Uncertainties on the Frontier: Rescue Therapy in Pandemic Influenza

ECMO was developed clinically in 1954 as an intraoperative technique to support patients during cardiac surgery, and was first used to treat a trauma patient with acute respiratory distress syndrome (ARDS) in 1971.² Since that time, ECMO has demonstrated its value in pediatric intensive care and is a common therapy for neonates and children requiring cardiopulmonary support.³ Research to evaluate the effectiveness of ECMO has been difficult to perform and ethically controversial.^4,5 

Unfortunately, clinical trials of ECMO for treatment of ARDS in adults in the 1970s were disappointing, tainting its use for many years. However, as advancements have been made in the care of mechanically ventilated patients and in ECMO technology, there has been a renewed interest in investigations of ECMO in ARDS. A very recent large, multicenter, randomized controlled trial conducted in the United Kingdom, conventional ventilation or ECMO for severe adult respiratory failure (CESAR),⁶ demonstrated better survival without disability at 6 months in those who were randomized to receive ECMO compared to those who received usual intensive care.

It is not surprising that rescue therapies, including ECMO, have featured prominently in early accounts of H1N1 treatment. There simply had not been time to conduct the research in this population at the point where providers were faced with selecting from a limited number of therapeutic options. Decision making often occurred in a context in which conventional therapies were failing and there was little left to offer the patient and family. In Australia and New Zealand, during the Southern hemisphere winter months of 2009 (June to August), about 12% of all patients with H1N1 who were admitted to an ICU received ECMO⁷; for institutions where ECMO was offered, a third of all H1N1 ICU patients were treated with ECMO. Interestingly, during roughly the same period in Canada (April to August 2009; spring and summer in the Northern hemisphere), ECMO was instituted for only 4.2% of ICU patients with H1N1.⁸ 

Other rescue therapies have been suggested for patients with H1N1 influenza and a worsening condition, including high-frequency oscillatory ventilation, prone positioning, neuromuscular blockade, inhaled nitric oxide, prostacyclins, corticosteroids, and exogenous surfactant.^8,9 In Canadian data, several other rescue therapies were reported more commonly than ECMO, including neuromuscular blockade (28% of patients), inhaled nitric oxide (13.7%), and high-frequency oscillatory ventilation (11.9%).⁸ An algorithm for use of rescue therapies in ARDS was recently proposed; extracorporeal interventions are suggested to follow other, less invasive strategies.¹⁰ 

Because rescue therapies are employed at the point of failure of conventional therapy, it is difficult to assess risk and benefit. The results of the CESAR trail were published in November 2009, months after the first wave of critically ill H1N1 influenza patients were treated with ECMO. Assessment of potential benefit for an individual patient frequently occurs on a case-by-case basis, in which case any benefit would seem to outweigh the risk of imminent death. Often, the calculation of risk and benefit must be extrapolated from previous indications and experience; such extrapolations may or may not accurately reflect the new situation.

The outcomes obtained in individual cases influence providers’ beliefs about the efficacy of a particular rescue therapy and its subsequent wider adoption. If we see a patient improve following an intervention, we are convinced that the intervention contributed to the good outcome and has merit. Conversely, if our patient does not survive following the same intervention, we may be inclined to think that death was inevitable. We must be careful to remember that our own experience in individual cases does not provide generalizable evidence. Wolfson et al,¹¹ in a report of ECMO used as rescue therapy for an adolescent post-stem cell transplant, summarizes this dilemma:

There are certainly examples where novel technology turns out to be life saving and becomes standard of care. There are also examples that serve as cautionary tales, in which therapies with great promise based on efficacy in a particular population are no help (or are harmful) in a different population. The story of rescue therapy for breast cancer using high-dose chemotherapy with autologous bone marrow transplant provides such a warning.¹² 

During the 1980s, with few effective treatments for aggressive breast cancer and small studies that hinted high-dose chemotherapy with autologous bone marrow transplant might help, both oncologists and patients became enthusiastic about this highly toxic and risky intensive rescue therapy. Insurance companies resisted payment based on a lack of convincing evidence that the therapy was effective. Unfortunately, randomized clinical trials showed that high-dose chemotherapy with autologous bone marrow transplant was no better than (and was perhaps worse than) standard treatment at the time.

Additional research and experience may uphold the conclusions of the CESAR trial that ECMO is beneficial in ARDS. If so, use of the technology in the adult critical care setting is likely to expand. In the data reported from Australia and New Zealand, only 4 patients received ECMO for ARDS in 2008; 61 patients were treated during the same period in 2009.⁷ Whereas this increase was attributed to the large number of H1N1 influenza cases, it seems likely that ECMO use will continue to increase beyond 2008 levels. The complexity of ECMO has led to its concentration in centers with specialty expertise in the technology. As the procedure continues to diffuse into critical care practice, there will be increasing pressures to expand the number of institutions where ECMO is offered.

Haile and Schears¹³ describe ECMO as “by far the most complex life-sustaining technology employed.” Successful implementation of ECMO is staff intensive and requires services of a perfusionist, anesthesiologists and critical care physicians with specialty knowledge, and nurses with expertise in care of both the patient and the equipment. Such expertise is most easily developed and maintained in settings where the procedure is performed frequently. Even in settings with substantial experience in ECMO, the procedure remains complex and personnel intensive. Peek and colleagues⁶ argue that

ECMO places substantial demands on bedside caregivers under ideal circumstances, and increased numbers of patients exacerbate these demands. Corley et al¹ documented nurses’ concerns that established ECMO procedures and staffing were unable to be met during the patient surge of the Australian summer of 2009, and that staff distress accompanied the high demands in an environment of unmatched resources. Safety issues related to novel technology include communication among providers, technical competence of staff, and staffing. These factors are heavily influenced by how healthy the work environment is, and will influence whether an individual unit can safely incorporate novel technologies.

ECMO is an expensive procedure, both in personnel time and in money. Although the CESAR trial included a cost analysis component, the investigators acknowledge that their United Kingdom data cannot be applied to other health care systems. A host of factors that are unique to each health care system (including patient severity of illness, treatment outcomes, structure of the health care system, and costs) preclude generalizations about the cost effectiveness of ECMO in the United States. As health care reform progresses and cost-benefit ratios of treatment undergo enhanced scrutiny, additional research regarding costs of ECMO is warranted.

At the heart of the quote that opened this editorial are 3 questions for individuals and institutions to consider. First, what can we do? Answering this requires exploring all of the possible options, including those with which we may have less experience. Second, what can we do that will help? This question acknowledges the tension between our desire to improve the patient’s likelihood of a good outcome and the desire to do no harm. It is answered in light of the best available evidence, accepting that even the best evidence may be imperfect and will certainly change as more research is reported. Third, what can we do well? Here, we need to examine not only what is theoretically possible, but what is possible given the desire to maximize good outcomes and do no harm. Examination of these questions may mean that the best option will be to transfer the patient to an institution where more is possible, or it may mean concerted efforts to expand the repertoire of things we do well.

Critical care has always operated on the frontiers of health care. Struggles associated with the use of new technology, or older technology in new circumstances, will continue to challenge us. Procedures that were cutting edge a decade ago are commonplace now, and the trend to disseminate extraordinary interventions into routine practice is likely to continue. As we expand the boundaries of care for the critically ill, we will need thoughtful deliberation about what our individual units can accomplish and what will be in the best interest of patients, their families, and society in general.