Should We “Rescue” Patients With 2009 Influenza A(H1N1) and Lung Injury From Conventional Mechanical Ventilation?
2010; Elsevier BV; Volume: 137; Issue: 4 Linguagem: Inglês
10.1378/chest.09-2915
ISSN1931-3543
AutoresRolf D. Hubmayr, Joseph C. Farmer,
Tópico(s)Mechanical Circulatory Support Devices
ResumoIn 2009, the world experienced a novel influenza A(H1N1) [A(H1N1)] pandemic, which stressed critical care delivery systems with an onslaught of patients with severe, life-threatening respiratory failure. Case series from different parts of the world now provide a fairly comprehensive account of patient characteristics and outcomes1Domínguez-Cherit G Lapinsky SE Macias AE et al.Critically ill patients with 2009 influenza A(H1N1) in Mexico.JAMA. 2009; 302: 1880-1887Crossref PubMed Scopus (740) Google Scholar, 2Jain S Kamimoto L Bramley AM 2009 Pandemic Influenza A(H1N1) Virus Hospitalizations Investigation Team et al.Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009.N Engl J Med. 2009; 361: 1935-1944Crossref PubMed Scopus (1485) Google Scholar, 3Kumar A Zarychanski R Pinto R Canadian Critical Care Trials Group H1N1 Collaborative et al.Critically ill patients with 2009 influenza A(H1N1) infection in Canada.JAMA. 2009; 302: 1872-1879Crossref PubMed Scopus (1119) Google Scholar, 4Louie JK Acosta M Winter K California Pandemic (H1N1) Working Group et al.Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California.JAMA. 2009; 302: 1896-1902Crossref PubMed Scopus (855) Google Scholar, 5Centers for Disease Control and Prevention (CDC) Intensive-care patients with severe novel influenza A (H1N1) virus infection—Michigan, June 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 749-752PubMed Google Scholar and have raised interesting questions about risk factors and disease modifiers of acute lung injury and ARDS. We have learned that patients with A(H1N1) who are admitted to ICUs tend to be comparatively young, frequently obese, and more frequently pregnant. Those who suffer from ARDS can be very difficult to oxygenate by conventional means. Consequently, during a 2-month time span at the peak of the epidemic in Australia and New Zealand, 68 patients with influenza-associated ARDS were transitioned to extracorporeal membrane oxygenation (ECMO) after presumed failure of conventional treatment.6Davies A Jones D Bailey M Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators et al.Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome.JAMA. 2009; 302: 1888-1895Crossref PubMed Scopus (1275) Google Scholar The severity of ARDS before commencement of ECMO was reflected in median values as follows: lowest ratio of Po2 in blood relative to the fractional concentration of oxygen in inspired gas, 56; highest positive end-expiratory pressure, 18 cm H2O; highest peak airway pressure, 36 cm H2O; highest Pco2, 69 torr; and lowest pH, 7.2. Many of these patients failed other “rescue” attempts, such as prone positioning and high-frequency oscillatory ventilation (HFOV), as well as nitric oxide and prostacyclin supplementation. Remarkably, 71% of patients managed with ECMO were alive at ICU discharge and one-third were ultimately discharged home. Overall, mortality at the time of the report (some patients were still in ICUs, rehabilitation facilities, and other institutions) was 21%.In this issue of CHEST (see page 752), Miller et al7Miller III, RR Markewitz BA Rolfs RT et al.Clinical findings and demographic factors associated with ICU admission in Utah due to novel 2009 influenza A(H1N1) infection.Chest. 2010; 137: 752-758Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar report clinical findings and demographic factors associated with ICU admission in Utah due to the 2009 A(H1N1) infection. They identified 47 patients with influenza during a 6-week observation period, 30 of whom developed ARDS. Mortality was limited to patients with ARDS and was 27% (8/30). The observational report supports earlier findings regarding age distribution, as well as obesity, as independent risk factors. Furthermore, they also observed that nonwhite patients who lacked medical insurance were disproportionately likely to require ICU care. This finding parallels as yet unpublished data from Kumar and colleagues in Winnipeg, who noted an increased incidence of severe respiratory failure in native Canadian Indians who developed A(H1N1) and who required hospitalization (A. Kumar, personal communication). None of the patients reported by Miller and colleagues received rescue therapies, even though the severity of illness in this population was generally comparable to that of patients cared for in other centers.A significant number of previously reported negative and/or inconclusive clinical trials have dampened enthusiasm regarding prone positioning and nitric oxide supplementation for ventilator-dependent patients with severe ARDS. That is not to say that these interventions have disappeared from clinical practice or could not be defended on a case-by-case basis. However, they simply should not be considered the standard of care for patients with severe hypoxic respiratory failure. In contrast, interest in rescue therapies such as HFOV and ECMO has increased substantially. Both rescue modalities were largely abandoned after two clinical trials several decades ago showed them to be inefficacious.8The HIFI Study Group High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants.N Engl J Med. 1989; 320: 88-93Crossref PubMed Scopus (415) Google Scholar, 9Zapol WM Snider MT Hill JD et al.Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study.JAMA. 1979; 242: 2193-2196Crossref PubMed Scopus (1167) Google Scholar In hindsight, both trials suffered from serious design flaws because the deleterious consequences of ventilator-associated lung injury were not fully appreciated at the time. Since then, neonatologists and pediatricians have readily embraced HFOV as a first-line treatment of respiratory distress. In contrast, most adult intensivists remain skeptical and tend to reserve HFOV for patients with very severe gas exchange impairments. The eagerly anticipated results of the Canadian Oscillation for ARDS Treated Early trial may help clarify these lingering controversies.ECMO for adults has received a lot of attention since the recent publication of the Conventional Ventilation or ECMO for Severe Adult Respiratory Failure trial.10Peek GJ Mugford M Tiruvoipati R CESAR Trial Collaboration 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.Lancet. 2009; 374: 1351-1363Abstract Full Text Full Text PDF PubMed Scopus (2303) Google Scholar In this trial, 180 patients with severe ARDS, those who could not be safely ventilated up to a pH > 7.20, were randomly assigned to either receive usual care on site or were transferred to a single center with ECMO capabilities. Six-month-disability-free survival favored transfer to the ECMO center (63% vs 47%; P < .03). However, as pointed out by others, these results are hardly an endorsement of ECMO as the future standard of “ARDS rescue care.” Only 75% of patients who were transferred to the ECMO center actually received ECMO. Those patients who did not receive ECMO but were cared for at the ECMO center had substantially better outcomes than those receiving equivalent care in referring hospitals. Notably, conventional treatment was not standardized across the 103 study sites.Uncertainty surrounding the clinical evidence in support of these rescue therapies leads us to wonder, how we should define failure of conventional mechanical ventilation? Most clinicians become nervous when the plateau pressure exceeds 30 cm H2O, the Fio2 approaches 1.0, the arterial O2 saturation falls below 90%, and/or the pH drops below 7.2. Each of these thresholds may be defended on empirical as well as biologic grounds, but we should not delude ourselves into thinking that these are evidence-based, iron-clad safety boundaries. For example, who really knows how the absolute risk of a plateau pressure > 30 cm H2O “stacks up” against the risk associated with gaining vascular access for an ECMO run? Similarly, there is an ongoing, healthy debate about how to balance the injury risk of lung overdistension against the risk of lung underrecruitment. The plateau pressure threshold of 30 cm H2O may well fall victim to this debate. Why couldn't a young patient without vascular disease survive, without harm, a time-limited reduction in O2 saturation to 80%? Although we have learned much about the cell and molecular biology of reactive oxygen species, we have yet to integrate this knowledge into widespread clinical management strategies. Until we do, who is to say that an Fio2 of 1.0 cannot be tolerated for some duration of time without long-term consequence? Or, there are those who believe hypercapnic acidosis to be lung protective11Laffey JG Jankov RP Engelberts D et al.Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury.Am J Respir Crit Care Med. 2003; 168: 1383-1390Crossref PubMed Scopus (85) Google Scholar—are they wrong? Should this influence when we refer patients with hypercapnic acidosis for ECMO consideration?These concerns about appropriate definitions of conventional treatment failure are not easily resolved. However, and until they are, they remain as confounding assumptions in virtually all clinical trials of ARDS rescue therapies. We therefore endorse experimental and clinical research on topics such as permissive hypoxemia, therapeutic hypercapnia, and the mechano-biology of lung injury. We are quite encouraged that care providers in Utah were able to achieve acceptable management end points and outcomes without having to rely on experimental rescue therapies.7Miller III, RR Markewitz BA Rolfs RT et al.Clinical findings and demographic factors associated with ICU admission in Utah due to novel 2009 influenza A(H1N1) infection.Chest. 2010; 137: 752-758Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar ECMO remains a resource-intensive treatment modality, with a steep learning curve and the need for a nimble, dedicated staff. Very few health-care systems are in a position to offer such treatment on a routine basis and with consistently low iatrogenic risk. As a corollary, transporting a critically ill patient with severe respiratory failure to a facility with ECMO capabilities is also a significant risk.There is nothing more helpless than to sit at the bedside of a patient, adjusting ventilator settings while the severity of respiratory failure continues to worsen. When “the knobs are tuned up as high as they go,” now what? Given the recent successes of ECMO in patients with A(H1N1), some leaders have questioned whether ECMO should be more broadly available. At this time, and for the reasons enumerated above, we do not support the position that as a nation we should invest in the development of additional ECMO centers to be prepared for the next wave of influenza cases. We believe the influenza events of 2009 should drive more probing discussions about acceptable physiologic end points and management thresholds for patients with severe gas exchange failure. However, and in the interest of transparency, we acknowledge that the care of young adults with life-threatening respiratory failure invokes appropriate emotions and responses. Desperate circumstances trigger desperate responses so that we will undoubtedly continue to offer ECMO (and other rescue therapies) to some patients who we fear will die unless we change their clinical trajectories. In 2009, the world experienced a novel influenza A(H1N1) [A(H1N1)] pandemic, which stressed critical care delivery systems with an onslaught of patients with severe, life-threatening respiratory failure. Case series from different parts of the world now provide a fairly comprehensive account of patient characteristics and outcomes1Domínguez-Cherit G Lapinsky SE Macias AE et al.Critically ill patients with 2009 influenza A(H1N1) in Mexico.JAMA. 2009; 302: 1880-1887Crossref PubMed Scopus (740) Google Scholar, 2Jain S Kamimoto L Bramley AM 2009 Pandemic Influenza A(H1N1) Virus Hospitalizations Investigation Team et al.Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009.N Engl J Med. 2009; 361: 1935-1944Crossref PubMed Scopus (1485) Google Scholar, 3Kumar A Zarychanski R Pinto R Canadian Critical Care Trials Group H1N1 Collaborative et al.Critically ill patients with 2009 influenza A(H1N1) infection in Canada.JAMA. 2009; 302: 1872-1879Crossref PubMed Scopus (1119) Google Scholar, 4Louie JK Acosta M Winter K California Pandemic (H1N1) Working Group et al.Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California.JAMA. 2009; 302: 1896-1902Crossref PubMed Scopus (855) Google Scholar, 5Centers for Disease Control and Prevention (CDC) Intensive-care patients with severe novel influenza A (H1N1) virus infection—Michigan, June 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 749-752PubMed Google Scholar and have raised interesting questions about risk factors and disease modifiers of acute lung injury and ARDS. We have learned that patients with A(H1N1) who are admitted to ICUs tend to be comparatively young, frequently obese, and more frequently pregnant. Those who suffer from ARDS can be very difficult to oxygenate by conventional means. Consequently, during a 2-month time span at the peak of the epidemic in Australia and New Zealand, 68 patients with influenza-associated ARDS were transitioned to extracorporeal membrane oxygenation (ECMO) after presumed failure of conventional treatment.6Davies A Jones D Bailey M Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators et al.Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome.JAMA. 2009; 302: 1888-1895Crossref PubMed Scopus (1275) Google Scholar The severity of ARDS before commencement of ECMO was reflected in median values as follows: lowest ratio of Po2 in blood relative to the fractional concentration of oxygen in inspired gas, 56; highest positive end-expiratory pressure, 18 cm H2O; highest peak airway pressure, 36 cm H2O; highest Pco2, 69 torr; and lowest pH, 7.2. Many of these patients failed other “rescue” attempts, such as prone positioning and high-frequency oscillatory ventilation (HFOV), as well as nitric oxide and prostacyclin supplementation. Remarkably, 71% of patients managed with ECMO were alive at ICU discharge and one-third were ultimately discharged home. Overall, mortality at the time of the report (some patients were still in ICUs, rehabilitation facilities, and other institutions) was 21%. In this issue of CHEST (see page 752), Miller et al7Miller III, RR Markewitz BA Rolfs RT et al.Clinical findings and demographic factors associated with ICU admission in Utah due to novel 2009 influenza A(H1N1) infection.Chest. 2010; 137: 752-758Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar report clinical findings and demographic factors associated with ICU admission in Utah due to the 2009 A(H1N1) infection. They identified 47 patients with influenza during a 6-week observation period, 30 of whom developed ARDS. Mortality was limited to patients with ARDS and was 27% (8/30). The observational report supports earlier findings regarding age distribution, as well as obesity, as independent risk factors. Furthermore, they also observed that nonwhite patients who lacked medical insurance were disproportionately likely to require ICU care. This finding parallels as yet unpublished data from Kumar and colleagues in Winnipeg, who noted an increased incidence of severe respiratory failure in native Canadian Indians who developed A(H1N1) and who required hospitalization (A. Kumar, personal communication). None of the patients reported by Miller and colleagues received rescue therapies, even though the severity of illness in this population was generally comparable to that of patients cared for in other centers. A significant number of previously reported negative and/or inconclusive clinical trials have dampened enthusiasm regarding prone positioning and nitric oxide supplementation for ventilator-dependent patients with severe ARDS. That is not to say that these interventions have disappeared from clinical practice or could not be defended on a case-by-case basis. However, they simply should not be considered the standard of care for patients with severe hypoxic respiratory failure. In contrast, interest in rescue therapies such as HFOV and ECMO has increased substantially. Both rescue modalities were largely abandoned after two clinical trials several decades ago showed them to be inefficacious.8The HIFI Study Group High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants.N Engl J Med. 1989; 320: 88-93Crossref PubMed Scopus (415) Google Scholar, 9Zapol WM Snider MT Hill JD et al.Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study.JAMA. 1979; 242: 2193-2196Crossref PubMed Scopus (1167) Google Scholar In hindsight, both trials suffered from serious design flaws because the deleterious consequences of ventilator-associated lung injury were not fully appreciated at the time. Since then, neonatologists and pediatricians have readily embraced HFOV as a first-line treatment of respiratory distress. In contrast, most adult intensivists remain skeptical and tend to reserve HFOV for patients with very severe gas exchange impairments. The eagerly anticipated results of the Canadian Oscillation for ARDS Treated Early trial may help clarify these lingering controversies. ECMO for adults has received a lot of attention since the recent publication of the Conventional Ventilation or ECMO for Severe Adult Respiratory Failure trial.10Peek GJ Mugford M Tiruvoipati R CESAR Trial Collaboration 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.Lancet. 2009; 374: 1351-1363Abstract Full Text Full Text PDF PubMed Scopus (2303) Google Scholar In this trial, 180 patients with severe ARDS, those who could not be safely ventilated up to a pH > 7.20, were randomly assigned to either receive usual care on site or were transferred to a single center with ECMO capabilities. Six-month-disability-free survival favored transfer to the ECMO center (63% vs 47%; P < .03). However, as pointed out by others, these results are hardly an endorsement of ECMO as the future standard of “ARDS rescue care.” Only 75% of patients who were transferred to the ECMO center actually received ECMO. Those patients who did not receive ECMO but were cared for at the ECMO center had substantially better outcomes than those receiving equivalent care in referring hospitals. Notably, conventional treatment was not standardized across the 103 study sites. Uncertainty surrounding the clinical evidence in support of these rescue therapies leads us to wonder, how we should define failure of conventional mechanical ventilation? Most clinicians become nervous when the plateau pressure exceeds 30 cm H2O, the Fio2 approaches 1.0, the arterial O2 saturation falls below 90%, and/or the pH drops below 7.2. Each of these thresholds may be defended on empirical as well as biologic grounds, but we should not delude ourselves into thinking that these are evidence-based, iron-clad safety boundaries. For example, who really knows how the absolute risk of a plateau pressure > 30 cm H2O “stacks up” against the risk associated with gaining vascular access for an ECMO run? Similarly, there is an ongoing, healthy debate about how to balance the injury risk of lung overdistension against the risk of lung underrecruitment. The plateau pressure threshold of 30 cm H2O may well fall victim to this debate. Why couldn't a young patient without vascular disease survive, without harm, a time-limited reduction in O2 saturation to 80%? Although we have learned much about the cell and molecular biology of reactive oxygen species, we have yet to integrate this knowledge into widespread clinical management strategies. Until we do, who is to say that an Fio2 of 1.0 cannot be tolerated for some duration of time without long-term consequence? Or, there are those who believe hypercapnic acidosis to be lung protective11Laffey JG Jankov RP Engelberts D et al.Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury.Am J Respir Crit Care Med. 2003; 168: 1383-1390Crossref PubMed Scopus (85) Google Scholar—are they wrong? Should this influence when we refer patients with hypercapnic acidosis for ECMO consideration? These concerns about appropriate definitions of conventional treatment failure are not easily resolved. However, and until they are, they remain as confounding assumptions in virtually all clinical trials of ARDS rescue therapies. We therefore endorse experimental and clinical research on topics such as permissive hypoxemia, therapeutic hypercapnia, and the mechano-biology of lung injury. We are quite encouraged that care providers in Utah were able to achieve acceptable management end points and outcomes without having to rely on experimental rescue therapies.7Miller III, RR Markewitz BA Rolfs RT et al.Clinical findings and demographic factors associated with ICU admission in Utah due to novel 2009 influenza A(H1N1) infection.Chest. 2010; 137: 752-758Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar ECMO remains a resource-intensive treatment modality, with a steep learning curve and the need for a nimble, dedicated staff. Very few health-care systems are in a position to offer such treatment on a routine basis and with consistently low iatrogenic risk. As a corollary, transporting a critically ill patient with severe respiratory failure to a facility with ECMO capabilities is also a significant risk. There is nothing more helpless than to sit at the bedside of a patient, adjusting ventilator settings while the severity of respiratory failure continues to worsen. When “the knobs are tuned up as high as they go,” now what? Given the recent successes of ECMO in patients with A(H1N1), some leaders have questioned whether ECMO should be more broadly available. At this time, and for the reasons enumerated above, we do not support the position that as a nation we should invest in the development of additional ECMO centers to be prepared for the next wave of influenza cases. We believe the influenza events of 2009 should drive more probing discussions about acceptable physiologic end points and management thresholds for patients with severe gas exchange failure. However, and in the interest of transparency, we acknowledge that the care of young adults with life-threatening respiratory failure invokes appropriate emotions and responses. Desperate circumstances trigger desperate responses so that we will undoubtedly continue to offer ECMO (and other rescue therapies) to some patients who we fear will die unless we change their clinical trajectories.
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