Inflammatory bowel disease includes Crohn’s disease as well as ulcerative colitis. Glucocorticosteroids are one of the classic treatments for inflammatory bowel disease, but long-term use of glucocorticosteroids is prone to a range of side effects and can lead to adrenal hypofunction. For patients with inflammatory bowel disease whose medical treatment is ineffective or who have intestinal perforation, intestinal obstruction, intestinal fistula and other complications and need to receive surgical treatment, how to reasonably apply glucocorticoids during the perioperative period to prevent the emergence of adrenal crisis and protect adrenal function is of great significance to ensure surgical safety and reduce surgical complications.
1.Preface
Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease of the intestine, including Ulcerative colitis (UC) and Crohn’s disease (CD), whose pathogenesis may be caused by infection, genetics, immunity The pathogenesis of these diseases may be caused by infection, genetics, immunity and other factors acting on susceptible populations, causing disruption of the intestinal immune response, resulting in inflammatory lesions and structural destruction of intestinal tissue. Traditional pharmacological treatment of inflammatory bowel disease includes aminosalicylic acid preparations, glucocorticoids and immunosuppressive agents, whose basic pharmacological action is to suppress or regulate excessive inflammatory responses, and is the basis for the treatment of IBD. Long-term application of glucocorticosteroids is likely to lead to adrenal hypofunction, which increases the risk of perioperative period and postoperative complications in IBD.
2.Application and mechanism of glucocorticoids in IBD
Corticosteroids belong to the steroid group, including a variety of hormones secreted by the adrenal cortex. According to their physiological functions, they can be divided into three categories: ① glucocorticoids; ② salt corticoids; ③ nitrogen corticoids. The corticosteroids commonly used in clinical practice refer to glucocorticoids. Trade names include hydrocortisone, corticosterone and synthetic prednisolone, prednisone and dexamethasone. They have anti-inflammatory, immunosuppressive, anti-toxic and anti-shock effects on metabolism, hematopoiesis, nervous system and tissue healing. Since Truelove applied prednisolone to treat UC with good results, glucocorticoids have been used to treat IBD for 40 years, and they are still important drugs for the treatment of IBD. They can prevent the conversion of arachidonic acid into free arachidonic acid in cellular phospholipids, reduce the production of inflammatory mediators such as leukotrienes and oxygen radicals, reduce the chemotactic activity of neutrophils, reduce the inflammatory response of IBD and improve toxic manifestations.
(1) Oral glucocorticoids can induce rapid remission of ulcerative colitis and are also effective in moderate to severe ulcerative colitis where aminosalicylic acid is ineffective. The standard treatment dose is prednisone 40-60 mg/d or 1 mg/kg/d, tapered from the 12th week for 14-16 weeks. For refractory ulcerative colitis where oral hormones are ineffective, intravenous methylprednisolone 40-60 mg/d or hydrocortisone 200-300 mg/d may be used instead, with preferential intravenous use recommended given the lesser side effects of methylprednisolone [4].
(ii) Glucocorticoids are the fastest acting and more efficacious drugs for the treatment and induction of CD remission. The commonly used dose of prednisone is 0.5-0.75 mg/kg/d, and up to 1 mg/kg/d in severe cases, with remission in about 2 months.
The new glucocorticoid Budesonide, a 16α-hydroxyprednisolone, has a large molecular weight, high local concentration in the intestine, and is rapidly metabolized by the liver after absorption.
3.The characteristics of IBD perioperative period
When patients with ulcerative colitis develop toxic megacolon, perforation, bleeding, intolerable extraintestinal symptoms such as gangrenous sepsis, erythema nodosum, hepatic impairment, arthritis, etc. and cancer; when patients with Crohn’s disease develop intestinal obstruction, stricture, intestinal fistula, etc. then surgery is required. The purpose of surgical treatment for ulcerative colitis is to remove the diseased intestinal canal to get rid of the disease at its root and prevent cancer. Commonly used procedures include total colectomy ileostomy, colectomy ileorectal anastomosis, colectomy rectal mucosal debridement ileostomy anal anastomosis, etc. In the case of Crohn’s disease, the nature and location of the lesion are taken into account in the form of stenosis segmental angioplasty, segmental resection anastomosis, temporary or permanent ileostomy or colostomy, etc.
Perioperative glucocorticoid application and protection of adrenal cortical function, to improve the tolerance of surgical stress in patients with long-term glucocorticoid use, is the primary issue for IBD patients to pass through the perioperative period safely. The normal human being secretes about 20 mg of hydrocortisone per day, which can reach more than 10 times of the basal amount under stressful conditions. For patients with inflammatory bowel disease, their adrenaline function is relatively insufficient due to long-term hormone therapy, and they cannot secrete the corresponding glucocorticoids under the stressful condition of surgery, which has the risk of inducing adrenal insufficiency.
4.Theoretical basis for the application of glucocorticoids in the perioperative period of IBD
META analysis at home and abroad shows that the prophylactic use of glucocorticoids in the perioperative period of IBD patients is important for reducing the degree of surgical stress, reducing the occurrence of postoperative respiratory complications, regulating patients’ cardiac and pulmonary functions, reducing postoperative complications and suppressing systemic inflammatory reactions, and improving patients’ general status. To a certain extent, glucocorticoids affect the metabolism of substances in the body, improve the level of serum albumin and transferrin, thus correcting the postoperative hypoproteinemia, and also alleviate the symptoms of nausea and vomiting that often occur after surgery. For patients with IBD who have low adrenal cortical function due to long-term glucocorticoid use, perioperative glucocorticoid use can also effectively protect adrenal function and prevent adrenal crisis.
Glucocorticoids are normally secreted in the body as adrenocorticotropic hormones. The gene action pathways in the nucleus can be categorized as trans-suppression and translational activation. The regulatory protein synthesis process of transforming growth factor-β is induced as well as activated. In addition, glucocorticoids can also interact with cell membranes and exert non-genetically mediated effects. Recent studies have used the ratio of glucocorticoid effector cell drug concentrations to serum drug concentrations to measure the net effect of glucocorticoid metabolism and immune effects in patients with IBD, and to reflect changes in systemic immune responses during hormone therapy.
(1) Although endogenous glucocorticoid secretion increases after surgical trauma, there is a relative deficit of glucocorticoids in the body compared to the rapid and massive secretion of adrenaline by sympathetic nerves in the early postoperative period;
(2) Protein catabolism is greater than anabolic metabolism after surgical trauma, and glucocorticoid receptor catabolism increases and synthesis decreases, as well as the down-regulation effect of endogenous glucocorticoids on their receptors, resulting in a decrease in glucocorticoid receptor levels after surgery;
Interleukins (IL) IL21, IL22, IL26 and tumor necrosis factor (TNF) can reduce the sensitivity of glucocorticoid receptors, while IL22 and IL24 can greatly reduce the affinity of glucocorticoid receptors, thus causing stress disorder of glucocorticoid receptor levels.
In patients with IBD who have been using glucocorticoids for a long time, the adrenal gland function is further damaged by surgical trauma in the presence of declining adrenal gland function.
In conclusion, the appropriate increase of glucocorticoids in the perioperative period of IBD to supplement the relative deficiency of glucocorticoids can, to a certain extent, increase the production of hormone receptor complexes, thus improving the effect of hormones on target cells. On the one hand, it can reduce the release of pro-inflammatory cytokines such as IL21, IL22, IL26, IL28 and TNF, and on the other hand, it can increase the level of anti-inflammatory cytokines such as IL24 and IL21, which can effectively reduce the damage of inflammatory mediators in the expanded stress response of the body, thus reducing the degree of tissue damage and postoperative complications. This is the theoretical basis for the perioperative application of glucocorticoids in IBD patients.
5.Application of glucocorticoids in the perioperative period of IBD
For patients with IBD using corticosteroids, we must judge how to supplement hormones in the perioperative period according to the size of the surgical invasion and the length of the operation before surgery.
For patients with IBD treated with glucocorticoids daily, if a moderate procedure such as a simple intestinal fistula repair is performed, prednisone 10 mg is administered preoperatively, hydrocortisone 50 mg is administered intraoperatively, and 20 mg is given intravenously every 8 hours on the first postoperative day, for a total of 60 mg of hydrocortisone.
Patients with IBD who are scheduled for total colectomy should receive 40 mg of prednisone 2 hours before surgery and 50 mg of hydrocortisone every 8 hours thereafter, and continue for 48-72 hours after surgery. The maintenance dose was started on the third or fourth postoperative day.
For patients with IBD who have stopped using corticosteroids for more than 6 months, no hormone therapy can be used before surgery, and intraoperative cortisol 200-300mg can be administered intravenously.
④If symptoms such as sudden onset of hyperthermia, nausea, vomiting, diarrhea, water loss, agitation or even coma occur during any period of the perioperative period due to rapid reduction of glucocorticoids, sudden discontinuation or stress, the patient should be treated immediately as adrenal crisis, and hydrocortisone 100-200mg should be administered intravenously for the first 1-2 hours, and the total amount should be 500-600mg or more for the first 5-6 hours. And change to intramuscular corticosteroid acetate injection 25-50mg every 6-12h, then change to oral prednisone transition to maintenance amount, generally need more than l-2 weeks, if after the above treatment has not been able to maintain blood pressure, can be used deoxycorticosterone, the treatment dose depends on the condition.
In conclusion, for patients with IBD requiring surgical treatment, a prophylactic glucocorticoid dosing regimen must be designed based on the preoperative medications and the size and duration of the surgery. The duration of the stress response should be estimated and the dose required for the stress should be administered without overdose. If the surgery is successful and there are no complications, the plasma cortisol concentration usually returns to normal 24 to 48 hours after surgery. When postoperative complications occur and the stress reaction persists, continuous glucocorticoid use should be considered according to the specific situation in order to effectively protect adrenal function and prevent the occurrence of adrenal crisis.
6. Conclusion
Glucocorticoids are one of the classic drugs for the medical treatment of patients with inflammatory bowel disease. The reasonable use of glucocorticoids in the perioperative period of IBD can regulate the insufficient secretion of endogenous glucocorticoids and the temporary hypofunction of glucocorticoid receptors, effectively protect adrenal function and prevent the occurrence of adrenal crisis, and reduce postoperative complications as well as reduce systemic inflammatory reactions. However, since there are so many negative effects of hormones, it is our effort to reduce the hormone dosage to the smallest and lowest dose while ensuring the treatment.