点击显示 收起
Department of Thoracic Medicine II, Chang Gung Memorial Hospital, Taipei, Taiwan
ABSTRACT
Rationale: Adrenal insufficiency is a common disorder in critically ill patients with mechanical ventilation and is usually associated with higher mortality and poor clinical outcome.
Objectives: To determine whether stress dose corticosteroid supplementation can improve ventilator weaning and clinical outcome in patients with adrenal insufficiency.
Methods: A prospective, randomized, placebo controlled, double-blinded study was conducted in the intensive care unit of a tertiary teaching hospital. A total of 93 mechanically ventilated patients were enrolled in the ventilator weaning trial. Adrenal function was assessed in all patients. Patients with adrenal insufficiency were randomized to the treatment group (50 mg intravenous hydrocortisone every 6 h) and the placebo group.
Measurements and Main Results: The successful ventilator weaning percentage was significantly higher in the adequate adrenal reserve group (88.4%) and in the stress dose hydrocortisone treatment group (91.4%) than in the placebo group (68.6%). The weaning period was shorter in the hydrocortisone treatment group than in the placebo group. No significant adverse effects were observed in the corticosteroid treatment group.
Conclusions: For patients with respiratory failure, early identification of adrenal insufficiency and appropriate supplementation with stress dose hydrocortisone increase the success of ventilator weaning and shortens the weaning period.
Key Words: adrenal insufficiency hypothalamic-pituitary-adrenal axis stress dose hydrocortisone ventilator weaning
The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the host stress response. During stress, stimulation of the HPA axis increases corticotropin release and enhances adrenal secretory activity (1, 2). Adrenal insufficiency (AI) is not uncommon in the intensive care unit (ICU), and may occur during severe sepsis (3–6). The diagnosis can be confirmed through laboratory assessment of adrenocortical function. However, diagnostic criteria vary (7–11), which can cause misdiagnosis. Application of corticosteroid treatment in patients with sepsis has remained debatable since the clinical introduction of cortisone in 1949. The safety and effectiveness of corticosteroid supplements have not been proved for all patients with sepsis (12, 13). Despite this, some studies (14–17) found that extremely ill patients with persistent shock requiring vasopressors and prolonged mechanical ventilation may benefit from physiologic corticosteroid supplement. These results implied that critically ill patients may have relative AI.
Ventilator weaning (VW) is the transitional period between total ventilatory support and spontaneous breathing and is a crucial issue in ICUs (18). Rapid and successful VW can shorten the length of stay, decrease morbidity and mortality, and reduce costs (19). Although the reasons remain unclear, patients requiring reintubation after failed extubation have a poor prognosis and higher hospital mortality (20). Several pathophysiologic mechanisms explain why some patients fail a VW trial (21), but few clinically practical indices have been defined. In the past, adrenal function has usually been evaluated after VW failure. The relationship between AI and VW remains largely unclear for critical care clinicians. On the basis of the concept that early diagnosis and treatment of AI may influence patient outcomes, we hypothesized that corticosteroid repletion in patients with impaired adrenal reserve would improve VW. Part of the preliminary results of the study has been previously reported in the form of an abstract (22).
METHODS
Patients
Chang Gung Memorial Hospital is a 3,000-bed tertiary teaching facility. The ICU is a 26-bed unit that cares for patients with critical medical conditions. The study started on May 1, 2003, and ended on December 31, 2003. All patients enrolled in the study were under mechanical ventilation for more than 72 h via endotracheal tubes. The primary etiology of their respiratory failure was recovering, and vasopressor agents and sedative medication had been discontinued for at least 24 h before the study commenced. These patients were hemodynamically stable, neurologically intact (Glasgow coma score > 11), and waiting for VW. Patients received regular corticosteroid medication before or during the admission, and patients without adequate cough reflex were excluded. The study was performed with the approval of the hospital ethics committee. Informed consent from each enrolled patient or a close relative was obtained.
Study Protocol
The study was a prospective, randomized, placebo-controlled, double-blinded study. Cortisol concentrations were measured with a competitive immunoassay using direct chemiluminescent technology (ADVIA Centaur Assay; Bayer, Leverkusen, Germany) in the clinical pathology laboratory of the hospital. The morning cortisol level (between 7:00 and 9:00 A.M.) was checked when patient condition met the VW criteria. Plasma cortisol concentrations above 25 μg/dl (694 nmol/L) were considered to reflect intact adrenal function. If the morning cortisol level was below 25 μg/dl, a high-dose adrenocorticotropin (ACTH) stimulation test was performed with a 250-μg intramuscular cosyntropin injection with blood samples taken immediately before and 60 min after the test. An intact adrenal reserve was defined as an increase in serum cortisol of greater than 9 μg/dl (250 nmol/L), whereas an increase in serum cortisol of less than 9 μg/dl was defined as AI (5, 23). Patients with AI were randomized to the treatment group (50 mg intravenous hydrocortisone every 6 h during the weaning period) and the placebo group (normal saline). In the corticosteroid supplement group, the treatment of intravenous corticosteroid covered the entire weaning period and it was shifted to oral cortisone acetate after successful weaning or weaning failure. When the weaning period ended, these patients with AI, including the placebo group and the corticosteroid group, were shifted to 75 mg oral cortisone acetate in the morning and 37.5 mg in the afternoon. Randomization was according to a computer-generated random-number table. The flow chart of the study is presented in Figure 1. The Acute Physiology, Age, and Chronic Health Evaluation III (APACHE III) score (24), rapid shallow breathing index (RSI) (25), etiology of respiratory failure, underlying disease, and arterial blood gas analysis were recorded for all patients before VW was attempted.
All enrolled patients underwent a protocol-driven VW strategy. The respiratory therapists screened for the weaning criteria daily.
The criteria for starting weaning were as follows:
No suspected increased intracranial pressure
No unstable coronary artery disease
Heart rate less than 140 beats/min
SpO2 greater than 92%
Positive end-expiratory pressure less than 8 cm H2O
FIO2 less than 0.35
Intact cough reflex
Pressure-support mode ventilation with pressure lower than 8 cm H2O
Patients meeting the criteria entered a 2-h spontaneous breathing T-piece trial. The criteria to terminate spontaneous breathing trial were as follows:
Respiratory rate greater than 35 breaths/min for more than 5 min
Saturation of less than 90% for more than 30 s of good-quality measurement despite O2 supplementation being no more than 50% FIO2
A 20% decrease or increase in heart rate for more than 5 min
Systolic blood pressure greater than 180 or less than 90 mm Hg for at least 1 min of continuous recording or repeated measurements
Agitation, anxiety, or diaphoresis confirmed as a change from baseline and present for more than 5 min
If the patient went through the spontaneous breathing trial successfully, extubation was performed. Successful weaning was defined as the patient not requiring reintubation or additional respiratory support, such as noninvasive positive-pressure ventilation within 48 h of extubation. If the patient was not weaned successfully and the total ventilator period was more than 14 d, the patient was defined as weaning failure. Tracheostomy was recommended for long-term care. All complications during VW were recorded.
Statistical Analysis
All demographic data, ICU length of stay, hospital stay, and duration of weaning were expressed as mean ± SD or frequency (%) where appropriate and were analyzed with one-way analysis of variance tests. The Bonferroni test was used for multiple comparisons among means of the three groups. The 2 test (with Yates' correction) was applied to successful VW results and hospital mortality. Multivariate logistic regression was used to analyze the demographic variables and underlying disease between the corticosteroid group and the placebo group. A p value of 0.05 or less was considered to be statistically significant.
RESULTS
Patient Characteristics
During the study period, 472 ventilated patients were admitted in the ICU and 179 patients were evaluated for this study. Ninety-three patients who met the inclusion criteria were enrolled in the study (Figure 1). After initial evaluation of adrenal function, 23 patients were found to have normal adrenal function and 70 were diagnosed with AI. Patients with AI were randomly selected by computer to the treatment group (n = 35) and the placebo group (n = 35). Demographic data for the groups are shown in Table 1. No statistical differences among the three groups were found in terms of age, sex, APACHE III, RSI, ventilator days before randomization, or PaO2/FIO2. The mean morning cortisol level was significantly higher in the group with adequate adrenal reserve than in the AI groups. In the AI groups, there was no statistical difference between the corticosteroid treatment group and the placebo group in comparisons of morning cortisol levels. The main respiratory failure etiologies and the underlying diseases are shown in Table 2.
Successful Weaning
In adequate adrenal reserve group, 20 patients were successfully weaned from ventilator but three patients failed after extubation. In corticosteroid treatment group, 32 patients were successfully weaned, one failed the T-piece trial, and two failed after extubation. In the placebo group, 24 patients were successfully weaned, two failed the T-piece trial, and nine failed after extubation (Table 3). For patients with adequate adrenal reserve and the patients with AI receiving corticosteroid treatment, the success rate for weaning was similar. For patients with AI receiving placebo treatment, the successful weaning rate was significantly lower than in the other two groups (p = 0.035). The results of ICU length of stay, hospital stay, duration of weaning, and hospital mortality in the three groups are presented in Table 3. The results of multivariate logistic regression analysis of the demographic characteristics and underlying diseases of the corticosteroid supplement group and the placebo group are presented in Table 4.
Complications
No statistically significant complications, such as new-onset hyperglycemia, nosocomial infection, and gastrointestinal bleeding, were found to be increased in the corticosteroid treatment group.
DISCUSSION
In this study, stress dose corticosteroid supplementation before extubation of patients with AI led to a significantly higher success rate for VW and a shorter weaning duration than in the placebo group. This is the first study to use morning cortisol level and ACTH stimulation tests to determine adrenal reserve before extubation, thereby demonstrating an association between AI and extubation outcomes. The results suggest that evaluation of adrenal function before weaning is useful in routine ICU practice.
Although cortisol is one of the most widely studied hormones, it is probably one of the least understood. The definition of AI remains controversial (3, 5, 23, 26). A cortisol level greater than 25 μg/dl was considered adequate adrenal reserve in many textbooks and recent studies (8, 10). ACTH stimulation is essential to exclude AI, especially when the cortisol level is below 25 μg/dl. The cut-off value of increment of cortisol after ACTH stimulation test remains debatable but an increment of less than 9 μg/dl (250 nmol/L) was considered insufficient in critically ill patients (5, 23). The morning cortisol level and ACTH stimulation test provide a reliable evaluation of adrenal function. In addition to playing a role in septic shock, physiologic corticosteroid replacement may be beneficial in patients with other critical illnesses, including trauma, burns, and medical and surgical conditions where AI is evident (27, 28). To date, there are no published data indicating that stress dose corticosteroids improve the success of VW in the ICU. Our study suggests that patients with adequate adrenal function have a similar success rate of VW to patients with AI receiving stress dose hydrocortisone. It can be claimed that ICUs should routinely test adrenal function before VW. In the present study, hospital mortality, ICU length of stay, and hospital stay did not statistically differ between the hydrocortisone treatment group and the placebo group, although the mean ICU length of stay was shorter in the hydrocortisone treatment group compared with the placebo group. Because such results could reflect the influence of multiple factors on hospital mortality, ICU length of stay, and hospital stay, corrected AI may not produce improvement. The limitation of our study is the small patient number in each group. However, the result inspired us to conduct a larger and multicenter study to prove the present finding. Another limitation of the study is that we cannot explain the result from physiology. A good animal model study is required to clarify the underlying mechanism.
Although corticosteroid supplementation has benefited patients with septic shock in recent studies (4), the actual pathophysiology remains unclear. Keh and coworkers (29) reported that low-dose hydrocortisone supplementation increased arterial pressure and systemic vascular resistance, and decreased inotropic agent requirements in patients with septic shock. The increased respiratory work in a VW trial challenges the cardiopulmonary system and HPA axis, potentially leading to hemodynamic instability. Hypoglycemia caused by AI may also contribute to hemodynamic instability. Possibly, low-dose hydrocortisone therapy improves VW success rates by improving hemodynamic stability.
A high incidence of AI (> 75%) in patients with severe sepsis was reported by Annane and coworkers (4). The high prevalence (75.3%) of AI in our study was surprising and implied a problem of ignorance. Presentation of AI is nonspecific and asymptomatic. Cooper and Stewart (23) suggested that the threshold for investigating AI should be low because of the limitations of physical examination, particularly in patients with septic shock.
What test should be included in routine weaning profiles is still controversial. Manthous and coworkers (30) suggested that most currently used weaning parameters are better at identifying the cause of respiratory failure rather than predicting who will succeed with spontaneous breathing. Shikora and coworkers (31) noted that patients meeting accepted predictive work of breathing criteria frequently require reintubation within 48 h of extubation. Correcting AI may prove an ideal measure of VW.
Conclusions
In conclusion, AI should be suspected in the critically ill when morning cortisol concentrations are lower than 25 μg/dl, and this can be confirmed if cortisol increments are less than 9 μg/dl with ACTH stimulation testing. Evaluation of AI is recommended for all patients before extubation since stress dose corticosteroid supplementation in patients with AI can improve the chances of successful VW, shortening the duration of weaning such that patients with AI are comparable with patients with adequate adrenal reserves.
Acknowledgments
The authors thank An-Chen Feng for assistance in statistical advice.
FOOTNOTES
Originally Published in Press as DOI: 10.1164/rccm.200504-545OC on November 4, 2005
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993;329: 1246–1253.
Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune- mediated inflammation. N Engl J Med 1995;332:1351–1362.
Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med 2001;163:1520–1523.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche 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.
Annane D. Time for a consensus definition of corticosteroid insufficiency in critically ill patients. Crit Care Med 2003;31:1868–1869.
Manglik S, Flores E, Lubarsky L, Femandez F, Chhibber VL, Tayek JA. Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial. Crit Care Med 2003;31: 1668–1675.
Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med 2003;139:194–204.
Zaloga GP, Marik P. Hypothalamic-pituitary-adrenal insufficiency. Crit Care Clin 2001;17:25–41.
Schmidt IL, Lahner H, Mann K, Petersenn S. Diagnosis of adrenal insufficiency: evaluation of the corticotropin-releasing hormone test and basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease. J Clin Endocrinol Metab 2003;88:4193–4198.
Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003;31:1441–1450.
Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629–1638.
Balk RA. Steroids for septic shock: back from the dead (Pro). Chest 2003;123:490S–499S.
Sessler CN. Steroids for septic shock: back from the dead (Con). Chest 2003;123:482S–489S.
Annane D. Corticosteroids for septic shock. Crit Care Med 2001;29:117S–120S.
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723–732.
Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645–650.
Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038–1045.
Tobin MJ. Of principles and protocols and weaning. Am J Respir Crit Care Med 2004;169:661–667.
Stoller JK, Xu M, Mascha E, Rice R. Long-term outcomes for patients discharged from a long-term hospital-based weaning unit. Chest 2003;124:1892–1899.
Epstein SK. Ciubotaru RL. Independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation. Am J Respir Crit Care Med 1998;158:489–493.
Mancebo J. Weaning from mechanical ventilation. Eur Respir J 1996;9: 1923–1931.
Huang CJ, Lin SM, Lin HC, Kuo HP. Association between adrenal insufficiency and ventilator weaning in critically ill patients: a randomized control study . Am J Respir Crit Care Med 2004;169: A122.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727–734.
Knaus WA. APACHE 1978–2001: the development of a quality assurance system based on prognosis: milestones and personal reflections. Arch Surg 2002;137:37–41.
Krieger BP. Isber J. Breitenbucher A. Throop G. Ershowsky P. Serial measurements of the rapid-shallow-breathing index as a predictor of weaning outcome in elderly medical patients. Chest 1997;112:1029–1034.
Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill. Chest 2002;122:1784–1796.
Burchard K. A review of the adrenal cortex and severe inflammation: quest of the "eucorticoid" state. J Trauma 2001;51:800–814.
Rivers EP, Gaspari M, Sadd GA, Mlynarek M, Fath J, Horst HM, Wortsman J. Adrenal insufficiency in high risk surgical ICU patients. Chest 2001;119:889–896.
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 2003;167:512–520.
Manthous CA, Schmidt GA, Hall J. Liberation from mechanical ventilation: a decade of progress. Chest 1998;114:886–901.
Shikora SA, Bistrian BR, Borlase BC, Blackburn GL, Stone MD, Benotti PN. Work of breathing: reliable predictor of weaning and extubation. Crit Care Med 1990;18:157–162.