Adjunctive extracorporeal carbon dioxide removal in refractory status asthmaticus

Abstract

Status asthmaticus (SA) is a life-threatening disorder. Severe respiratory failure may require extracorporeal membrane oxygenation (ECMO). Previous reports have demonstrated utility of ECMO in SA in various patients with varying success. A 25-year-old man was admitted with status asthmatics and severe hypercapnic respiratory failure. Despite tailored ventilator therapies, such as pressure control ventilation and maximal pharmacological therapy, including general anaesthesia, the patient’s condition deteriorated rapidly. Veno-venous ECMO (VV-ECMO) was provided for respiratory support. The patient’s clinical condition improved over the following 72 hours and was discharged from the intensive care unit on day 3. This case report demonstrates the successful use of VV-ECMO in a patient with severe respiratory failure due to SA, who failed to respond to maximal therapy. This case adds support to a growing body of literature that shows that ECMO can be used with success for refractory status asthmaticus.

Background

The mortality of patient requiring intensive care unit (ICU) admission for status asthmaticus (SA) remains as high as 8% in one series.¹ The pathophysiology of asthma involves airway smooth muscle constriction, airway oedema, airway plugging by mucus or cellular debris and airway remodelling. Pharmacotherapy with bronchodilators and systemic corticosteroids are the cornerstones of medical therapy, designed to reduce this pathophysiological airflow obstruction and improve symptoms for patients with acute asthma. Patients suffering from a combination of persistent or worsening hypercapnia, respiratory muscle fatigue and a decline in mental status require mechanical ventilation (MV) along with lung protective ventilator strategies (eg, low tidal volume ventilation, relative short inspiratory time and longer expiratory times with decreased respiratory rates) and aggressive pulmonary hygiene.²

MV can cause increased air trapping and dynamic hyperinflation (DHI). DHI, also known as auto-positive end expiratory pressure (auto-PEEP), is a phenomenon that occurs when a new breath begins before the lung has reached the static equilibrium volume. Patients with acute severe asthma exacerbation are at risk for DHI, which may lead to alveolar rupture and haemodynamic compromise and death.³ Furthermore, severe bronchospasm may lead to impaired venous return. This cardiac tamponade-like pathophysiology can lead to obstructive shock and potentially even cardiac arrest.⁴ When conventional therapeutic options are not successful in critically ill asthma patients, novel therapies such as extracorporeal membrane oxygenation is entertained as a possible salvage therapeutic modality.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an alternative method of cardiopulmonary support for respiratory failure in which oxygen is added and carbon dioxide (CO₂) is removed through an extracorporeal membrane via central cannulation of the venous system.⁵ Selective CO₂ removal can also be achieved with this technology.⁶ The goal of this therapy is to facilitate ventilation and oxygenation of the patient while minimising risk of ventilator induced lung injury while correcting acute respiratory acidosis to allow time for the inflammatory process to subside. Maximising the effects of specific ventilator strategies to alleviate DHI without allowing profound hypercapnia, such as decreasing the minute ventilation, shortening the inspiratory time and using a high inspiratory flow rate, is made feasible with ECMO facilitating gas exchange. There is a substantial body of evidence supporting VV-ECMO in acute respiratory distress syndrome (ARDS). The most notable example is the CESAR trial by Peek et al, which showed a mortality benefit for ECMO in H1N1 influenza and ARDS.^7 8 The evidence for ECMO in refractory hypercapnic respiratory failure is much less robust.

In this case, we report an adult patient with status asthmaticus who had acute hypercapnic respiratory failure with severely reduced lung compliance in the setting of high levels of dynamic hyperinflation that was refractory to conventional mechanical ventilation strategies.

Case presentation

A 25-year-old man with a history of severe persistent asthma since childhood presented to our emergency room with an acute exacerbation of asthma. He admitted to non-compliance with daily prednisone and a short-acting beta-agonist nebuliser which he had been prescribed. He did not see a pulmonologist regularly. He endorsed a prior history of greater than 10 intubations for asthma and required multiple chest thoracostomy tube placements in setting of pneumothoraces that he suffered while on the ventilator. He denied recreational drugs other than daily cigarette use (20 pack-year smoker). He does not have any relevant family history.

Investigations

Initial arterial blood gas (ABG) in the emergency room demonstrated a profound primary respiratory acidosis at pH 6.99/partial pressure of carbon dioxide (PaCO₂) 123/partial pressure of oxygen (PaO₂) 249/respiratory rate 18/oxygen saturation (SaO₂) 99%. On physical exam, he was in severe respiratory distress and could not speak in full sentences. Chest radiography was negative for pneumothorax or pneumonia but showed enlarged lung volumes.

Differential diagnosis

• status asthmaticus

• pneumothorax

• pneumonia

• pulmonary embolism

• pulmonary oedema

• treatment

In light of these findings, the patient was endotracheally intubated in the emergency room. Initial ventilator settings were tidal volume 350 cc/respiratory rate 14/PEEP 5 cm H₂O/fraction of inspired oxygen (FiO₂) 100%. This corresponded to between 5 and 6 mL/kg of ideal body weight. He was given naloxone 4 mg in 10 divided doses, methylprednisolone 125 mg, albuterol aerosol, magnesium sulfate 4 mg, ketamine at multiple doses up to a total of 500 mg, fentanyl at 3 µg/kg in multiple doses up to a total of 210 µg and epinephrine subcutaneous at 0.01 mg/kg in three divided doses every 20 min. Therapy was tailored not only to asthma exacerbation but also to possible narcotic overdose in a young patient who was unable to provide medical history at time of initial presentation. He was admitted to the ICU.

In the ICU, the patient proved extremely difficult to ventilate. Repeat ABG showed pH 7.14/pCO₂ 78/pO₂ 150/respiratory rate 20/SaO₂98% on ventilator settings of tidal volume 350 cc/respiratory rate 14PEEP 5 cm H₂O/FiO₂50%. Assist control and pressure-regulated volume control ventilation modalities were attempted but was unsuccessful as the peak inspiratory pressure rose to 40 mm Hg concurrent with a declining tidal volume to around 100 mL. An expiratory hold manoeuvre revealed 15 mm Hg of auto-PEEP. He was frequently alarming for high-peak airway pressures >50 mm Hg. We initiated paralysis with cisatracurium and sedation with a ketamine drip. The ketamine was selected in part for its bronchodilator effect. Additional bronchodilator and anti-inflammatory medications were represcribed with methylprednisolone 125 mg, continuous aerosolised albuterol and ipratropium and subcutaneous terbutaline. Heliox was attempted when the ventilation parameters did not improve, but its administration did not yield any benefits. Inspiratory to expiratory time was increased to 1:9 in a stepwise fashion.

Despite maximal efforts, the patient's minute ventilation was merely 2.5 L/min and the patient still demonstrated evidence of severe DHI. To prevent catastrophic haemodynamic collapse, the patient required repeated disconnection from the ventilator and was manually ventilated with a bag-valve mask in an attempt to relieve the auto-PEEP. Repeat ABG after our manoeuvres worsened to pH 7.11/pCO₂ 89/PaO₂ 129/respiratory rate 20/SaO₂98% while being bagged. Consultation with cardiothoracic surgery for ECMO was performed at this time.

After consultation with the cardiothoracic team, a joint decision was made to place VV-ECMO. He was cannulated within one and a half hours of his ICU admission. Unfractionated heparin was commenced at rate of 900 U/hour for systemic anticoagulation while on ECMO. Initial ECMO settings were FIO2=1.0, sweep gas flow 4.0 L/min and blood flow of 4.3 L/min. We continued with ventilator settings tidal volume 350 cc/respiratory rate 10/PEEP 5 cm H₂O/FiO₂50% and his next ABG on ECMO was pH 7.32/PaCO₂ 46/PaO₂ 133/respiratory rate 22/_SaO299% (table 1).

Table 1.

Arterial blood gas, haemodynamic and ventilator parameters

	Initial emergency room evaluation	Initial ICU management	Prior to ECMO	10 min after ECMO	1 hour after ECMO	8 hours after ECMO	At ECMO discontinuation
pH	6.99	7.14	7.11	7.32	7.45	7.36	7.42
PaO2 (mm Hg)	249	150	129	516	103	107	113
PaCO2 (mm Hg)	123	78	89	46	29	44	39
HCO3 (mmol/L)	18	20	20	22	22	24	26
Base Excess (mmol/L)	−8.3	−5.6	−5.6	−2.8	−2.6	−0.9	1.4
SaO2 (%)	99	98	98	99	99	98	99
FiO2 (%)	80	100	100	100	50	50	40
Heart rate (bpm)	122	94	104	108	115	103	68
Mean arterial pressure (mm Hg)	134	87	82	68	59	68	90
Mode of mechanical ventilation	N/A	AC	PRVC	PRVC	PRVC	PRVC	PRVC
Peak inspiratory pressure (cm H2O)	NA	40	40	37	38	38	38
Plateau pressure (cm H2O)	NA	18	19	19	18	25	24
Tidal volume (mL)	NA	300	300	300	290	660	670
Respiratory rate (brpm)	30	14	10	10	10	10	16
Minute ventilation (L)	NA	4.2	3.0	3.0	2.9	6.6	10.7
ECMO FiO2	NA	NA	NA	1.0	1.0	1.0	1.0
ECMO sweep gas flow (L/min)	NA	NA	NA	4.0	5.5	4.0	4.0
ECMO blood flow (L/min)	NA	NA	NA	4.3	4.3	4.8	4.9

AC, assist control; bpm, beat per minute; brpm,  breathe per minute; ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; HCO₃, bicarbonate; ICU, intensive care unit; PaCO2, partial pressure of carbon dioxide; PaO₂, partial pressure of oxygen; PRVC, pressure regulated volume control; SaO2, oxygen saturation.

Outcome and follow-up

These settings were continued for 24 hours, at which time his ABG significantly improved to pH 7.42/PaCO2 40/PaO2 91/respiratory rate 26/SaO2 99. Pressure support ventilation was initiated in light of these improved gas exchange parameters concurrent with an improved physical examination with improvement of bronchospasm. He was extubated 36 hours after ECMO initiation and the ECMO catheters were decannulated on the same day. He was discharged from ICU 72 hours after being admitted with intact neurological and improved respiratory function.

Discussion

This patient had refractory SA that precipitated respiratory arrest, leading to severe derangements in gas exchange.² The pathophysiology of hypoxaemia and hypercapnia in acute asthma is due to low ventilation/perfusion mismatch, shunting and hypoventilation.⁹ Carbon dioxide removal within the ECMO circuit is accomplished by applying a high sweep gas flow of oxygen within the artificial lung which facilitates a concentration gradient for carbon dioxide to traverse the artificial lung membrane. This extracorporeal removal of carbon dioxide is also referred to as ECCO₂R. This function of ECMO directly addresses the physiological derangements in SA.

Although physiologically attractive and potentially helpful, the literature on the use of ECMO in SA remains sparse. Without rigorous randomised controlled trials and in the setting of known side effects of ECMO application (eg, bleeding, haemolysis, infection, acute kidney injury and deep venous thrombosis),¹⁰ routine use of ECMO for the asthmatic patient has not yet entered routine clinical practice and remains controversial. However, in cases of life-threatening dynamic hyperinflation due to status asthmaticus, ECMO should be considered a salvage therapy.

Historically, the use of ECMO has primarily utilised in paediatric population, in which ECMO is a proven modality for the treatment of severe respiratory failure since its inception.^11–13 Research in the adult population has been studied primarily for management of severe ARDS. The earliest randomised trial was by Zapol et al in 1979¹⁴ which did not demonstrate a survival benefit. However, selection bias, use of obsolete technology and evolving diagnostic definitions of ARDS has rendered this pioneering study less relevant to current medical management. Subsequent studies done over the decades had shown mixed results with regards to mortality benefit.^{8 15–17}

However, with the publication of the landmark CESAR trial in 2009,⁷ there was a resurgence of interest in this technique as a salvage therapy for refractory respiratory failure. CESAR, a randomised control trial of 90 patients with severe ARDS randomised to ECMO or conventional therapy that demonstrated a 31% reduction in the relative risk and a 16% reduction in the absolute risk of 6-month survival without disability. While such rigorous studies are not available in the asthma realm, we believe ECMO should be considered as a tool in the armamentarium of the intensivist for refractory status asthmaticus.

Mikkelsen et al¹⁸ analysed data from the Extracorporeal Life Support Organization registry and had found a suggestion for survival advantage for ECMO in patients with asthma compared with other forms of acute respiratory failure. However, the conclusions are limited by an inability to compare ECMO to other therapies and limited external validity as the database had included data from an earlier era in which the ECMO technology was not as advanced as it is now. One multicentre European case series of 16 patients of ECMO use in SA had demonstrated good efficacy in improving gas exchange parameters and leading to successful extubation without neurological sequelae in all study patients.¹⁹ In addition, there are case reports highlighting application of ECMO for SA in unique clinical scenarios including patients who with plastic bronchitis,²⁰ in the setting of secondary pneumothorax,²¹ in pregnancy²² and following atracurium administration.²³

A recent study by Braune et al, the ECLAIR study,²⁴ prospectively followed 25 patients with COPD and acute hypercapnic respiratory failure requiring non-invasive positive pressure ventilation (NIPPV) and were initiated onto ECMO for certain predefined criteria and were compared with historical controls. The results demonstrated that for the patients in the study arm who had failed NIPPV and required MV, there was a statistically significant reduced duration of MV. This study may serve as a modern example of the closest template for a study of ECMO in the asthma population. However, physiological differences between the two obstructive lung diseases may preclude adequate interpolation of these results.

Despite the limited evidence base for use of ECMO in status asthmatics, it is our expert opinion that the initiation of ECMO should be considered when severe DHI or respiratory acidosis persists despite optimal conventional management. Our case illustrates the application of these principles in treatment of this patient successfully and without chronic respiratory disability or other sequelae.

Learning points.

• Status asthmaticus requiring intensive care unit admission entails a high mortality (up to 8%)

• Extracorporeal membrane oxygenation (ECMO) has established efficacy in the literature for treatment of adult acute respiratory distress syndrome, but is not as rigorously studied for status asthmaticus.

• ECMO use can be considered in cases of refractory status asthmaticus as salvage therapy.