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Revista Brasileira de Terapia Intensiva

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ISSN: 0103-507X
Online ISSN: 1982-4335

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Linck Júnior A, Rego Filho EA, Moriya LK, Cardoso JR. Frequência de insuficiência adrenal em crianças com sepse. Rev Bras Ter Intensiva. 2011;23(4):478-483



Original Article - Clinical Research

Adrenal insufficiency in children with sepsis

Frequência de insuficiência adrenal em crianças com sepse

Arnildo Linck Júnior, Eduardo de Almeida Rego Filho, Luiza Kazuco Moriya, Jefferson Rosa Cardoso

IPediatric Intensive Care Unit, Hospital Universitário Regional do Norte do Paraná, Universidade Estadual de Londrina - UEL - Londrina (PR), Brazil
IIDepartment of Pediatrics and Pediatric Surgery, Universidade Estadual de Londrina - UEL - Londrina (PR), Brazil
IIIDepartment of Physical Therapy, Universidade Estadual de Londrina - UEL - Londrina (PR), Brazil

Conflicts of interest: None.

Submitted on March 20, 2011
Accepted on October 13, 2011

Corresponding author:

Arnildo Linck Júnior
Rua Mato Grosso, 1541 - Apto 501
Zip Code: 86010-180 - Londrina (PR), Brazil
E-mail: [email protected]



OBJECTIVE: To determine the frequency of adrenal insufficiency in children diagnosed with sepsis that were staying in pediatric intensive care units and to establish the association between adrenal function and the use of vasoactive drugs, mechanical ventilation time and mortality.
METHODS: A cohort-designed study was conducted to assess the incidence of adrenal insufficiency in children aged 29 days to 12 years who were diagnosed with sepsis using the adrenocorticotropic hormone (ACTH) stimulation test.
RESULTS: Thirty-nine children were included in the study. The frequency of adrenal insufficiency was 30.7% (12 patients). Children with adrenal insufficiency had an increased need for vasoactive drugs as well as longer mechanical ventilation times; however, the differences were not statistically significant. A Kaplan-Meier curve indicated lower survival rates among the adrenal insufficiency children, but the differences were not statistically significant (p = 0.1263). No differences were identified between the adrenal sufficiency and adrenal insufficiency groups in regards to mechanical ventilation time, use of vasoactive drugs, infection type and chronic disease.
CONCLUSION: This study determined the frequency of adrenal insufficiency in children with sepsis and its relationship to increased mortality within the first 28 post-admission days. No statistically significant association was found between adrenal insufficiency and mechanical ventilation time or the use of vasoactive drugs.

Keywords: Sepsis, Adrenal insufficiency, Corticotropin-releasing hormone, Vasoactive drugs, Children




The hypothalamic-pituitary-adrenal axis is responsible for homeostasis and is activated under stressful conditions, such as severe disease, trauma, anesthesia and surgery, leading to increased serum cortisol levels. This axis is mostly activated by the release of inflammatory cytokines. The mobilization of endogenous steroid stocks is responsible for the maintenance of the vascular tonus and endothelial integrity, control of vascular permeability and distribution of total body water, in addition to adrenergic receptor sensitization. Continuous axis stimulation leads to the exhaustion of cortisol stocks and adrenal insufficiency.(1)

Total adrenal insufficiency is rare, with an incidence between 2 and 3% among critically ill patients, and its primary triggering events are hemorrhage and post-traumatic tissue destruction.(2) Secondary dysfunction occurs after cortisol stocks are exhausted. In addition, secondary dysfunction can also be caused by peripheral resistance to adrenocorticotropic hormone (ACTH) Sepsis is one of the most common total adrenal insufficiency triggering events. Other clinical conditions may contribute to partial adrenal failure, such as autoimmune adrenalitis, disseminated tuberculosis, metastasis and partial hemorrhagic gland destruction.(2)

The main clinical features leading to adrenal insufficiency are related to hemodynamic conditions, with symptoms typically associated with hypovolemic shock, reduced afterload, myocardial depression and increased peripheral vascular resistance, or typical hyperdynamic shock with increased cardiac output and reduced peripheral vascular resistance. Under such conditions, arterial hypotension is the most common clinical outcome.(3) Baseline cortisol is widely variable during severe symptom manifestations, and its fluctuation is associated with a poor prognoses.

The baseline cortisol measurement has been widely used to diagnose adrenal insufficiency, both in experimental models and clinical trials. The findings of previous studies indicated that increased serum cortisol is a response to trauma and severe disease. However, as the variables impacting the measurement of baseline cortisol levels and the differences between free and globulin-bound forms have become known, new adrenal function assessment methods have been examined. The results of several studies, including many multicenter trials, indicate that the most trustworthy way to evaluate adrenal insufficiency is the adrenocorticotropic hormone (ACTH) stimulation test. The use of this test allows for not only the diagnosis of adrenal insufficiency but also the adrenal insufficiency status to be rated and quantified prior to deciding the appropriate therapeutic approach.(4,5)

ACTH acts directly on the adrenal cortex to promote cortisol secretion. The ACTH stimulation test represents an alternative to the diagnosis of secondary adrenal insufficiency, with different methodologies in accordance with dosage.(6) Lower ACTH doses (e.g., one microgram) are more sensitive.(7)

Therefore, the main objectives of this study were to determine the frequency of adrenal insufficiency in children diagnosed with sepsis who were staying in pediatric intensive care units and to establish the association between adrenal function and the use of vasoactive drugs, mechanical ventilation time and mortality.



During the first phase of the study, children with a sepsis diagnosis were selected in accordance with the presence of signs representing a systemic inflammatory response syndrome in association with clinical or laboratory evidence of an infection, all in accordance previously published criteria.(8) The following were considered symptoms of organ dysfunction: serum lactate > 2.2 mmol/L, urinary output < 1 mL/kg/h, base excess < -3, partial oxygen pressure/inspired oxygen fraction ratio (PaO2/FiO2) < 300 and altered consciousness level. Arterial hypotension was defined as a systolic blood pressure (SBP) below the 5th age percentile, i.e., SBP < (70 mmHg + 2 times the age in years). The sample included children with the following criteria: an age range of 29 days to 12 years, clinical and laboratory criteria for sepsis and admission to the pediatric intensive care unit of Hospital Regional do Norte do Paraná from August 2004 to July 2005. This was a cohort-designed study.

A systemic inflammatory response was diagnosed by fever or hypothermia, tachycardia, tachypnea or hyperventilation and white blood cell changes, including absolute leukocyte counts and ratio of immature cells in the peripheral blood for all patients in the study. Clinical tests, chest X-rays, urinalysis from single sample, blood chemistry, cytology and the culturing of specific sites were used to evaluate and diagnose infection.

Newborns were excluded from the patient sample. In addition, exclusion criteria also included known hypothalamus-pituitary-adrenal axis abnormalities; chronic use of corticosteroids, phenytoin, and phenobarbital; recent use of rifampicin or etomidate; and diagnosis of disseminated tuberculosis or acquired immunodeficiency syndrome (AIDS).

After patient selection, serum cortisol was evaluated by removal of two mL of blood into a non-anticoagulant bottle. The collection was conducted by the first author for all patients. Next, ACTH stimulation was conducted using a one-microgram dose of intravenous adrenocorticotropic hormone followed by a new cortisol assessment 60 minutes post-stimulation. Withdrawn blood was then centrifuged, frozen and stored (at -4ºC) for later analysis. Cortisol levels were evaluated by radioimmunoassay. Sampling was conducted within the first 24 hours post-admission to the intensive care unit in cases where sepsis was the admission diagnosis or within the first 24 hours post-sepsis diagnosis when sepsis developed during the hospital stay.

A patient was considered to have adrenal insufficiency when the post-ACTH stimulation cortisol level increased by less than 9 mcg/dL over the baseline value.(9) This value for adrenal insufficiency diagnosis was based on a study by Annane et al.(4)

We analyzed the rate of adrenal insufficiency in the study sample and the patient clinical outcomes as compared to patients with normal adrenal function. Vasoactive drug requirements and lengths of use, mechanical ventilation needs and times, laboratory evidence of impaired cardiac output using serum lactate dosage and demographics were all analyzed. In addition, the overall group mortality within 28 days post-admission and the total length of stay until the outcome (i.e., death or discharge from the intensive care unit) were assessed.

The demographics and clinical features were analyzed by comparing children with and without an adrenal insufficiency diagnosis. The numerical variables were assessed for their normal distribution (Shapiro-Wilk test). Variables that were determined to not have a normal distribution are presented as medians and quartiles. The categorical variables are presented as absolute and relative frequencies. The Mann-Whitney test was used to compare the numerical group variables. The association between the primary endpoint (with or without adrenal insufficiency) and categorical variables were assessed using the Fisher exact test. In addition, the survival curve of the groups was compared using a Kaplan-Meier plot. The statistical significance level was established at 5% (p < 0.05). The statistical analyses were conducted using the Statistical Package for Social Science (SPSS, version 11.5).

This study was approved by the ethics committee of Hospital Universitário Regional do Norte do Paraná (EC 099/14). The legal representatives of the patients were appropriately informed about the study and signed a written informed consent form.



During the study period, 39 children were enrolled and divided into three age ranges. Eighteen patients were less than one year-old, seven were between one and two years-old and fourteen were above two years-old. These groups had similar demographic data, such as gender and age range (Table 1). When the sample was divided into two or fewer years-old children and more than two years children, a larger proportion of the older children had adrenal insufficiency, but the difference was not statistically significant (p = 0.057). Of the 39 children, 20 were male and 19 female.

Moreover, 12 (30.7%) had tests indicative of adrenal insufficiency. The median baseline cortisol values were 17.2 mcg/dL. The post-ACTH cortisol values were 32.4 mcg/dL, and the median post-stimulation response was 11.7 mcg/dL. Among the 12 children with adrenal insufficiency, six were male and six female.

The overall mortality was 25.6% (10 patients). An analysis of the outcomes suggests that death was more common in children with adrenal insufficiency than among normal functioning children; however, this difference was not statistically significant (p = 0.13). The analysis of 28-day mortality indicated a significantly increased death rate for the adrenal insufficiency group (p = 0.043, Table 2). The Kaplan-Meier curve also indicated lower survival rates among adrenal insufficiency children, but the difference was not statistically significance (p = 0.1263) (Figure 1).

Serum lactate tissue perfusion testing demonstrated no significant difference between the groups (p = 0.654). In addition, no differences were found for chronic disease or type of infection. The duration of circulatory support with catecholamines was longer in adrenal insufficient children but did not reach statistical significance (p = 0.061). The mechanical ventilation time was not statistically different between the groups (p = 0.374).



Secondary adrenal insufficiency is common is children with septic shock and other organ stress conditions.(10-13) In such conditions, the hypothalamus-pituitary-adrenal axis is activated, initially leading to increased free cortisol.(14) Next, the entire axis is exhausted and peripheral cortisol resistance leads to the development of adrenal insufficiency.(15-17) The related adrenal dysfunction incidence is variable and depends on both the sample profile and the diagnosis criteria.(18,19)

The results of this study confirm the existence of adrenal insufficiency in children suffering septic shock. These results are concordant with the results found by Pizarro et al. using similar diagnosis methods. They found an incidence of 44% in a 57-child sample.(20)

A dynamic test was performed using a low ACTH dose (one microgram). A study by Annane et al.(4) was used as the model for adrenal function assessment in our sample (9 mcg/dL response). This criterion was also used by Marik et al.(7) However, a 250-microgram ACTH dose was used in a study by Pizarro et al.(20) Dynamic ACTH testing has been used in most of the studies assessing adrenal insufficiency prevalence and incidence, both in adults and children.(21-24) In addition, other diagnostic methods are available, such as baseline cortisol, free cortisol and serum ACTH dose measurement.

In a study by Kleijn et al., an assessment of children with meningococcal disease found lower cortisol and ACTH values than non-diseased children.(6) Marik et al. examined baseline cortisol levels to diagnose adrenal insufficiency, in addition to a dynamic ACTH test. The respective insufficient frequencies were 61% for baseline values and 22% after the dynamic test.(7)

In this study, the 28-day overall mortality was 58%, with a significantly larger number of adrenal dysfunction patients dying (p < 0.001). The Kaplan-Meier curve also indicated lower survival likelihood for patients with adrenal function impairment. However, this difference was not significant. An analysis of the clinical outcome indicated no association between the diagnosis of adrenal insufficiency and length of hospital stay or mechanical ventilation time. These results are different from other studies. The vasoactive drug-use duration was longer in children with adrenal insufficiency, but the difference was not statistically significant. In a study by Hatherill et al. of a similar sample, a higher adrenal insufficiency (52%) frequency was found, along with increased vasoactive drug-use duration requirements in the adrenal insufficiency group. In addition, the adrenal insufficiency group had a worsened prognosis. In concordance with our results, Hatherill et al. found no statistically significant association between adrenal insufficiency and mechanical ventilation time.(10)

In a study by Loisa et al.,(5) after analyzing the adrenal function of 41 patients, the deficiency group was found to have a longer stay in the intensive care unit and remain longer under mechanical ventilation; both differences were significant. Adrenal insufficiency, along with higher ACTH doses, was diagnosed by these authors in six patients. In both studies, unfavorable clinical outcomes were related to disease severity or refractory septic shock independent of adrenal function.

In our study, admission and prognostic scores were analyzed, but no associations with adrenal function or clinical outcome were found. In addition, the timing of the dynamic ACTH test was debated. This patient sample was conducted within the first 24 hours post-admission or post-sepsis diagnosis. This was both arbitrary and punctual, as impairment of adrenal function may take place at other times during hospitalization and sepsis progression. New methodologies should be developed for systematic adrenal function assessment and determination of the optimal time for dynamic ACTH testing.

In this study, adrenal insufficiency was shown to be common in septic patients. However, when compared with the findings of other authors, our frequency was lower, and no association with the clinical outcome was found. The small sample size was limiting, as was the unavailability of pre-admission assessments. Additional studies with larger sample sizes that would allow improved diagnostic criteria are warranted so are clinical trials to assess the treatment of adrenal insufficiency in pediatric patients.



This work is dedicated to Professor Eduardo de Almeida Rego Filho for his direct contribution to the study, as well as the Service of Pediatrics and pediatric ICU of Hospital Universitário Regional do Norte do Paraná.



1. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflamation. N Engl J Med. 1995;332(20):1351-62.

2. Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med. 1997;337(18):1285-92.

3. Van den Berghe G. Neuroendocrine axis in critical illness. Curr Opin Endocrinol Diabetes. 2001;8(1):47-54.

4. Annane D, Sébille V, Troché G, Raphaël JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropín. JAMA. 2000;283(8):1038-45.

5. Loisa P, Rinne T, Kaukinen S. Adrenocortical function and multiple organ failure in severe sepsis. Acta Anaesthesiol Scand. 2002;46(2):145-51.

6. De Kleijn ED, Joosten KF, Van Rijn B, Westerterp M, De Groot R, Hokken-Koelega AC, Hazelzet JA. Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease. Pediatr Infect Dis J. 2002;21(4):330-6.

7. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med. 2003;31(3):141-5.

8. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ; ACCP/SCCM Consensus Conference Committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. Chest. 2009;136(5 Suppl):e28.

9. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348(8):727-34.

10. Hatherill M, Tibby SM, Hilliard T, Turner C, Murdoch IA. Adrenal insufficiency in septic shock. Arch Dis Child. 1999;80(1):51-5.

11. Manglik S, Flores E, Lubarsky L, Fernandez 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(6):1668-75.

12. Knapp PE, Arum SM, Melby JC. Relative adrenal insufficiency in critical illness: a review of the evidence. Curr Opin Endocrinol Diabetes. 2004;11(3):147-52.

13. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003;139(3):194-204. Review. Erratum in: Ann Intern Med. 2004;140(4):315.

14. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141(1):47-56.

15. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-71. Erratum in: JAMA. 2008;300(14):1652. Chaumet-Riffaut, Philippe [corrected to Chaumet-Riffaud, Philippe].

16. Wiilliamson DR, Lapointe M. The hypothalamic-pituitary-adrenal axis and low-dose glucocorticoids in the treatment of septic shock. Pharmacotherapy. 2003;23(4):514-25. Review.

17. Sessler CN. Steroids for septic shock: back from the dead? (Con). Chest. 2003;123(5 Suppl):482S-9.

18. Balk RA. Steroids for septic shock: back from the dead? (Pro). Chest. 1993;123(5 Suppl):490S-9.

19. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet. 1991;337(8741):582-3.

20. Pizarro CF, Troster EJ, Damiani D, Carcillo JA. Absolute and relative adrenal insufficiency in children with septic shock. Crit Care Med. 2005;33(4):855-9.

21. Menon K, Lawson M. Identification of adrenal insufficiency in pediatric critical illness. Pediatr Crit Care Med. 2007;8(3):276-8.

22. Sarthi M, Lodha R, Vivekanandhan S, Arora NK. Adrenal status in children with septic shock using low-dose stimulation test. Crit Care Med. 2007;8(1):23-8.

23. Pizarro CF, Troster EJ. Adrenal function in sepsis and septic shock. J Pediatr (Rio J). 2007;83(5 Suppl):S155-62.

24. Marik PE, Pastores SM, Annane D, Medruri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M; American College of Critical Care Medicine. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-49.



This study was conducted at the Hospital Universitário Regional do Norte do Paraná, Universidade Estadual de Londrina - UEL - Londrina (PR), Brazil.



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