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* From the Memphis Lung Research Program, Baptist Memorial Hospitals; Veterans Affairs Medical Center; and the Department of Medicine, College of Medicine, University of Tennessee, Memphis, TN. Supported by the Baptist Memorial Health Care Foundation and by the University of Tennessee, Memphis, Clinical Research Center.
Correspondence to: G. Umberto Meduri, MD, FCCP, Professor of Medicine, University of Tennessee-Memphis, Division of Pulmonary and Critical Care Medicine, 956 Court Ave, Room H316, Memphis, TN 38163; e-mail: umeduri{at}utmem1.utmem.edu
ARDS
is a life-threatening disease of multifactorial etiology caused by a
direct or indirect insult to the pulmonary lobules. We have tested a
therapeutic intervention on a previously defined model of
ARDS,1
in which the three fundamental elements of a
disease process2
—pathogenesis, structural alterations,
and functional consequences—were described during the course of the
disease. In this single "hit" model, degree and duration of the
host defense response (HDR) determine the adaptive vs maladaptive
evolution of the reparative process and final outcome. We have reported
previously that patients with unresolving ARDS have biological and
morphologic evidence of intense, protracted, and dysregulated pulmonary
inflammatory and fibrotic activity. Over time, these patients have
persistent and exaggerated elevation in plasma and BAL tumor necrosis
factor-
, interleukins (IL)-1ß, IL-6, IL-8,3
4
migration inhibitor factor,5
soluble intercellular
adhesion molecule-1 (unpublished data, Thomas L. Petty Aspen Lung
Conference, 41st Annual Meeting, Aspen, CO, June 3–6, 1998) and
procollagen aminoterminal propeptide type I (PINP), and type III
(PIIINP) levels.5
During the first week of ARDS, cytokine
levels declined in all survivors, while levels remained persistently
elevated in all nonsurvivors. Histologic findings of open lung biopsy
specimens provided morphologic evidence of persistent activation of the
HDR, including (1) new injury to the endothelial and epithelial
surfaces of previously spared pulmonary lobules with associated
intravascular coagulation and extravascular fibrin deposition and (2)
progressive fibroproliferative obliteration of the previously involved
lobules, with transformation of the initially fibrinous exudate into
myxoid connective tissue matrix and eventually into dense acellular
fibrous tissue.6
Glucocorticoids inhibit the inflammatory pathways at virtually all levels and exert most of their effects through specific, ubiquitously distributed intracellular glucocorticoid receptors.7 After steroid binding, activated glucocorticoid receptors inhibit the transcriptional activation of several cytokines and cell adhesion genes by binding to transcription factors (type II mechanism) or blocking their activation.7 Glucocorticoids also suppress the synthesis of phospholipase A2, cyclooxygenase 2, and nitric oxide synthase genes and decrease the production of prostanoids, platelet-activating factor, and nitric oxide—key inflammatory molecules. Glucocorticoids also have an inhibitory effect on fibrogenesis and act in synergy with IL-1 receptor antagonist and the anti-inflammatory cytokines IL-4, IL-10, and IL-13 to control the HDR.7
Large randomized studies have previously shown that a short
course (
24 h) of high-dose methylprednisolone (MP) in patients
with early ARDS is ineffective. Because the half-life of MP is
approximately 180 min, a sustained pharmacologic effect in
life-threatening protracted lung inflammation (ie, status
asthmaticus, Pneumocystis carinii pneumonia, etc) can be
achieved only with prolonged administration aimed at disease
resolution. In experimental acute lung injury, glucocorticoid
administration was shown previously to be effective in decreasing lung
collagen and edema formation as long as treatment was prolonged, while
drug therapy withdrawal rapidly negated this positive
influence.8
Several uncontrolled
studies6
9
10
have reported a significant improvement in
lung function during prolonged MP administration in patients
with unresolving ARDS and have found that survival correlated with
improvement in lung function. In phase II trials involving 34 patients,
we reported mortalities of 17% in 29 patients who improved lung
function (responders) and 100% in 5 nonresponders.6
11
Additional findings of phase II trials are shown in Table 1
.
|
MP or placebo was given daily as IV push every 6 h (one fourth of the daily dose) and changed to a single per os dose when oral intake was restored. A loading dose of 2 mg/kg was followed by 2 mg/kg/d from day 1 to 14, 1 mg/kg/d from day 15 to 21, 0.5 mg/kg/d from day 22 to 28, 0.25 mg/kg/d on days 29 and 30, and 0.125 mg/kg/d on days 31 and 32. If the patient was extubated prior to day 14, treatment was advanced to day 15 of drug therapy and tapered according to schedule.8 The protocol contained (1) a provision for blindly crossing over patients who did not improve LIS by at least 1 point after 10 days of treatment (Table 1) and (2) procedures for infection surveillance, including weekly bronchoscopy with bilateral BAL.8 Because MP blunts the febrile response to an infection, this latter intervention was essential for minimizing the random variation generated by the potential morbidity and mortality of untreated nosocomial infections. The study was designed as a sequential phase III clinical trial and projected to recruit 100 patients. The decision to end the trial was made when the test statistic exceeded the upper boundary of the triangular test of Whitehead, and the null hypothesis was rejected at a significance <0.05 and a power > 0.95.
At study entry (day 9 ± 1 of ARDS), the two groups had similar LIS,
PaO2/fraction of inspired oxygen, and multiple
organ dysfunction syndrome (MODS) scores. By study day 10, all patients
in the MP group had improved conditions (
1 point reduction in LIS) vs
two of eight (25%) in the placebo group; four patients whose
conditions failed to improve were blindly crossed over to MP (as
dictated by the protocol). Changes observed by study day 10 are
reported for MP vs placebo: LIS (1.7 ± 0.1 vs 3.0 ± 0.2;
p < 0.0001), PaO2/fraction of inspired
oxygen (262 ± 19 vs 148 ± 35; p = 0.0003), MODS score
(0.7 ± 0.2 vs 1.8 ± 0.3; p = 0.0008), and successful extubation
(7 vs 0; p = 0.051). Thus, improvement in LIS was observed in two of
four of those crossed over to MP (day 18 of ARDS) after 10 days of
placebo therapy. Extubated patients were discharged from the ICU on
unassisted breathing, all but one within 4 days of removal from
mechanical ventilation. ICU mortality for the treatment group vs the
placebo group was 0% vs 62% (p = 0.002); hospital-associated
mortality for the two groups was 12% vs 62% (p = 0.03). Improvement
in LIS after 10 days of treatment and hospital survival were
correlated (r = 0.688 ± 0.165).
The rate of complications between the two groups was similar. During MP treatment, pneumonia frequently developed in patients without fever (44%), and infection surveillance, including weekly surveillance with bilateral bronchoscopic BAL, was useful for early detection of pneumonia and other serious infections.8 None of the recognized and appropriately treated infections developing during MP therapy affected resolution of ARDS or clinical outcome.
Terminating this sequential trial very quickly biases the estimate of the treatment effect and raises the concern that the statistically significant difference in outcome was not due to a true effect of the tested intervention (MP treatment and infection surveillance) but to a potential lack of comparability between the two groups to the extent that the treatment effect might merely have reflected some confounding variable, such as severity of illness. Based on the APACHE (acute physiology and chronic health evaluation) III, LIS, and MODS scores at entry and on the day of randomization, we have not detected any confounding variable that could have explained the differences in outcome between the two groups. Moreover, longitudinal measurements of inflammation and fibrosis demonstrated a significant and sustained biological effect, making the possibility of a type I error unlikely.
PINP and PIIINP levels reflect collagen synthesis (fibrogenesis)
in tissue repair independent of disease etiology.5
During
the first week of ARDS, nonimprovers (patients recruited for the
randomized study), as opposed to improvers (patients with 1 point
reduction in LIS), had a progressive rise in plasma PINP and PIIINP
levels (day 5; p = 0.004), and BAL PIIINP correlated with static
pulmonary compliance (r = -0.75; p = 0.03) and
PaO2/FiO2 (r = 0.69;
p = 0.05). MP treatment, initiated on day 9 ± 1 of ARDS, was
associated with a rapid and sustained reduction in mean plasma and BAL
PINP and PIIINP levels, while no reduction was observed during placebo
administration. By day 3 of treatment, mean plasma PINP and PIIINP
levels decreased from 100 ± 9 ng/mL to 45 ± 8 ng/mL
(p = 0.0001) and 31 ± 3 ng/mL to 12 ± 3 ng/mL (p = 0.0008),
respectively. After 8 to 15 days of MP, mean BAL PINP and PIIINP levels
decreased from 63 ± 25 ng/mL to 6 ± 23 ng/mL (p = 0.002) and
42 ± 5 ng/mL to 10 ± 3 ng/mL (p = 0.003), respectively.
Estimated partial correlation coefficients indicated that as plasma
PINP and PIIINP levels decreased over the first 7 days of MP treatment,
positive end-expiratory pressure decreased, while
PaO2/FiO2 increased.
In conclusion, we have conducted a "holistic" level of inquiry—biology, pathology, physiology, and outcome—in both uncontrolled and controlled studies involving 92 patients with unresolving ARDS, 50 of whom received prolonged MP treatment, and provided findings to support a single "hit" model of ARDS where progression of the disease and final outcome are related to excessive and unregulated activity of the HDR. These studies provide strong support for a linkage between biological and physiologic response that can be affected by prolonged MP administration.
Acknowledgements
ACKNOWLEDGMENT: Sincere thanks to Drs. Elizabeth Tolley and David Armbruster for their critical review.
References
This article has been cited by other articles:
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  C. Sartori and M.A. Matthay Alveolar epithelial fluid transport in acute lung injury: new insights Eur. Respir. J., November 1, 2002; 20(5): 1299 - 1313. [Abstract] [Full Text] [PDF]
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