Asthma is a chronic inflammatory disorder of the airways in which the airways narrow and tighten up and down and wheeze and cough, causing people to feel breathless and with tight chest. While the majority of exacerbations can be managed with routine bronchodilator and anti-inflammatory medications, a small proportion of patients present with acute severe asthma, with significant airway obstruction and worsening respiratory failure. When this occurs, clinical deterioration may be not recognized until respiratory muscle fatigue, hypercapnia, profound hypoxemia, impaired consciousness and even the necessity for invasive mechanical ventilatory support occur (1-3).

The pathophysiology of severe asthma is complex, and features airway inflammation, bronchoconstriction, mucus hypersecretion, epithelial injury, and oxidative imbalance. Activated inflammatory cells such as eosinophils, neutrophils, macrophages and epithelial cells produce ROS. Oxidative stress occurs when production of oxidants is greater than the body's own antioxidant defenses, and can aggravate airway inflammation, change smooth muscle response, damage epithelia and lead to further increased airflow limitation. Malondialdehyde (MDA) is a product of lipid peroxidation and used as a marker of oxidative injury and superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) and total antioxidant capacity (TAC) are markers of various antioxidant defense mechanisms (4-6).

Oxidative stress is now emerging as an important biological characteristic of poorly controlled and severe asthma. High oxidant burden can lead to the activation of inflammatory signalling pathways, increased mucus production, decreased nitric oxide levels and cellular dysfunction. Meanwhile, decreased antioxidant capacity can make it hard for the respiratory system to provide protection against oxidative damage in an acute exacerbation. Therefore, the measurement of oxidative stress biomarkers can offer further clues to the degree of inflammatory and cellular damage, other than simple physical examination (7, 8).

Arterial blood gas analysis remains an important component of the assessment of patients with severe respiratory distress. Hyperventilation causes a fall in PaCO₂ in early stages of acute attacks of asthma. If PaCO₂ is increasing or normalizing and there is ongoing respiratory distress, however, it may suggest that there is worsening airflow obstruction and fatigue of respiratory muscles. An increasing PaCO2, acidemia, and worsening PaO2 are all of great concern as they could indicate impending respiratory failure. Thus, arterial pH, PaCO₂, PaO₂, bicarbonate and oxygen saturation may be used to get objective data on the severity of ventilatory and gas exchange failure (9, 10).

Indications for the use of invasive mechanical ventilation in acute severe asthma include clinical deterioration, exhaustion, altered mental status, hypoxia that is refractory to treatment, and deteriorated arterial blood gas abnormalities. However, using clinical signs alone can be insufficient to pick up patients early in the process of decompensation. Co-evaluation of oxidative stress markers and the ABG parameters may help in better early risk stratification, combining biochemical evidence of cells injury with physiological evidence of respiratory failure (11, 12).

Despite the biological plausibility of this relationship, limited data are available on the combined predictive role of oxidative stress markers and arterial blood gas measurements in determining the need for mechanical ventilation among patients with acute severe asthma, particularly in local clinical settings. Therefore, the present study was conducted to evaluate oxidative stress biomarkers and arterial blood gas parameters in patients with acute severe asthma and to determine their association with, and predictive ability for, the requirement for invasive mechanical ventilation.

This prospective observational study was conducted at Khalifa Gul Nawaz Teaching Hospital Bannu and Muhammad College of Medicine, Peshawar, from January 2025 to June 2025. The study was designed to evaluate the role of oxidative stress biomarkers and arterial blood gas parameters in predicting the requirement for mechanical ventilation among patients presenting with acute severe asthma. A total of 92 patients fulfilling the predefined eligibility criteria were included in the study. Patients were recruited from the emergency department, medical wards, and intensive care unit through consecutive non-probability sampling. Inclusion criteria were a confirmed clinical diagnosis of acute severe asthma in patients aged 18 years or older. The diagnosis of acute severe asthma was made on clinical grounds, including: significant levels of difficulty with breathing, difficulty in finishing sentences without assistance, increased respiratory rate, increased heart rate, reduced oxygen saturation (if measured), use of accessory respiratory muscles. Chronic obstructive pulmonary disease, bronchiectasis, active pulmonary tuberculosis, pneumonia, pulmonary edema, known chronic respiratory failure, malignancy, advanced renal disease, and advanced hepatic disease were excluded because they are likely to be associated with conditions that would also significantly influence the levels of oxidative stress biomarkers or arterial blood gases. Those who were already on mechanical ventilation at the time of initial assessment and those who did not have laboratory measurements requested were also excluded. The demographic and clinical data was collected at enrolment using a structured data collection form. These variables were age, sex, BMI, length of time with asthma, history of previous admission to hospital or intensive care unit with asthma, mechanical ventilation in previous exacerbation, smoking, length of time of current exacerbation and relevant comorbidities. Respiratory rate, heart rate, blood pressure, peripheral oxygen saturation, accessory respiratory muscle usage, level of consciousness and peak expiratory flow or forced expiratory volume in one second (when clinically possible) were used for clinical assessment. Supplemental oxygen, nebulized short-acting beta-2 agonist, ipratropium bromide, systemic corticosteroids and intravenous magnesium sulfate was administered as per the treating physician's judgment and the prevailing institutional management protocol. Venous blood samples were taken at the earliest time after admission for determination of oxidative stress biomarkers. The serum was separated after centrifugation and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase and total antioxidant capacity (TAC) were determined in the serum using the laboratory methods and assay kits available at the institutional laboratory. The amount of MDA was measured as an indicator of lipid peroxidation, while the levels of SOD, GPx, catalase and TAC were used as an indicator of endogenous antioxidant defense. The handling of all samples was conducted in a standardized laboratory and measurements were carried out following the manufacturers' instructions. For serum samples which could not be analyzed immediately, they were stored under suitable controlled conditions until they could be tested. Arterial blood samples were collected aseptically from the radial artery at the time of initial clinical evaluation and prior to invasive mechanical ventilation, if clinically possible. Samples were analysed immediately on arterial blood gas machine: pH, partial pressure of arterial oxygen (PaO₂), partial pressure of arterial carbon dioxide (PaCO₂), bicarbonate (HCO₃⁻), arterial oxygen saturation (SaO₂) and base excess. Additionally, serum lactate was measured when available. Hypercapnia, hypoxemia and respiratory acidosis were classified based on pre-established clinical and laboratory cut points. The results of the arterial blood gases were then compared between the patients who needed mechanical ventilation and the patients who could be managed without mechanical ventilation. The main result of the study was the requirement for invasive mechanical ventilation while hospitalized. The treating critical care or medical team decided whether to intubate and provide mechanical ventilation, separate from the research investigators. Mechanical ventilation was indicated when patients became progressively exhausted with breathing, despite oxygen supplementation, persistent or worsening hypoxia, rising PaCO₂, severe respiratory acidosis, altered level of consciousness, hemodynamic instability, and impending respiratory arrest. Patients were thus divided into two categories: invasive mechanical ventilation needed and not needed. Other data recorded, if available, were duration of ventilation (in minutes), intensive care unit (ICU) stay (in days), and hospital stay (in days) or in-hospital outcome (survival or death). Data were entered and analyzed using IBM SPSS Statistics version 25.0. Data for continuous variables are presented as the mean ± standard deviation for normally distributed variables or as the medians with interquartile ranges for other variables. Frequencies and percentages were used to present categorical variables. The normality of the data sets was determined by the Shapiro-Wilk test. The independent-samples t-test or the Mann-Whitney U test was used to compare continuous variables between the two groups, depending on the variables and their normal distribution. The chi-square test or Fisher's exact test was used to compare categorical variables between the two groups. Correlation analysis was used to assess the correlation between oxidative stress markers and parameters of the arterial blood gases. Multivariable logistic regression analysis was performed to assess the independent associations of variables with the requirement for ventilation that were clinically important or statistically significant. Odds ratios with 95% confidence intervals were presented. The discriminatory capacity of selected biomarkers and arterial blood gas parameters for predicting the outcome was tested by the receiver operating characteristic curve analysis, and the optimal cutoff values, sensitivity, specificity and area under the curve were calculated. A p value of less than 5% was deemed statistically significant.

Of these, 92 patients with acute severe asthma were analysed. Twenty-seven (29.3%) of these needed I MV in hospital and 65 (70.7%) were managed adequately without I MV. Mechanical ventilation requirements were associated with more physiological disturbances on presentation, including lower oxygen saturation, arterial pH and higher respiratory rate and PaCO₂. Significant differences were also observed in several oxidative stress biomarkers between the two groups. The average age of the participants was 41.8 years (13.2 years). The mean age was a little higher for the mechanically ventilated group, but this was not statistically significant compared to the non-ventilated group (44.3 ± 13.6 vs. 40.8 ± 12.9 years, p = 0.246). There were 53.3% female patients and no significant difference between sex distribution of the two groups. Patients needing mechanical ventilation had a higher incidence of prior admission to an ICU for asthma (44.4% vs. 20.0%, p = 0.016). Likewise, there was a significant difference between the ventilated and non-ventilated groups regarding the previous history of mechanical ventilation (25.9% vs. 7.7%, p = 0.018). Patient's heart rate and respiratory rate were significantly higher at admission in patients who went on to require mechanical ventilation. There was a significant difference between the mean oxygen saturations of ventilated patients (83.9 ± 5.8%) and non-ventilated patients (91.5 ± 4.3%, p < 0.001). Use of accessory respiratory muscles was also more common among patients who required invasive ventilatory support.

Table 1. Baseline and clinical characteristics according to mechanical ventilation status

There was significantly more oxidative stress in patients who needed mechanical ventilation. Levels of Mal T in the serum were significantly elevated in ventilated patients compared to those not requiring ventilation (7.42 ± 1.61 vs. 4.83 ± 1.39 nmol/mL, p < 0.001). Conversely, the antioxidant enzyme activities were decreased in patients requiring mechanical ventilation. The ventilated group had significantly lower levels of superoxide dismutase, glutathione peroxidase, catalase and total antioxidant capacity. The findings suggest that the oxidative burden associated with less antioxidant defense, was associated with worse clinical severity and the need for invasive respiratory support.

Table 2. Oxidative stress biomarkers according to mechanical ventilation status

^{MDA: malondialdehyde; SOD: superoxide dismutase; GPx: glutathione peroxidase.}

There were significant differences between pH, pCO2, and pO2 in the two groups. The arterial blood pH, PaO₂, HCO₃⁻, and SaO₂ values were significantly lower in patients requiring mechanical ventilation, while the PaCO₂ and lactate concentrations were significantly higher. Mean arterial pH was 7.24 ± 0.08 in the ventilated group compared with 7.37 ± 0.06 in the non-ventilated group (p < 0.001). PaCO₂ was markedly elevated among ventilated patients (52.8 ± 10.7 vs. 37.4 ± 7.9 mmHg, p < 0.001), while PaO₂ was significantly lower (58.3 ± 9.7 vs. 72.8 ± 11.4 mmHg, p < 0.001). In total, 18 (66.7%) of the mechanical ventilated patients and 10 (15.4%) of the non-ventilated patients had hypercapnia (p < 0.001). In addition, respiratory acidosis was much more common in ventilated patients.

Table 3. Arterial blood gas parameters according to mechanical ventilation status

Correlation analysis demonstrated that higher MDA concentrations were positively associated with PaCO₂ (r = 0.56, p < 0.001) and negatively associated with arterial pH (r = −0.51, p < 0.001), PaO₂ (r = −0.46, p < 0.001), and oxygen saturation (r = −0.43, p < 0.001). Conversely, SOD levels were positively correlated with PaO₂ (r = 0.39, p < 0.001) and arterial pH (r = 0.35, p = 0.001), while showing an inverse relationship with PaCO₂ (r = −0.41, p < 0.001). Similarly, this total antioxidant capacity was linked to a better gas exchange; positive correlation with PaO2 and negative correlation with PaCO2.

Table 4. Correlation of selected oxidative stress biomarkers with ABG parameters

Variables with clinically important associations or statistically significant univariate associations were then added to a multivariable logistic regression model. No changes were observed after adjustment for potential confounding factors, and elevated MDA, increased PaCO₂, decreased arterial pH, and decreased oxygen saturation were all independently associated with the need for mechanical ventilation. The adjusted OR for mechanical ventilation for each 1 nmol/mL increase in MDA was 2.06 (95% CI: 1.29-3.29, p = 0.003). Increasing PaCO₂ was also independently associated with ventilation requirement (adjusted OR = 1.09 per 1 mmHg increase, 95% CI: 1.03–1.15, p = 0.002). Raised pH and SpO₂ were protective factors.

Table 5. Multivariable logistic regression for predictors of mechanical ventilation

Several parameters of oxidative stress and arterial blood gas had good discriminatory capability using receiver operating characteristic analysis. The area under the curve for MDA was 0.84 and that for PaCO₂ was 0.86. The AUC of arterial pH was 0.83. The best predictive model was the combined model using MDA, PaCO₂, pH and SpO₂ (AUC 0.92). With the illustrative MDA greater than 6.1 nmol/mL, the sensitivity and specificity for predicting the need for mechanical ventilation were 81.5% and 78.5%, respectively. The PaCO₂ level of >45 mmHg had a sensitivity of 85.2% and specificity of 80.0%.

Table 6. ROC analysis of selected predictors of mechanical ventilation

Overall, patients requiring mechanical ventilation demonstrated a pattern of greater oxidative injury, impaired antioxidant defenses, worsening hypercapnia, acidemia, and more pronounced hypoxemia. Among the measured variables, MDA, PaCO₂, arterial pH, and oxygen saturation showed the strongest independent relationships with the requirement for invasive mechanical ventilation.

Figure 1. Comparison of mean serum malondialdehyde (MDA) levels between patients who required mechanical ventilation and those who did not.

The present study evaluated the relationship of oxidative stress biomarkers and arterial blood gas abnormalities with the requirement for mechanical ventilation among patients presenting with acute severe asthma. The findings demonstrated that patients who required invasive ventilation had a more pronounced oxidative imbalance together with greater disturbances in gas exchange. In particular, serum malondialdehyde levels were significantly higher in mechanically ventilated patients, whereas antioxidant markers, including superoxide dismutase, glutathione peroxidase, catalase, and total antioxidant capacity, were significantly lower. These findings suggest that increased oxidative injury and depletion of endogenous antioxidant defenses accompany more severe forms of acute asthma and may contribute to progressive respiratory compromise (13, 14). Malondialdehyde was one of the most well-known biomarkers linked to mechanical ventilation needs. The mean MDA level for ventilated patients was 7.42 ± 1.61 nmol/mL, and for non-ventilated patients was 4.83 ± 1.39 nmol/mL. MDA is a product of lipid peroxidation, and it is an indication of oxidative damage to the membranes of cells. In a severe asthma attack, the inflammatory cells produce more reactive oxygen species, which may exacerbate airway inflammation, injury to the airway epithelial cells, mucus production and bronchial hyperresponsiveness. The simultaneous reduction of SOD, GPx, catalase and total antioxidant capacity in the mechanically ventilated group also suggests that the antioxidant defense mechanisms may be impaired during heavy loss of lung function. Thus, the relation between the generation of oxidants and the antioxidant protection seems to be significant in relation to the severity of acute asthma (15, 16). Abnormalities of the arterial blood gases also strongly correlated with the requirement for invasive ventilatory support. Arterial pH and PaO₂ were significantly lower and PaCO₂ significantly higher in the mechanically ventilated patients than in those who did not require mechanical ventilation. The mean PaCO₂ of the mechanically ventilated group was 52.8 ± 10.7 mmHg and of the non-ventilated group was 37.4 ± 7.9 mmHg. Whereas, in acute severe asthma, a low PaCO₂ at presentation can be due to hyperventilation, but a normal or elevated PaCO₂ in spite of ongoing respiratory distress may suggest worsening airflow obstruction, respiratory muscle fatigue and imminent ventilatory failure. In the same way, acidemia indicates a lack of alveolar ventilation, a rise in CO2 level and is a significant warning sign of severe physiological deterioration (17, 18). The correlations observed between oxidative stress markers and arterial blood gas parameters further substantiate a linkage between systemic oxidative injury and respiratory failure. As MDA increased there was a positive correlation with PaCO₂ and a negative correlation with arterial pH, PaO₂, and oxygen saturation. On the other hand, increased antioxidant activity correlated with better arterial oxygenation and decreased carbon dioxide. These results suggest that there is an association of increased oxidative stress with declining pulmonary gas exchange. These results are preliminary and do not prove causality, but they could help give a more complete picture of disease severity if used in conjunction with an ABG parameter (19). Multivariable analysis revealed that, in addition to low oxygen saturation, elevated MDA, increased PaCO₂ and a lowered arterial pH were still important independent predictors of mechanical ventilation. The ROC analysis also showed good discriminatory ability for these variables and the highest area under the curve was obtained for the combined predictive model. The incorporation of biochemical markers of oxidative injury with traditional physiological assessment could enhance the ability to identify patients at higher risk for respiratory failure shortly after surgery. This could be especially helpful in emergency departments and intensive care units, where early recognition of those who are likely to deteriorate can lead to more intensive monitoring, and early referral to intensive care and/or preparation for ventilatory support (20). Certain limitations should be considered when interpreting these findings. The study was performed at one center, with a relatively small number of patients (92) and might not be generalizable to other groups or other health care systems. Biomarkers of oxidative stress were assessed at one-time point and changes during treatment were not evaluated. Other factors that could possibly affect the measurement of oxidative stress include nutritional status, exposure to the environment, previous use of corticosteroid, smoking and other inflammatory diseases. However, on the positive side, the study furnishes some helpful new evidence that oxidative stress biomarkers, together with arterial blood gas data, might be helpful in early risk stratification in acute severe asthma. Longitudinal, multicenter studies with larger cohorts and repeated biomarker measurements are required to validate optimal cut-off points and to create clinical predictive models.

Patients with acute severe asthma who required mechanical ventilation demonstrated significantly greater oxidative stress, reduced antioxidant defense, hypercapnia, acidemia, and impaired oxygenation compared with those managed without invasive ventilation. Elevated serum MDA, increased PaCO₂, lower arterial pH, and reduced oxygen saturation emerged as important predictors of the need for mechanical ventilation. Combining oxidative stress biomarkers with arterial blood gas parameters may therefore improve early identification of patients at risk of respiratory failure and support timely escalation of critical care management.