Objective: status asthmaticus not responsive to therapy are not a prerogative of severe asthma. We report the case of a severe status asthmaticus refractory to medical therapy, undergoing Invasive Mechanical Ventilation (IMV) and extra-corporeal carbon dioxide removal (ECCO₂R). Since it was life-threating situation, the equip decided to administer off-label Omalizumab, a drug with an anti-IgE action.

Data synthesis: After the drug administration patients clinically improved, White Blood Cell (WBC) count in Broncho-Alveolar Lavage (BAL) decreased rapidly and the patient can be weaned from ECCO₂R and IMV. Finally, patient was discharged from ICU to hospital ward and then to home.

Conclusion: Off-label use of Omalizumab provided a fast WBC reduction in BAL and fast recovery in a paediatric severe status asthmaticus refractory to all treatment.

Abbreviations: BGA: Blood Gas Analysis; ECCO₂R: Extra Corporeal Carbon dioxide Removal; ED: Emergency Department; ICU: Intensive Care Unit; NIV: Non-Invasive Ventilation; OTI: orotracheal intubation; SABA: Short-Acting Beta2 selective adrenergic Agonists.

Copy right Statement: Content published in the journal follows Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0). © Colombo D (2023)

Journal: Open Journal of Clinical and Medical Case Reports is an international, open access, peer reviewed Journal mainly focused exclusively on the medical and clinical case reports.

Citation: Colombo D, Guzzo A, Merlo F, Battista M, Orsatti C, Cammarota G, Nicali R. Near Fatal Asthma: Acute Effect of Omalizumab in Paediatric Patient Undergoing Extracorporeal Carbon Dioxide Removal (ECCO2R). Open J Clin Med Case Rep. 2023; 2018.

Severe asthma is a life-threatening condition that is particularly challenging in patients who do not respond to conventional therapy [1]. In critically ill patients admitted with severe asthma, Invasive Mechanical Ventilation (IMV) is often required to stabilize the respiratory status. Anaesthetic medical drugs in combination with Extracorporeal Carbon Dioxide Removal System (ECCO₂R) are well-described rescue therapies used to treat patients suffering from severe status asthmaticus [1].

In particular, the use of extracorporeal carbon dioxide removal system (ECCO₂R) has been proposed as a bridge therapy to curb hypercapnia and acidosis [8-10].

The medical treatment of asthmatic access does not involve the use of biological drugs, which are usually used for its prevention. Among them, omalizumab is an approved drug used for IgE-mediated moderate-to-severe asthma that is refractory to high-dose inhaled corticosteroids and long-acting beta2 agonist [11]. In addition, omalizumab is not indicated for the relief of acute bronchospasm or status asthmaticus [12].

We report a case of severe asthma refractory to conventional and rescue therapies in a pediatric patient, in whom omalizumab was effectively used to revert the life-threatening condition.

Patient information

A 17-year-old boy with a history of allergic asthma treated with on-demand SABA presented to our emergency department with severe acute asthma exacerbation. He had previously suffered from a few asthma attacks, requiring, in one case, hospital admission.

Clinical findings and diagnostic assessment

The boy presented to our ED with hypoxemic Acute Respiratory Failure (ARF) after 12 hours of asthma exacerbation managed at home with oral steroids and a salbutamol Metered-Dose Inhaler (MDI). In the ED, he received maximal high-dose nebulized salbutamol, intravenous methylprednisolone, nebulized epinephrine, intravenous magnesium sulphate and O₂-therapy, without any benefits. After 24 hours from the symptoms’ presentation, he was finally admitted to the ICU. On ICU admission, the patient presented with increased work of breathing (respiratory rate 35/minutes; use of inspiratory accessory muscles), inability to speak, orthopnea, and mild hypercapnia on blood gas analysis (BGA): pH 7.36, paO₂ 92 mmHg, paCO₂ 43 mmHg, and HCO₃- 24 mEq/L. Thus, Invasive Mechanical Ventilation (IMV) after Orotracheal Intubation (OTI) was performed (V_T 560 mL; RR 9 bpm; I/E 1:7; PEEP 0, FiO₂ 50%).

Timeline and therapeutic interventions

On day 1, immediately after OTI, severe respiratory acidosis (pH 7,27; PaCO₂ 56 mmHg; PaO₂ 101 mmHg; HCO₃- 26 mEq/L) was observed at BGA in combination with a high airway resistance, significant gas trapping, and a high time constant (τ)(airway resistance 59 cmH₂O/L/s; PEEPi 12 cm H₂O; τ 17s). With the aim of facing off hypercarbia and respiratory acidosis, veno-venous ECCO₂R was started [13].

Once a high flow 13.5 French dual lumen catheter (MAHURKAR ™, Covidien™, Minneapolis, USA) was placed in the left femoral vein under ultrasound guidance, veno-venous ECCO₂R was started (PrismaLung+, Baxter - Deerfield, IL), and the operational parameters of veno-venous ECCO₂R were set as follows: a blood flow of 450 mL/min and a sweep gas flow of 10 L/min. Pre -and post-filter blood gas analyses showed a ΔCO₂ of 32.1 mmHg corresponding to 71.1% of the total CO₂ extraction. Systemic anticoagulation was initiated using unfractionated heparin (mean, 1617± 295 IU/h) to maintain an aPTT of 71.1 ± 26.8 seconds. Bronchodilation was supported by continuous infusion of ketamine and inhaled sevoflurane.

On day 2, pH was compensated for by a slight increase in bicarbonate levels and a sensitive reduction in PaCO₂ levels due to ECCO₂R (pH 7.37; PaCO₂ 48 mmHg; PaO₂ 102 mmHg; HCO₃- 28.6 mEq/L). I.v. theophylline and magnesium sulphate were also added. Chest radiography was performed, and pneumothorax was excluded.

On day 3, airway resistance reached its maximum value in the presence of persistent gas trapping and a high τ (airway resistance 130 cmH2O/L/s; PEEP_TOT 10 cm H₂O; τ 37 s). A rebound in the total IgE level was observed (2421 UI/mL). Film array respiratory panel analyses conducted on the bronchoalveolar lavage (BAL) assay excluded major infections.

On day 4, the BGA was as follows: pH, 7.37; PaCO₂ 59 mmHg; PaO₂, 70 mmHg; and HCO₃, 34 mEq/L. Bronchospasm was still clinically present with audible inspiratory and expiratory wheezing, confirmed by severe alterations in respiratory mechanics (R 125 cm H₂O/L/s; PEEPi 9.2 cm H₂O; τ 30.5 s).

Owing to the lack of a clinically relevant impact and the risk of renal injury induced by prolonged administration, sevoflurane was discontinued [14]. The day after, in consideration of the severe status of asthmaticus refractory to all the medications employed, an allergology specialist was consulted (AF) and the off-label administration of omalizumab was commenced. A single dose of Omalizumab 900 mg was injected subcutaneously, according to body weight and IgE level [12].

BAL was sampled before omalizumab administration for the following three days. Leukocyte count data are shown in Figure 1. The leukocyte count gradually decreased over the next 3 days. Figure 1 depicts how airway resistance decreased soon after omalizumab administration, suggesting its efficacy for clinical improvement. The reduction in white blood count (WBC) in BAL fluid supports this hypothesis (Figure 1). The patient’s respiratory condition progressively improved within 2 days of omalizumab administration; therefore, theophylline and magnesium sulphate were discontinued.

On day 7, as mechanical measurements improved (R 21 cm H₂O/L/s; PEEPi 2 cm H₂O; τ 6.5 s), RR increased to 12 bpm, while maintaining a good gas exchange (pH 7.41, PaCO₂ 48 mmHg, PaO₂ 73 mmHg, HCO₃- 31.3 mEq/L).

On day 8, due to further improvements in ventilatory mechanics, ECCO₂R and ketamine were also discontinued. The ECCO₂R treatment lasted 185 h, with the ECCO₂R membrane cartridge replaced every 72 h. Therefore, weaning from IMV was initiated until extubation on day 9. Immediately after extubation, the patient was assisted by non-invasive ventilation (NIV) with neurally adjusted ventilatory assist (NAVA) (Servo-U, Getinge, Sölna, SW) [15,16] via an oro-nasal mask. In the absence of muscular fatigue or dyspnea, NIV was rapidly discontinued. The ECCO₂R catheter was removed 24 h after spontaneous breathing, without any complications. The patient was monitored in the ICU for 72 h and then discharged to the medical ward. On day 18, the patient was discharged without any further exacerbation of in-hospital asthma.

Outcomes and follow-up

Asthmatic status lasted several days, and the patient remains deeply sedated, paralyzed and mechanically ventilated with continuous VV-ECCO₂R in absence of complications. After extubation, he started his new chronic therapy with a long-acting bronchodilator (beclomethasone/formoterol spray), oral montelukast, and was finally referred to a specialized center for the administration of omalizumab.

The administration of Omalizumab provided respiratory mechanic improvement and reduction of WBC in BAL.

The humanized monoclonal anti-IgE antibody omalizumab rapidly neutralizes free IgE [17] and inhibits IgE receptor binding by steric inhibition [18]. To our knowledge, its use in acute asthma exacerbations has not been described in pediatric patients. Our clinical observations suggest that omalizumab might be useful in the critical context of refractory asthma Ig-E mediated.

Our patient did not respond to any standard medical treatment, including oxygen, inhaled SABA, inhaled short-acting muscarinic antagonists, systemic glucocorticoids, magnesium sulphate [19,20] and theophylline [21,22].

When intubation and mechanical ventilation became necessary, intravenous ketamine and inhaled sevoflurane were added as second-line therapies [4,6]. Mechanical ventilation carries the risk of serious complications due to dynamic hyperinflation, such as barotrauma and hemodynamic instability [23]. As bronchospasm is associated with prolongation of the respiratory system τ, due to expiratory flow limitation and increased flow resistance, slower emptying of alveoli may result in significant gas trapping (PEEPi) [24]. The interventions aimed at minimizing the increase in PEEPi, including a low respiratory rate with normal or slightly increased tidal volume (HVLR high volume low-rate ventilation) and a reduced I/E ratio, were, in turn, responsible for hypercapnia and respiratory acidosis worsening [25].

The use of ECCO₂R allowed for the reduction of tidal volume and minute ventilation, limiting lung overinflation and gas trapping. However, we were unable to wean the patient from this supportive therapy, which cannot be applied for prolonged periods [8,26]. Off-label use of omalizumab was then considered and administered.

The reduction of symptoms, the disappearance of signs of inflammation in BAL, and the normalization of ventilation parameters occurred rapidly in the 48 hours following the introduction of omalizumab, suggesting a potential cause-effect relationship.

According to its prescribing information, Omalizumab “is not indicated for the relief of acute bronchospasm or status asthmaticus” [12]. It is also explicitly not indicated “for other allergic conditions”. Despite this, after the publication of clinical cases [27] and case series [28] indicating its efficacy, it is currently being studied as a treatment for food allergies in prospective trials [29]. This report suggests that omalizumab administration could play a role in acute asthmatic attack in a selected population.

Asthma exacerbations can be fatal. Data from the WHO Mortality Database estimated that global asthma mortality in the 5-34-year age group did not decrease appreciably from 1993 to 2006 [30,31]. Specifically, in Italy, mortality has reduced from 0.19 deaths per 100.000 people in 1993 to 0,06 per 100.000 people in 2006 [30], but in developed countries, we are now experiencing signals of upward rebound in mortality [32,33]. According to data from the US, asthma exacerbation rates among children < 18 years old with current asthma decreased from 62% in 2001 to 48% in 2014 but increased in 2016 to 54% [34].

Our case suggests that the combination of ECCO2R delivered via a dialysis machine and omalizumab may be an effective treatment option for status asthmaticus in the young population. In addition, these treatments can also be safely applied in secondary hospitals to avoid potentially harmful transportation, thus contributing to reduced mortality from NFA in pediatric patients.

Acknowledgment

The authors congratulate the ICU and dialysis teams of SS. Trinità Hospital, Borgomanero for their daily efforts and dedication to all patients.

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