The treatment of status asthmaticus in the intensive care unit: A narrative review

Abstract

Asthma is a common chronic respiratory disease where exacerbations can be associated with significant morbidity, mortality, and economic burden. Severe asthma exacerbations (SAEs) represent life-threatening episodes of symptom burden that require intensive care treatment. While outpatient asthma management is well-established by major organizational guidelines, there are limited evidence-based recommendations for treatment of SAEs requiring intensive care. This narrative review synthesizes current literature regarding conventional inpatient asthma therapies, ventilation strategies, and emerging rescue modalities for management of SAEs, including inhaled anesthetics and veno-venous extracorporeal membrane oxygenation and discusses future areas of interest for research. Until more robust clinical data is available, intensivists should weigh the potential risks and benefits of more advanced rescue therapies and consider a multidisciplinary approach to determining those most likely to benefit from these interventions.

Keywords

status asthmaticus severe asthma exacerbation mechanical ventilation inhaled anesthetics VV-ECMO

Introduction

Asthma is a common, chronic, non-infectious respiratory disease characterized by episodes of reversible airflow obstruction, bronchial hyperresponsiveness, and often excessive type 2 (Th2) inflammatory cell proliferation. It also commonly has overlap with the atopic spectrum of diseases mediated through exaggerated IgE responses, including atopic dermatitis and allergic rhinitis. In a CDC survey focused on the national burden of asthma, there were an estimated 13.8 million adults with asthma in the United States (US) during 2001 to 2003, suggesting a population-level prevalence of 6.7%.¹ Of those, 55.6% reported at least one asthma attack in the past 12 months, and there were 299,300 hospital discharges in the US with a primary diagnosis of asthma exacerbation (2.2% of all adults with asthma). Some 4010 adult deaths were attributed to asthma (0.03% of all adults with asthma).¹

Intensive care unit (ICU)-specific data are less straightforward to obtain, but a large meta-analysis of 215 hospitals’ inpatient admissions in 2000 showed N = 29,430 admissions for asthma, of which 10.1% (n = 2976) were admitted to the ICU and 2.1% (n = 632) were intubated.² Intubated patients were admitted for 4.5 days longer and incurred >$11,000 in additional costs over non-ICU admissions.² Clearly then, status asthmaticus, hereafter referred to as severe asthma exacerbations (SAEs), constitute life-threatening, economically burdensome events. In fact, the total annual cost burden of asthma in the United States, including direct healthcare costs and absentee-related economic losses, was estimated to be $81.9 billion in 2013.³ Thankfully, multiple highly effective biologic agents targeting Th2 inflammation have been developed in recent years and have been associated with markedly decreased rates of exacerbation.^4–6 However, global warming and subsequent climate change are expected to increase allergic disease burdens, including asthma, so treatment of SAEs remains a topic of significant relevance.⁷

Literature review and current guideline recommendations

Several guidelines exist for the diagnosis and management of asthma, including the ERS/ATS guidelines⁸ and the Global Initiative for Asthma.⁹ However, most guidelines target recommendations at the outpatient management of asthma, rather than SAEs. A recent review in 2024 discussed the current therapeutic landscape in life-threatening SAEs, as well as the feasibility of rescue treatment modalities including non-invasive positive pressure ventilation (NIPPV), mechanical ventilation (MV), extracorporeal carbon dioxide (CO₂) removal, and veno-venous extracorporeal membrane oxygenation (VV-ECMO).¹⁰ However, guideline-based recommendations on inpatient-level SAEs are significantly lacking. The summary below assesses the evidence base of the most commonly utilized SAE treatments, as well as more unconventional rescue therapies.

In general, the backbone of SAE treatment is the use of systemic glucocorticoids, continuous or frequent administration of nebulized short-acting bronchodilators, respiratory support when indicated using either NIPPV or MV, the allowance of so-called “permissive hypercapnia,” and treatment of any other underlying infections. Less commonly utilized rescue therapies include intravenous (IV) or inhaled magnesium, ketamine or epinephrine infusion, and an admixture of helium and oxygen known as heliox. We will discuss each in turn.

Literature search strategy

There is not a strong evidence base of randomized controlled trials (RCTs) for the treatment of SAEs in adults with asthma. Much of current clinical practice has been derived either from trials in children or infants, or from prospective case series in adults. In this narrative review, using the PubMed search term “Status Asthmaticus” [Mesh], we searched for all RCTs conducted between 1965 and 2025 on SAEs. There were N = 46 results, only n = 5 of which were performed in adults having an exacerbation necessitating an emergency department (ED) visit or hospitalization (the remainder were outpatient exacerbations). Using the PubMed search term ““Asthma” [Mesh] AND “exacerbation””, we searched for all RCTs conducted between 1965 and 2025 written in English and being listed as occurring exclusively in patients aged 19 years or older. There were N = 446 results, only n = 31 of which were performed in adults having an exacerbation necessitating an ED visit or hospitalization. Exclusion criteria for this review included studies that only included pediatric patients, only studied outpatient management of asthma, or that were not written in English.

Conventional treatments in status asthmaticus

Medications in status asthmaticus

Systemic steroids

Systemic steroids have long been used to treat asthma.¹¹ Historically, large or even pulse-dose steroids (methylprednisolone 1000 mg) have been used in SAEs.¹² However, interest in higher doses was tempered after cases of steroid-associated myopathies were reported.¹³ One early RCT found no benefit with methylprednisolone 500 mg over 100 mg IV,¹⁴ and a Cochrane Review came to a similar conclusion.¹⁵ Consequently, typical practice is now to use medium-dose systemic glucocorticoids (prednisone 40 mg to 1 mg/kg) for at least 5 days or until clinical improvement.^15,16 GINA Guidelines suggest prednisone 50 mg, hydrocortisone 200 mg, or dexamethasone 12–16 mg as reasonable daily doses.⁹ No strong RCT data exists for steroid weaning strategies, and strategies are typically driven by provider preference and individualized to patient improvement, although expert consensus statements do exist.¹⁷

Inhaled bronchodilators

A foundational medication in the treatment and stabilization of SAEs are short-acting −2 adrenergic agonists (SABAs), primarily albuterol.¹⁸ The IV use of SABAs for SAEs has been used in the past, with salbutamol being the most studied agent.¹⁹ In children experiencing SAEs, continuous SABA nebulization has been shown in a single-center RCT to be more effective than intermittent nebulization,²⁰ but continuous administration is often chosen in the ICU setting to decrease the logistical burden of repeated nebule administrations. It is unclear if adding short-acting muscarinic antagonists (SAMAs) to a SABA improves symptomatic control, as one RCT showed no significant benefit to adding ipratropium to levalbuterol for SAE patients presenting to the ED²¹; however, few if any adverse effects have been demonstrated, so SAMAs are often used as baseline or adjunctive therapy.

Magnesium

Early single-center studies suggested that IV magnesium may reduce hospitalization rates for ED patients,²² but subsequent trials have failed to show benefits.^23,24 A Cochrane Review assessing inhaled magnesium suggested possible but uncertain additive benefit to patients already receiving SABAs and SAMAs, but it is important to note that the studies in the meta-analysis did not contain patients admitted to the ICU setting.²⁵ GINA guidelines state that it is reasonable to consider intravenous magnesium sulfate administration if intensive initial treatments are ineffective after the first hour. In the 2025 guidelines, inhaled magnesium is not recommended due to lack of demonstrated efficacy.⁹ It is reasonable to administer magnesium early in the course of presentation to the hospital as a single dose of intravenous magnesium sulfate given its relative safety, however, there are no guidelines that suggest continuous magnesium infusion or targeting serum levels of magnesium.

Epinephrine

There is historic experience with the use of IV epinephrine in children with SAEs,^26,27 but in that population IV epinephrine was compared directly to inhaled SABA and did not show significant clinical differences.²⁸ Given the more invasive nature of an IV infusion over a nebulized treatment, nebulized SABAs came to be favored over IV epinephrine or IV SABA administration. However, physiologic arguments for epinephrine use seem plausible and center on its potent beta agonistic bronchodilatory effects as well as concerns about SABA delivery to target receptors in severely bronchospastic lungs with poor airflow. As such, epinephrine remains in the armamentarium of rescue therapies for SAEs.¹⁰ GINA guidelines recommend IM epinephrine for acute asthma associated with anaphylaxis and angioedema but do not recommend its routine use for other causes of asthma.⁹

Ketamine

A prospective, observation trial of N = 11 patients without a control group showed that ketamine infusion improvements in mean peak inspiratory pressure (PIP), partial pressure of carbon dioxide in arterial blood (P_aCO₂), and pressure of oxygen in arterial blood (P_aO₂).²⁹ However, in several single-center RCTs, ED administration of IV ketamine has not decreased hospitalization rates for SAEs.^30,31 A systematic review in 2022 found no net benefit in the use of ketamine for SAEs.³² Overall, evidence supporting ketamine infusion — either to avoid hospitalization or as an adjunct during ICU admission — is mixed and sparse, but it is typically well tolerated and does hold theoretical bronchodilatory effects. It is primarily used as a sedative in intubated asthma patients for theoretical bronchodilatory effects rather than as a primary asthma therapy.

Ventilation strategies

NIPPV

A stronger evidence base for NIPPV exists for COPD than for asthma, but NIPPV is commonly used for SAEs when patients exhibit poor air movement, respiratory distress, or altered levels of consciousness secondary to their acute respiratory acidosis. It is also used as a temporizing therapy to avoid the need for MV. The largest study to date assessing NIPPV in SAEs was a single-center retrospective review assessing N = 186 asthma admissions.³³ Most patients were treated with CPAP rather than BiPAP or other NIPPV modes, including patients with decreased levels of consciousness; on average, the modality appeared well tolerated with a low prevalence of subsequent intubation.³³ BiPAP does allow inspiratory support not delivered by CPAP, which theoretically should provide benefit in fatiguing asthma patients with hypercapnia. Given that MV does not improve the underlying pathophysiology of asthma and patients are much more difficult to manage after intubation, a trial of NIPPV is preferred over MV whenever possible in SAEs.

Mechanical ventilation

Mechanical ventilation in SAE is often complicated by high airway resistance and obstructive pathology with resultant air trapping. Mechanical ventilation strategies for SAEs thus prioritize maximizing expiratory time while ensuring tidal volume delivery. Volume delivery can best be guaranteed with a volume-controlled mode, which also often has the advantage of shorter inspiratory times than pressure-controlled modes. The choice of a square waveform best minimizes inspiratory time.

A key goal of mechanical ventilation in SAE is to allow adequate time for exhalation through bronchospastic airways. This strategy relies on a low respiratory rate maintained with sedation or paralytics if necessary to maintain a low inspiratory time: expiratory time (I:E) ratio. Naturally, a low respiratory rate will often require tolerating some level of hypercapnia, a strategy referred to as permissive hypercapnia. This strategy comes from a recognition that normalizing a patient’s pH from their SAE-induced primary respiratory acidosis risks serious adverse effects (e.g., air trapping, pneumothorax, or autoPEEP leading to cardiovascular collapse). Hypercapnia, even marked hypercapnia, is generally well tolerated in patients with asthma.¹ Accordingly, the purpose of NIPPV or MV in SAE is not per se to reduce P_aCO₂ but rather to keep the patient alive long enough for their bronchospasm to improve from other therapies (steroids, bronchodilators, etc.).

In addition to low inspiratory times and low respiratory rate, ventilator management in SAE requires careful management of pressures. Careful application of PEEP can help minimize work of breathing and improve respiratory dynamics, but SAE patients are at high risk for dynamic hyperinflation and auto-PEEP significantly higher than external PEEP levels that have been set. Frequent assessment for breath stacking and autoPEEP is important to avoid the associated adverse effects. Unrecognized dynamic hyperinflation, in the setting of either NIV or mechanical ventilation, will increase intrathoracic pressure, reduce venous return, cause RV compromise, and can induce hemodynamic collapse and cardiac arrest. This is a common cause of mortality in SAE.

Because of high airway resistance, SAE patients will also experience high peak pressures. It should be recognized that these high inspiratory pressures are usually due to high airway resistance and not transmitted to alveoli, thus not dangerous to the lungs. High peak pressures should be tolerated on volume control modes as needed to ensure adequate volume is delivered. Plateau pressures, rather than inspiratory pressures, should be monitored. It is important to note, though, that uptrending peak pressures may be a sign of dynamic hyperinflation and should prompt evaluation of plateau pressures rather than being ignored.

Heliox

The admixture of 70 to 80% helium and 20 to 30% oxygen, termed “heliox,” has a density one-third that of room air. Its theorized benefit is that its lower density will reduce airflow turbulence and thus ease ventilation; this is predicated on the observation that airflow is turbulent out to tenth generation airways and laminar thereafter.³⁴ Despite this promising hypothesis, systematic reviews on heliox in SAEs have found no clinically meaningful benefit in the general asthma population.^35,36 In a 2006 Cochrane review, it was noted that studies examining patients with severe obstruction were more likely to show significant improvement while mild to moderate disease did not.³⁶ It is worth noting that most study populations have been small and heterogeneous with wide ranges of clinical severity from mild to severe changes in pulmonary function, various formulations of helium-oxygen mixtures, and use of heliox to washout atmospheric air or as a driving gas for nebulizer therapy. A recent randomized control trial in severe COPD exacerbations requiring NIPPV found heliox was well tolerated and did improve some clinical parameters, suggesting that for severe obstructive respiratory failure, which includes SAEs, heliox remains an option when more traditional methods of ventilation have failed.³⁷

Conclusions on conventional therapies

The strength of the evidence base for SAE treatments is lacking, especially regarding adults admitted into an ICU setting on NIPPV or MV. However, it appears that systemic steroids, short-acting bronchodilators, and intravenous magnesium all appear safe and likely effective at treating SAEs. Epinephrine and ketamine IV infusions remain optional adjunctive therapies, with less clear clinical benefit and potential adverse effects. Ventilation options with either NIPPV or MV focused on permissive hypercapnia appear safe and well tolerated, especially in the predominantly younger population of SAE patients. Heliox may have some small added benefits as a rescue therapy in severe obstructive disease, but it lacks consistently demonstrated benefits that would necessitate its more regular use. Table 1 provides a summary of standard dosing recommendations for the conventional therapies discussed above. Finally, there is emerging interest in initiating biologic therapies targeted at Th2 inflammation during SAEs, rather than waiting until the outpatient setting for chronic symptom control.³⁸ So far, only compassionate-use case reports of this practice exist,^39–43 but given the success of biologic asthma medications in reducing severe exacerbations when given as an outpatient therapy, future directions could include larger scale studies looking at these medications in SAEs.

Table 1.

Summary of asthma medication dosing.

Medication class	Route	Medication and dose	Special considerations
Systemic steroids	IV	Prednisone 40–60 mg PO x 5 days	PO route preferred
	PO	Methylprednisolone 125 mg IV
		Dexamethasone (IV or PO) 12–16 mg daily for 1-2 days
SABA	Nebulized	Albuterol 2.5–5 mg every 1–4 h, or continuous nebulization (5–15 mg/hr)	MDI with spacer preferred in less severe cases
SAMA	Nebulized	Ipratropium 500 mcg every 4–6 h	Robust evidence in the emergency department setting, no evidence of benefit in the inpatient setting
Magnesium	IV	2 g over 20 min
Epinephrine	IV or IM	0.3–0.5 mg IM	Recommended in asthma associated with anaphylaxis, otherwise data is less clear. No clear dosing recommendations for infusion rescue therapy
Epinephrine		1–20 mcg/min IV
Ketamine	IV	1–2 mg/kg/hour	Used as sedative in patients requiring MV
Heliox	Inhaled	Concentration of 70–80% helium mixed with 20–30% oxygen

Unconventional therapies for status asthmaticus

Inhaled anesthetics for asthma

In cases where an SAE is refractory to conventional asthma therapies, patients may require endotracheal intubation due to respiratory collapse or somnolence from worsening hypercapnia and respiratory acidosis. For these patients, additional therapeutic interventions can be administered via the endotracheal tube.

Mechanistic potential for inhaled anesthetics

While traditionally utilized for induction and maintenance of general anesthesia, it is well-established that IAs result in relaxation of bronchial smooth muscles.^44–48 Accordingly, interest in leveraging IAs to alleviate airway obstruction in refractory SAEs has been reported since the early 1980s4⁴⁹ However, evidence supporting their use in SAEs is primarily derived from case reports and retrospective case series.

The exact mechanisms of how IAs achieve unconsciousness, amnesia, analgesia and smooth muscle relaxation are not completely understood; however, it is hypothesized that they act by reducing intracellular calcium.⁵⁰ This effect is mediated through inhibition of protein kinase C and calcium release from sarcoplasmic reticulum, and voltage-dependent calcium channels.^50,51 Additionally, IAs have been postulated to increase the intracellular cyclic adenosine monophosphate (CAMP) which binds to free calcium, promoting smooth muscle relaxation via a negative feedback mechanism.⁴⁴ For IAs to effectively cause bronchodilation, they must diffuse through the bronchial and tracheal lumen to reach smooth muscle.⁵¹ The rate of diffusion is related to the gradient and solubility coefficients from the airway lumen to the smooth muscle.⁵¹

Evidence base for inhaled anesthetics

Although a majority of IAs can result in bronchodilation, there is growing evidence that not all IAs are equally effective. A study examining isoflurane for severe refractory status asthmaticus in children mentioned that newer agents like sevoflurane have been shown to be even more effective bronchodilators than isoflurane.⁵² Isoflurane has demonstrated efficacy in improving alveolar minute ventilation in children with severe, life-threatening status asthmaticus who exhibit resistance to conventional treatments.⁵² This improvement translated to reductions in peak airway pressure, improved alveolar ventilation, and decreased arterial P_aCO₂, thereby theoretically mitigating the risks of barotrauma, dynamic hyperinflation, and cardiovascular compromise.⁵² Alternatively, sevoflurane has been shown to decrease respiratory system resistance more effectively than halothane or isoflurane.⁴⁸

A systematic review of sevoflurane use identified 13 uncontrolled studies encompassing 18 clinical cases.⁵¹ The findings noted a wide range of administered IA concentration, ranging from 0.25 % to 8%.⁵¹ Interestingly, however, 16 of the 18 patients had reported clinical improvement.⁵¹ Similarly, in a pediatric cohort, 6 of 13 patients exhibited immediate improvements in blood gas parameters following initiation of IA at concentrations between 1% and 8%.⁵³ One retrospective study showed that isoflurane, administered at end-tidal concentrations between 1% and 1.5%, resulted in notable improvements in arterial blood CO2 levels and exhaled tidal volumes.⁵⁴ In another case report, isoflurane was initiated at 0.8% and titrated to 1.2%, with further dose escalation limited due to safety concerns.⁴⁹

There are other logistical concerns when utilizing IAs for SAE treatment through a conventional ICU ventilator. Higher minimum alveolar concentrations (MAC) may be required when IAs are introduced via ventilatory circuits.⁵⁵ One study used 3.5 MAC initially and then titrated down after 12 h to 1.5 MAC, with notable ventilatory volume improvements. This may be explained by the pathophysiology of SAEs in which early higher concentrations were necessary due to initial dead space ventilation. In the case of severe obstructive pathology, there is decreased distribution to distal airways, which leads to impaired gas exchange and delivery of gas at the alveolar level, limiting systemic drug uptake. This was also reflected in lower measured expired end-tidal measurements of isoflurane compared to anesthesia machine delivered measurements, suggesting impaired absorption of IA.⁵⁵ Finally, the use of desflurane has in one study shown paradoxically to increase peak inspiratory pressure, so alternatives such as sevoflurane and isoflurane are preferable.⁵⁶

The administration of IA has been reported using different modalities including anesthetic conserving device ACD, such as the AnaConDa (Sedana Medical, Sundbyberg, Sweden) and Mirus system (Mirus, TIM GmbH, Koblenz, Germany) using traditional ventilator circuit.^44,46,57 These devices are inline vaporizers that connect to the Y piece of the traditional ventilator circuit and are compatible with most ventilators.⁴⁶ Alternatively anesthetic operating room ventilators were also proposed to provide IA therapies.

Pragmatic concerns for anesthetic use

If IAs are used outside of the operating room or not under anesthesiology trained ICU physicians’ potential adverse events must be considered. Although prolonged use >48 h of IAs have been used in the cases of ICU sedation and treatment with a good safety profile, ICU teams must be aware of risk of malignant hyperthermia and have appropriate protocols in place.⁴⁶ All IAs have dose-dependent side effects, including decreased mean arterial pressure, cardiac output, and respiratory depression.^45,46 One theoretical consideration specifically for sevoflurane is the potential for nephrotoxicity through the formation of compound A; however, the true impacts of Compound A have not been demonstrated in humans.⁴⁵

When to consider inhaled anesthetics

At present, there is no standardized decision algorithm for when to initiate the use of IAs or VV-ECMO for refractory SAEs.⁵⁸ In a single-center study of N = 11 pediatric SAE cases requiring MV over a 5-year period,⁵² an attempt at protocolizing IA use was undertaken. If patients after 6 h of maximal conventional treatments had worsening respiratory acidosis (arterial pH 7.25) or hypercapnia (P_aCO₂ > 80) and clinically observed poor air entry with peak inspiratory pressures of >45 cmH₂O, they were considered candidates for isoflurane. If at this same six-hour mark P_aO₂ remained <50 mmHg, lactate levels exceeded 2 mmol/L, or the oxygenation index was >40, VV-ECMO was initiated.⁵² In a more recent retrospective report with similar aims, the authors noted that 6 out of their N = 7 patients in status asthmaticus would go on to require VV-ECMO support (58). Similarly, another study reported that 8 of the 13 patients on IAs for status asthmaticus were still escalated to VV-ECMO.⁵⁹

Conclusions of inhaled anesthetics in status asthmaticus

Inhaled anesthetics offer a promising yet underutilized therapeutic option for refractory status asthmaticus, particularly in patients requiring MV. While IAs have demonstrated bronchodilatory effects and improvements in ventilation parameters, their use remains largely supported by case reports and small retrospective studies, with no standardized protocols or dosing guidelines currently available. The variability in dosing strategies and clinical outcomes highlights the need for controlled studies to establish optimal administration protocols and safety measures.

VV-ECMO in status asthmaticus

More extreme presentations of SAEs exist, where the severity of presenting airway obstruction and subsequent acute respiratory failure may necessitate intubation and MV, and even result in cardiorespiratory arrest. The CDC reports about 3500 deaths occurred in the United States secondary to asthma in 2021 despite declining incidence of SAEs due to improving asthma therapies.⁶⁰ Unfortunately, patients with SAEs requiring intubation are at risk of barotrauma and volutrauma as well as refractory hypoxemia and hypercapnia from heterogeneous areas of air trapping, atelectasis, and mucus plugging. VV-ECMO has been considered a potential salvage therapy in these situations due to its ability to allow for gas exchange (oxygenation and ventilation) while also minimizing associated ventilator-induced lung injury. The ability to minimize ventilator support can also decrease auto-PEEP and dynamic hyperinflation, which may improve venous return and hemodynamic stability. Several case reports, case series, and registry studies have assessed outcomes of VV-ECMO in SAEs; however, there is minimal RCT evidence to support its use.

The Extracorporeal Life Support Organization (ELSO) registry has been reviewed several times to assess outcomes of asthma treated with VV-ECMO. These reviews found a relatively consistent rate of survival to hospital discharge of around 83% when VV-ECMO was used for asthma.^61,62 Complication rates ranged from 65% to 79%. The most common complication was hemorrhage (28.3% overall; 22.9% in survivors vs 55.6% in non-survivors). Cannulation site bleeding represented 48% of bleeding complications, while surgical site bleeding was 30% and gastrointestinal hemorrhage was 9%. Cannulation site bleeding, surgical site bleeding, and pulmonary hemorrhage were all associated with increased risk of mortality, while gastrointestinal hemorrhage was not. Multi-system organ failure was the most common feature associated with mortality.⁶²

A UK-based multicenter retrospective cohort review of primarily VV-ECMO-treated patients (n = 1205) found a 95% survival rate when VV-ECMO was used for asthma compared to 74% survival rate when it was used for other causes of respiratory failure.⁶³ Three single-center retrospective cohort studies reviewed their institutional treatment of SAEs with VV-ECMO and showed 100% survival to hospital discharge.^64–66 Importantly, the strength of these findings are limited due to relatively small sample sizes of N = 10, N = 16, and N = 26 patients. One of these studies showed effective clearance of P_aCO₂ from average of 93 at initiation to 43 after 24 h with significant decreases in respiratory rate, tidal volume, peak inspiratory pressure, intrinsic PEEP, and plateau pressures.⁶⁶ Some 77% of this cohort was extubated while on VV-ECMO, and none required re-intubation. Complications of cannulation most commonly included deep vein thrombosis (46%) and hemorrhage requiring blood transfusion (15%).⁶⁶

A large administrative database review of VV-ECMO-capable centers matched n = 82 patients with SAEs treated with VV-ECMO to n = 164 patients with SAEs who did not receive VV-ECMO (conventional care). They showed patients treated with VV-ECMO had a reduced risk of mortality in both multiple covariate- and propensity-adjusted analyses, as well as a separate sensitivity analysis (OR 0.34 – 0.61). There was associated increased cost of hospitalization (greater than $100,000) but no change in ICU LOS, hospital LOS, or duration of MV.⁶⁷

Criteria for treatment with VV-ECMO candidacy in SAEs is not well-established due to lack of large RCTs with established inclusion criteria, but the decision typically involves complex multidisciplinary discussion between critical care and cardiothoracic surgery teams. In general, institutions consider VV-ECMO in patients with refractory hypoxemia or hypercapnia despite optimized MV and maximizing medical management including inhaled bronchodilators, corticosteroids, magnesium infusion, and deep sedation with possible neuromuscular blockade. Additional considerations include patients with evidence of barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema) presumed secondary to their ventilatory support requirements.⁶⁶ Overall, referral for VV-ECMO evaluation and possible transfer to capable facility should occur early for nearly every SAE where the resource is available to allow for sufficient time for multidisciplinary discussion of the patient’s care.

It is important to note that a percutaneous approach rather than a surgical cutdown approach to cannulation, often at bedside by intensivists or surgeons, has become standard practice. In the largest ELSO registry study of 12,592 ECMO cannulations, the percutaneous approach was associated with lower mortality, cannulation site bleeding, and systemic infection. Percutaneous cannulations were performed in 32% of patients in 2008 and increased to 84% of cannulations by 2019.⁶⁸ Use of ultrasound has become critical both in its use for vascular access as well as cannula positioning. Ultrasound can help identify critical anatomy structures to avoid arterial puncture (in venous access), determine vascular patency and appropriate cannula size, and prevent vascular dissection, arteriovenous fistula creation, and piercing the inguinal ligament. Real-time echocardiography, either transthoracic or transesophageal, is important in identifying wire migration or complications related to cannula insertion.⁶⁹

In summary, VV-ECMO has been shown to be an effective management strategy for management of SAEs. Most data on the topic are retrospective in nature but do show high survival rates. Additional studies are necessary to establish standardized criteria for initiation of extracorporeal treatments for SAEs However, despite its high costs and complication rates, VV-ECMO can be considered as an adjunct when standard medical therapy has failed, as it seems it can be a life-saving measure in appropriately selected patients.

Conclusions on rescue therapies

Given the rarity of SAEs requiring ICU level of care with MV, high-quality RCTs assessing specific rescue therapies such as VV-ECMO or IAs face substantial challenges. ELSO-based multi-center trials for ECMO have proven feasible for ARDS, so it is possible such a multi-center effort could be organized for SAEs. In the absence of such substantial efforts, single-center RCTs or prospective cohort studies could allow more confidence in the use of VV-ECMO or IAs for status asthmaticus.

For now, both IAs and VV-ECMO should remain in the intensivists’ armamentarium for refractory SAEs, with perhaps a slightly stronger evidence base in support of VV-ECMO over IAs. In the meantime, these support modalities should not replace rigorous adherence to current conventional medical and ventilatory support. Future areas of substantial research interest include whether the initiation of biologic, anti-Th2-directed anti IL-4/5/13/TSLP therapies while hospitalized results in better post-hospitalization symptom control or even shorter hospital stays.

Limitations

This article is a narrative review and is therefore subject to several limitations. The literature search was conducted using a single database, which may have resulted in the omission of relevant studies in other databases. Study selection was non-systematic, introducing the potential for selection bias. Additionally, no formal assessment of study quality or risk of bias was performed, so the findings should be interpreted as descriptive.

Footnotes

ORCID iDs

Andrew A. Alberter

Erin Niles

Elizabeth K. Powell

Ethical considerations

There are no human participants in this article and informed consent is not required.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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