.3 ± 16.6 | 23.8 ± 14.6 | 0.141 |
Bicarbonate (mmol/L) | 18.5 ± 4.0 | 18.7 ± 4.3 | 0.739 |
Lactate (mmol/L) | 3.8 ± 3.0 | 3.9 ± 3.4 | 0.828 |
Creatinine (mg/dL) | 1.1 ± 0.5 | 1.1 ± 0.5 | 0.886 |
Creatine kinase (U/L) | 3,036.3 ± 6,094.2 | 3,648.7 ± 5,078.7 | 0.478 |
Troponin I (ng/mL) | 4.4 ± 8.5 | 3.6 ± 6.1 | 0.511 |
Phosphate (mg/dL) | 3.9 ± 1.7 | 3.7 ± 1.3 | 0.349 |
Albumin (g/dL) | 4.2 ± 0.4 | 4.2 ± 0.5 | 0.629 |
Sodium (mmol/L) | 140.0 ± 3.9 | 141.0 ± 3.5 | 0.104 |
Potassium (mmol/L) | 4.2 ± 0.6 | 4.2 ± 0.6 | 0.688 |
Calcium (mg/dL) | 8.8 ± 0.6 | 8.8 ± 0.6 | 0.732 |
Chloride (mmol/L) | 106.6 ± 4.8 | 107 ± 4.6 | 0.646 |
Values are presented as mean±standard deviation or number (%).
CO, carbon monoxide; GCS, Glasgow Coma Scale; ED, emergency department; HBO2, hyperbaric oxygen therapy; COHb, carboxyhemoglobin.