Ventilatory and ECMO treatment of H1N1-induced severe respiratory failure: results of an Italian referral ECMO center

Since the first outbreak of a respiratory illness caused by Influenza A (H1N1) virus in Mexico [1], several reports have described the need of intensive care [2‐4] or extracorporeal membrane oxygenation (ECMO) assistance [5] in young and often healthy patients.

Beginning August 2009, the Italian Ministry of Health and the Tuscany Ministry of Health issued instructions to identify and establish referral centers able to care for the more severely ill influenza patients. Therefore, several referral centers were identified throughout the national territory among the hospitals already experienced in extracorporeal respiratory support techniques. The referral ECMO centres, in addition to being capable of guaranteeing the most advanced treatment in influenza related respiratory failure, were also entrusted with providing support to the nearby hospitals and assuring safe transportation.

In the present investigation we report our experience, as an ECMO referral center, in H1N1-induced acute respiratory distress syndrome (ARDS) and we present the critical care service planning in response to the H1N1 pandemic.

Following the instructions of the Italian Ministry of Health and Tuscany Regional Ministry of Health, an Emergency Medical Service was established in the Careggi Hospital in Florence Italy for the novel pandemic influenza.

The Careggi Hospital ECMO Team is composed of: an intensivist, a cardiac surgeon, a cardiologist, a nurse, and a perfusionist. All of the members of the team are properly trained in ECMO treatment. An ambulance and a car are equipped with an ECMO circuit, a transport ventilator and all of the materials needed to initiate extracorporeal support in the peripheral hospitals, and permit safe transportation while on extracorporeal circulation to our referral hospital.

The requirement of ECMO was decided based on the Italian Ministry of Health criteria (Table 1).

From September 2009 to January 2010, all patients admitted to our ICU with severe respiratory failure due to H1N1 infection were included in this study. Patient demographics and clinical characteristics were collected from institutional ICU database (FileMaker Pro, FileMaker, Inc, USA), from Italian Group for the Evaluation of Interventions in Intensive Care Medicine database (GiViTI Margherita Project, Istituto Mario Negri, Bergamo, Italy) and from ECMO national network database. Discrete variables are expressed as counts and percentages, whereas continuous variables are reported as medians with 25th to 75th interquartile range (IQR). The Internal Review Board approved this retrospective study and informed consent for data publication was obtained from the patients or relatives.

Our study population is young, comprising mainly healthy subjects, as previously reported [1, 2, 15]. Risk factors are similar to other studies, such as obesity, diabetes and pregnancy.

In the present case series, bacterial infection rate at presentation was low. Previous reports showed incidence of secondary superinfection by Streptococcus Pneumoniae, Staphylococcus Aureus, Pseudomonas Aeruginosa, Acinetobacter Baumannii, Escherichia coli [1, 3, 2]. In our experience, we found two cases (16.7%) of co-infection with Legionella Pneumophila, which is, to the best of our knowledge, a new epidemiological data, since no other case has been reported in literature. It is questionable whether Legionella Pneumophila infection occurred before or after H1N1 pneumonia. However, it could be that H1N1 pneumonia was associated with a lower reactivity of the immune system, as suggested by the low leucocytes count reported in our sample and by other Authors [3, 2, 1].

One young patient presented heart failure, and viral myocarditis was suspected. The association of influenza with myocarditis is debated [16], and H1N1 related myocarditis, has rarely been reported [17]. Furthermore, in our patient prolonged pre-hospital hypoxia was present and myocardial hypoxemia damage might have been involved. The patient required inotrope/vasoactive support for several days and eventually recovered fully with normal heart function.

Our observations confirm the responsiveness of this infection to antiviral therapy. We adopted a two-modality administration, both oral and inhaled. Our choice was made in consideration of the decrease in gut motility and adsorption usually observed in critically ill patients.

The World Health Organization (WHO) has questioned the sensibility of RT-PCR analysis for H1N1 in pharyngeal swab sample, encouraging analysis on samples from the lower respiratory tract. We routinely monitor H1N1 infection on three compartments: pharyngeal swab, subglottic aspiration, and bronchoalveolar lavage. In our experience, bronchoalveolar lavage at admission was positive in all patients while pharyngeal swab resulted positive in only 75% of cases.

As shown in Figure 1, RT-PCR from pharyngeal swab at ICU admission failed to demonstrate the viral infection in 3 patients. Similarly, the time course showed that RT-PCR from pharyngeal swab resulted negative in an average time of 3 days after therapy start. Conversely RT-PCRs from bronchoalveolar lavage remained positive for a longer period and resulted more reliable for infection monitoring and assessment of the efficacy of administered therapy.

Based on our experience, RT-PCR from bronchoalveolar lavage resulted to be the most reliable method to diagnose and monitor H1N1 infection, since pharyngeal swab does not offer enough sensibility, neither for antiviral therapy initiation nor for antiviral therapy management. As subglottic aspiration resulted persistently negative, we do not recommend this sampling for diagnosis and monitoring of H1N1 infection.

Despite the severe clinical pictures, we experienced a very low mortality rate: only one patient out of 12 died (8,3%). One of the surviving patients presented a lung cavern for a past pulmonary infection, and deceased for a secondary superinfection by Aspergillus, probably already colonizing lung parenchyma before the onset of viral infection.

Our mortality rate is surprisingly low in comparison to a larger series of H1N1 patients, even when extracorporeal support technique were employed [5, 18]. Our finding can be related to the small number of patients included the study and definitive comparison with larger studies could be misleading. However, despite the severity of symptoms and the rapid progression to ARDS, H1N1 respiratory failure presents a relatively benign course when adequately treated, if compared to non-H1N1 induced ARDS, reported to have a mortality rate from 37% to 43% [19‐22]. Several factors may account for the favourable outcome in our series. All patients received protective ventilation. In particular, ECMO support permitted the maintenance of patients under a protective tidal volume with a respiratory rate below 12 per min, and a FiO₂ below 60%, compared with non-ECMO patients who needed a higher respiratory rate and FiO₂ to maintain an acceptable pulmonary gas exchange.

The availability of easily accessible tools for pulmonary mechanics evaluations on modern ventilators allowed an individualized and appropriate setting of ventilation pressure within the thresholds of so called "protective ventilation" [23]. Furthermore, early access to ECMO resource allowed the maintenance of protective ventilation even in more severe patients (Table 4). In this regard, lactate dehydrogenase is commonly considered a marker of lung damage, and in H1N1 pneumonia is reported as high [1]. In our ECMO patients, lactate dehydrogenase values presented lower levels than in non-ECMO patients (445 U/L vs 627 IU/L, respectively), suggesting that in ECMO patients the reduced need of pulmonary ventilation could reduce lung ventilatory stress and enhance healing, regardless of the more impaired lung condition.

However, it is possible that, since the technique has gained popularity and experience gathered to demonstrate its feasibility, we used ECMO also in patients who might previously have been successfully treated conventionally, and this may have influenced mortality.

Moreover, more than half of our ECMO patients needed to be land-transported from other hospitals in an advanced stage of respiratory failure. This may have further encouraged an early treatment with ECMO to ensure the safest transport.

Bleeding is commonly reported during ECMO treatment [24], and either anticoagulation or platelet and coagulation cascade activation through oxygenator and pump is involved [25].

In our population bleeding also occurred more frequently in ECMO patients, and they required more transfusions compared to non ECMO patients. Nevertheless, in our experience, bleeding from cannulas insertion site or from upper airways, despite requiring transfusion, were not life threatening, and could be managed. In only two cases did severe bleeding occur in the lower respiratory tract. Fortunately in one case it occurred during weaning from ECMO, and it ceased after extracorporeal support removal. The other patient died from pulmonary aspergillosis and the haemorrhage could be also related to parenchyma disruption caused by the fungus.

Monitoring heparin regimen is extremely important during extracorporeal circulation, and activated clotted time is commonly measured bedside. Some debate exists regarding the optimal range and the accuracy of point-of-care measuring devices [26‐28]. In our protocol, we usually measured aPTT every two hours with Hemochron Jr. in order to closely monitor heparin administration in the low range of dosage.

In our clinical practice, lung recovery and response to treatment are daily assessed by LUS examination, following several recent reports which underline the reliability of LUS in the evaluation and management of chest disorders [10, 29]. Despite CT-scan is the reference technique for evaluating lung lesions, it requires a transitory disconnection of the patient from the ventilator to permit the transportation radiology suite with potential risk of alveolar de-recruitment and worsening of oxygenation. Moreover, severe complications have been reported in intra-hospital transportation of critically ill patients [30, 31]. As we recently reported [13], the routine use of bedside LUS has significantly reduce of the number of CT-scan and chest X-ray examinations in critical patients. The potential clinical benefit of reducing in-hospital transport for diagnostic radiology, it can be particularly relevant in patients with ECMO. In these patients, in fact, transportation requires time and a significant commitment of resources, although it was proved feasible both for in-hospital [32, 33] and for inter-hospital long distance transportations [34, 35].

Another advantage of LUS is the ability to evaluate the effectiveness of alveolar recruitment manoeuvres with the possibility to visualize real-time imagines of lung parenchyma re-aeration [8, 10, 29]. Finally, pleural effusions can be accurately diagnosed and monitored with LUS and in case of need for treatment an ultra-sound guided technique is recommended [36, 13]. This option seems to be particularly appropriate ECMO patients, where bleeding for conventional chest tube placement can occur in consideration of the need of heparin infusion.

The present case series comprises a small number of patients, and naturally, it cannot be considered a high grade of evidence trial. However, our experience might be helpful for intensivists challenging H1N1-induced ARDS. For H1N1 infection monitoring (or diagnosis, if patient was intubated before) bronchoalveolar lavage can be more reliable than pharyngeal swab in order of the higher sensitivity. In our clinical practice, ECMO therapy resulted safe and feasible in the context of a life threatening condition, and it might be taken into consideration as a therapeutic choice rather than a rescue solution in experienced centers.