Original Article

24/01/2005
EXOGENOUS SURFACTANT IN THE INTENSIVE CARE UNIT: EXPECTATIONS BEYOND SCIENCE

Wolfgang S. Strohmaier
Karl Franzens University, Graz, Austria
Ludwig Boltzmann Inst., for Experimental and Clinical Traumatology, Vienna, Austria

“Most therapies that fail to show benefit in well-conducted, randomised, controlled trials are abandoned by both clinical investigators and pharmaceutical companies. Treatment with exogenous surfactant for the acute respiratory distress syndrome (ARDS) appears to enjoy a different status.”

These are the introductory words of a comment (1) on the results of two multicenter trials (2) with a recombinant surfactant in ARDS which show no significant differences in mortality between the patients who were repeatedly treated with surfactant and those who did not receive surfactant. These two trials have failed although numerous experimental and several clinical trials before have suggested that application of exogenous surfactant may be beneficial for the treatment in patients with ARDS.

This article intends to plead for a more pragmatic approach, basically by asking a few questions. These questions will definitively not always be entirely scientific, but they will be straightforward and to a certain extent speculative in the sense of (yet) missing scientific proof.

Why are results from experimental and clinical trials so divergent?
The present situation is strikingly paradox: On the one hand, a constantly increasing number of animal models in experimental lung injury continuously reveals new insights into the pathophysiology of lung injury on every level between organ dysfunction and the related molecular triggers. And even more experimental work demonstrated the therapeutic efficacy of exogenous surfactant. On the other hand, there is a long list of clinical trials that failed. The obvious disappointment is a good deal related to underachieving the high expectations raised by experimental studies that were simply too convincing.

There are some main differences between experimental and clinical studies which are not normally in the focus of attention, but have the potential to seriously confound the conclusions:

• Age (Laboratory animals are young)
• Co-morbidities (Laboratory animals are healthy)
• Heterogeneity of enrolled patients (Laboratory animals represent a very homogeneous group)
• Medical, technical and personal “fluctuations” (Protocols, equipment and staff can be kept almost constant during experiments)

This list is by far not complete, but it may help to open a discussion on how experimental work can be organized internationally, without narrowing creativity, aimed at enhancing comparability and clinical relevance to reduce the gap between expectation and science.

Is there a link between Ventilation, Outcome and Surfactant?
It was completely unexpected – as also the premature stop of the study (3) shows – that one of the oldest tools in intensive care medicine, namely ventilation, had to be somehow re-defined to substantially lower mortality. The theoretical basis for studies addressing the impact of various parameters of ventilation came from the development of the pathophysiologic concept of “Ventilator Induced Lung Injury” (VILI). This concept describes the role of high tidal volumes and high airway pressures in the progression of early lung dysfunction to ARDS. The most important underlying mechanisms were identified to be cell stretch and shear stress (for review see 4). These findings put the lung into focus and stimulated research to protect the lung from VILI, thereby protecting the whole organism. At present two strategies are available: the first is lung protective ventilation with low tidal volumes (~ 6 mL/ kg body weight). The second is the administration of exogenous surfactant. It has been known for a long time that exogenous surfactant facilitates gas exchange in injured lungs and therefore allows less invasive (= lower tidal volumes and pressures) ventilation modes. So, obviously, there is a clear link between ventilation, outcome and surfactant.

Is ARDS the right target?
All recent studies on the use of exogenous surfactant, including the latest one, have targeted ARDS. Patients were enrolled with ARDS independent of origin – many of them were septic – and, moreover, treatment was started delayed ~ 22 hours after the diagnosis of ARDS, in line with the intention to treat not later than 48 or 72 hours respectively. In comparison to earlier studies this was a fundamental progress because exogenous surfactant was and often still is seen as a rescue treatment like extra-corporeal membrane oxygenation (ECMO). Interestingly, even in these very sick, often septic patients transient improvements or positive trends could be demonstrated. Taking together these findings and the lessons on the early successful use of exogenous surfactant from neonatology it is not advisable to wait with a potent treatment until the disease has gained its own momentum.

Do we treat the right patients?
It was mentioned above that there is a big difference in the homogeneity of laboratory animals and the patients enrolled in clinical trials. Moreover, it is stated in the discussion of every failed clinical trial in this field that this very lack of patients homogeneity contributed to the unsatisfying results. Although it is a great goal to successfully treat patients independent of the type or severity of a disease, it remains wishful thinking that we can achieve this with one drug given to all patients at the same time in the same manner. But a rethinking seems to be on the way, since a post hoc analysis of the data from the last trial (2) indicates that patients with direct lung injuries can benefit of treatment with exogenous surfactant. This analysis indirectly confirms the work from Marraro and colleagues (5) who report convincing results from treating patients after aspiration and lung contusion. This approach is also supported by new experimental studies (6) demonstrating that initiation of ventilation immediately after an aspiration trauma is deleterious for the lung.

Putting selected types of lung injury, namely the direct ones, into the focus of future considerations has consequences for the definitions of outcome and endpoints. Conventionally treated, these types of lung injury have a lower mortality rate. However, early treatment with exogenous surfactant is reported to reduce invasiveness of ventilation and to increase ventilatory free days. These improvements bear the potential to reduce the frequency of complications, like ventilator associated pneumonia, to shorten the length of stay in the ICU and thereby reduce post traumatic morbidity.

These questions together with many others not asked here and their respective answers, whether presently known or not, may lead to a very pragmatic approach. A future clinical trial driven by expectation could therefore have the following features:

• Early lung dysfunction is the target
• Only patients with direct lung injury are enrolled
• Surfactant is given as early as possible
• Primary endpoints are vent free days, frequency of complications, LOS in the ICU and morbidity

It is obvious that this approach creates new questions – “what is early lung dysfunction” and “when is surfactant given early” probably being among the first ones. It is also obvious that many more questions need to be answered, but the motto should be that science has to prove or disprove concepts and theories, but there should always exist expectations beyond science.

REFERENCES

1. Baudouin SV. N Engl J Med 2004; 351: 853 – 855 (PubMed)
2. Spragg et al. N Engl J Med 2004; 351: 884 – 892 (PubMed)
3. ARDS Network Investigators. N Engl J Med 2000; 342:1301-1308 (PubMed)
4. Frank JA and Matthay MA. Crit Care 2003; 7: 233 – 241 (Full Text)
5. Marraro G. J Matern Fetal Neonatal Med. 2004;16 Suppl 2:29-31 (PubMed)
6. Hermon M. et al. SHOCK 2005;23(1):59-64 (PubMed)

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