An early scoring system to predict mechanical ventilation for botulism: a single-center-based study

Abstract

BACKGROUND:

Early identification of patients requiring ventilator support will be beneficial for the outcomes of botulism. The present study aimed to establish a new scoring system to predict mechanical ventilation (MV) for botulism patients.

METHODS:

A single-center retrospective study was conducted to identify risk factors associated with MV in botulism patients from 2007 to 2022. Univariate analysis and multivariate logistic regression analysis were used to screen out risk factors for constructing a prognostic scoring system. The area under the receiver operating characteristic (ROC) curve was calculated.

RESULTS:

A total of 153 patients with botulism (66 males and 87 females, with an average age of 43 years) were included. Of these, 49 patients (32.0%) required MV, including 21 (13.7%) with invasive ventilation and 28 (18.3%) with non-invasive ventilation. Multivariate analysis revealed that botulinum toxin type, pneumonia, incubation period, degree of hypoxia, and severity of muscle involvement were independent risk factors for MV. These risk factors were incorporated into a multivariate logistic regression analysis to establish a prognostic scoring system. Each risk factor was scored by allocating a weight based on its regression coefficient and rounded to whole numbers for practical utilization ([botulinum toxin type A: 1], [pneumonia: 2], [incubation period ≤1 day: 2], [hypoxia <90%: 2], [severity of muscle involvement: grade II, 3; grade III, 7; grade IV, 11]). The scoring system achieved an area under the ROC curve of 0.82 (95% CI 0.75–0.89, P<0.001). At the optimal threshold of 9, the scoring system achieved a sensitivity of 83.7% and a specificity of 70.2%.

CONCLUSION:

Our study identified botulinum toxin type, pneumonia, incubation period, degree of hypoxia, and severity of muscle involvement as independent risk factors for MV in botulism patients. A score ≥9 in our scoring system is associated with a higher likelihood of requiring MV in botulism patients. This scoring system needs to be validated externally before it can be applied in clinical settings.

INTRODUCTION

Botulism is a severe neuroparalytic disease that can cause paralysis or even death.[1] Foodborne botulism often results from ingestion of food contaminated with botulinum neurotoxins (BoNTs). Among patients with botulism, acute respiratory failure (ARF) is associated with a six-month mortality rate of 30%.[2,3] Even among patients with mild symptoms at admission, ARF may still develop.

Mechanical ventilation (MV), either invasive or non-invasive, can save botulism patients from ARF.[3] For patients with severe respiratory failure, invasive MV in assist-control (A/C) mode or synchronized intermittent mandatory ventilation (SIMV) mode is recommended to ensure airway patency and effective ventilation, as well as relieving muscle fatigue. A meta-analysis has indicated that this approach may reduce the need for rescue therapies of life-threatening hypoxemia and even decrease the mortality rate in critically ill patients.[4] In addition, for patients with mild to moderate respiratory failure who maintain good consciousness and an ability to cough and clear airway secretions, non-invasive ventilation in continuous positive airway pressure (CPAP) or SIMV mode is suggested to ensure normal ventilation without the use of an endotracheal airway. This approach decreases complications related to a stay in the intensive care unit (ICU), length of hospitalization, and mortality in certain patient groups.[5] A previous study revealed that approximately 35% of botulism patients necessitated MV during an outbreak in Thailand.[2] The use of MV is expected to increase for botulism patients requiring treatment in the ICU.[6,7] Therefore, employing a model to identify patients at high risk of requiring MV is of great clinical significance. Here, we designed this study to identify risk factors of MV in patients with botulism and used them to construct a scoring system.

METHODS

Botulism is typically diagnosed clinically, epidemiologically (with known exposure and typical neurologic symptoms) or through laboratory testing. At our institution, a presumptive diagnosis is first made based on typical symptoms alone, and then a definitive diagnosis is established based on laboratory findings of BoNTs in serum or suspected foods.

A retrospective study was conducted from 2007 to 2022 at the Second Hospital of Hebei Medical University in China. Patients with clinically or laboratory-confirmed foodborne botulism in the emergency department were recruited. The inclusion criteria were as follows: (1) diagnosis based on the epidemiological characteristics and clinical manifestations outlined in the Diagnostic Criteria and Treatment principles for Food Poisoning Caused by Botulinum Neurotoxins (WS/T 83-1996) published by the Ministry of Health of the People’s Republic of China; (2) laboratory confirmation of botulinum toxin type using a lanthanide-based high-sensitivity fluorescence immunoassay (FICA) or enzyme-linked immunosorbent assay (ELISA) in patient serum; and (3) patients who did not receive antitoxin treatment upon admission. Those with obvious intracranial lesions, peripheral neuropathy from other causes, incomplete medical records, or inability to cooperate during physical examination were excluded. The patients were divided into two groups based on the need for ventilator support.

Demographic and clinical data at admission were recorded, including sex, age, botulinum toxin type, incubation period, symptoms such as dizziness, fatigue, abdominal pain, nausea, vomiting, and diarrhea, as well as muscle involvement classified as grade I (only eye muscles affected), grade II (eye and oropharyngeal muscles affected), grade III (respiratory muscles + grade II), or grade IV (skeletal muscles + grade III). Additionally, the number of comorbidities, degree of hypoxia, body mass index (BMI), and incidence of pneumonia (confirmed by high-resolution computed tomography [HRCT] in patients with symptoms such as cough, sputum, and fever) were recorded. Furthermore, we also analyzed 30 laboratory parameters in peripheral blood samples from all patients within 24 h of admission.

The number of patients requiring MV (including non-invasive and invasive ventilation) during their hospital stay was documented. In clinical practice, the decision to initiate ventilator support is usually based on the following outcomes. (1) Hypoxia: clinical signs such as difficulty in breathing, cyanosis, altered consciousness, sweating, and lung crackles. (2) Blood gas analysis: if the arterial oxygen pressure (PaO₂) falls below 50 mmHg (1 mmHg=0.133 kPa) and the carbon dioxide pressure (PaCO₂) rises above 50 mmHg in breathing room air in a resting state, severe hypoxia and carbon dioxide retention are indicated. (3) Pulmonary function testing: if the lung capacity is less than 1/3 to 1/4 of the predicted normal value, it indicates respiratory muscle weakness, impaired deep inspiration and effective coughing.

The SPSS 23.0 statistical software was used for the analysis. Normal distribution was assessed with the Shapiro-Wilk normality test. Unless otherwise noted, all the data are expressed as the mean ± standard deviation (SD). The t-test, χ² test, or Fisher’s exact test were employed to analyze the differences of variables between two groups. First, a univariate analysis was conducted to identify risk factors of MV in patients with botulism. Second, statistically significant factors (P<0.05) obtained from the univariate analysis were included in a multivariate logistic regression analysis, and regression coefficients were calculated. Third, the nearest integer value to the regression coefficient was assigned as the influencing factor score value to establish an early MV risk scoring system.[8-11] Fourth, the predictive performance of the scoring system was assessed by constructing a receiver operating characteristic (ROC) curve. The area under the ROC curve (AUC) was calculated, an appropriate cut-off value was selected, and the sensitivity, specificity, positive predictive value, and negative predictive value were determined.

RESULTS

General data

A total of 153 botulism patients (66 males and 87 females) were included. The clinical data are summarized in Table 1.

Table 1.

Demographics and clinical characteristics of the botulism patients (n=153)

Predictors of MV in botulism patients

The incidence of botulinum toxin type A was higher in patients requiring MV than in those requiring no MV (59.2% vs. 33.7%, P=0.003). Patients with an incubation period ≤1 d were more likely to require MV than those with an incubation period >1 d (89.8% vs. 10.2%, P<0.001). The incidences of grade I, II, III, IV muscle involvement in the ventilator support group were 2.0%, 16.3%, 44.9% and 36.7%, respectively. The results indicated that more severe muscle involvement in botulism patients predicted a higher likelihood of requiring MV (P<0.001). In patients with hypoxia <90%, the percentage of MV was higher in patients requiring MV than in those requiring no MV (69.4% vs. 44.2%, P=0.004). However, there were no statistically significant differences in sex, age, dizziness/fatigue, abdominal pain, nausea/vomiting, diarrhea, number of comorbidities, BMI, vital signs or laboratory data between the two groups (Table 2 and supplementaryTable 1).

Table 2.

Baseline characteristics of the patients

Logistic regression analysis and establishment of the scoring system

The univariate analysis revealed that botulinum toxin type A, pneumonia, incubation period ≤1 d, degree of hypoxia <90%, and severity of muscle involvement were associated with the need for MV (Table 3). Furthermore, we incorporated these significant factors into the multivariate logistic regression analysis, and the results were consistent between the univariate and multivariate analyses (Table 3). Ultimately, we identified five indicators (pneumonia, botulinum toxin type, incubation period, degree of hypoxia, and severity of muscle involvement) as independent predictors of MV.

Table 3.

Clinical risk factors for prediction of mechanical ventilation

Furthermore, we developed an MV risk scoring system for botulism patients. Each risk score was assigned with a weight based on its corresponding regression coefficient and then rounded to integer values for practical application. Botulinum toxin type A was assigned with 1 point. Pneumonia, incubation period of ≤1 d, and hypoxia degree <90% at admission were each assigned with 2 points. Muscle involvement grade II was assigned with 3 points, muscle involvement grade III with 7 points, and muscle involvement grade IV with 11 points (supplementary Table 2).

The ROC curve generated from the scoring system demonstrated an AUC of 0.82 (95% CI: 0.75–0.89, P<0.001) (Figure 1). Furthermore, we determined an optimal cut-off point of 9, corresponding to a maximum Youden index of 0.5386 (supplementary Table 3). At this cut-off value, the scoring system achieved a sensitivity of 83.7%, a specificity of 70.2%, a positive predictive value of 56.95%, and a negative predictive value of 90.12% in predicting the need for MV.

Figure 1.

ROC curve generated from the scoring system. ROC:receiver operating characteristic.

DISCUSSION

In this study, we identified pneumonia, botulinum toxin type, incubation period, degree of hypoxia, and severity of muscle involvement as independent risk factors for predicting the need for MV. An ROC curve area of 82% was obtained for the scoring system based on these factors, demonstrating its robustness in predicting the risk of MV at a cut-off of 9.

Our study confirmed that botulinum toxin type A was a predictor of the need for MV in botulism patients. It is widely recognized that toxins A, B, E, and F can cause various human diseases,[12] and the prevalence varies across geographic regions.[13] However, in Hebei Province, China, we detected that the most common botulinum toxin types were A and B. In the present study, patients with botulism caused by botulinum toxin type A had a significantly higher likelihood of requiring MV than patients with botulism caused by botulinum toxin type B. This difference may be attributed to variations in toxicity, target sites, duration of action, and affinity for neural tissue receptors among different toxins. Similar studies have shown that botulinum toxin type A, the most potent among the seven toxins, has a slower metabolism, a longer duration of action, and a stronger receptor affinity for tissues.[14-16] Its lethal oral dose for a 70-kg individual is approximately 70 µg, indicating a significantly stronger toxicity compared to type B.[16] One study also reported that serum specimens from patients with botulinum toxin type A were more likely to be positive in both the early and late stages of poisoning, suggesting that botulinum toxin type A increases the risk of developing severe symptoms.[17] Therefore, early detection of botulinum toxin types is crucial for the selection of antitoxins and the implementation of resuscitation.

Our research revealed that incubation period was an independent risk factor for MV in botulism patients. Symptoms typically start 18–36 h after exposure to foodborne BoNTs. In foodborne botulism, the consumption of improperly processed food leads to symptoms of nausea, vomiting, and diarrhea in the early stage of poisoning. Among the 197 outbreaks from 1920 to 2014 worldwide, the median incubation period between food intake and the onset of symptoms is reported to be 24 h.[6] Therefore, we chose a 24-hour (1-day) incubation period as a reference. Patients with an incubation period ≤1 d had a significantly higher likelihood of needing MV than did those with an incubation period >1 d. This conclusion may be attributed to various factors, such as the speed and quantity of toxin absorption and individual variability. Similar research has confirmed that a shorter incubation period is associated with a prolonged duration of MV.[18] Additionally, patients with a longer incubation period have a more favorable prognosis, with 3.35 times higher likelihood of successful weaning from the ventilator than patients with a shorter incubation period.[18] Thus, when managing patients with botulism in clinical scenarios, if the incubation period is ≤1 d, oxygen levels, blood gas analysis, and lung capacity should be well evaluated before tracheal intubation and MV.

Our research revealed that the level of hypoxia is an independent predictor of the need for MV in botulism patients. Specifically, patients with SpO₂ less than 90% were at a higher risk of requiring MV. Botulinum toxin may induce hypoxia through two mechanisms: diaphragmatic paralysis and partial or complete upper airway obstruction.[19,20] In cases of botulism, inadequate inspiration or airway obstruction typically precedes insufficient ventilation, with hypoxia or respiratory distress occurring shortly before respiratory failure.[21] Therefore, based on the indicator of hypoxia, defined as SpO₂ below 90%, the potential need for MV may be predicted before the onset of respiratory failure, thus effectively preventing respiratory failure in patients.

Our research highlighted a significant correlation between early pneumonia and the need for MV in patients with botulism. BoTNs do not directly cause pneumonia but can paralyze cranial nerve muscles to damage the upper respiratory tract, resulting in pharyngeal collapse or the accumulation of secretions.[22] Moreover, BoTNs also exert deleterious effects on respiratory muscles, including the diaphragm and intercostal muscles, causing subsequent complications, such as aspiration pneumonia.[23] Therefore, early chest CT scans are essential for detecting aspiration pneumonia and assisting in the selection of appropriate antibiotics, thereby improving the prognosis of patients with botulism.

Our research also validated that the severity of muscle involvement was an independent risk factor for predicting the need for MV in patients with botulism. Typical clinical manifestations of botulism include paralysis of the cranial nerve and descending muscle.[23] Muscle involvement deteriorates progressively over a sequence of ocular symptoms, oropharyngeal symptoms, respiratory muscle symptoms, and limb muscle symptoms. Consistently, a previous study demonstrated a positive correlation between the severity of muscle involvement and the duration of MV, suggesting that MV should be prolonged in patients with more severe muscle involvement.[24,25] Miceli et al[26] revealed a potential correlation between postprandial hypotension and the need for MV in individuals afflicted with botulism, suggesting that diaphragmatic paralysis induced by BoTNs at the level of the celiac ganglion could result in respiratory failure necessitating ventilatory assistance. In the present study, however, we found no differences in blood pressure between the groups requiring MV and those not requiring MV.

An efficient scoring system can help clinicians manage patients with botulism as follows. A preliminary diagnosis can be determined solely based on clinical observations, regardless of botulinum toxin type. Subsequently, a definitive diagnosis of BoNTs would be made using a lanthanide-based high-sensitivity FICA on serum and suspected foods. Following this, the patient is subjected to our scoring system. If a score is higher than 9, it suggests that the patient faces a higher likelihood of respiratory failure, and his or her blood gas parameters and pulmonary function should be actively monitored to prepare for MV.

Limitations

Our investigation has several limitations. First, this was a single-center retrospective analysis with a small sample size, which is characterized by inherent design bias and a lack of external validation. Second, the study cohort predominantly consisted of individuals affected by type A and type B BoTNs, with the exclusion of type E from this study. Third, due to the limited availability of clinical data, additional factors that may impact the initial prognosis of botulism, including laboratory testing parameters for botulism and certain autonomic nervous system parameters, were not integrated into our scoring system.

CONCLUSION

In conclusion, our study identified botulinum toxin type, pneumonia, incubation period, degree of hypoxia, and severity of muscle involvement as independent risk factors for MV in botulism patients. Furthermore, a score ≥9 in our scoring system is associated with a higher likelihood of requiring MV in botulism patients. The scoring system needs to be validated externally by further studies before it can be applied in a clinical setting.