Clinical efficacy of dexamethasone on diabetic ketoacidosis complicated with acute pancreatitis: A randomized controlled study

Abstract

Background:

This study aimed to provide a clinical basis for the therapy of diabetic ketoacidosis (DKA) complicated with acute pancreatitis (AP) through exploring the clinical efficacy of dexamethasone.

Methods:

A total of 106 DKA patients complicated with AP admitted to Wuxi People’s Hospital Affiliated to Nanjing Medical University from January 2020 to December 2022 were selected and randomly divided into a study group (n = 53) and a placebo group (n = 53) according to the random number table method. The study group patients were given dexamethasone, while the placebo group patients were treated using placebos. Subsequently, changes of laboratory indexes and clinical symptoms before and after treatment were compared between the 2 groups, as well as adverse events after treatment.

Results:

There was no significant difference between the 2 groups in terms of general information (P > .05), indicating that the 2 groups patients were comparable. Before treatment, laboratory indexes and clinical symptoms between the 2 groups were not significantly different (P > .05). After treatment, compared with the placebo group, patients in the study group exhibited lower levels of indicators such as random venous blood glucose, serum sodium, serum chlorine, urea nitrogen, urine glucose, urine ketone, serum amylase, and triglyceride and higher levels of PH value and serum potassium, with a statistically significant difference (P < .05); also, the study group patients were improved significantly in clinical symptoms such as abdominal pain, nausea and vomiting, polydipsia and polyuria, diarrhea, disorders of consciousness and hypotension or shock (P < .05). Moreover, the possibility of adverse events in the study group after treatment was much lower than that in the control group (17.0% vs 58.5%) (P < .05).

Conclusion:

Dexamethasone has a good clinical effect on DKA patients complicated with AP.

1. Introduction

Diabetic ketoacidosis (DKA) is one of the common complications of diabetic patients,^[1] and usually, clinical symptoms of DKA are manifested as aggravation of thirst and polydipsia, vomiting, abdominal pain, and coma. Owing to characteristics like acute onset, rapid deterioration and high mortality, DKA is prone to inducing multiple organ dysfunction and resulting in death if patients do not receive timely treatment.^[2,3] Acute pancreatitis (AP) serves as one of the most prevalent complications for DKA patients, and the clinical symptoms are mainly manifested as vomiting, fever, and abdominal pain.^[4] Generally, DKA and pancreatitis can be induced and promoted by each other, and overlapping may exist in their clinical manifestations. It is reported that the incidence of DKA complicated by AP is approximately 11%.^[5] At present, insulin combined with nutritional support is the main therapy for DKA complicated with AP. A related study has claimed that the application of nutritional support combined with insulin in treating DKA complicated with AP can increase serum protein levels of patients, reduce inflammation, and improve the body’s immune function. However, the mechanism has not yet been clarified.^[6] Additionally, under the stimulation of various etiologies in vivo and in vitro, AP leads to the activation of pancreatic enzymes in the pancreas of the human body and induces inflammatory reactions such as digestion, edema, and hemorrhage in the pancreatic tissues, greatly affecting the treatment of patients with diabetes.^[2] Currently, exploring effective therapy for DKA complicated with AP is urgent.

Clinically, glucocorticoids present with extensive and complicated functions. It is worth noting that the functions of glucocorticoids vary with the dose. Physiological doses of glucocorticoids are mainly responsible for regulating the metabolism of sugar, protein and fat; while the supraphysiologic dose (pharmacologic dose) plays a role in anti-inflammation, antivirus, anti-immune, and anti-shock.^[7] Dexamethasone belongs to glucocorticoids. As early as 1952, some experts first reported the role of glucocorticoid dexamethasone in the treatment of AP.^[8] On the one hand, dexamethasone can inhibit a variety of inflammatory mediators, significantly attenuate the response of the body to bacterial endotoxin stimulation, improve cell tolerance, thereby reducing the damage caused by endotoxin. On the other hand, dexamethasone also acts as a good oxygen free radical scavenger, which can effectively relieve tissue damage, block the signal conduction of inflammatory mediators, and then inhibit the pathological process of inflammatory response. Additionally, dexamethasone is able to obviously improve microcirculatory perfusion in patients with organ dysfunction.^[9] Nevertheless, the efficacy of dexamethasone on DKA complicated with AP has not been researched yet. Therefore, we explored the effect of dexamethasone on DKA complicated with AP in this study. Through a series of experiments, we expected to provide relevant data support for the clinical treatment of DKA complicated with AP.

2. Data and methods

2.1. Participants and trial design

A total of 106 cases of DKA complicated with AP admitted to Wuxi People’s Hospital Affiliated to Nanjing Medical University from January 2020 to December 2022 were selected and randomly divided into a study group (n = 53) and a placebo group (n = 53) according to the random number table method. The patients in the study group were treated with dexamethasone, while those in the placebo group were given placebo treatment. General information of both groups was collected. This prospective study is reported using the CONSORT guidance for randomized, controlled trials.

2.2. Inclusion criteria

The inclusion criteria were shown as follows:

1. The symptoms of DKA met the diagnostic code of Guidelines for the prevention and control of type 2 diabetes in China (2017 Edition)^[10].

2. The symptoms of AP satisfied the diagnostic code of Guidelines for the management of acute pancreatitis published by Chinese Medical Association^[11].

3. pH < 7.32 or HCO3- < 15 mmol/L, blood glucose ≥ 16.7 mmol/L and blood ketone ≥ 5 mmol/L.

4. Imaging indicated severe inflammatory changes in the pancreas.

5. Patients and their families were informed of and agreed to this study.

2.3. Exclusion criteria

Patients were excluded if they:

1. Were characterized by dexamethasone allergy.

2. Were pregnant or breastfeeding, and had a clear pregnancy plan in the near term.

3. Suffered from critical heart, liver and kidney diseases or severe immunodeficiency and infectious diseases.

4. Occurred cognitive dysfunction, schizophrenia, and drug dependence.

5. Accompanied with other endocrine diseases.

6. Suffered from lactic acidosis, hyperosmolar hyperglycemic state and other acute complications.

2.4. Ethics approval and consent to participate

This study was approved by the Ethics Committee of Wuxi People’s Hospital Affiliated to Nanjing Medical University (KY23061), and all the subjects signed the informed consent form.

2.5. Therapeutic methods

Patients in both groups received various symptomatic treatments such as fluid replacement and maintaining acid-base balance. In the placebo group, patients underwent symptomatic management + placebo treatment; they were injected with normal saline intravenously at a dose of 5 mg once a day, for continuous 7 days. In the study group, patients received symptomatic management + dexamethasone treatment; a small dose of dexamethasone was administered intravenously with a dose of 5 mg once per day, for consecutive 7 days.

2.6. Outcome measures

2.6.1. Laboratory test index.

Through a variety of tests, the observation was performed on the changes and the restoration of normal value in terms of random venous blood glucose, pH, serum potassium, serum sodium, serum chlorine, urea nitrogen, urine glucose, urine ketone, serum amylase, and triglyceride for the 2 group patients before and after treatment.

2.6.2. Clinical symptoms.

Referring to the gastrointestinal symptom rating scale, the clinical symptoms of patients in the 2 groups before and after treatment were compared, including diarrhea, polydipsia, polyuria, abdominal pain, nausea and vomiting, disorder of consciousness, hypotension or shock.

2.7. Adverse events

The adverse events of the 2 groups during the treatment were compared and analyzed, including infection, gastrointestinal diseases, kidney or urinary system diseases, and heart diseases.

2.8. Statistical methods

This study is mainly compare efficacy between arms. The following formula was used to calculate the required sample size: $N={(\frac{\mathrm{Z}1-\mathrm{\alpha }/2\sqrt{2\mathrm{p}(1-\mathrm{p})}+\mathrm{Z}1-\mathrm{\beta }\sqrt{\mathrm{p}1(1-\mathrm{p}1)+\mathrm{p}2(1-\mathrm{p}2)}}{\mathrm{p}1-\mathrm{p}2})}^2$. Where n was the sample size, P1 represents the study group with a response rate of 0.45 and P2 represents the placebo group with a response rate of 0.20 according to our previous study, P = (P1 + P2)/2, the power was set at 80% with a 2-tailed alpha set at 0.05. Thus, a sample size of 53 participants per group (106 in total) was calculated.

Data analysis was carried out using statistical software SPSS 22.0. Measurement data were expressed as mean ± standard deviation, and t test was used for comparison between 2 groups. Enumeration data were expressed as n (%), and chi-square test was performed for inter-group comparison. P < .05 indicated statistically significant differences.

3. Results

3.1. Comparison of the general information between the 2 patient groups

Firstly, 106 patients were included in this paper and randomly divided into a study group (n = 53) and a placebo group (n = 53) according to the random number table method. The placebo group consisted of 28 males and 25 females, including 25 cases of type I diabetes and 28 cases of type II diabetes; the age ranged from 30 to 67 years, and the mean age was (48.75 ± 7.14) years; the duration of disease ranged from 6 to 14 years, and the mean duration was (9.62 ± 2.07) years; body mass index (BMI) was 17.14 to 31.95 kg/m², and the mean was (24.96 ± 3.24) kg/m². The study group was composed of 32 males and 21 females, including 30 cases of type I diabetes and 21 cases of type II diabetes; the age varied from 32 to 65 years, and the mean age was (49.55 ± 6.83) years; the duration of disease was 5 to 13 years, and the mean duration was (9.43 ± 1.77) years; the BMI ranged from 18.50 to 31.74 kg/m², and the mean was (24.40 ± 3.66) kg/m². There was no statistically significant difference in age, gender, BMI, duration of disease, type of diabetes, previous history of DKA, and history of alcohol use between the 2 groups (P > .05). Therefore, general information of the 2 groups of patients was comparable (Table 1).

Table 1.

Comparison of the general information between the two group patients.

	Placebo group (n = 53)	Study group (n = 53)	X2/t	P value
Age (yr)	48.75 ± 7.14	49.55 ± 6.83	−0.584	.561
Gender (%)			0.614	.433
Male	28 (52.8)	32 (60.4)
Female	25 (47.2)	21 (39.6)
Body mass index (kg/m2)	24.96 ± 3.24	24.40 ± 3.66	0.853	.396
Duration of disease (yr)	9.62 ± 2.07	9.43 ± 1.77	0.505	.615
Type of diabetes (%)			0.945	.331
Type I	25 (47.2)	30 (56.6)
Type II	28 (52.8)	23 (43.4)
Previous history of DKA (%)			0.396	.529
No	15 (28.3)	18 (34.0)
Yes	38 (71.7)	35 (66.0)
History of alcohol use (%)			0.622	.430
No	29 (54.7)	33 (62.3)
Yes	24 (45.3)	20 (37.7)

Measurement data were expressed as ($\overline{\mathrm{x}}\pm \mathrm{s}$), and enumeration data were expressed as n (%).

DKA = diabetic ketoacidosis.

3.2. Comparison of laboratory tests between 2 groups

There was no significant difference in laboratory indexes between the 2 groups before treatment (P > .05). After treatment, the study group patients showed relatively lower levels of random venous blood glucose, serum sodium, serum chlorine, urea nitrogen, urine glucose, urine ketone, serum amylase, and triglyceride while much higher levels of pH and serum potassium than the placebo group patients. Laboratory indexes between the 2 groups after treatment were significantly different (P < .05) (Table 2).

Table 2.

Comparison of laboratory indexes between the two groups before and after treatment.

	Before treatment		t	P value	After treatment		t	P value
	Placebo group (n = 53)	Study group (n = 53)			Placebo group (n = 53)	Study group (n = 53)
Venous blood glucose (mmol/L)	27.364 ± 5.221	27.562 ± 5.199	−0.196	.845	14.62 ± 2.74	9.52 ± 3.07	9.023	<.001
pH	6.49 ± 0.52	6.45 ± 0.48	0.447	.656	7.00 ± 0.58	7.43 ± 0.17	−5.192	<.001
Serum potassium (mmol/L)	3.68 ± 0.53	3.70 ± 0.72	−0.154	.878	3.97 ± 0.58	4.93 ± 0.61	−8.331	<.001
Serum sodium (mmol/L)	152.90 ± 4.40	153.34 ± 4.52	−0.508	.613	148.78 ± 3.17	138.98 ± 2.58	17.444	<.001
Serum chlorine (mmol/L)	101.60 ± 2.31	101.75 ± 2.36	−0.337	.737	88.30 ± 2.50	83.98 ± 2.62	8.670	<.001
Urea nitrogen (mmol/L)	13.34 ± 1.64	13.69 ± 1.47	−1.165	.247	12.26 ± 1.52	9.24 ± 1.40	10.665	<.001
Urine glucose (g/L)	2.38 ± 0.44	2.45 ± 0.56	−0.674	.502	2.07 ± 0.34	1.70 ± 0.45	4.797	<.001
Urine ketone (mg/L)	179.27 ± 15.38	181.90 ± 14.50	−0.903	.368	141.76 ± 16.69	122.22 ± 13.42	6.643	<.001
Serum amylase (U/L)	436.68 ± 30.47	433.58 ± 30.5	0.523	.602	89.37 ± 12.77	67.32 ± 13.89	8.508	<.001
Triglyceride (mmol/L)	2.98 ± 0.53	2.96 ± 0.62	0.202	.840	1.44 ± 0.36	1.13 ± 0.45	3.836	<.001

Measurement data were expressed as ($\overline{\mathrm{x}}\pm \mathrm{s}$).

3.3. Comparison of clinical symptoms between 2 groups

As shown in Table 3, before treatment, there was no significant difference in clinical symptoms such as abdominal pain, nausea and vomiting, polydipsia and polyuria, diarrhea, disorder of consciousness, hypotension or shock between the 2 groups (P > .05). After treatment, positive dynamic changes could be observed in the clinical symptoms/syndromes in both groups, and such changes were more significant in the study group. Specifically, patients in the study group had better improvement in abdominal pain (30.2% vs 13.2%), nausea and vomiting (18.9% vs 5.7%), polydipsia and polyuria (26.4% vs 11.3%), diarrhea (17.0% vs 3.8%), disorder of consciousness (15.1% vs 1.9%), and hypotension or shock (11.3% vs 0%), in comparison with those in the placebo group (P < .05).

Table 3.

Comparison of clinical symptoms between the two groups.

	Before treatment		X2	P value	After treatment		X2	P value
	Placebo group (n = 53)	Study group (n = 53)			Placebo group (n = 53)	Study group (n = 53)
Abdominal pain (%)	53 (100)	53 (100)	-	-	16 (30.2)	7 (13.2)	4.498	.034
Nausea and vomiting (%)	25 (47.2)	24 (45.3)	0.038	.846	10 (18.9)	3 (5.7)	4.296	.038
Polydipsia and polyuria (%)	32 (60.4)	30 (56.6)	0.155	.693	14 (26.4)	6 (11.3)	3.944	.047
Diarrhea (%)	27 (50.9)	25 (47.2)	0.151	.698	9 (17.0)	2 (3.8)	4.970	.026
Disorder of consciousness (%)	10 (18.9)	12 (22.6)	0.229	.632	8 (15.1)	1 (1.9)	4.371	.037
Hypotension or shock (%)	7 (13.2)	8 (15.1)	0.078	.780	6 (11.3)	0 (0)	4.417	.036

“-” indicated no exact value; enumeration data were expressed as n (%).

3.4. Incidence of adverse events in 2 groups

By the end of treatment, 9 cases of clinical adverse events were observed in the treatment group and 31 in the placebo group (Table 4). The difference in the total incidence of adverse events between the 2 groups was statistically significant (P < .001). To be specific, the incidence of infection was lower in the study group (n = 6, 11.3%) than that in the placebo group (n = 16, 30.2%), with a significant difference (P < .05). Furthermore, compared with the placebo group, the study group exhibited a lower incidence of adverse events in terms of gastrointestinal disorders (1.9% vs 15.1%), renal or urinary disorders (3.8% vs 17.0%), and cardiac disorders (0% vs 11.3%), with significantly different (P < .05).

Table 4.

Comparison of adverse events between the two groups.

	Placebo group (n = 53)	Study group (n = 53)	X2	P value
Adverse events (%)	31 (58.5)	9 (17.0)	19.433	<.001
Infection (%)	16 (30.2)	6 (11.3)	5.736	.017
Gastrointestinal disorders (%)	8 (15.1)	1 (1.9)	4.371	.037
Renal or urinary disorders (%)	9 (17.0)	2 (3.8)	4.970	.026
Cardiac disorders (%)	6 (11.3)	0 (0)	4.417	.036

Enumeration data were expressed as n (%).

4. Discussion

AP, accompanied with an incidence of about 10% to 15%, is a prevalent complication of DKA.^[12] Due to some similar clinical manifestations of the 2, misdiagnosis and missed diagnosis are common in the diagnosis process, bringing great challenges to the treatment of patients with DKA combined with AP.^[13] In addition, the abnormal activation of pancreatic enzymes in patients with AP leads to edema, digestion and necrosis of pancreatic tissue, thereby resulting in the release of a large number of inflammatory mediators and leaving the body in a state of immune dysfunction. Serum amylase is an important laboratory index for the diagnosis of AP; and more specifically, a considerable number of DKA patients are accompanied by an increase in serum amylase.^[14,15] Moreover, DKA induces neurohumoral regulation abnormalities or cause metabolic disorders of the body, then results in the leakage of amylase from pancreatic acinus to the blood circulation, thereby aggravating the hyperamylasemia and encouraging the occurrence of AP.^[5] In this study, we aimed to provide a relevant reference for the treatment of DKA combined with AP via investigating the clinical efficacy of dexamethasone.

The pathophysiological process of AP consists of acute-phase reaction, systemic infection and residual infection.^[16,17] During the acute-phase reaction, the body occurs pancreatic microcirculation disorder, pancreatic swelling, acinar injury, and massive pancreatic enzyme exudation; besides, owing to the activation of macrophages, a large number of proinflammatory factors (endotoxin, viral or fungal antigens, enterotoxins, etc) promote the release of cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-8, and platelet activating factor; the release of above cytokines over-activates the white blood cells, triggers a cascade effect of inflammatory mediators, and then makes the rapid development of AP from local lesions to systemic inflammatory response syndrome and contributes to a large number of pancreatic tissue necrosis complicated with multiple organ dysfunction syndrome.^[18] In this paper, compared with the placebo group, the study group showed significantly improved random venous blood glucose, pH, serum potassium, serum sodium, serum chlorine, urea nitrogen, urine glucose, urine ketone, serum amylase, and triglyceride after treatment. Such outcome indicated that dexamethasone could significantly improve and promote the recovery of normal values of various laboratory indexes, which was similar to the related reports.^[19] It can be further concluded that dexamethasone is not only able to reduce the inflammatory response by inhibiting the production of certain inflammatory mediators, but also important to block the worsening pathological process of AP.^[20] Additionally, relative to the placebo group, sufficient dexamethasone treatment improved the abdominal pain symptoms of patients in the study group. Moreover, the improvement of the study group patients was significantly superior to the placebo group in symptoms like nausea and vomiting, polydipsia and polyuria, diarrhea, and disorder of consciousness.

Also, the study group patients exhibited notably decreased other serious complications, declined death risk, and shortened disease duration compared with the placebo group patients. Just similar to the results reported by related researches, dexamethasone treatment can effectively alleviate various clinical symptoms in DKA patients with AP.^[18] Furthermore, 9 patients (17.0%) in the study group and 16 patients (58.5%) in the placebo group suffered from adverse events; the incidence rate of adverse events was lower in the study group than that in the placebo group. Overall, dexamethasone promotes the rehabilitation of patients on the basis of ensuring the safety of medication and plays a positive role in reducing the occurrence of adverse events, so it is a safe and effective treatment. However, the probability of infection in the study group was higher than other adverse events. Therefore, when applying dexamethasone to treat DKA complicated with AP, doctors should actively prevent the occurrence of infection, shorten the course of the disease, and alleviate the pain of the patients.

5. Conclusion

In summary, dexamethasone can significantly promote the recovery of DKA patients complicated with AP, improving the index levels such as venous blood glucose, pH, serum potassium, serum sodium, serum chlorine, urea nitrogen, urine glucose, urine ketone, serum amylase, and triglyceride, ameliorate the clinical symptoms, reduce the risk of death, and accompany by a certain degree of safety. Therefore, dexamethasone is worth a promotion and application in the treatment of DKA complicated with AP.

Author contributions

Conceptualization: Junfeng He.

Data curation: Jing Zhang.

Formal analysis: Jing Zhang.

Investigation: Junfeng He.

Methodology: Junfeng He.

Resources: Jing Zhang.

Writing – original draft: Junfeng He.

Writing – review & editing: Jing Zhang.