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Severe respiratory failure is a well-recognized complication of pH1N1 influenza infection. Limited data regarding the efficacy of rescue therapies, including high-frequency oscillatory ventilation and extracorporeal membrane oxygenation, have been previously reported in the setting of pH1N1 influenza infection in the United States.Retrospective, single-center cohort study.Pediatric, cardiac, surgical, and medical intensive care units in a single tertiary care center in the United States.One hundred twenty-seven consecutive patients with confirmed influenza A infection requiring hospitalization between April 1, 2009, and October 31, 2009.Electronic medical records were reviewed for demographic and clinical data.The number of intensive care unit admissions appears inversely related to age with 39% of these admissions <20 yrs of age. Median duration of intensive care unit care was 10.0 days (4.0–24.0), and median duration of mechanical ventilation was 8.0 days (0.0–23.5). Rescue therapy (high-frequency oscillatory ventilation or extracorporeal membrane oxygenation) was used in 36% (12 of 33) of intensive care unit patients. The severity of respiratory impairment was determined by Pao2/Fio2 ratio and oxygenation index. High-frequency oscillatory ventilation at 24 hrs resulted in improvements in median Pao2/Fio2 ratio (71 [58–93] vs. 145 [126–185]; p < .001), oxygenation index (27 [20–30] vs. 18 [12–25]; p = .016), and Fio2 (100 [70–100] vs. 45 [40–55]; p < .001). Extracorporeal membrane oxygenation resulted in anticipated improvement in parameters of oxygenation at both 2 hrs and 24 hrs after initiation of therapy. Despite the severity of oxygenation impairment, overall survival for both rescue therapies was 75% (nine of 12), 80% (four of five) for high-frequency oscillatory ventilation alone, and 71% (five of seven) for high-frequency oscillatory ventilation + extracorporeal membrane oxygenation.In critically ill adult and pediatric patients with pH1N1 infection and severe lung injury, the use of high-frequency oscillatory ventilation and extracorporeal membrane oxygenation can result in significant improvements in Pao2/Fio2 ratio, oxygenation index, and Fio2. However, the impact on mortality is less certain.