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In ARDS there is extensive ongoing tissue inflammation. Decreasing this inflammation in the lung would make a marked improvement in gas exchange allowing lower FiO2s, avoiding high tidal volumes and elevated ventilating pressures that may be the cause of additional lung injury and decreased survival. This lung inflammation would seem to be a promising target for corticosteroids. Corticosteroids have strong antiinflammatory action by means of multiple pathways; they can switch off genes activated during the inflammatory process.
There has been a number of studies looking at corticosteroids in ARDS with varying results. The use of high-dose corticosteroids in the early phase of ARDS failed to show a survival benefit in four different trials. In persistent ARDS (>7 days) patients treated with moderate-dose corticosteroids saw an improvement in lung function and survival in one study of 24 patients. However, some studies have shown that patients with sepsis and ARDS treated with high-dose corticosteroids had an increased risk of secondary infections. Possible risks of corticosteroids include hypergylcemia, poor wound healing, psychosis, pancreatitits, and prolonged muscle weakness.
From August 1997 to November 2003, the ARDS Clinical Trials Network (ARDSnet) performed a multicenter, randomized controlled trial of corticosteroids in patients with persistent ARDS. The results were recently published in the April 20th, 2006 issue of the New England Journal of Medicine (2). The study involved 180 patients that were being ventilated 7 to 28 days after the onset of ARDS and had a PaO2/FiO2 ratio of less than 200. Patients then either received a placebo or a tapering dose of methylprednisolone over 14 days. Patients were weaned from the ventilator by protocol and patients were followed until they died, discharged home or day 180, whichever came first. Complete description of the study protocol and method can be found at www.ardsnet.org.
Primary outcome of the study was mortality at 60 days. Secondary outcomes included the number of ventilator free days during the first 28 days, the number of days without organ failure in the first 28 days, infectious complications during the first 28 days, and changes in inflammation markers on day 7. of the 180 patients enrolled, 91 were randomly assigned to the placebo group and 89 to the methylprednisolone group.
There was no significant difference in the 60 day mortality rate between the placebo group (28.6%) and the methylprednisolone group (29.2%). Patients who had a ARDS for more than 13 days before being enrolled had a significantly increased mortality rate in the methylprednisolone group. The methylprednisolone group had significantly more ventilator free days during the first 28 days and at 180 days, also they were able to breathe without assistance sooner than the placebo group. The placebo group was less likely to require resuming assisted ventilation compare to the methylprednisolone group though (9% vs. 28%). There was difference in the rate of nosocomial infections and the methylprednisolone group had lower rates of pneumonia and septic shock than the placebo group. All of the serious cases (nine) of neuropathy or myopathy occurred in patients treated with methylprednisolone.
The duration of this study was over seven years and during that time there were some dramatic changes in the practice of critical care medicine. The use of low tidal volumes in ALI/ARDS patients, tight blood glucose control, corticosteroids for refractory septic shock, activated protein-C for severe sepsis, strategies for ventilator associated pneumonia, and sedation with daily wakening protocols all became standard ICU practices. There then becomes the possibility that these practices may have had influence in the outcome of some patients.
The results from this study do not support the routine use of corticosteroids in patients with persistent ARDS even though it may improve the patients cardiopulmonary status. It is also suggested that treatment with corticosteroids started 14 days after the onset of ARDS may be harmful.
It is not understood by what means corticosteroids can cause beneficial pulmonary and cardiovascular effects after 7 days but when started after 14 days increases mortality in ARDS patients. One theory is that the inhibition of the inflammatory response in both the early and late phases may negatively interfere with physiologic defense mechanisms triggered by inflammation. Inflammation plays a major role in ARDS and therapies that regulate is detrimental effect without suppression of its beneficial action may be they key to significantly improving mortality in ARDS patients. To determine the optimal time of intervention in this complex process of proinflammatory and inflammatory, better monitoring methods of immune response satus are necessary. But it appears from this study that there may be a narrow window of opportunity somewhere between 7 and 14 days after onset that pulmonary, cardiovascular and even outcome may be improved.
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(1) Suter PM: Lung Inflammation in ARDS - Friend or Foe? N Eng J Med. 2006 Apr 20; 354(16): 1739.
(2) Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006 Apr 20; 354(16): 1671-84.
This past Friday I had the pleasure of spending the day Dr. Peter Brindley and his patient simulation team from Capital Health in Edmonton. They brought their expertise to Saskatoon and allowed us to experience the wonderful tool simulation can be for a medical team. I played RT all day while different groups consisting mostly of physicians and nurses ran through different scenarios.
