NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Pharmacological management of physiological stress
Evidence review J
NICE Guideline, No. 243
1. Pharmacological management at times of physiological stress
1.1. Review question
What is the clinical and cost effectiveness of pharmacological treatments for managing periods of physiological stress in people with adrenal insufficiency including:
- a)
planned and emergency invasive procedures
- b)
pregnancy and intrapartum care
- c)
intercurrent illness and periods of physiological stress including minor (for example, colds) and major illnesses (for example, severe infection, cardiac events)?
1.1.1. Introduction
In times of physiological stress, the body produces additional cortisol. Under such circumstances, cortisol improves the efficiency of the heart, maintains blood pressure, ensures an adequate supply of glucose for cells to use for energy, and helps reduce inflammation.
Individuals with adrenal insufficiency are unable to produce high amounts of cortisol to meet the requirements for normal functioning during physiological stress. A failure to increase glucocorticoid replacement in times of physiological stress may place individuals at risk of adrenal crisis or even death. The amount of additional glucocorticoid required is different depending on the type of stressor, whilst severe illnesses such as sepsis, patients being in the intensive care unit or undergoing surgery require parental hydrocortisone. Although it is known that additional glucocorticoid dosing is recommended during periods of increased physiological stress, there is significant variation in clinical practice.
This review considers the clinical- and cost-effectiveness of pharmacological treatments for people with adrenal insufficiency at times of physiological stress.
1.1.2. Summary of the protocol
For full details see the review protocol in Appendix A.
Table 1
PICO characteristics of review question.
1.1.3. Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A. A summary of the criteria for assessing guidelines using the AGREE II tool is included in Appendix K and a more detailed description of its application is included in the methods document.
Declarations of interest were recorded according to NICE’s conflicts of interest policy.
1.1.4. Effectiveness evidence
1.1.4.1. Included studies
A search was conducted for randomised studies comparing the administration of additional doses or corticosteroids to no additional doses or placebo at times of physiological stress in patients with adrenal insufficiency. One RCT was included in the review (Glowniak 19975) and is summarised in Table 2 below. Evidence from this study is summarised in the clinical evidence summary below (Table 4).
Glowniak included 17 male patients who were on long-term corticosteroid therapy and who had secondary adrenal insufficiency as determined by results of cosyntropin testing. They were all undergoing major surgical procedures and were randomised to receive stress doses of corticosteroids or placebo.
The committee wished to look for additional evidence through searches for non-randomised studies. However, these did not identify any additional non-randomised studies for inclusion. The committee agreed that the management of physiological stress is one of their priority areas for this guideline and therefore, in the absence of any research evidence, wished to review existing guidance documents to inform their recommendations. For that reason, a further systematic review of the literature was carried out to identify adrenal insufficiency guidelines that include recommendations on pharmacological management at times of physiological stress.
Eight guidelines were identified and included in the review.
- One was for children only with any type of AI (Mushtaq 20237)
- One was for adults and children with primary AI due to 21-hydroxylase deficiency (Speiser 201810).
See the study selection flow chart in Appendix C, study evidence tables in Appendix D, forest plots in Appendix E and GRADE tables in Appendix F.
1.1.4.2. Excluded studies
See the excluded studies list in Appendix J.
1.1.5. Summary of studies included in the effectiveness evidence
Table 2
Summary of studies included in the evidence review.
Table 3
Summary of guidelines included in the review.
See Appendix D for full evidence tables.
1.1.6. Summary of the effectiveness evidence
Table 4
Clinical evidence summary: glucocorticoids versus placebo. See Appendix F for full GRADE tables.
1.1.7. Economic evidence
1.1.7.1. Included studies
No health economic studies were included.
1.1.7.2. Excluded studies
No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.
See also the health economic study selection flow chart in Appendix G.
1.1.8. Economic model
This area was not prioritised for new cost-effectiveness analysis.
1.2. The committee’s discussion and interpretation of the evidence
1.2.1. The outcomes that matter most
The committee considered all outcomes listed in the protocol to be critical and of equal importance in decision-making. These outcomes included mortality, Health-related Quality of Life, incidence of adrenal crisis, acute and long-term cumulative adverse events of drugs, admission to hospital or ITU and psychological morbidities such as incidence of stress or PTSD.
The only evidence found was on blood pressure during surgical procedures and up to 3 days after. These were reported separately as lowest systolic and lowest diastolic blood pressure and change in systolic and diastolic blood pressure. The study was in a small group of male patients with secondary adrenal insufficiency and therefore the committee did not think this was enough evidence to support recommendations. Further literature searches for non-randomised studies did not retrieve any additional evidence.
The committee considered pharmacological management of physiological stress a priority area where recommendations would be highly valuable to healthcare professionals. They were aware of the existence of several national and international guidelines and wished to consider them in this review to assess their quality and consolidate the recommendations across them. Therefore, an additional systematic review of the literature was conducted to identify published guidelines that include recommendations on the pharmacological management of adrenal insufficiency at times of physiological stress.
1.2.2. The quality of the evidence
The clinical evidence for all outcomes in the included RCT was graded very low. This was largely due to the very serious risk of bias arising from the randomisation process and very serious imprecision. The study was in a small group of people and there was very low certainty in the evidence it provided. Therefore, the committee did not consider these results in their decision making.
A further systematic review of the literature was conducted to identify adrenal insufficiency guidelines that include recommendations on pharmacological management at times of physiological stress. Eight guidelines were identified and included in this review. Five guidelines covered all types of AI (primary, secondary and tertiary). Two of those were specifically for adults although one included some recommendations for children, one was for children only and two were for adults and children. Two guidelines covered primary AI in both children and adults one of them was specific to primary AI due to 21-hydroxylase deficiency.
The included guidelines were assessed by 2 reviewers using the AGREE II tool. This instrument is intended for assessing the quality of systematically developed clinical practice guidelines, including assessments of methodological rigour, transparency, and applicability. Where information was lacking, authors were contacted to provide further clarification.
The included guidance documents scored between 39% and 100% for scope and purpose. The overall aim, specific health questions and population covered by the guidelines were generally well described but details such as the potential health impact of the guidelines were sometimes lacking or limited.
The guidance documents scored between 0% and 100% for stakeholder involvement. Generally, they were not assessed as having been developed by a broadly representative group of relevant professionals and did not report that the views of intended users (practitioners, patients and their families) were represented. Correspondence with authors revealed that some guidelines had sought the views of patient organisations. Only one of the guidelines (BSPED) clearly stated that there was stakeholder involvement which included various professional and patient organisations.
Scores for rigour of development were low, ranging from 0% to 40%. Details on whether a systematic process had been used to search for and synthesise evidence, were not clearly described. The committee acknowledged that this is to be expected as research on adrenal crisis is difficult to conduct and very limited. Therefore, guideline authors may not see the need for conducting systematic searches of the evidence and may directly resort to expert opinion. However, this should not preclude authors from explaining the methods used to formulate the recommendations and how final decisions were arrived at (e.g., informal consensus or formal consensus techniques such as Delphi).
The included guidance documents scored between 56% and 100% for clarity of presentation. Recommendations were well presented, and key recommendations were clearly identifiable. However, some guidelines were lacking in clarity regarding different management options and therefore scored lower in this domain.
Scores for applicability were very low and ranged between 0% and 25%. There was a lack of advice on how the recommendations could be put into practice, and potential resource implications and no monitoring or auditing criteria were suggested. It was also unclear whether the likely barriers and facilitators to implementation and strategies to improve uptake of the guidance were considered.
The included guidance documents scored between 0% and 100% for editorial independence. Declaration of any bias or competing interests from guidance development group members and statement on whether the views of the funding bodies had influenced the content of the guidelines were not always clearly reported. One guideline did not include any declarations and others did so with varying degrees leading to a lack of transparency in editorial independence.
Once the assessment of the 6 domains (23 items) is completed, the AGREE II tool suggests two overall assessments. One is a rating of the overall quality of the guideline and the other asks whether the guideline would be recommended for use in practice. However, the review of external guidelines was not intended to recommend a particular guideline but to obtain an overview of the recommendations in national and international guidelines to inform the committee’s recommendations or to cross-refer to specific recommendations if they would add efficiencies to the guideline development process and add value to NICE guidance. The committee also acknowledged that whilst rigour of development would normally be considered a high priority in evaluating guidelines, they were aware of the difficulty in producing evidence-based guidelines for AI due to the limited research in this area. Their experience from conducting this systematic review had also proved that. They acknowledged that, knowing that there is limited evidence, most guideline authors do not conduct any literature searches and make recommendations solely on consensus. This inevitably leads to all the guidelines scoring low for rigour of development as they lack any details for assessing the rigour of their systematic reviewing process. Therefore, the committee agreed that prioritising specific domains that would help their decision-making would be more informative than assessing the guidelines based on an overall score. The committee agreed, that in the absence of evidence, a high-quality guideline should include a wide range of experience and expert opinion that represents the views of the intended users including patient representatives. The guideline should include a clear description of the methods by which opinions were sought and incorporated and final recommendations were reached (e.g. informal consensus, Delphi).
In addition, for the committee to consider cross referring to external guideline recommendations, they should be applicable to a UK setting. Therefore, the committee agreed that stakeholder involvement, particularly patient representation, and suitability to UK settings should be given strong consideration when assessing the quality of the guidelines as they will be more informative than an overall score.
Adults
Although the majority of the guidelines scored low for stakeholder involvement, the committee agreed that the recommendations were applicable to UK settings and were generally in agreement on how to manage pharmacological treatment at times of physiological stress. They were also in line with the committee’s expertise and current practice. Therefore, the committee wished to make their own consensus recommendations, informed by these guidelines. The committee found that the Woodcock guideline11 which included recommendations from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK included the most comprehensive and clear recommendations on pharmacological management in the perioperative period. The guideline had scored 67% for stakeholder involvement and was directly applicable to UK settings. The committee wished to cross refer to some of the recommendations in the guideline if it was deemed to be of high enough quality. Therefore, the guideline recommendations were further assessed using the NICE second stage assessment process for evaluating the applicability and acceptability of recommendations from external guideline developers. This includes additional considerations such as inequality and cost impact considerations (see Appendix L for full details).
In the NICE second stage assessment, the committee further scrutinised the Woodcock recommendations and confirmed that they are up to date, in line with current practice and unlikely to change in the near future as no new significant research was being conducted in this area. Although the guideline was found to lack patient views, the committee did not have any concerns about its compatibility with cultures and no health inequality issues were identified. The guideline did not include any health economic evidence or economic modelling. In addition, no economic evaluations were identified in the health economic literature review for the NICE guideline nor was it feasible to undertake any economic modelling. Therefore, unit costs were presented to the committee to aid consideration of cost-effectiveness.
The Woodcock recommendations were found to be of high quality using the AGREE II tool, as well as acceptable and applicable to the NHS setting using the NICE second stage assessment of recommendations. Therefore, the committee were confident in cross-referring to Woodcock guidelines for recommendations on glucocorticoid supplementation in the pre- intra- and postoperative period.
Children under 16yrs
The BSPED guideline7 scored 100% for stakeholder involvement as it was developed by a multidisciplinary group including paediatric endocrinologists, a paediatric endocrinology trainee, paediatric endocrinology clinical nurse specialists and a paediatric pharmacist. The BSPED guideline committee had also sought feedback and input from a variety of stakeholders including clinical specialist society members and patient groups. In addition, the guideline was developed in the UK and was directly applicable to NHS settings. The committee agreed that although other guidelines did include some recommendations for children, the BSPED guideline, in addition to scoring highly in the priority domains, was also more comprehensive, clearly laid out and easy to follow. The committee decided that rather than duplicate the efforts, a cross referral to the BSPED recommendations would be the best option. Therefore, in order to increase their confidence in the BSPED recommendations a second stage assessment of the guideline recommendations was conducted using the NICE process for assessing applicability and acceptability (see Appendix M for full details).
In the NICE second stage assessment, the paediatric specialists committee members reviewed the BSPED recommendations and agreed that they are up to date and in line with current clinical practice. The committee did not anticipate any constraints or barriers to implementation as the recommendations were in line with current clinical practice. In addition, no health inequality issues were identified. They did not have any concerns about compatibilities with cultures and values and no health inequality issues were identified. They noted that no health economic evidence or economic modelling was considered but were aware from the literature review that no economic evaluations were identified. Therefore, unit costs were presented to the committee to aid consideration of cost-effectiveness.
Overall, the BSPED guideline was considered to be of high quality using the AGREE II tool, as well as acceptable and applicable to the NHS setting using the NICE second stage assessment of recommendations. Therefore, the committee were confident in cross-referring to the BSPED website recommendations for pharmacological management at times of physiological stress in children and young people (sections 2-5).
The committee recognised that there is limited data directly comparing outcomes between different glucocorticoid supplementation strategies at times of physiological stress. They wanted to highlight the importance in the post-operative period for in-patients undergoing invasive procedures. Further research comparing these different strategies may provide evidence of benefit of one strategy over the other in terms of the clinical and cost effectiveness. This would help clinicians develop the most effective and pragmatic approach to adrenal replacement during major stress. Therefore, the committee made a research recommendation in this regard (see Appendix N).
1.2.3. Benefits and harms
Adults
All of the reviewed guidelines included recommendations on the importance of patient education on sick-day rules and the provision of additional supplies of glucocorticoids to cover periods of physiological stress. This was in line with committee recommendations that had already been discussed as part of the information and support review. Therefore, the committee made a cross-reference to those recommendations (see review A information and support and recommendations in section 1.1 of the guideline).. The committee highlighted that some people find it difficult to obtain additional supplies of corticosteroids and it is important that health professionals are aware of the importance of this to prevent adrenal crisis. They also highlighted that additional supplies of hydrocortisone should be provided in an immediate release formulation even to people who are on the modified release formulation to ensure faster replacement of cortisol levels.
The committee discussed that there is variation in practice regarding doubling a dose of hydrocortisone versus increasing the frequency of dosing. They recommended an increase to at least 40 mg a day because on balance this is easier for people to manage. The committee agreed a dose of oral hydrocortisone 2-4 times a day is the preferred option because it’s a shorter-acting glucocorticoid. However, the committee noted that significant intercurrent illness such as fever > 39°C, diarrhoea and vomiting, 4 times a day would be preferential. Four times a day is preferable because diarrhoea and vomiting means that hydrocortisone will not be absorbed adequately leading to a significant risk of adrenal crisis.
The committee discussed that for emergency management, hydrocortisone should be given as this is a lifesaving replacement therapy with no toxic dose. Therefore, the benefits of taking it far outweighed the risk of not taking it and having a potentially fatal adrenal crisis. However, , the committee wanted to highlight that increasing dosing too frequently or for prolonged periods of time can lead to symptoms of glucocorticoid excess such as Cushing’s syndrome. They were unable to define the duration of the increase in dosing as this varied according to the type of physiological stress and factors related to the individual.
For people who are already taking 10 mg of oral prednisolone, the committee did not recommend increasing the dose but considered splitting it into 2 equal doses across the day. This is to ensure there is some glucocorticoid cover over 24 hours because there can be a loss of diurnal variation in cortisol overnight in intercurrent illness.
The committee discussed that if absorption of oral glucocorticoids is difficult due to vomiting and/or diarrhoea then an injection of intramuscular or intravenous hydrocortisone could be given and medical help should be sought. Admission to hospital may be required and treatment should be provided in accordance with recommendations on emergency management (see section 1.7 of the guideline).
For adults having planned or emergency or invasive medical procedures, the committee endorsed the recommendations from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. The committee decided to cross refer to this as the two-stage quality assessment using AGREE II and the NICE checklist had increased their confidence in the recommendations and they agreed that they reflected current practice. The recommendations are summarised in tables 1 and 2 of the guideline (Woodcock et al).
Children under 16yrs
The committee reviewed the recommendations from the BSPED guideline8 and found them to be in line with their clinical expertise. They agreed that as the BSPED guideline was methodologically robust and had achieved high scores using the AGREE tool and the NICE second stage assessment checklist, a cross-reference should be made to the BSPED website recommendations for pharmacological management of physiological stress (sections 2-5).
Pregnancy care
There was limited evidence for women or people with adrenal insufficiency who are pregnant or planning pregnancy. Where guidelines made recommendations on pregnancy, an increase in glucocorticoid dosing was recommended particularly during the third trimester and labour. Therefore, the committee made consensus recommendations based on their experience, current best practice and the expert advice of a co-opted Consultant Obstetrician, Gynaecologist & Maternal Medicine Specialist.
Normal pregnancy is associated with increases in cortisol binding globulin (oestrogen induced), total plasma cortisol, free cortisol and aldosterone which combat the anti-glucocorticoid and anti-mineralocorticoid effect of progesterone, and therefore continuation of replacement doses of glucocorticoid and mineralocorticoid are essential in pregnancy to prevent adrenal crisis. Despite these increases in cortisol and aldosterone which are more apparent by the third trimester, few women with adrenal insufficiency routinely require increases in their replacement steroid doses. Clinical signs including symptoms of adrenal insufficiency, postural hypotension and hyponatraemia justify increases in replacement doses. Indiscriminate increases in glucocorticoids can result in unnecessary steroid excess which can cause maternal complications. Minimal hydrocortisone or prednisolone crosses the placenta to the foetus as they are inactivated by placental 11β-hydroxysteroid dehydrogenase. The committee noted it was important to advise women on the safety of hydrocortisone during pregnancy.
Sick-day rules apply in pregnancy as they do outside pregnancy. Many women will experience nausea and vomiting during pregnancy and may not be able to keep their medications down. Advice on taking glucocorticoids during periods of pregnancy related vomiting should be provided.. Some women experience hyperemesis gravidarum (HG) where nausea and vomiting are associated with pre-pregnancy weight loss, dehydration and electrolyte imbalance requiring intravenous fluid replacement and anti-emetics. Many units manage HG in an ambulatory setting. This is not appropriate for those with adrenal insufficiency who will usually require parenteral replacement of increased doses of replacement steroids, intravenous fluid replacement and closer monitoring of blood pressure and serum electrolytes, more suited to an inpatient setting.
For guidance during the birth, the committee reviewed the recommendations on steroid replacement regimens within the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies and agreed to cross-refer to this.
Glucocorticoid requirements decline following delivery and if replacement doses have been increased in pregnancy, they should be decreased to pre-pregnancy levels providing no complications which may require continuation of increased dosing.
Due to the limited research evidence in this area, the committee agreed to make a research recommendation (see Appendix N.1).
1.2.4. Cost effectiveness and resource use
No economic evaluations were identified for this review therefore unit costs were presented to aid the committee’s consideration of cost-effectiveness, these were the daily and monthly costs of hydrocortisone, prednisolone, and dexamethasone.
The committee made recommendations reflective of best clinical practice. They noted that best clinical practice is not current practice for all and fatalities as a result of people experiencing adrenal crisis in periods of physiological stress have occurred due to the lack of sick-day dosing. The committee noted that in instances where best clinical practice is not being employed – providing people with additional medication to cover periods of physiological stress is highly likely to be a cost-effective strategy. People with adrenal insufficiency experiencing physiological stress are at increased risk of adrenal crisis, which is not only life-threatening but also incurs high costs to the NHS as these people will most likely require a hospital admission. This hospital admission will include the cost of an inpatient stay in addition to intravenous hydrocortisone and fluids. These recommendations are not expected to have a significant resource impact.
No specific recommendation was made on the sick-day dosing regimen for those on dexamethasone as they considered that very few people are on this drug and therefore the dosing should decided upon on a case by case. It was noted that people who normally take modified release hydrocortisone, they should receive a prescription of immediate release hydrocortisone for the purposes of sick-day dosing. The sick-day dosing recommendations included recommendations to admit a person to hospital during periods of physiological stress if they are unable to absorb oral glucocorticoids, for example, during prolonged diarrhoea and vomiting; and give 100 mg intramuscular or intravenous hydrocortisone. There is a cost associated with an admission to hospital, however the committee highlighted that this was necessary to avert the risk of adrenal crisis, which is not only life-threatening but also incurs high costs to the NHS as these people will most likely require a hospital admission.
For those already in hospital for another reason and are severely unwell (for example with sepsis or in intensive care) they also would require intravenous or intramuscular hydrocortisone. The committee noted that health care professionals should consider seeking endocrinology specialist advice for these people as they may require further guidance on sick-day dosing.
Recommendations were made relating specifically to pregnancy care. These were based on committee expert opinion and overall reflect current practice and therefore are not expected to result in a significant resource impact. The exception to this is the recommendation to manage hyperemesis gravidarum in an inpatient setting rather than an outpatient setting. This is not current practice and the committee noted that deaths have been reported following outpatient management of hyperemesis gravidarum in people with adrenal insufficiency. The committee highlighted the importance of inpatient care and noted that although this is more costly than outpatient care, the population for whom this recommendation would apply is small and therefore this should not result in a significant resource impact. It was also noted that once vomiting is controlled, hyperemesis gravidarum can be managed in an outpatient setting with anti-emetics.
1.2.5. Recommendations supported by this evidence review
This evidence review supports recommendations 1.4.1 – 1.4.9 and 1.4.12 – 1.4.21 and the recommendation for research on the clinical and cost-effectiveness of glucocorticoid treatment in the post-operative period for people with known or at risk of adrenal insufficiency undergoing in-patient invasive procedures.
References
- 1.
- Araujo Castro M, Curras Freixes M, de Miguel Novoa P, Gracia Gimeno P, Alvarez Escola C, Hanzu FA. SEEN guidelines for the management and prevention of acute adrenal insufficiency. Endocrinologia, diabetes y nutricion. 2020; 67(1):53–60 [PubMed: 31003863]
- 2.
- Arlt W. Society for Endocrinology endocrine emergency guidance: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocrine connections. 2016; 5(5):G1–G3 [PMC free article: PMC5314805] [PubMed: 27935813]
- 3.
- BMJ Group and the Royal Pharmaceutical Society of Great Britain. British National Formulary. 2023. Available from: https://bnf
.nice.org.uk/ Last accessed: 05/11/2023. - 4.
- Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism. 2016; 101(2):364–389 [PMC free article: PMC4880116] [PubMed: 26760044]
- 5.
- Glowniak JV, Loriaux DL. A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency. Surgery. 1997; 121(2):123–129 [PubMed: 9037222]
- 6.
- Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. Journal of Internal Medicine. 2014; 275(2):104–115 [PubMed: 24330030]
- 7.
- Mushtaq T, Ali SR, Boulos N, Boyle R, Cheetham T, Davies JH et al. Emergency and perioperative management of adrenal insufficiency in children and young people: British Society for Paediatric Endocrinology and Diabetes consensus guidance. Archives of Disease in Childhood. 2023; 108(11):871–878 [PMC free article: PMC10646833] [PubMed: 37045585]
- 8.
- National Institute for Health and Care Excellence. Developing NICE guidelines: the manual. London. National Institute for Health and Care Excellence, 2014. Available from: https://www
.nice.org .uk/process/pmg20/chapter/introduction [PubMed: 26677490] - 9.
- Simpson H, Tomlinson J, Wass J, Dean J, Arlt W. Guidance for the prevention and emergency management of adult patients with adrenal insufficiency. Clinical Medicine (London, England). 2020; 20(4):371–378 [PMC free article: PMC7385786] [PubMed: 32675141]
- 10.
- Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2018; 103(11):4043–4088 [PMC free article: PMC6456929] [PubMed: 30272171]
- 11.
- Woodcock T, Barker P, Daniel S, Fletcher S, Wass JAH, Tomlinson JW et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency: Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia. 2020; 75(5):654–663 [PubMed: 32017012]
Appendices
Appendix A. Review protocols
A.1. Review protocol for pharmacological management at times of physiological stress (PDF, 220K)
A.2. Health economic review protocol (PDF, 136K)
Appendix B. Literature search strategies
The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.8
For more information, please see the Methodology review published as part of the accompanying documents for this guideline.
B.1. Clinical search literature search strategy (PDF, 196K)
B.2. Health Economics literature search strategy (PDF, 171K)
Appendix C. Effectiveness evidence study selection
Appendix D. Effectiveness evidence
Download PDF (159K)
Appendix E. Forest plots
E.1. Hydrocortisone vs placebo (PDF, 159K)
Appendix F. GRADE tables
Download PDF (213K)
Appendix G. Economic evidence study selection
Download PDF (201K)
Appendix H. Economic evidence tables
None
Appendix I. Health economic model
No original health economic modelling was undertaken for this review question.
Appendix J. Excluded studies
J.1. Clinical studies
Table 10Studies excluded from the clinical review
| Study | Reasons for exclusion |
|---|---|
| Arafah, Baha M (2020) Perioperative Glucocorticoid Therapy for Patients with Adrenal Insufficiency: Dosing Based on Pharmacokinetic Data. The Journal of clinical endocrinology and metabolism 105(3) [PubMed: 31996925] |
- Study does not contain outcomes of interest Pharmacokinetic outcomes e.g., cortisol half life |
| Aso, K., Izawa, M., Higuchi, A. et al. (2009) Stress doses of glucocorticoids cannot prevent progression of all adrenal crises. Clinical Pediatric Endocrinology 18(1): 23–27 [PMC free article: PMC4004880] [PubMed: 24790376] |
- Study does not include a multivariate analysis Retrospective analysis of 24 cases of adrenal crises in 9 patients with no multivariate analyses. |
| Bannon, C. A., Gallacher, D., Hanson, P. et al. (2020) Systematic review and meta-analysis of the metabolic effects of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency. Clinical Endocrinology 93(6): 637–651 [PubMed: 32621327] | - Systematic review used as source of primary studies |
| Blavin, L. R. and French, L. (1997) Perioperative steroids for secondary adrenal insufficiency. Journal of Family Practice 44(6): 532–3 [PubMed: 9191621] |
- Commentary article Summary and comment on Glowniak |
| Britt, R.C., Devine, A., Swallen, K.C. et al. (2006) Corticosteroid use in the intensive care unit: At what cost?. Archives of Surgery 141(2): 145–149 [PubMed: 16490890] | - Population not relevant to this review protocol |
| Bromberg, J S, Baliga, P, Cofer, J B et al. (1995) Stress steroids are not required for patients receiving a renal allograft and undergoing operation. Journal of the American College of Surgeons 180(5): 532–6 [PubMed: 7749527] |
- Commentary article Summary and commentary on Glowniak 1997 |
| Burger-Stritt, Stephanie, Kardonski, Pavel, Pulzer, Alina et al. (2018) Management of adrenal emergencies in educated patients with adrenal insufficiency-A prospective study. Clinical endocrinology 89(1): 22–29 [PubMed: 29617051] | - Study design not relevant to this review protocol |
| Chacko, Shireen R, Abraham, Ananth P, Asha, Hesarghatta Shyamasunder et al. (2020) Selective perioperative steroid supplementation protocol in patients undergoing endoscopic transsphenoidal surgery for pituitary adenomas. Acta neurochirurgica 162(10): 2381–2388 [PubMed: 32772164] | - Study design not relevant to this review protocol |
| Chihaoui, M., Mimita, W., Oueslati, I. et al. (2020) Prednisolone or hydrocortisone replacement in patients with corticotrope deficiency fasting during Ramadan result in similar risks of complications and quality of life: a randomized double-blind controlled trial. Endocrine 67(1): 155–160 [PubMed: 31552584] |
- Study does not contain an intervention relevant to this review protocol Study compares prednisolone to hydrocortisone during fasting. No stress dosing. |
| El-Maouche, Diala, Hargreaves, Courtney J, Sinaii, Ninet et al. (2018) Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients with Congenital Adrenal Hyperplasia. The Journal of clinical endocrinology and metabolism 103(6): 2336–2345 [PMC free article: PMC6276663] [PubMed: 29584889] |
- Study does not contain an intervention relevant to this review protocol Intervention is stress dosing education. |
| El-Sibai, Katia, Rajpal, Aman, Al-Aridi, Ribal et al. (2017) The impact of peri-operative dexamethasone administration on the normal hypothalamic pituitary adrenal response to major surgical procedures. Endocrine 58(1): 134–142 [PubMed: 28865040] |
- Population not relevant to this review protocol Participants with normal HPA function |
| Fleming, Louise Kathleen; Rapp, Carla Gene; Sloane, Rick (2011) Caregiver knowledge and self-confidence of stress dosing of hydrocortisone in children with congenital adrenal hyperplasia. Journal of pediatric nursing 26(6): e55–60 [PubMed: 22055384] |
- Study does not contain an intervention relevant to this review protocol - Population not relevant to this review protocol |
| Key, S J, Hodder, S C, Davies, R et al. (2003) Perioperative corticosteroid supplementation and dento-alveolar surgery. Dental update 30(6): 316–20 [PubMed: 12955953] | - Study design not relevant to this review protocol |
| Marik, P. E. and Varon, J. (2008) Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature. Archives of Surgery 143(12): 1222–6 [PubMed: 19075176] | - Systematic review used as source of primary studies |
| Miller, C. S.; Little, J. W.; Falace, D. A. (2001) Supplemental corticosteroids for dental patients with adrenal insufficiency: reconsideration of the problem. Journal of the American Dental Association 132(11): 1570–9quiz1596 [PubMed: 11806072] | - Systematic review used as source of primary studies |
| Miller, Netanella, Asali, Aula Atamna, Agassi-Zaitler, Moran et al. (2019) Physiological and psychological stress responses to labor and delivery as expressed by salivary cortisol: a prospective study. American journal of obstetrics and gynecology 221(4): 351e1–351e7 [PubMed: 31254523] | - Population not relevant to this review protocol |
| Mouri, Hideyuki, Jo, Taisuke, Matsui, Hiroki et al. (2020) Impact of glucocorticoid supplementation on reducing perioperative complications in patients on long-term glucocorticoid medication: A propensity score analysis using a nationwide inpatient database. American journal of surgery 220(3): 648–653 [PubMed: 32067706] |
- Population not relevant to this review protocol Patients on long term glucocorticoid supplementation but excludes patients who had adrenal insufficiency at admission. |
| Nilsson, A. G., Marelli, C., Fitts, D. et al. (2014) Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency. European Journal of Endocrinology 171(3): 369–77 [PMC free article: PMC4106399] [PubMed: 24944332] | - Study does not contain an intervention relevant to this review protocol |
| Owa, Takao, Mimura, Kazuya, Kakigano, Aiko et al. (2017) Pregnancy outcomes in women with different doses of corticosteroid supplementation during labor and delivery. The journal of obstetrics and gynaecology research 43(7): 1132–1138 [PubMed: 28422424] | - Population not relevant to this review protocol |
| Plener, Paul L, Zohsel, Katrin, Hohm, Erika et al. (2017) Lower cortisol level in response to a psychosocial stressor in young females with self-harm. Psychoneuroendocrinology 76: 84–87 [PubMed: 27889466] | - Population not relevant to this review protocol |
| Simunkova, K., Jovanovic, N., Rostrup, E. et al. (2016) Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure. European Journal of Endocrinology 174(1): 97–105 [PubMed: 26494876] |
- Study does not contain outcomes of interest Looks at effects of stress dosing on physical performance and outcomes are all exercise performance related. |
| Wang, Xiao, Heinrich, Daniel A, Kunz, Sonja L et al. (2021) Characteristics of preoperative steroid profiles and glucose metabolism in patients with primary aldosteronism developing adrenal insufficiency after adrenalectomy. Scientific reports 11(1): 11181 [PMC free article: PMC8160266] [PubMed: 34045650] | - Study does not contain an intervention relevant to this review protocol. |
| Weise, M., Drinkard, B., Mehlinger, S. L. et al. (2004) Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise. Journal of Clinical Endocrinology & Metabolism 89(8): 3679–84 [PubMed: 15292287] | - Data not reported in an extractable format or a format that can be analysed |
| Whittle, E. and Falhammar, H. (2019) Glucocorticoid Regimens in the Treatment of Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. Journal of the Endocrine Society 3(6): 1227–1245 [PMC free article: PMC6546346] [PubMed: 31187081] | - Systematic review used as source of primary studies |
| Yau, Mabel, Jacob, Marianne, Orton, Sarah et al. (2021) Perioperative stress dose steroid management of children with classical congenital adrenal hyperplasia: Too much or too little?. Journal of pediatric urology 17(5): 654e1–654e6 [PubMed: 34266748] | - Study does not contain outcomes of interest |
| Zaghiyan, Karen N, Murrell, Zuri, Melmed, Gil Y et al. (2012) High-dose perioperative corticosteroids in steroid-treated patients undergoing major colorectal surgery: necessary or overkill?. American journal of surgery 204(4): 481–6 [PubMed: 22748293] | - Population not relevant to this review protocol |
| Zaghiyan, Karen, Melmed, Gil, Murrell, Zuri et al. (2011) Are high-dose perioperative steroids necessary in patients undergoing colorectal surgery treated with steroid therapy within the past 12 months?. The American surgeon 77(10): 1295–9 [PubMed: 22127073] | - Population not relevant to this review protocol |
| Zaghiyan, Karen, Melmed, Gil, Murrell, Zuri et al. (2012) Safety and feasibility of using low-dose perioperative intravenous steroids in inflammatory bowel disease patients undergoing major colorectal surgery: A pilot study. Surgery 152(2): 158–63 [PubMed: 22503320] | - Population not relevant to this review protocol |
J.2. Health Economic studies
None.
Appendix K. AGREE II reviewer scoring
Download PDF (241K)
Appendix L. Woodcock et al: Discussion points for assessing recommendations pharmacological management at times of physiological stress
Download PDF (110K)
Appendix M. BSPED - Discussion points for assessing recommendations on pharmacological management at times of physiological stress
Download PDF (156K)
Appendix N. Recommendation for research
N.1. Research question (PDF, 179K)
Final
Evidence reviews underpinning recommendations 1.4.1 to 1.4.9 and 1.4.12 to 1.4.21 and recommendation for research 5 in the NICE guideline
This evidence review was developed by NICE
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
- Pharmacological management of physiological stressPharmacological management of physiological stress
Your browsing activity is empty.
Activity recording is turned off.
See more...