ABSTRACT

Corresponding Author:
Pravat Kumar Thatoi,
Flat-104, Aryabhatta Complex,
College Square,
Cuttack-753003,
Odisha, India.
E-mail: drpravatthatoi@yahoo.co.in

ABSTRACT

BACKGROUND

Cortisol (Glucocorticoid) is the main hormone in host response to stress. Its secretion from adrenal glands depends on integrity of hypothalamic-pituitary-adrenal (HPA) axis. Adrenocorticotropic hormone (ACTH) is the stimulant for cortisol secretion from adrenal glands. Adrenal insufficiency (AI) is often present in critically ill patients and is diagnosed by ACTH stimulation test using intravenous (IV) injection of Synacthen (Tetracosactide) which is not freely available in our part. Another synthetic corticotrophin (Acton Prolongatum) prepared by Ferring pharmaceuticals can be used for intramuscular (IM) ACTH stimulation test for assessment of adrenal function.

Aims & Objectives- To measure the basal serum cortisol level at 8.00-9.00 a.m. then at 60 min. & 3 hours after IM ACTH stimulation and to find out glucocorticoid response in critically ill patients.

Materials and Methods

A descriptive study was designed in the Medical ICU of SCB Medical College, Cuttack, 46 critically ill adult patients with various diseases admitted to Medical ICU and were having or suspected of having some degree of adrenocortical dysfunction on the basis of prolonged hypotension for more than 6 hours despite adequate fluid challenge and/or need for vasopressors/inotropes, were included in this study for the period from Sep. 2013 to Sep. 2015.

Results

Out of total 46 ill patients, 25 patients were diagnosed as adrenal insufficiency. Amongst them, 14 were male and 11 were female. Most of them presented with various combinations of hypotension, fever, nausea, vomiting, fatigue, pigmentation, weakness and irritability.

Conclusion

We concluded that intramuscular Acton Prolongatum can be used for ACTH stimulation test in critically ill patients to diagnose adrenal insufficiency (AI).

KEYWORDS

Critically ill patient, Intensive care unit (ICU), Adrenal insufficiency, Acton Prolongatum, ACTH stimulation test.

BACKGROUND

Severe illness and stress activate the hypothalamic-pituitary-adrenal (HPA) axis and stimulate the release of corticotrophin (adrenocorticotropic hormone or ACTH) from the pituitary gland, which in turn increases the release of cortisol from adrenal cortex.^{1, 2}

There was statistically significant difference in Basal cortisol, Post ACTH cortisol and Delta Cortisol between patients having AI and normal adrenal function.

DISCUSSION

The integrity of HPA axis is a major determinant of the host’s response to stress.^6,7 During stress, the activation of HPA axis is highlighted by increased corticotrophin release from the pituitary gland,¹⁰ enhanced adrenal secretory activity,^11,12 and high plasma cortisol levels However, whether endogenous glucocorticoid levels are adequate or constitute an independent predictor of death remains controversial.^1,13,14 There are some studies which reported lower cortisol levels in non-survivors compared with survivors.^15,16,17 For this reason, in stress, the evaluation of appropriateness of the activation of the HPA axis requires dynamic testing. Adrenal insufficiency is diagnosed when on stimulation test the peak serum cortisol is <500 nmol/L (18 µg/dL),¹⁸ alternatively it has been proposed that increment during ACTH stimulation test <250 nmol/L (9 µg/dL) or basal cortisol <83 nmol/L (3 µg/dL) can be considered as diagnostic of AI.^18,19

Diagnostic evaluation of suspected cases of adrenal insufficiency is hindered by non-availability of injection Synacthen. To overcome this limitation, we used Acton Prolongatum (Corticotrophin Carboxymethyl cellulose) as intramuscular ACTH stimulation test. During standard Synacthen stimulation test (SST), serum cortisol is taken at 30 min. and 60 min. intervals, because the serum cortisol (reflecting serum ACTH level) following injection of Synacthen peaks around this time. But the use of long acting corticotrophin carboxymethyl cellulose (Acton Prolongatum), plasma level of plasma 11- hydroxycorticosteroid reflecting the level of serum cortisol peaks around 1 to 3 hrs. (at 1 hr. 25.7 µg/100 mL and at 3 hrs. 37.4 µg/100 mL).²⁰ So we decided to take samples of serum cortisol at 0 hr., 1 hr. and 3 hrs. All the patients of control groups achieved normal stimulation of cortisol after intramuscular ACTH.

Intramuscular ACTH test with Acton Prolongatum is economically cheaper as compared to Synacthen. Synacthen costs around Rs. 3200 in the grey market. Each vial of Acton Prolongatum costs Rs. 1645 and contains 300 units (5 mL vial, 60 units/mL), thus 12 tests can be performed at a cost of Rs 130 each.

The incidence of adrenal insufficiency in critically ill patients presenting with shock varies and depends on the underlying disease and severity of illness. The reported incidence varies widely depending on the population of the patients studied and diagnostic criteria used to diagnose adrenal insufficiency.

Adrenal insufficiency: Subjects with post ACTH cortisol <500 nmol/L (18 µg/dL) and Incremental response is decreased if serum cortisol rise was <250 nmol/L (9 µg/dL) from basal cortisol level post ACTH.²¹

Abhay Gundgurthi et al²² has done a study-“Intramuscular ACTH Stimulation Test for Assessment of Adrenal Function” and reported sex distribution among AI patients M: F =28:9 and age distribution mean ± SD =33.0 ± 18.8 yrs. Present study shows the sex distribution among AI patients M: F =14:11 and mostly affected age group 31-45 years (48%) with mean ± SD is 46.76 ± 14.03 years. [Table-1] and [Table-3].

Hypotension refractory to fluids and requiring vasopressors is the most common feature of acute adrenal insufficiency.²³ In the present study, 100% patients (25 patients) have hypotension and 88% (22 patients) had weakness and fatigue and 72% (18 patients) had symptoms of nausea and vomiting. Out of 25 patients, 17 patients (68%) presented with fever. CNS dysfunction as irritability and depression is common, frequently as a result of underlying disease. In the present study, 29.97% (9 patients) presented with irritability and 13.33% (4 patients) presented with depression as clinical features. [Table-4].

Acute adrenal insufficiency occurs in patients who are unable to increase their production of cortisol during acute stress. This includes patients with hypothalamic and pituitary disorders (Secondary AI) and patients with destructive diseases of adrenal glands (primary AI). Most common cause of acute adrenal insufficiency is sepsis and the SIRS.^23,24 Abhay Gundgurthi et al²³ reported a mean basal cortisol 95.97 ± 83.32 nmol/L, post ACTH cortisol 270.32 ± 140.25 nmol/L and Delta cortisol 174.62 ± 113.57 nmol/L, in 37 adrenal insufficiency patients out of 89 studied patients. The present study shows mean basal cortisol of 137.51 ± 68.18 nmol/L, post ACTH cortisol 605.92 ± 389.67 nmol/L and Delta cortisol 135.51 ± 68.25 nmol/L in 25 adrenal insufficiency patients out of 46 studied patients. [Table-7]. Basal cortisol level solely cannot be relied on to detect all cases of AI.²³ From studied group, 17 patients had basal cortisol ≤500 nmol/L. and 25 patients had increment of S. cortisol ≤250 nmol/L. Out of 17 patients whose basal cortisol was <500 nmol/L, 5 patients had ˃250 nmol/L of S. cortisol after ACTH stimulation test.

14 patients from 25 patients had increment of S. cortisol ≤250 nmol/L, but they did not have basal cortisol ≤500 nmol/L. Only 9 patients had both basal cortisol ≤500 nmol/L and increment value of S. cortisol after ACTH ≤250 nmol/L. Two patients from control group had subnormal basal cortisol but showed increment ˃250 nmol/L S. cortisol after ACTH stimulation test. Hence, at best, basal cortisol can be used to screen for suspected AI and those with a low basal cortisol will need a stimulation test to confirm or exclude AI.

CONCLUSION

Adrenal insufficiency is often present in critically ill patients,²⁵ but difficult to prove due to non-availability of Synacthen stimulation test. In this study, we have shown that AI can be easily and efficiently diagnosed using Acton Prolongatum, which is an easily available long acting version of ACTH.

HPA dysfunction is common in severely ill patients. Even slight impairment of the adrenal response to severe illness can increase morbidity and mortality, and we believe that low serum cortisol levels may be the cause rather than the consequence of poor outcome in these patients. Therefore, a high index of suspicion for adrenal insufficiency is required in all critically ill patients, particularly those with refractory hypotension. All patients with suspected HPA dysfunction should be treated with stress doses of corticosteroids. The result of our study points to the possibility of existence of subnormal adrenocortical response in some critically ill patients, who do not respond adequately to the standard optimal therapy. Therapeutic implication arising out of the study is the possible role of glucocorticoids as an adjunctive therapy, in the hope of a more favourable outcome.