The Italian ECMO Network Experience During the 2009 Influenza A(H1N1) Pandemic: a Preparation

The Italian ECMO network experience during the 2009 Influenza A(H1N1) pandemic: a preparation for severe respiratory emergencies outbreaks.

Elettronic Supplementary Material

Nicolò Patroniti,1 Alberto Zangrillo,2 Federico Pappalardo, 2 Adriano Peris,3 Giovanni Cianchi,3

Antonio Braschi,4 Giorgio A Iotti,5 Antonio Arcadipane,6 Giovanna Panarello,6 Marco V Ranieri, 7

Pier P Terragni,7 Massimo Antonelli,8 Luciano Gattinoni,9 Fabrizio Oleari,10 Antonio Pesenti1, for the ECMOnet Italian ECMO network*

1 Additional Methods

Table E1: Characteristics of the ECMONet centers.

Geographical ICU ECMO Transport City Institution Location capacity capacity Coverage

Bari Ospedale Policlinico, Università di Bari South 16 2 Regional Bergamo Ospedali Riuniti di Bergamo North 16 2 Regional Bologna Ospedale S. Orsola-Malpighi, Università di Bologna North 12 2 Regional Florence Ospedale Careggi, Università di Firenze Center 10 4 Regional Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan North 6 2 National Università di Milano Milan Ospedale San Raffaele, Università Vita-Salute San Raffaele North 14 7 National Monza Ospedale San Gerardo, Università Milano-Bicocca North 10 4 National Naples Ospedale Federico II, Università di Napoli South 14 3 Regional Padua Azienda Ospedaliera Universitaria di Padova North 11 4 Regional Palermo Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione South 14 6 Regional Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia North 20 6 National Pavia Rome Ospedale A. Gemelli, Università La Sapienza Center 18 1 Regional Rome Policlinico Umberto I, Università Cattolica del Sacro Cuore Center 18 2 Regional Turin Ospedale San Giovanni Battista-Molinette, Università di Torino North 14 7 National

Data collection

We recorded patients demographics including age, sex, height, weight, and predefined comorbidities. We recorded information on the typical influenza symptoms, time of presumed onset of symptoms, type and onset of antiviral and antibiotics therapy, timing of hospital admission, ICU admission, endotracheal intubation, ECMO institution, and duration of mechanical ventilation prior to ECMO institution. Data on respiratory variables, ventilator setting, hemodynamics, selected laboratory data, use of vasoactive, antibiotics, and corticosteroids drugs, main indicators of organ dysfunction, computation of Sequential Organ Failure Assessment Score (SOFA), use of respiratory rescue therapies including recruiting maneuvers, prone positioning, nitric oxide, high frequency and oscillatory ventilation, use of continuous renal replacement therapy (CRRT) were collected before

ECMO institution. The same data with the adjunction of ECMO setting parameters were collected within 6 hour from ECMO institution, after one day and then every seven days from ECMO institution until patient discharge or death, and within 24 hour before ECMO disconnection.

2 Outcome variables included in-hospital mortality, days of mechanical ventilation, days of ICU, organ dysfunction at ICU discharge, complications related to ECMO.

Additional results

Ninety-two % of all patients had influenza like symptoms before hospitalization (94% and 82% respectively in the ARDSH1N1 and ARDSOther group), with the more frequent symptoms being fever

(80% of all patients, 84% and 64% respectively in the ARDSH1N1 and ARDSOther group), and cough

(56% of all patients, 58% and 45% respectively in the ARDSH1N1 and ARDSOther group). Six patients of ARDSH1N1 (12%) had a secondary respiratory infection (two with Legionella pneumophila, two with Acinetobacter baumanii, one with Pseudomonas aeruginosa, and one with Enterococcus spp).

Comparison between early and late ECMO institution

According to days of mechanical ventilation before institution of ECMO all patients were classified between those receiving ECMO within 7 days from the start of mechanical ventilation (ARDSEarly) and those receiving ECMO after more than 7 days of mechanical ventilation (ARDSlate).

Forty-eight of the 60 ECMO patients (22 of the patients transported while on ECMO, 17 of the patients referred from other hospitals but connected to ECMO after transportation, and 9 of the patients directly admitted to the ECMOnet centers) were connected to ECMO within 7 days after beginning of mechanical ventilation (ARDSEarly), thus fulfilling all eligibility criteria. The remaining

12 patients (6 of the patients transported while on ECMO, 3 of the patients referred from other hospitals but connected to ECMO after transportation, and 3 of the patients directly admitted to the

ECMOnet centers) where connected to ECMO after more than 7 days since the beginning of mechanical ventilation (ARDSLate).

There were no statistical significant differences between ARDSEarly and ARDSLate in terms of severity of respiratory failure and treatment before ECMO. ARDSEarly patients had significantly higher hematocrit and creatinine (Table E2).

3 Survival was significantly higher in ARDSEarly patients than in the ARDSLate ones. There were no other statistically significant differences between ARDSEarly and ARDSLate in terms of other outcome parameters (Table E3).

Considering only the population of patients fulfilling all eligibility criteria, survivors showed higher hematocrit, lower SOFA score, and lower bilirubin than nonsurvivors.

4 Table E2: Patient characteristics before ECMO institution: comparison between patients receiving ECMO within 7 days (ARDSEarly) and >7 days (ARDSLate) from onset of mechanical ventilation.

ARDSEarly ARDSLate (48) (12) Age, years 39 (32-46) 45 (35-55) Male sex 30 (63) 6 (50) BMI Kg*m-2 28·6 (25-37) 26 (24-31) MV days 1 (1-3) 11 (8-14) H1N1 confirmed 43 (90) * 6 (50) SAPS II 30 (23-37) 35 (24-50) Co-morbidity factors Obesity 19 (39) 4(33) Asthma and Chronic lung disease 6 (13) 1 (8) Pregnancy or postpartum 3 (6) 1 (8) Diabetes mellitus 5 (10) 0 (0) Respiratory severity and Ventilatory parameters before ECMO CRX infiltrate, quadrants (No.) 4 (3-4) 4 (4-4)

PaO2/FiO2 (mmHg) 63 (55-789) 59 (50-80)

PaCO2 (mmHg) 60 (50-75.5) 52 (46-73) pH 7.29 (7.21-7.40) 7.31 (7.23-7.4)

FiO2 1 (1-1) 1 (1-1)

PEEP (cmH2O) 16 (14-19) 16 (10-20) Vt/Kg (ml/Kg) 6.3 (5-8.4) 5.6 (4.4-7.0) Respiratory Rate (bpm) 25 (20-33) 30 (27-33)

Peak Airway Pressure (cmH2O) 33 (30-38) 33 (31-45)

Mean Airway Pressure (cmH2O) 24 (22-25) 27 (21-30) Acute Lung Injury Score 3.67 (3.27-3.75) 3.75 (3.25-3.75)

OI (mmHg*cmH2O) 36 (29-44) 36 (30-53) Rescue therapies and adjunctive therapies before ECMO Recruitment maneuvers 33 (69) 8 (67) Prone positioning 12 (25) 4 (33) HFOV 2 (4) 2 (17) iNO 7 (15) 3 (25) Vasoactive drugs 30 (63) 7 (58) Steroid therapy 15 (31) 6 (50) None 15(31) 3(25) Non respiratory organ function before ECMO HR (bpm) 104 (90-120) 103 (80-112) Mean Arterial Pressure (mmHg) 76 (65-86) 78 (60-81) SOFA score 7 (6-9) 6 (8-10) Ht (%) 34.7 (30-38.2) * 31 (27-33) Platelet count (*103 /µL) 149 (104-239) 166 (120-351) Creatinine (mg/dL) 0.9 (0.7-1.3) * 0.7 (0.5-0.9) Bilirubin (mg/dL) 0.9 (0.6-1.5) 0.9 (0.6-1.1) BMI, body mass index; MV, mechanical ventilation; SAPS II, simplified acute physiology score; CRX, chest X ray;

PaO2/FiO2, arterial partial pressure of oxygen to inspired oxygen fraction ratio; PaCO 2, arterial partial pressure of carbon dioxide; PEEP, positive end-expiratory pressure; Vt/Kg IBW, tidal volume indexed by ideal body weight; Lung

Injury Score, OI, oxygenation index (computed as FiO2 * mean airway pressure * 100/PaO2); HFOV, high frequency oscillatory ventilation; iNO, inhaled nitric oxyde; SOFA, Sepsis related organ failure assessment; Ht, hematocrit. Data presented as No (%) for categorical variables and median (interquantile range) for parametric variables.

* p<0.05 ARDSEarly vs ARDSLate

5 Table E3: Patient outcomes. Comparison between patients receiving ECMO within 7 days (ARDSEarly) and >7 days (ARDSLate) from onset of mechanical ventilation.

ARDSEarly ARDSLate (48) (12)

Survival at ICU discharge No. (%) 37 (77) 4 (33) *

Survival at hospital discharge No. (%) 37 (77) 4 (33) #

Tracheostomy No. (%) 22 (46) 7 (58)

Infection No. (%) 24 (50) 6 (50)

CRRT 12 (25) 5 (42)

Lenght of ICU stay (median (IQR))

All patients 21 (14-36) 26 (16-41)

Survived patients 22 (14-33) 34 (19-45)

Length of Hospital stay (median (IQR))

All patients 40 (25-51) 34 (19-43)

Days of MV (median (IQR))

All patients 17 (12-34) * 28 (18-43)

Days of ECMO (median (IQR))

All patients 10 (7-17) 12 (6-26)

Cause of death No. (% of death causes)

MOF due to sepsis 8 (67) 2 (25)

CNS hemorrhage 1 (8) 1 (12.5)

Acute liver failure 1 (8) 1 (12.5)

Right heart failure - 1 (12.5)

Septic shock 2 (17) 3 (37.5)

ECMO related major complications No. (No. of complication related deaths)

CNS hemorrhage - 1 (1)

Abdominal bleeding 2 (0) -

Airways bleeding 1 (0) -

Cannulation complications 4 (0) -

CRRT, continuous renal replacement therapy; ICU, intensive care unit; MV, mechanical ventilation, MOF, multiple organ failure; CNS, central nervous system. Data presented as No (%) for categorical variables and median

(interquantile range) for parametric variables.

* p<0.05 ARDSEarly vs ARDSLate

6 Details on ECMO material

Figure E1: Histogram of Number of concurrent patients receiving ECMO at theECMONet centers. The maximum number of patients treated concurrently at the 14 ECMOnet centers was 16 patients.