Substance Use Disorder as Risk Factor for Intubation in Angioedema: A Nationwide Cohort Study

INTRODUCTION

Angioedema (AE) is characterized by a rapid swelling of dermal, subcutaneous, or submucosal tissue, most commonly affecting the face and mucosa of the head and neck.¹ While symptoms of AE are generally self-limited, involvement of the larynx can result in life-threatening airway obstruction requiring emergency intervention.²

Pathophysiologically, AE occurs due to increased vascular permeability and excessive fluid extravasation into surrounding tissue, and the process is classified by its primary inflammatory mediator: either histamine or bradykinin.³ Histaminergic AE is the result of mast cell degranulation and is most often caused by an acute IgE-mediated allergic reaction, which can be triggered by allergies to certain foods, insect-stings, latex, drugs, or other stimuli.⁴ Histaminergic AE can also be the result of non-IgE-mediated “pseudoallergic” responses, which are caused by direct mast cell stimulation at the MRGPRX2 receptor by certain drugs such as opioids and radiocontrast media.⁵ Additional etiologies of mast cell-related AE include aspirin or NSAID-associated hypersensitivity reactions, as well as chronic urticaria.^6-8

Major etiologies of bradykinin-mediated AE include drug action and C1-esterase deficiency. Angiotensin-converting enzyme (ACE) inhibitors, which inhibit the breakdown of bradykinin, are the most common cause of drug-induced AE, with studies estimating that 0.1%–0.7% of patients taking ACE inhibitors develop AE.^{2, 6, 9} Other medications including angiotensin receptor blockers (ARBs), neprilysin inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, calcium channel blockers (CCBs), mTOR inhibitors, and fibrinolytic agents have also been associated with an increased risk of AE, especially when used in combination with ACE inhibitors.^10-15 C1-inhibitor deficiency exists in the hereditary form, as in hereditary angioedema (HAE), or in the acquired form, most often seen in elderly patients with an associated lymphoproliferative or autoimmune disorder.^{16, 17}

AE accounts for approximately 117,000 emergency department (ED) visits per year.¹⁸ A 2019 study estimated the rate of AE-related hospitalization in the US population at 4.4 per 100,000.¹⁹ Tongue, glottis, or laryngeal swelling can put the patient with AE at risk for airway compromise and are frequent indications for hospitalization.²⁰ Therefore, hospitalization can be used as a proxy measure of the severity of AE. Typical initial medical management of undifferentiated AE includes antihistamines, corticosteroids, and epinephrine, although these are less likely to be effective in bradykinin-mediated AE.²¹ Evaluation by nasopharyngeal laryngoscopy is recommended for patients with suspected upper airway involvement. In severe cases of airway obstruction, intubation or cricothyrotomy/tracheotomy may be necessary.²²

Kostis et al. published results from a multicenter, randomized, double-blind, active-controlled trial studying 25,302 patients with hypertension that compared the safety and efficacy of omapatrilat, an inhibitor of both neprilysin and ACE, to the ACE inhibitor enalapril. Of the 12,557 patients in the enalapril group, 0.7% developed AE, compared with 2.2% in the omapatrilat group.²³ Analysis from the so-named OCTAVE trial found populations with a higher risk for developing AE while on enalapril included those older than 65 years, African Americans, women, and patients with a history of drug rash or seasonal allergies.^{10, 24, 25} Women, smokers, and patients with a prior history of AE have also been shown to have a higher risk of developing AE.²⁴ However, factors that contribute to the development of particularly severe presentations of AE are not yet well understood.

Substance use disorders (SUDs), which involve excessive use of alcohol, nicotine, cannabis or other illicit substances, have a lifetime prevalence of 2%–9% in the United States.²⁶ Recent studies have shown that SUD is associated with a systemic inflammatory state, which may result in increased baseline bradykinin levels in these patients.²⁷ Additionally, smokers were shown to have lower serum DPP-4 activity leading to decreased bradykinin breakdown, which has been proposed as a mechanism for increased rates of AE in this population.²⁸ We hypothesized that SUD is a risk factor for severe presentations of AE and may lead to an increased rate of adverse outcomes. In this national database retrospective cohort study, we estimated the risk of hospitalization, intubation, and tracheotomy as a result of AE among patients with various SUDs compared with matched individuals without SUDs.

MATERIALS AND METHODS

RESULTS

The demographic characteristics of the patients with AE and the sample sizes as a function of SUD subtype are shown in Table I. Patients with SUD were older (mean age: 53.2 ± 14.3 years) than those without SUD (49.4 ± 20.3 years). There were more men in the SUD population (49% vs. 34%), and the percentage of African Americans was higher in the SUD (37%) than in the non-SUD (24%) sample. The prevalence of adverse socioeconomic determinants of health was also higher in the SUD population than in patients without SUD (7% vs. 2%). AE patients with SUD had a higher lifetime prevalence of measured comorbidities and were more likely to be taking ACE inhibitors (all p < 0.001).

Among the AE population, the risk of hospitalization ranged from 20.4% for tobacco use disorder to 30.4% for cocaine use disorder, all significantly higher than the 8.0% in the non-SUD population (p < 0.001). The RRs for hospitalization between SUD and non-SUD cohorts after propensity score matching for demographics (age, gender, and ethnicity), adverse socioeconomic determinants of health, and comorbid conditions remained significantly higher for all SUD subtypes, the highest being for alcohol and cannabis use disorders (RR = 1.85, 95% CI: 1.73–1.98 for alcohol; RR = 1.85, 95% CI: 1.68–2.04 for cannabis; RR = 1.79, 95% CI: 1.60–1.99 for cocaine; RR = 1.75, 95% CI: 1.67–2.04 for tobacco; and RR = 1.81, 95% CI: 1.62–2.03 for opioids) (see Table II).

The Risk Ratios for intubation between SUD and non-SUD cohorts after propensity score matching for also remained significantly higher for all SUD subtypes, the highest being for cannabis use disorder (RR = 2.75, 95% CI: 2.31–3.27 for alcohol; RR = 3.67, 95% CI: 2.69–5.02 for cannabis; RR = 2.96, 95% CI: 2.17–4.05 for cocaine; RR = 2.44, 95% CI: 2.44–2.78 for tobacco; and RR = 2.14, 95% CI: 1.89–3.51 for opioids) (see Table III).

The RRs for tracheotomy between SUD and non-SUD cohorts after propensity score matching for were significantly higher for only alcohol and tobacco use disorders, the highest being for alcohol use disorder (RR = 2.82, 95% CI: 1.73–4.58 for alcohol; RR = 1.75, 95% CI: 0.82–3.55 for cannabis; RR = 1.6, 95% CI: 0.73–3.52 for cocaine; RR = 2.45, 95% CI: 1.79–3.34 for tobacco; and RR = 1, 95% CI: 0.42–2.40 for opioids) (see Table IV).

DISCUSSION

In this retrospective cohort study, the authors report that the overall risk for hospitalization among patients presenting with AE ranged from 20.4% for tobacco use disorder to 30.4% for cocaine use disorder, all significantly higher than the 8.0% in a population without SUD. The authors propose that hospitalization is an indicator of clinical severity in AE; therefore, all SUD subtypes in this study were associated with a higher risk for severe presentation of AE.

This study shows significant differences in adverse socioeconomic factors and comorbidities between the SUD group and non-SUD group. After propensity matching for age, gender, ethnicity, adverse socioeconomic factors, and common comorbidities, the risk of hospitalization from AE remained significantly higher in the SUD subtype groups compared with the matched non-SUD subtype groups. Although risk for hospitalization is likely dependent on a complex interaction of many factors, these results suggests that SUD independently increases risk of adverse outcomes in patients who develop nonhereditary AE.

The outcomes of intubation and tracheotomy were also studied using propensity-matched SUD and non-SUD groups. Each SUD subtype that was studied was associated with a higher risk of intubation following AE, ranging from RR of 2.44 in tobacco use disorder to RR of 3.96 in cannabis use disorder. A systemic inflammatory state caused by long-term substance use may contribute to the increased risk of intubation. The outcome of tracheotomy, which may indicate that patients were difficult to intubate or were intubated for a prolonged period, was significantly higher only in the alcohol and tobacco use disorder groups compared with matched non-SUD groups (RR = 2.82 and RR = 2.45, respectively).

To our knowledge, this is the first study looking specifically at individual SUDs as risk factors for severe AE. There are several studies in the literature exploring other risk factors or predictive clinical findings for adverse outcomes in AE. Loftus, et al. found in an 875 patient retrospective review that significant risk factors for severe cases of AE included older age, Hispanic race, ACEi-induced AE type, American Society of Anesthesiologists class III or above, coexistent cardiopulmonary disease, and a positive smoking history.³⁰ They found that hospitalization or airway intervention was seen in 20.2% of smokers compared with 7.8% of nonsmokers. In comparison, our study saw 19.7% of smokers were hospitalized versus 11.5% of nonsmokers in propensity-matched cohorts.

Kieu et al. found in a case series of 311 AE patients who were evaluated with flexible laryngoscopy that those with edema of the face, upper lip, or lower lip were at lower risk for airway intervention, while involvement of the tongue, soft palate, vallecula, aryepiglottic folds, and true vocal cords were at highest risk for airway intervention.³¹ Additionally, they found that dysphagia, dysphonia, drooling, respiratory distress, and globus sensation were associated with higher risk of airway intervention. Clinical evaluation and direct visualization with laryngoscopy remain the mainstay of deciding whether to intubate.

Identifying high-risk patients is important as the number of AE hospitalizations are increasing progressively, from 12,078 in 2001 to 18,050 in 2014 according to Shrestha, et al.¹⁹ Further studies should examine if an increasing number of risk factors in an individual patient increases the risk of adverse events from AE.

Lochbaum et al. highlight the importance of concomitant medications that can increase risk of developing AE in patients also taking ACE inhibitors. Direct DPP-4 inhibitors (i.e. gliptins) pose only a minor risk of AE development when taken alone, but may pose a higher risk when taken together with ACE inhibitors.³² Similarly, mTOR inhibitors like sirolimus and everolimus, which are immunosuppressants typically used in transplant patients, have been implicated in increasing the risk of AE in patients taking ACE inhibitors. Byrd et al. compared 145 transplant patients who were taking ACE inhibitors versus non-transplant, ACE inhibitor-exposed controls and found that the transplant group was significantly more likely to develop AE.²⁸ Further studies should ask whether patients taking ACE inhibitors concomitantly with DPP-4 inhibitors or immunosuppressants are at higher risk for severe cases of AE.

Strengths of this study include a large sample size which allows us to study a relatively infrequent outcome in specific patient populations (e.g., individual SUDs).

One limitation is that the ICD codes used by TriNetX do not categorize AE by etiology. For example, studying a cohort of ACE inhibitor AE patients may reveal high-risk patients when prescribing ACE inhibitors. Furthermore, application of these data is difficult, as the laryngoscopy findings and clinical presentation are key for evaluating severity of AE in a time-limited, practical setting.

CONCLUSION

This is the largest study to date studying SUD as a risk factor for severe forms of AE. Each SUD subtype studied was associated with a higher risk of hospitalization and intubation when presenting with AE. Physicians should be aware of certain risk factors that may require a higher acuity level of care, including history of tobacco and cannabis use.