Incidence of Adrenal Insufficiency and Cushing’s Syndrome After Long-Term Epidural Steroid Injections Over Six Months or Longer: A Preliminary Study

Figures & data

Table 1 Demographic and Clinical Characteristics of Variables

Variables	Subgroup	N (%)	AI	Non-AI	p value
Subject		17 (100)	2 (11.8)	15 (88.2)
Diagnosis		17 (100)			1
	HNP	15 (88.2)	2 (100)	13 (86.7)
	Spinal stenosis	2 (11.8)	0 (0)	2 (13.3)
Age, years		17 (100)	56.5 ± 6.4	63.5 ± 9.4	0.331
Sex		17 (100)			1
	M	4 (23.5)	0 (0)	4 (26.7)
	F	13 (76.5)	2 (100)	11 (73.3)
BMI, kg/m^2		17 (100)	23.1 ± 0.6	23.1 ± 2.2	0.987
Duration of pain before enrollment		17 (100)	31.0 ± 1.4	30.7 ± 24.5	0.369
Location of pain	Back	8 (47.1)	1 (50)	7 (46.7)
	Leg	4 (23.5)	1 (50)	3 (20.0)
	Back & Leg	5 (29.4)	0 (0)	5 (33.3)
Total duration of ESIs, months		17 (100)	26.0 ± 1.4	16.9 ± 8.5	0.176
Total dose of steroid, mg		17 (100)	270.0 ± 42.4	228.0 ± 96.1	0.550
Total dose/body weight, mg/kg		17 (100)	4.7 ± 0.7	4.0 ± 1.8	0.551
Total numbers of ESIs		17 (100)	16.5 ± 2.1	12.3 ± 8.1	0.486
Numbers of ESIs/years, N/years		17 (100)	7.7 ± 1.3	7.4 ± 3.3	0.529
Serum ACTH, pg/mL		17 (100)	22.4 ± 23.2	30.5 ± 17.4	0.558
SC normality on D0		17 (100)			1
	No	7 (41.2)	1 (50)	6 (40)
	Yes	10 (58.8)	1 (50)	9 (60)
SC normality on D42		17 (100)			0.022*
	No	3 (17.6)	2 (100)	1 (6.7)
	Yes	14 (82.4)	0 (0)	14 (93.3)

Notes: Categorical variables were expressed as subject numbers (N) and %. Continuous variables are expressed as mean ± standard deviation (SD). *p < 0.05 compare DO to D42 (Student’s t-test).

Abbreviations: AI, adrenal insufficiency; BMI, body mass index; ESI, epidural steroid injection; ACTH, adrenocorticotropic hormone; SC, salivary cortisol; D0, day 0; D42, day 42; and HNP, herniated nucleus pulposus.

Table 2 Results of ACTH Stimulation Test, LNSC, Symptoms of AI, Cushing’s Syndrome, Total Duration of ESIs in Months, and Total Number of ESIs

Subjects	SeC0, μg/dL	SeC30, μg/dL	SeC60, μg/dL	LNSC, μg/dL	AI Sx (Y/N)	CS Sx (Y/N)	Total Duration of ESIs in Months	Total Number of ESIs
1	10.08	16.12	27.23	0.049	N	N	63	24
2	14.32	27.66	33.18	0.049	N	N	68	25
3*	4.66	9.89	12.84	0.034	N	N	27	15
4	22.13	29.52	33.21	0.271	N	N	17	8
5	1.53	16.03	22.43	0.306	N	N	14	10
6	11.30	18.39	25.08	0.201	N	N	6	6
8	12.49	27.54	21.76	0.014	N	N	6	7
9	6.68	24.20	26.35	0.012	N	N	55	30
10	17.40	26.48	33.00	0.188	N	N	20	14
11	10.79	20.67	24.51	0.166	N	N	11	6
12	9.04	18.49	25.99	0.207	N	N	6	4
13	9.15	26.33	30.81	0.042	N	N	70	15
14	8.41	23.11	26.80	0.032	N	N	24	15
15	13.25	29.13	30.76	0.248	N	N	16	8
16	8.49	19.50	23.94	0.030	N	N	20	6
17*	1.18	5.12	6.85	0.027	N	N	25	18
18	22.22	28.27	34.19	0.048	N	N	6	6

Notes: The diagnostic criterion for adrenal insufficiency was peak serum cortisol concentration <18 μg/dL after parenteral administration of 250 μg cosyntropin (ACTH stimulation test). Serum cortisol concentration was measured at baseline, 30 minutes, 60 minutes after 250 μg of cosyntropin injection. The diagnostic criterion for iatrogenic Cushing’s syndrome was LNSC > 0.34 μg/dL, which was measured during 2300~2400 on day 41. The symptoms of AI were fatigue, loss of appetite, weight loss, nausea, vomiting, abdominal pain, and muscle and joint pain. Symptoms of Cushing’s syndrome were a moon face, central obesity, muscle and skin atrophy, poorly controlled diabetes, and extreme physical stress. * were AI subjects. There was no subject with Cushing’s syndrome in this study.

Abbreviations: SeC0, serum cortisol at baseline; SeC30, serum cortisol at 30 minutes; SeC60, serum cortisol at 60 minutes; ACTH, adrenocorticotropic hormone; LNSC, late-night salivary cortisol; Sx, symptoms; AI, adrenal insufficiency; CS, Cushing’s syndrome; ESI, epidural steroid injection.

Figure 1 Flow diagram of the study.

Table 3 Results of Univariate Binary Logistic Regression Analysis Using Incidence of AI as Response

Predictors	Subgroup	OR (95% CIs)	p value
Diagnosis			0.997
	Spinal stenosis vs HNP	17792121.958 (0 - Inf)	0.997
Age, years		1.104 (0.906–1.345)	0.329
Age			0.993
	60–69 vs 50–59	1.2 (0.059–24.473)	0.906
	70–79 vs 50–59	62873202.581 (0 - Inf)	0.997
Sex			0.997
	F vs M	0 (0 - Inf)	0.997
BMI, kg/m^2		1.007 (0.483–2.097)	0.986
Duration of ESIs, months		1.002 (0.935–1.073)	0.961
Duration of ESIs, months			1
	12–24 vs 6–12	1 (0 - Inf)	1
	>24 vs 6–12	0 (0 - Inf)	0.998
Total dose of steroid, mg		0.749 (0.427–1.315)	0.314
Total dose/body weight, mg/kg		93568.213 (0–1025282875745282)	0.332
Total numbers of ESIs		0.935 (0.781–1.121)	0.469
Total numbers of ESIs			0.856
	10–20 vs <10	0 (0 - Inf)	0.996
	>20 vs <10	0 (0 - Inf)	0.996
Serum ACTH, pg/mL		1.041 (0.916–1.183)	0.538
Serum cortisol (baseline), ug/dL		1.739 (0.922–3.282)	0.088
FBS on D0, mg/dL		1.05 (0.95–1.159)	0.341

Notes: There was no predictor that was associated with the incidence of AI after long-term ESIs. Control response was non-AI and case response was AI.

Abbreviations: BMI, body mass index; ESI, epidural steroid injection; ACTH, adrenocorticotropic hormone; FBS, fasting blood sugar; HNP, herniated nucleus pulposus; AI, adrenal insufficiency.

Table 4 Fixed Effect of Time and Covariates

	β	SE	p value
(Intercept)	-0.246	0.290	0.410
Age	0.002	0.002	0.374
Sex	0.036	0.044	0.422
Total dose of ESIs	-0.067	0.180	0.716
Total number of ESIs	0.001	0.002	0.758
BMI	0.007	0.009	0.453
Time	0.003	0.001	0.002

Notes: Time means days on which SC was measured days (D0, D1, D7, D21, D28, D35, and D42). β is the coefficient of fixed effect and SE is standard error of β.

Abbreviations: SC, salivary cortisol; ESI, epidural steroid injection; BMI, body mass index.

Table 5 Comparison of the Slope of SC Concentration Between AI and Non-AI Groups

Variable	N (%)	AI (N = 2, 11.8%)	Non-AI (N = 15, 88.2%)	p value
Slope of mixed effect model (SC)	17 (100)	0.000281 ± 0.000467	0.002814 ± 0.000328	0.015
Slope of linear regression (SC)	17 (100)	−0.000764 ± 0.001064	0.002953 ± 0.000566	0.059

Notes: Variables were expressed as mean ± standard error (SE). p value was computed using Mann–Whitney U-test.

Abbreviations: SC, salivary cortisol; AI, adrenal insufficiency.

Table 6 Comparison of the Mean SC at Each Time Between the AI and Non-AI Groups

Variables	N (%)	AI (N = 2, 11.8%)	Non-AI (N = 15, 88.2%)	p value	p value Adjusted by FDR
SC on D0	17 (100)	0.088 ± 0.026	0.155 ± 0.032	0.551	0.643
SC on D1	17 (100)	0.032 ± 0.003	0.036 ± 0.007	0.94	0.94
SC on D7	17 (100)	0.118 ± 0.065	0.199 ± 0.033	0.412	0.577
SC on D21	17 (100)	0.054 ± 0.026	0.203 ± 0.029	0.132	0.231
SC on D28	17 (100)	0.030 ± 0.015	0.186 ± 0.028	0.088	0.205
SC on D35	17 (100)	0.044 ± 0.014	0.248 ± 0.029	0.015	0.053
SC on D42	17 (100)	0.058 ± 0.003	0.222 ± 0.029	0.015	0.053

Notes: Variables were expressed as subject number (N) and % or mean ± standard error (SE). p value was computed using Mann–Whitney U-test and then adjusted with FDR as a multiple test correction method.

Abbreviations: SC, salivary cortisol; AI, adrenal insufficiency; FDR, false discovery rate.

Figure 2 Comparison of the increment rate of SC concentration according to time between the AI group and non-AI groups. (A) Comparison of the mean difference of the slope of the mixed effect model between the AI and non-AI groups expressed as 1/4Q, median, and 3/4Q. (B) Comparison of the mean difference of the slope of linear regression between the AI group and non-AI groups expressed as 1/4Q, median, and 3/4Q. *p value < 0.05.

Abbreviations: SC, salivary cortisol; AI, adrenal insufficiency; Q, quartile.

Figure 3 Comparison of the trend of SC for each patient. Black dotted line is linear regression line estimated using population. Red dashed line is the fitted line estimated using a mixed effect model. Blue solid line is linear regression line estimated using subject-specific data. Blue point circle is SC level measured at the corresponding time. X axis shows the time represented as day. Cases 03 and 17 were AI subjects.

Abbreviations: SC, salivary cortisol; AI, adrenal insufficiency.

Figure 4 Time trend of mean SC according to complication. The time course and response pattern (mean ± SD) in SC. After the experimental ESI, SC concentrations of all subjects were initially suppressed (D1). In most of the subjects in the non-AI group, SC concentration returned to the normal range of values. However, in the AI group, the SC concentration did not return to the normal range.

Abbreviations: ESI, epidural steroid injection; SC, salivary cortisol; AI, adrenal insufficiency; SD, standard deviation.