Fludrocortisone

To the Editor.

The recent study by Dr. Confalonieri and colleagues (1), about the beneficial effect of low-dose hydrocortisone on the outcome of severe community-acquired pneumonia, deserves close attention. According to the article, Confalonieri did not examine his patients for any adrenal impairment. In fact, neither cortisol levels at baseline nor response to the corticotropin test were measured to assess for possible adrenal insufficiency. The patients enrolled had severe community-acquired pneumonia and a substantial degree of critical illness that could predispose them to adrenal insufficiency, in which case they could benefit from hydrocortisone treatment.

Annane and coworkers (2), in a study about the effect of treatment with low dose hydrocortisone and fludrocortisone on mortality in patients with septic shock, have shown that only those with adrenal insufficiency (nonresponders to the corticotropin test) had a reduced risk of death after administration of corticosteroids. In Annane and coworkers' trial, patients with adrenal insufficiency (nonresponders to the corticotropin test) were more likely to draw benefit from cortisol replacement, i.e., 1 month survival rates 37% versus 47% (p = 0.02), ICU survival rates 30% versus 42% (p = 0.01), and hospital survival rates 28% versus 39% (p = 0.02). Patients who responded normally to the corticotropin test (cortisol increment of more than 9 µg/dl after 250 µg of corticotropin) had no benefit from corticosteroid therapy (1 month mortality rates: 61% versus 53%, p = 0.81) (2). Confalonieri and coworkers cited this study, but did not point out this important distinction. The benefits from corticosteroid replacement in septic patients who are not in shock and not adrenally insufficient is still not known.

In the future, any study about the role of corticosteroids in treatment of severe community-acquired pneumonia should include assessment for adrenal reserve before drawing any conclusions and providing generalized recommendations.

Conflict of Interest Statement: A.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

AHMAU JALLOUL

Louisiana State University Health Sciences Center

Shreveport, Louisiana

References

1. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Delia Porta R, Giorgio C, Blasi F, Umberger R, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-248.

2. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al. Effect of treatment with low doses of hydrocorlisonc and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.

From the Authors:

The letter from Dr. Restrepo and colleagues addresses an important limitation of our study (1)-the unplanned differences in distribution of patients receiving conventional ventilation and noninvasive positive pressure ventilation (NPPV) among treated and control groups. We are fully aware of the effect of conventional and noninvasive ventilation in patients with severe community-acquired pneumonia. In a previous randomized study of patients with severe community-acquired pneumonia and Pa^sub O2^:FI^sub O2^ 6 hours) worse than that reported in our studies (1, 2), NPPV was shown to be beneficial in one recent trial (4). Patients with COPD were excluded from our study and contributed to a large number (n = 25) of ineligible patients. Other patients were excluded for asthma (n = 6), neoplasm (n = 11), or failure to meet all inclusion criteria (n = 27).

Table 1 compares the response observed in the two groups of ventilated patients. On study day 8, the number of patients on conventional ventilation versus NPPV was 14 versus 1 and 3 versus 3, for the control and hydrocortisone-treated group, respectively. The incorrect conclusions reached by Dr. Restrepo and colleagues are the result of an incomplete explanation of the data in our article (1). Table 1 shows that the number of patients still on conventional ventilation on study day 8 was significantly different (14 [87%] versus 3 [43%]; p = 0.045) between the two groups.

The purpose of our study was to evaluate the effect of hydrocortisone infusion on organ dysfunction associated with pulmonary and systemic inflammation. Notably, improvement in Pa^sub O2^:FI^sub O2^ and chest radiograph score by day 8 was observed with hydrocortisone treatment irrespective of the initial mode of ventilation. As a group, those receiving NPPV had, in comparison to patients receiving conventional ventilation, a shorter duration of mechanical ventilation (p = 0.001) and lower mortality (p = 0.07). The only NPPV failure was a control patient. These findings underscore the potential advantages of NPPV in this patient population and the need-in a future trial evaluating mortality as a primary end point -to use a dynamic allocation scheme that allows stratification by initial mode of mechanical ventilation (1).

Dr. Restrepo and colleagues direct our attention to the subgroup of patients who initially received conventional ventilation and are at increased risk for ventilator-associated complications and mortality. A reasonable argument is made that the larger number of patients in the placebo group receiving conventional ventilation (16 versus 7) skewed the overall results in favor of hydrocortisone. A review of the variables shown in Table 1, however, shows within this group a response to hydrocortisone with a significant reduction in C-reactive protein level, multiple organ dysfunction syndrome (MODS), chest radiograph scores, and incidence of delayed septic shock. These findings suggest that modulation of systemic and pulmonary inflammation with prolonged low-dose hydrocortisone might benefit this group, at higher risk for sepsis-related complications, the most.

We believe that our study supports the original hypothesis, and the data shown in Table 1 indicate that the findings also apply to patients initially placed on conventional ventilation. We recognize the limitations of this small study and made suggestions for a future larger trial with the primary aim to investigate the effect of hydrocortisone infusion on mortality.

The letter by Dr. Jalloul addresses the issue of relative adrenal insufficiency and response to hydrocortisone treatment in patients with septic shock. Two recent meta-analyses (6, 7) have addressed this issue in extensive detail. In our study, only two hydrocortisone-treated patients had septic shock at study entry, and it is unlikely that relative adrenal insufficiency (which was not tested) might have occurred at study entry in patients without shock. Nevertheless, several patients randomized to placebo developed septic shock after study entry, and we cannot exclude that some might have had subclinical adrenal insufficiency at study entry or a blunted adrenal response to ACTH when they developed shock. The lack of an ACTH stimulation test prior to randomization or in conjunction with the development of delayed septic shock is a limitation of this study. Unfortunately, this issue was not fully appreciated in 1999 when the study was designed.

Conflict of Interest Statement: C.U.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.U. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

G. UMBERTO MEDURI

REBA UMBERGER

University of Tennessee Health Science Center

Memphis, Tennessee

MARCO CONFALONIERI

Azienda Ospedaliero-Universitaria di Trieste

Trieste, Italy

References

1. Confalonieri M, Urbino R, Potena A, Piatella M, Puccio G, Delia Prta R, Giorgio C, Blasi F, Umberger R, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-248.

2. Confalonieri M, Delia Porta R, Potena A, Carbone G, Delia Porta R, Tolley EA, Meduri GU. Acute respiratory failure in patients with severe community-acquired pneumonia: a prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med 1999;160:15851591.

3. Antonelli M, Conti G, Moro ML, Esquinas A, Gonzalez-Diaz G, Confalonieri M, Pelaia P, Principi T, Gregoretti C, Beltrame F, et al. Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study. Intensive Care Med 2001;11:1718-1728.

4. Ferrer M, Esquinas A, Leon M, Gonzalea G, Alarcón A, Torres A. Noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial. Am J Respir Crit Care Med 2003;168:1438-1444.

5. Annane D, Sebille V, Charpentier C, Bollaert PE, François B, Korach JM, Capelier G, Cohen Y, Azoulay E, Troché G, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.

6. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Metaanalysis: the effect of steroid on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47-56.

7. Annane D, Bellisant E, Bollaert PE, Bregel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and metaanalysis. BMJ 2004;329:480-488.

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