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ARDS, acronyms and the Pinocchio effect

2010; Wiley; Volume: 65; Issue: 10 Linguagem: Inglês

10.1111/j.1365-2044.2010.06508.x

1365-2044

N. Soni,

Intensive Care Unit Cognitive Disorders

How can there be a biomarker for what is imaginary? – well-known intensivist, 2010 A speciality should, by definition, have a special interest, a distinguishing feature or a characteristic that sets it apart. The concept of Intensive Care was derived from the polio epidemic where ventilation was used to support a paralysed respiratory system, allowing time for muscle function to recover. Organ support characterised the speciality. It was inevitable that, when patients were regularly presenting with failing lungs or kidneys, the common clinical and physiological patterns would be recognised, and called syndromes ('syndrome' literally meaning 'running together'). In 1967, Ashbaugh et al. described a severe chest syndrome with a classic X-ray appearance associated with a time of onset between 1 and 96 h [1]. It was secondary to a collection of very disparate primary illnesses, mainly direct chest trauma but also infection and others including pancreatitis. It was called adult respiratory distress syndrome, ARDS. Life-threatening and necessitating ventilation, it immediately fell under the auspices of an emerging speciality, Intensive Care, which had the capability to ventilate. Over several years the syndrome was defined and refined radiologically, clinically and physiologically, so that by 1994 a consensus conference issued criteria for both ARDS and its milder form, acute lung injury (ALI). The syndrome now had a recognisable and measurable spectrum of severity [2]. Now it could be readily identified in clinical practice, ARDS was a focal point for teaching and was accessible to research. By defining the syndrome more physiologically, it could be studied as a single entity and the common pathways in lung injury could be identified. This raised the prospect of a 'treatment' that could target this pathway. A recognisable common pattern effectively homogenised the wide range of causes of lung failure and allowed far easier recruitment of large numbers of patients to studies. Those studies involved methods ranging from basic science techniques, exploring inflammation in the ARDS-affected lung, through epidemiology, to the assessment of clinical supportive measures such as ventilation. It became a fruitful source of funding. The syndrome became central to the capability, competence and credibility of the emerging speciality. 'ARDS' became synonymous with Intensive Care. The raison d'etre of Intensive Care Medicine remained organ support, but the speciality no longer merely supported failing organs, it became acknowledged as expert in recognising conditions, such as ARDS. Furthermore, ARDS provided an excellent model for a way around the problem of studying 'organ failure'– which encompasses a broad range of causative conditions, the heterogeneity of which hampers research and hence advances in the speciality. By defining the syndrome, a single quantifiable entity emerged, and by implication this could be linked to the common final pathway. Add a numerical scale for the spectrum of severity of ALI and ARDS, and a convincingly robust research model evolves. The techniques of defining and quantifying a homogenous endpoint of an organ failure could be easily applied elsewhere. Acute renal failure (ARF) is now defined by the degree of organ failure. It was a small step to apply this more broadly to other common patterns such as sepsis and the systemic inflammatory response syndrome (SIRS), that predispose to organ failure [3, 4]. Pattern definition allows 'lumping' together of all comers that meet the criteria for that pattern or syndrome. The common diagnosis then opens the door to discussion, teaching and research in terms of diagnostics, mechanisms and therapeutics. These patterns of symptoms, signs and numerical indices are now indispensible to Intensive Care Medicine. The results have been impressive. These syndromes are established in common parlance, are part of teaching and a central theme at almost every meeting. They are the core feature of the speciality and attract both prestige and – more pragmatically – funding. The explosion in basic science knowledge of the response of the lung to injury is phenomenal, and this also follows for the other syndromes. Equally impressive is the development of support techniques and evaluation of their efficacy as well as other effects. These 'new' conditions now sit centre stage in Intensive Care Medicine. It would appear that this is all positive. An emerging speciality has defined new conditions that it is recognised as being expert in identifying, treating, researching and teaching, and is hence characterised by these conditions. The clue that there is a problem is the relatively consistent failure of the number of syndrome-related 'magic bullet' trials. And ARDS leads the way – nothing works but the results are better anyway. Curiously, the epidemiology is changing. Sepsis follows closely but to date only activated protein C has been positive [5] So wherein lies the problem? The flaw is fundamental. A syndrome (and its acronym) is not a disease and the pattern does not acknowledge a cause. Rather, the syndrome allows tacit acceptance of the probable existence of a common pathway and an unspoken understanding that its cause is immaterial. The exception was the eloquent description by Pelosi et al. of the different natural histories of intrinsic and extrinsic ARDS, the implication being that the mechanistic differences are dependent on the cause [6]. This should have challenged the status quo, but rather than looking more closely at the range of causes of ARDS and their natural history, recognition of two common pathways was incorporated into the default position. The clinical risk with ARDS and other acronyms is that the real emphasis shifts to the syndrome and its supportive management, often dismissing the importance of the underlying cause. The treatments are ventilation for lung failure, dialysis for renal failure, and correction of the haemodynamic problems in sepsis or septic shock. In each, the cause is quietly divorced from the syndrome, is relegated to being one of a list of known causes of the syndrome and hence becomes irrelevant. But surely the cause and its management help define the natural history of the illness? For example, the type of pneumonia and its specific treatment will affect the impact on the lung. Compare pneumococcus, swine flu, mycoplasma and tuberculosis, and then add in age, immunocompromise and fluid shifts. All can produce ARDS and each potentially has a very different natural history that is quite different from trauma, fat embolism, aspiration and pancreatitis – all of which were included by Ashbaugh et al. [1]. In acute renal failure, acute glomerulonephritis, myoglobinuria and non-steroidal inflammatory drug toxicity have different natural histories. Curiously, the RIFLE classification, geared to make sense of acute renal failure, fails at the first hurdle by being disease independent [7, 8]. At present, acute liver failure is still defined by cause and no one would seriously consider the cause unimportant, yet it would be temptingly easy to create a single syndrome with a catchy acronym. Are these so different from hypoxaemia associated with non-specific X-ray changes? Even these acronyms are relatively focused compared with SIRS and sepsis. These terms 'lump' together such disparate conditions as meningococcal infection in a fit 18-year-old, faecal peritonitis in an unfit 80-year-old, urosepsis in general and necrotising fasciitis, on the basis of a collection of relatively non-specific symptoms and signs. There is no acknowledgement of the wide range of exo- and endotoxins that all have very different and sometimes very specific effects. At least 'sepsis' acknowledges that infection, albeit in many guises, must be part of the cause, and 'source control' recognises that there is a cause. 'SIRS' does not even have that to recommend it and is just a cluster of non-specific signs of general inflammation [9, 10]. Conditions like ARDS, ALI, ARF, sepsis, SIRS and others are central to Intensive Care Medicine as a speciality. They are not specific illnesses and there is no direct link to their own causation. They are convenient collective terms, so why are they so important? This could be described as the 'Pinocchio effect'. Geppetto, a toymaker eager to fill a void in his life, created a toy to be his little boy. With some magic, the toy was so lifelike it behaved like a boy, but no matter how much he wished it be otherwise, in reality it was always a toy [11]. So it is with Intensive Care Medicine, where the desire to produce diagnoses that can be used clinically and scientifically has resulted in harnessing syndromes and giving them real disease status. If any confirmation was needed, it is the eagerness to find biomarkers for these acronyms as if they were real diseases. Hence the quotation at the top of this Editorial. Does this matter? Several generations of intensivists have grown up with ARDS, ARF, SIRS, sepsis and now possibly posterior reversible encephalopathy syndrome (PRES). They pervade the science and hence the literature of the speciality. They are the flagship conditions of Intensive Care Medicine and the speciality owes much of its recognition to the exploration, dissemination and proliferation of these syndromes. The Pinocchio effect, whereby these syndromes are treated as real diseases, makes this an unfortunate and potentially compromising reality, both at the bedside and in research. The acronym acquires diagnostic status and the mantra of 'treat the cause' is of only secondary interest. Management and treatment of the syndrome are to the detriment of the search for the cause. Frequently, the argument is that the cause is no longer relevant, engendering the acronym with the potential to become its own cause. In clinical practice, cause and effect blur but even the potential benefits to research pose problems. The acronyms transform population heterogeneity magically into syndrome homogeneity and readily give the numbers needed. The homogeneity of the syndromes is comforting but imaginary, so it is hardly surprising that specific treatments given to non-specific conditions consistently fail to reverse the syndromes. To succeed would confirm the transition of syndrome to a real disease state, and that therefore there is an identical pathway for all comers and specific interventions are possible. It would confirm that cause is genuinely unimportant. Pinocchio would be a real flesh and blood boy and no longer a toy. Paradoxically, a positive finding from a magic bullet trial, without a clear defined mechanism, should be a cause for concern rather than a relief. There have been positive aspects of the rise of the acronym. Organ failure syndromes have allowed support modalities to be examined. The syndrome provides a population requiring specific support and can be used to test the efficacy and iatrogenicity of that support. Support reverses effects not causes. The now classic ARDSnet trial seems to have identified that ventilation causes iatrogenic problems and that some modes cause fewer problems than others [12]. This approach can be used with other modes of support such as dialysis, or the pharmacological support of the cardiovascular system. The research focus is on the method of support, not the condition, and in this scenario less detriment is not the same as treatment benefit. The other benefit of acronyms is in basic science research, where syndromes have generated interest and funding to unravel the mechanisms of injury, such as that affecting the lung. It is interesting that basic sciences models of injury invariably use a single, specific, reproducible mechanism to mimic a syndrome of many different causes. Geppetto was as attached to his marionette as Intensive Care Medicine is to its syndromes. Impressive driving forces maintain the status of these acronyms. They produce big numbers for the randomised trials on which modern evidence based medicine is fixated. Unfortunately, the erroneous assumption that the heterogeneity of causation is very much secondary to the homogeneity of the syndrome is both self-sustaining and defeating, but at present it does not seem open to debate. Funding is attracted to track record and to populist topics such as ARDS and sepsis. Abandon acronyms and this infrastructure fails. Tradition is powerful and these acronyms are the foundation of the speciality and have helped build and establish credibility. The textbooks are full of acronyms and their definitions, diagnosis and management, as is the world of evidence based medicine. Many intensivists (acronymists) have spent their careers working with acronyms and are deeply attached to them. Could Geppetto have forsaken his puppet? ARDS, ALI, sepsis, SIRS and ARF are now more of a problem than a benefit. Unless Intensive Care Medicine comes to terms with acronyms and what they really mean, clinical management will stumble on, hamstrung by these syndromes, and clinical trials will continue to be a futile waste of money. True, the current infrastructure may fail if acronyms are relegated to history, but the speciality will recover and will be empowered by the makeover. There may even be progress. Almost every previous generation of clinicians has had to come to terms with the redundancy of concepts that were popular but unhelpful. The renaissance taught us that old ideas were not always great ideas. Textbooks can be rewritten and will be less repetitive. Will Geppetto relinquish Pinocchio? I doubt it, and while the world is convinced that Pinocchio is a little boy all will be well, but when the puppet is recognised as a puppet, damage limitation could be a problem. It is time that Intensive Care Medicine acknowledges the Pinocchio effect before everyone else does. In the story it takes a magic fairy to transform Pinocchio into a real boy. Now, where can we find one of them…? No external funding and no competing interests declared.