A specific nursing educational program in patients with Cushing’s syndrome

Cushing’s syndrome (CS) is a rare endocrine disease, due to cortisol hypersecretion. CS patients have comorbidities, often still present after biochemical cure. Specific nursing healthcare programs to address this disease and achieve improved health related quality of life (HRQoL) are lacking. Thus, an educational nursing intervention, through the development and promotion of specific educational tools, appears to be justified. The objective of this study is to assess the effectiveness of an educational nursing program in CS patients on HRQoL, clinical parameters, level of pain and physical activity, patterns of rest, and use of health resources. A prospective, randomized study was conducted in two reference hospitals for CS. Sixty-one patients (mean age 47 ± 12.7 years, 83.6 % females) were enrolled and divided into 2 groups: an “intervention” group where educational sessions were performed over 9 months and a “control” group, without these sessions. Specific questionnaires were used at the beginning and end of the study. After educational sessions, the intervention group had a better score in the CushingQoL questionnaire (p < 0.01), reduced level of pain (p < 0.05), improved physical activity (p < 0.01) and healthy lifestyle (p < 0.001) compared to the control group. A correlation between the CushingQoL score and reduced pain (r = 0.46, p < 0.05), improved physical activity (r = 0.89, p < 0.01), and sleep (r = 0.53, p = 0.01) was observed. This educational nursing program improved physical activity, healthy lifestyle, better sleep patterns, and reduced pain in CS patients, influencing HRQoL and reducing consumption of health resources. Moreover, the brief nature of the program suggests it as a good candidate to be used in CS patients.

22 randomized study was conducted in two reference hospitals 23 for CS. Sixty-one patients (mean age 47 ± 12.7 years, 24 83.6 % females) were enrolled and divided into 2 groups: 25 an ''intervention'' group where educational sessions were 26 performed over 9 months and a ''control'' group, without 27 these sessions. Specific questionnaires were used at the 28 beginning and end of the study. After educational sessions, 29 the intervention group had a better score in the Cush-30 ingQoL questionnaire (p \ 0.01), reduced level of pain 31 (p \ 0.05), improved physical activity (p \ 0.01) and 32 healthy lifestyle (p \ 0.001) compared to the control 33 group. A correlation between the CushingQoL score and 34 reduced pain (r = 0.46, p \ 0.05), improved physical 35 activity (r = 0.89, p \ 0.01), and sleep (r = 0.53, 36 p = 0.01) was observed. This educational nursing program 37 improved physical activity, healthy lifestyle, better sleep 38 patterns, and reduced pain in CS patients, influencing 39 HRQoL and reducing consumption of health resources.
40 Moreover, the brief nature of the program suggests it as a 41 good candidate to be used in CS patients.
109 Of the final sample, 45 were considered cured (repeat-110 edly normal 24-h urinary-free cortisol, serum cortisol 111 suppression after overnight 1 mg dexamethasone 112 \50 nmol/L or adrenal insufficiency with hydrocortisone 113 substitution therapy); 24 had undergone radiotherapy and 114 nine suffered hypopituitarism. Sixteen were active, all on 115 medical therapy with ketokonazole and eight also with 116 metyrapone.
117 Remission was re-confirmed in all patients after the 118 9 months of follow up. No patients developed any recur-119 rence during that period. The two cohorts of patients had 120 similar clinical characteristics, and no differences in 121 duration of remission were present. The patients were 122 followed up long term over the years, and they were not in 123 the early phase of surgical remission. Moreover, eucorti-124 solemia was confirmed in all patients on medical therapy.
125 Sociodemographic and clinical variables were collected 126 during a clinical interview and included personal data, age, 127 sex, education level, employment status, and social activ-128 ity. Anthropometric variables included weight, height, 129 body mass index (BMI), waist, and hip circumference, and 130 systolic and diastolic blood pressure. Details related to CS 131 like type of surgery, size of the lesion, symptoms, treat-132 ments, and recurrence were also collected. Table 1 shows 133 the baseline clinical characteristics of the study partici-134 pants. Table 2 shows urinary-free cortisol (UFC), ACTH 135 values, and comorbidities at the end of the study.
136 Patients were randomized into two groups: (1) Inter-137 vention group (31 patients), who followed a specific 138 nursing interventional program and (2) Control group (30 139 patients), who did not undergo the specific nursing inter-140 ventional program. This randomization was stratified by 141 center, by a computer generation of random numbers.

142
Nursing educational intervention

143
The educational intervention was carried out over 144 9 months in the University School of Nursing, HSP. There 145 were 5 visits: 4 educational sessions and 1 last visit, when 146 questionnaires were repeated and final data were collected.
147 The 4 educational sessions lasted 2 h, with intervals 148 between sessions of 30 to 40 days, with a compulsory 149 attendance for all the sessions. The first educational session 150 was named as ''baseline'' (visit 1), and the last was named 151 as ''final visit'' (visit 4). The study finalized (visit 5, ''end 152 of study'') 9 months after the baseline session. All educa-153 tional sessions were conducted by a nurse experienced in  Table 3.

157
There was a progression in the different contents and in 158 the patient's autonomy in the management of the knowl-159 edge of the disease, as indicated in Table 2. Educational 160 resources with reference material were offered to the 161 patient and family throughout the visits, and all the mate-162 rials were in Spanish.

163
All questionnaires were administered at baseline (visit 164 1) and end of the study (visit 5), both to the control group 165 and to the intervention group by the nurse who conducted 166 the educational sessions. The time to complete all ques-167 tionnaires was approximately one hour.

168
The intervention group received the educational pro-169 gram progressively during 4 sessions; it included 170 knowledge on CS, comorbidities, treatments, general 171 management, and autonomy in healthy lifestyles 172 ( Table 2). By contrast, the control group only attended 173 their usual medical appointments, with the information 174 given by their doctor during scheduled visits, without any 175 specific monitoring program or educational intervention 176 visits (''treatment as usual'').
177 Three sessions were patients group sessions (2nd, 3rd, 178 and 5th), attended only by the patients, and in the other two 179 sessions (1st, 4th), the patients could be accompanied by 180 their families ( Table 2). The aim of these latter sessions 181 was that the relatives participated in the learning process 182 and in the promotion of healthier lifestyles.
183 This specific nursing interventional program had four 184 main priorities:  tional Physical Activity Questionnaire (IPAQ) [32, 206 33]; it collects weekly physical activity measured in 207 METs (Metabolic Equivalent of Task). One MET is a 208 physiological measure expressing the energy cost of 209 physical activities. It is defined as the energy cost of 210 sitting quietly and is equivalent to a caloric con-211 sumption of 1 kcal/kg/h. There are three levels of 212 physical activity: low, moderate, and high. It is 213 estimated that compared with sitting quietly, a 214 person's caloric consumption is three to six times 215 higher when being moderately active (3)(4)(5)(6) 216 and more than 6 times higher when being vigorously 217 active ([6 METs).

-Level of rest or sleep measured with the Oviedo Sleep
219 Questionnaire (OSQ) [34,35] and with two specific 220 questions asking for the number of hours of rest and for 221 the self-reported satisfaction with rest (the answer was 222 ''yes'' or ''no'').
223 -The use of health resources the number of hospital 224 admissions during the study period, of unscheduled 225 visits or outpatient visits to their own endocrinologist 226 or other health providers, was included.

239
Statistical analysis 240 Statistical analysis was performed using SAS version 9.3 241 software program (SAS Institute, USA). The normality 242 assumption was tested using the Kolmogorov -Smirnov Two types of analyses were done for all variables: one 249 compared the differences between control group and 250 intervention group, firstly at baseline and secondly at the 251 end of the study. The other type of analysis compared the 252 changes within each group (on one hand control group and 253 on the other hand intervention group) in all the variables, 254 throughout the study. Both analyses used Student t tests. 255 Pearson test was used to find correlations between 256 variables. A statistically significant level of \0.05 was 257 considered.

259
Of the 61 patients enrolled (30 in the control group without 260 educational intervention and 31 in the intervention group 261 with educational intervention), 57 (93.4 %) completed the 262 study as planned in the protocol; 4 patients ended prema-263 turely for various reasons (illness or moving to another city).
264 No significant differences in terms of baseline clinical 265 characteristics were detected between control and inter-266 vention group (Table 1).
267 The majority were women (83.6 %), with a mean age of 268 47 ± 12.7 years. A mean of 2.5 years had elapsed from the 269 onset of symptoms to diagnosis (range 0-8 years). The 270 mean time from diagnosis to the study was 10.5 years; only 271 4.9 % of patients reported having received health No changes in the CushingQoL score were evidenced 283 within the intervention group. By contrast, the control 284 group decreased their CushingQoL score from baseline to 285 the end of the study (59.27 ± 19.79 vs. 48.49 ± 20.02, 286 p \ 0.01), indicating a worsening in HRQoL, (Fig. 1). 287 Finally, the subgroup of patients of the intervention group 288 with worse HRQoL at baseline showed an improvement in 289 the CushingQoL score at the end of the study (p \ 0.01).
290 Pain 291 Pain intensity was less in the intervention group than in the 292 control group, at the end of the study (5.00 ± 4.06 vs. 293 5.97 ± 4.72, p \ 0.05). 294 Moreover, the final pain intensity fell in the intervention 295 group compared to its baseline scores (7.21 ± 4.36 vs. 296 5.00 ± 4.06, p \ 0.01). By the contrast, no differences in 297 pain intensity have been evidenced in the control group 298 compared to its baseline scores (Fig. 2). 299 Finally, there was a positive correlation between 300 reduced level of pain and improvement in HRQoL 301 (r = 0.46, p \ 0.05).
302 Physical activity 303 The percentage of high physical activity level was higher in 304 the intervention group compared to control group, at the 305 end of the study (46.4 vs. 10.3 %, p \ 0.01).

306
Moreover, an increase in the percentage of patients with 307 high physical activity level (from 17.9 to 46.4 %, 308 p \ 0.001) was observed in the intervention group. By the 309 contrast, physical activity did not vary from baseline to the 310 end of the study in the control group. 311 Finally, there was a positive correlation between high 312 physical activity level and the improvement in HRQoL 313 (r = 0.89, p \ 0.01).
314 Rest 315 The OSQ indicated insomnia and hypersomnia in CS patients 316 at baseline, without differences between intervention and 317 control group. Moreover, no changes were seen between 318 baseline and the end of the study in either group. 319 However, there was a significant improvement in self-320 reported quantity (= number or hours, 7.53 ± 1.10 vs. 321 6.39 ± 1.34, p \ 0.05) and quality of rest (measured as the 322 percentage of patients that referred satisfaction with the 323 rest, 64 vs. 89 %, p \ 0.05) throughout the study, in the 324 intervention group. 325 Finally, there was a positive correlation between the 326 quantity of rest and the improvement in HRQoL (r = 0.53, 327 p = 0.01).

329
There was more adherence to educational instructions on 330 healthy lifestyle in the intervention group compared to 331 control group at the end of the study (4.00 ± 0.38 vs. 332 2.76 ± 0.29, p \ 0.001).
333 Moreover, an improvement in the adherence to educa-334 tional instructions on healthy lifestyle was seen in the 335 intervention group at the end of the study compared to 336 baseline (3.19 ± 0.32 vs. 4.00 ± 0.38, p \ 0.05). By con-337 trast, adherence worsened in the control group throughout 338 the study period (3.00 ± 0.37 vs. 1.66 ± 0.29 p \ 0.05). 370 Furthermore, patients who participated in the educa-371 tional sessions had better HRQoL than patients who did 372 not participate, at the end of the study. In particular, 373 patients with worse HRQoL at the baseline showed a 374 greater improvement at the end of the study, indicating 375 that those patients with severe impairment in their 376 HRQoL benefit more from the educational intervention 377 than the rest. Fig. 1 CushingQoL questionnaire scores in control and in intervention groups at baseline and at the end of the study. No differences in the CushingQoL score were evidenced at baseline between the groups. The intervention group had a better CushingQoL score than control group, at the end of the study (p \ 0.01). No changes in the CushingQoL score were evidenced in the intervention group throughout the study period. The control group decreased CushingQoL score throughout the study period (p \ 0.01) Fig. 2 Pain intensity in the control group and in the intervention group at baseline and at the end of the study, evaluated with the SPQ (Spanish Pain Questionnaire). No differences in the SPQ score were evidenced at baseline between the groups. Pain intensity was less in the intervention group than in the control group at the end of the study (p \ 0.05). The final pain intensity fell in the intervention group throughout the study period (p \ 0.01). No differences in pain intensity were evidenced in the control group throughout the study period Endocrine 123 Journal : Large 12020 Dispatch : 11-9-2015 Pages : 11 h DISK CS patients complained that the complex and specific 379 characteristics of their disease and the absence of specific 380 health education made it difficult for them to cope and to 381 carry out their everyday activities. In fact, only 4.9 % of 382 our patients reported any health education over the years, 383 without a clear specificity on CS comorbidities. Thus, the 384 intervention group had a strong motivation which favored 385 following all the education sessions and to improve their 386 healthstyle. 387 This nursing educational intervention prevented deteri-388 oration of HRQoL in the intervention group, improving 389 indicators of social life, confidence, relaxation, and pain 390 measured by the CushingQoL questionnaire. This ques-391 tionnaire indicated improvements in different health indi-392 cators, such as rest and physical activity, suggesting that an 393 appropriate educational intervention in each of them has an 394 additive effect on the final end point, in this case HRQoL. 395 This improvement was particularly evident in older, less 396 educated, unemployed patients, or housewives; interest-397 ingly, the educational sessions were particularly useful in 398 this group of patients, referred to as the most vulnerable in 399 the literature, and therefore less likely to acquire healthy 400 habits [14,15,17,18,46]. 401 Educational programs are used in a range of chronic 402 illnesses to enable patients to gain personal control and 403 self-efficacy. Studies indicate that educated patients man-404 age their symptoms more effectively, leading to a better 405 HRQoL, with an enhanced sense of wellbeing and a 406 reduction in healthcare costs [47]. In other words, patient 407 education plays an essential role in promoting safe self-408 management practice. When developing and applying a 409 competency-based patient education program, patients 410 learn how to manage the disease and its consequent 411 comorbidities; this leads to a better psychological status 412 that also improves their physical status [16,48]. The 413 worsening in HRQol in the control group is an intriguing 414 point, and we do not have a clear explanation. It may be 415 related to the lack of a specific education. The educational 416 intervention focused on multiple dimensions that all toge-417 ther helped to improve HRQol; by contrast, routine medical 418 approach could only deal with the medical dimension.

419
The results obtained in terms of HRQoL suggest new 420 research fields, such as the relationship between the edu-421 cational programs and the different bio-psycho-social 422 characteristics of patients; they also suggest the need to use 423 different health resources as nursing programs. 424 The reduction in perceived pain intensity in the inter-425 vention group after the educational sessions of our study 426 may be related to different causes, approached during the 427 sessions; these include a greater adherence to analgesic 428 treatment, learning healthy posture patterns and increased 429 daily physical activity. In addition, this reduction of pain 430 generated a positive impact on other areas of health and 431 HRQoL, such as rest, fatigue, and physical activity, as 432 confirmed by the patients and as evidenced in similar studies 433 in the literature [49,50]. It is known that specific exercise 434 protocols and walking programs have a positive effect on the 435 HRQoL of elderly individuals with osteoarthritis [51,52].
436 Insomnia is another problem in CS patients, creating a 437 state of fatigue and anxiety that limits their HRQoL. The 438 significant improvement in self-reported quantity (number 439 of hours) and quality of rest (satisfaction) throughout the 440 study in the intervention group clearly improved HRQoL.
441 Apart from the intervention on sleep habits, the reduction 442 of pain and the increased physical activity may also have 443 positively influenced the sleep quality and quantity. Our 444 study found a significant increase in the percentage of 445 patients with a high physical activity level in the inter-446 vention group; due to the motivation, they had during the 447 educational sessions. Data are emerging regarding the 448 positive effect of physical activity level on rest in chronic 449 diseases; moreover, the relationship between sleep quality 450 and physical activity is bidirectional [53,54].
451 Regarding nutritional habits, the intervention group 452 learned specific diet recommendations and correct eating 453 habits during the sessions, which included a workshop on 454 preparation of balanced diets. Moreover, the active par-455 ticipation of the family in the group sessions favored 456 patient's engagement in changing eating behaviors. The 457 intervention group significantly improved compliance to 458 healthy lifestyle food habits at the end of the study; by 459 contrast, the control group worsened during the study 460 period. This is in line with literature data on educational 461 processes in chronic diseases leading to changes in eating 462 habits [55][56][57].
463 Regarding sexuality, even if there was not improvement 464 after the educational program it is important to mention 465 that a significant percentage of patients (both men and 466 women) reported alterations, mainly erectile dysfunction 467 and low sexual desire. As far as we know, this is the first 468 study to address this issue with validated instruments. Limitations of our study included a limited time of the 491 educational sessions; a longer educational program might 492 have helped the patients in reducing their cardiometabolic 493 comorbidities (reducing BMI and weight) and to improve 494 further their HRQoL. Indeed the important role of the 495 nursing management in education is well known, in par-496 ticular that a structural evaluation of cardiovascular risk 497 factors and an integrated nurse-led approach can success-498 fully reduce risk in cardiovascular patients [58]. 499 The number of daily smoked cigarettes only tended to 500 be lower in the intervention group; possibly a longer time 501 of educational sessions might have helped to stop smoking. 502 All active patients were on medical therapy, and 503 eucortisolemia was confirmed in all patients. In ''naïve'' 504 patients, the educational sessions would probably have 505 been more effective. However, on one hand, it is not ethic 506 to maintain naïve of treatment a CS patient for 9 months, 507 and on the other hand, controlling this condition during the 508 study would influence the results of the program. 509 Regression analysis could have been done; however, we 510 preferred to do t tests because regression analysis would 511 evaluate the change along the time and not the values at 512 baseline or at the end of the study. 513 Finally, the number of patients studied is relatively 514 small despite including patients from two 2 reference 515 centers, a problem which is practically unavoidable in rare 516 diseases, especially if followed up long-term over the 517 years.
518 Conclusions 519 A specific nursing educational program, addressed to CS 520 patients, obtained a positive modification of different living 521 habits, achieving an improvement of physical activity, 522 healthy lifestyle habits, sleep patterns, and reduction in 523 pain level. Even if the program only included 4 educational 524 sessions, it considerably influenced patient's HRQoL. In 525 particular, patients with worse HRQol at baseline showed a 526 greater improvement at the end of the study. Moreover, the 527 educational sessions allowed not only clinical improve-528 ment, but also a reduction of hospital admissions and 529 unscheduled visits. Finally, the brief nature of the program 530 makes it as a good candidate to be used in clinical man-531 agement of patients with CS.