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体外膜肺氧合治疗2009年甲型（H1N1）流感引起的急性呼吸窘迫综合征
The ANZ ECMO Influenza Investigators. JAMA. 2009; 302(17): 1888-1895

介绍及点评：杜斌

Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome

（CSCCM原创，转载请注明）

注：本文将同时发表于危重病医学杂志《Intensive Care Monitor》

《Intensive Care Monitor》是一本介绍危重病最新文献的杂志，旨在介绍最新的危重病医学文献，并配以评论或述评

杂志的官方网站 http://www.intensive-care-monitor.com 目前正在建设维护中，预计将于2010年初重新开通

[ ABSTRACT ]

Objective

To determine outcomes following extracorporeal membrane oxygenation (ECMO) in patients with acute respiratory distress syndrome (ARDS) due to influenza A (H1N1) as well as the incidence, patient characteristics and resource utilization

Introduction

The 2009 influenza season in the Southern Hemisphere resulted in a large number of patients admitted to ICUs with severe ARDS due to the H1N1 influenza A virus. Many patients required ECMO because of refractory hypoxaemia despite mechanical ventilation and rescue ARDS treatments

Study design

Retrospective, observational study

Patients and methods

Information on patients treated with ECMO at regional referral centres in Australia and New Zealand between June 1st and August 31st 2009 were obtained. Patients with confirmed or strongly suspected H1N1-related respiratory disease were included in the study.

Data were collected on demographics, clinical characteristics (including symptoms of influenza on admission), identification of infective organism, timing of intubation relative to symptom onset, severity of illness before intubation and before starting ECMO, duration of mechanical ventilation and ECMO, antiviral and antibiotic treatments received, duration of hospital stay and mortality.

For comparison, data on demographics, treatments and outcomes were collected on patients with confirmed H1N1 infection who did not receive ECMO.

Results

During the study period, 68 patients were treated with ECMO for influenza-associated ARDS and in 78% H1N1 was confirmed by polymerase chain reaction or viral culture. An additional 133 patients with influenza A received mechanical ventilation but no ECMO.

The incidence of ECMO use for H1N1 was 2.6 cases per million people (95%CI, 2.0–3.2). The median age was 34.4 years (interquartile range [IQR], 26.6 - 43.1 years), with a maximum of 23 patients being treated with ECMO concurrently.

This compares with a total of 4 patients receiving ECMO for ARDS in the 2008 influenza season.

The median intervals between onset of influenza symptoms and hospital admission, ICU admission and ECMO were 5 (IQR, 3–6) days, 5 (IQR, 3–7) days and 9 (IQR, 5–13) days, respectively.

Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a median PaO2/fraction of inspired oxygen (FIO2) ratio of 56 (IQR, 48–63), positive end-expiratory pressure of 18 (IQR, 15-20) cm H2O, a lowest pH of 7.2 (IQR, 7.1–7.3), a highest PaCO2 of 69 (IQR, 54–83) mm Hg and an acute lung injury score of 3.8 (IQR, 3.5–4.0).

The median duration of mechanical ventilation was 26 (IQR, 14–34] days for survivors and 14 (IQR, 7–29) days for non-survivors. The median duration of ECMO support was 10 (IQR, 7–15) days.

As of September 7th 2009, 48 of the 68 patients (71%; 95%CI, 60–82%) had survived to ICU discharge, of whom 32 had survived to hospital discharge and 16 remained as hospital inpatients, 14 patients (21%; 95% CI, 11%-30%) had died, while 6 remained in the ICU and 2 were still receiving ECMO.

Compared with patients who had not required ECMO, the ECMO cohort had longer durations of mechanical ventilation (median, 18 days vs. 8 days; p = 0.001), ICU stay (median, 22 days vs. 12 days; p = 0.001), and higher ICU mortality (23% vs. 9%; p = 0.01).

Discussion

During the 2-month study period, the ICUs at regional referral centres provided ECMO support to around a third of all cases of influenza A(H1N1)–associated respiratory failure requiring mechanical ventilation at these centres.

These patients were generally young adults with severe hypoxemia. The mortality rate was relatively low considering the severity of the disease.

The authors estimate that, based on the experience in Australia and New Zealand, the United States and the European Union might expect to provide ECMO to approximately 800 and 1300 patients during the 2009-2010 winter, respectively.

[ COMMENT ]

[注]：本文点评内容仅为作者个人的学术观点，不代表CSCCM及任何学术组织的推荐意见

Since the emergence of the novel 2009 influenza A (H1N1) in March 2009, the world has witnessed its rapid and global spread to almost all countries and territories from April to June 2009, which resulted in the declaration of the first phase 6 global influenza pandemic by the World Health Organization on June 11, 2009.

Although the clinical manifestation remains mild to moderate for the initial 3 to 6 days [1-3], about 25% of patients experience rapid deterioration, leading to ICU admission within one day after hospitalization [1].

Among the critically ill patients with confirmed or suspected 2009 Influenza A (H1N1), about half had ARDS or viral pneumonia, more than one-third developed severe sepsis or septic shock.

Supportive treatment included mechanical ventilation in 66% to 87% of the patients, vasopressors in 35.3%, and renal replacement therapy in 5.3% of ICU patients [1, 2].

All these facts suggested that mechanical ventilation represented the most common intervention during ICU stay.

However, in some of the cases, even with the use of high PEEP (up to 30 cmH2O), severe hypoxemia might be very difficult to correct [3].

In 68 patients with severe influenza-associated ARDS, Davies and his colleagues in Australia and New Zealand reported the dramatic treatment effect of extracorporeal membrane oxygenation (ECMO), i.e. 21% mortality rate at the end of the study period.

Although this was an observational study (the urgency of treatment and high workload might preclude the conduct of a randomized controlled trial), we could still have an impression of the severity of ARDS from the patient characteristics prior to commencement of ECMO.

Before initiation of ECMO, these 68 patients suffered from severe hypoxemia, as suggested by acute lung injury score of 3.8 (3.5-4.0), the lowest PaO2/FiO2 ratio of 56 (48-63), highest FiO2 of 1.0, and highest PEEP of 18 (15-20) cmH2O.

They also developed severe respiratory acidosis (pH 7.2, PaCO2 69 mmHg).

Apart from conventional mechanical ventilation, vigorous interventions had been performed before ECMO, in order to correct severe hypoxemia, including recruitment maneuver (67%), nitric oxide inhalation (32%), prostacyclin (22%), prone positioning (20%), and high-frequency oscillation (5%).

Bearing these in mind, the investigators should be congratulated for the low mortality rate reported.

The exact reasons for outcome improvement remain unclear, some were mentioned by the investigators.

Moreover, the limitations of the present study should not be neglected.

No definite inclusion/exclusion criteria were provided, the treatment protocol for ECMO was not standardized (even not reported), and there was no parallel control group.

All these facts remind us that the results of the present study might not be readily generalised to our patients, especially under the condition of little or no experience with the ECMO technique.

In addition, from our experience, in hemodynamically stable patients with influenza-associated severe hypoxemia, the clinical condition may improve significantly after few days of high PEEP and other supportive treatments, while patients with severe septic shock and/or DIC often represent the most difficult-to-treat group.

Therefore, to what extent ECMO may be of help to this patient population is interesting and remains unknown.

Nonetheless, in a prospective randomised controlled trial, the CESAR study investigators also reported statistically significant improvement in 6-month survival rate among ARDS patients (with similar severity-of-illness) treated with ECMO compared to conventional ventilatory support (67% vs. 47%, p = 0.03) [4].

The exciting results of these two studies might alert us about the comeback of ECMO as effective treatment of severe hypoxemia.

The inclusion criteria reported by the CESAR study investigators, i.e. potentially reversible respiratory failure, a Murray score of 3.0 or higher, or uncompensated hypercapnia with a pH of less than 7.2 despite optimum conventional treatment [4], may serve as selection criteria for potential candidates for ECMO in treatment of 2009 Influenza A (H1N1).

Reference

Jain S, Kaminoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009; 361 (early release)

The ANZIC Influenza Investigators. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009; 361 (early release)

Perez-Padilla R, de la Rosa-Zamboni D, de Leon SP, et al. Pneumonia and respiratory failure from Swine-origin influenza A (H1N1) in Mexico. N Engl J Med 2009; 361: 680-689

Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. JAMA 2009; 374; 1351-1363

The Bottom Line is in patients with severe hypoxemia secondary to 2009 Influenza A (H1N1), when conventional ventilatory support as well as interventions such as recruitment manuevers, nitric oxide inhalation, and prone positioning fails to improve oxygenation, ECMO may be considered as an alternative salvage treatment.

（CSCCM原创，转载请注明）

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