Association between time in range 70-180mg/dl in early stage and severity in patients with acute pancreatitis

doi:10.21203/rs.3.rs-2524261/v1

Background: It is not well understood whether glucose control in the early stage of acute pancreatitis(AP) is related to the outcome. This study aimed to investigate the association between blood glucose time in range (TIR) 70–180 mg/dL in the first 72 hours(h) on admission and the progression of AP.

Methods: Patients admitted with AP to the gastroenterology department of Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University between Jan 2017 and Dec 2021 were included and retrospectively evaluated. The percentage of TIR between 70 and 180 mg/dL in the first 72 h was calculated. According to the progress of AP at discharge, the patients were divided into mild pancreatitis(MAP) and moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP) group.We examined the association between TIR or TIR ≥70% and the severity of AP using logistic regression models with stratification by glycosylated hemoglobin (HbA1c) level of 6.5%. Receiver operating characteristic (ROC) curves were generated to assess the ability of TIR to predict MSAP or SAP.

Results: A total of 298 patients were included and 35 of them developed into MSAP or SAP. Logistic regression analyses indicated that TIR was independently associated with the incidence of more serious AP(OR=0.962 95% CI=0.941-0.983, P=0.001). This association remained significant in patients with HbA1c ≤6.5% (OR=0.928 95%CI=0.888-0.969, P=0.001).TIR≥70% was independently associated with reduced severity only in patients with well-antecedent control (OR=0.238; 95% CI= 0.071-0.802; P =0.020). TIR was not powerful enough to predict the severity of AP in both patients with poor antecedent glucose control (AUC=0.641) or with HbA1c＜6.5% (AUC=0.668).

Conclusions ：TIR was independently associated with severity in AP patients, particularly those with good antecedent glucose control.

acute pancreatitis

blood glucose time in range

severity

diabetes

glycosylated hemoglobin

Acute pancreatitis(AP), an inflammatory injury of pancreatic edema, bleeding and necrosis, is the leading cause of admission to hospital for gastrointestinal disorders in China and many other countries. According to the new Atlanta Classification of 2012 revision, AP now could be classified into mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP), and severe acute pancreatitis(SAP)[1]. Approximately 20% of patients develop moderate or severe acute pancreatitis, with multiple organ dysfunction or local complications, and a substantial mortality rate of 20–40% [2]. As a progressive disease, AP has the risk of developing from mild to severe even during the hospital stay[3]. Hence it is essential to explore the factors related to prognosis in the early stage of severity for decreasing serious complications and mortality rate.

A growing number of studies focus on the association between blood glucose and the outcome of acute pancreatitis. A post-hoc analysis of a prospective, international cohort of 2250 acute pancreatitis cases demonstrated that both on-admission and peak serum glucose was independently associated with AP severity[4]. Another prospective study found blood glucose level on admission (> 11.1 mmol/L) was a significant risk factor for the worsening of AP[5]. However, the blood glucose indicators used in these studies including mean and maximum blood glucose, glycosylated hemoglobin(HbA1C) and blood glucose on admission failed to reflect the glycemic fluctuation accurately during the onset.

Poor glycemic control was considered as an independent risk factor for the deterioration in acute severe diseases[6, 7]. Studies pertaining to glycemic control with critically ill patients recently focused on target blood glucose, trying to figure out the optimal level of blood glucose.

The blood glucose percentage of time in range(TIR) is a new metric suggested to be the unifying metric to account for hypoglycemia, glycemic variation, and hyperglycemia events[8, 9]. Recent research recognized the critical role played by TIR a prognostic factor for critically ill patients[10–13], and the impact of TIR varied among patients with different antecedent glucose control. However, little was known about the association between TIR in early stage and the progression of acute pancreatitis.

Accordingly, we conducted a retrospective study to investigate the association between TIR in the 72 hours of admission as a surrogate marker of glycemic control in early stage and disease progression in acute pancreatitis.

The study was approved by the ethics committee of the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University and performed in patients initially diagnosed with acute pancreatitis, who were admitted to the gastroenterology department between Jan 2017 and Dec 2021. All selected patients were fasting within the first 72h. We excluded patients younger than 18 years and patients with diabetic ketoacidosis. Patients with organ failure at admission ,the length of hospital stay less than three days, the number of blood glucose monitoring less than 4 times per 24 hour in first 72h, or pregnant were also ruled out. The characteristics of patients, including sex, body mass index(BMI), age, etiology, organ failure, history of diabetes were collected. Maximum C-reactive protein (CRPmax) ,triglyceride(TG),HbA1c values were measured.

Nurses used glucose monitors (GLUPAD, SINOMEDISITE, China) to test capillary blood every one to six hours. We collected all the blood glucose value of the patient in the first 72h on admission. Using the measured blood glucose values, we calculated the mean blood glucose, TIR (70–180mg/dL, which represented the percentage of time between 70 and 180 mg/dL) in the first 72h. Clinically significant hypoglycemia was defined as a glucose < 54mg/dL. The coefficient of variation (%CV),which represents glycemic variability, resulted from the division between the standard deviation and the average glucose multiplied by 100.

AP was diagnosed if 2 of following 3 criteria were met clinically:(1) acute, sudden, continuous and severe upper abdominal pain, which can radiate to the back; (2) Serum amylase and / or lipase activities were at least 3 times higher than the upper limit of normal; (3) Enhanced CT / MRI showed typical imaging changes of AP (pancreatic edema or peripancreatic effusion).

Patients were divided into two groups according to the severity of pancreatitis in the discharge diagnosis:(1) mild group : patients met the diagnostic criteria of AP without organ failure and local or systemic complications during hospitalization; (2) severe group: including MSAP and SAP that accompanied by transient organ failure (which can be recovered within 48 hours), or accompanied by single or multiple organ failure continuously (> 48 hours duration).

Statistics

Continuous data were displayed as median (interquartile range (IQR)) or mean (standard deviation(SD)) and comparisons were made between groups using the Mann–Whitney rank-sum test or Student’s t-test, respectively, as appropriate. Categorical data were showed as percentages and comparisons were made between groups using the χ² test. Logistic regression was conducted to investigate the independent association of TIR with severity. To detect the predictive accuracy of TIR on the severity, the Receiver Operating Characteristic Curve (ROC) was applied.

A total of 298 patients were included in the statistics. 35 patients developed MSAP or SAP while in hospital, of whom 24 patients developed MSAP and 11 patients developed SAP (Table1). Compared with non-severe counterparts，patients in severe group(MSAP or SAP) had a higher proportion of diabetes and extreme hypoglycemia, higher mean blood glucose values, HbA1c, TG levels(all p < 0.05) . The TIR of severe group and the proportion of TIR>70% were also lower (p < 0.05). When using TIR as a categorical variable based on a quartile of patients (<40.88%, 40.89%-70.18%, 70.19%-85.71%, and ≥85.72%), as illustrated by Figure 1a, the prevalence of severe cases decreased progressively across the categories of increasing TIR (p for trend<0.001). In figure 1b ,a trend of decreasing CRP_max levels was also observed (p for trend<0.001).

Logistic regression analysis revealed that TIR was significantly associated with risk of developing in SAP or MSAP in the crude and adjusted models including age, sex, BMI,TG, HbA1c, diabetes and etiology as covariates (OR=0.962 95%CI=0.941-0.983,p=0.001) shown in table 2.This association remained significant with severity in patients with HbA1c＜6.5% adjusting for age, sex, BMI,TG, diabetes and etiology (OR=0.928 95%CI=0.888-0.969,p=0.001).By contrast, in patients with HbA1c ≥6.5%, there was no significant association between TIR and severity in either unadjusted or adjusted logistic regression models (OR=0.971,95%CI=0.942-1.000, p=0.053).

In table3 ,TIR 70-180mg/dl≥70% in first 72h was independently associated with reduced severe cases only in patients with well antecedent controlled blood glucose after adjusting for age, sex, BMI,TG, diabetes and etiology(OR=0.238; 95% CI= 0.071-0.802; p =0.020).

We assessed the prediction probabilities by comparing the area under the receiver operating characteristic curve (AUC). The ROC analysis (Fig. 2) showed that TIR as a continuous variable failed to predict the severity in patients with HbA1c＜6.5%(AUC=0.668) or ≥6.5% (AUC=0.641). It was neither a powerful predictor of severity in overall patients regardless of antecedent blood glucose (AUC=0.647).

This single-center retrospective analysis of AP patients reveals that blood glucose in the TIR 70 to 180 mg/dL in first 72 hours on admission is strongly associated with decreased incidence of severe cases. When stratified with different antecedent glucose control status, this association was also observed in patients with well controlled blood glucose before admission according to logistic regression analysis while was not discovered in well controlled counterparts.

These data expand on the limited literature that has explored the relationship between glucose control and progression of AP. Several reports showed that patients with DM had greater incidence of acute pancreatitis compared with non-diabetics[14, 15],indicating that long-term poorly controlled blood glucose may lead to the occurrence of pancreatitis. In mice models, it was observed that diabetes aggravated acute pancreatitis and suppresses regeneration of the exocrine tissue[16].The possible mechanisms include hyperlipidemia[17],pre-inflammatory state[16], immune dysfunction and oxidative stress that caused by chronic hyperglycemia. On the other hand, pancreatitis could cause fluctuation in blood glucose, and mechanisms may lie in: Firstly, stress hyperglycemia that mainly occur in the early stage of onset, and a variety of inflammatory factors stimulate the increase of the release of glucagon, glucocorticoid and other hyperglycemic hormones; Secondly, microcirculation disturbance of pancreatic tissue characterized by edema, ischemia, necrosis that result in destruction of islet, after which a large amount of insulin release and insufficient nutrition can lead to hypoglycemia. However, the association between glycemic level in the early stage and the outcome of pancreatitis is rarely reported. Aniko Nagy et al[4] found on admission and peak in-hospital serum glucose concentrations had a significant dose-dependent relationship with AP severity after adjusting DM, age, gender and etiology. Additionally, a hospital glucose peak > 7mmol/L is associated with a 15 times higher probability of severe AP. Another retrospective study[18] displayed the glycemic lability index upon admission contributed independently to the risk of mortality ,which was better able to predict the death of severe pancreatitis than was on mean glucose level.

As a suitable metric of the efficacy and safety of glycemic control, TIR has recently received increasing attention, with many studies suggesting that it has an important correlation with the prognosis of severe disease. In previous studies exploring the relationship between TIR and mortality in critically ill patients, Matthew Signal discovered TIR 72–126mg/dl ≥ 50% was independently associated with reduced organ failure[19]. They also found TIR ≥ 70% was independently associated with increased chances of survival over TIR ≥ 50% or TIR ≥ 30% in further study[20].We observed that in the first 72 hours on admission, patients who developed to SAP or MSAP had significantly lower levels of TIR, as well as less proportion of patients with TIR above 70%. In another word, patients with TIR greater than 70% at an early stage are less likely to progress to SAP or MSAP. CRP is considered as one of the biomarkers reflecting the severity of the inflammation[21]. Given the TIR have a statistically significant dose-dependent relationship with maximal CRP level, we supposed that patients with extreme low TIR at early stage possibly suffered from more severe inflammation.

The patients were further divided into two groups according to antecedent glucose control as reflected by HbA1c level. In these patients with HAb1c less than 6.5%, TIR in first 72 hours was negatively associated with the occurrence of SAP or MAP, regardless of the confounders adjusted. No apparent association was found in those with HbA1c ≥ 6.5%. Similarly, well-controlled patients with TIR 70–180 mg/dL greater than 70% in first 72 hours were less likely to progress to SAP or MSAP, while patients with HbA1c ≥ 6.5% under the same conditions did not benefit.

The observed association of TIR in early stage and outcome of severity in AP patients with varied antecedent glucose control was akin to those of earlier studies on critically ill patients and mortality. Krinsley et al[11]demonstrated that patients in TIR 70 to 140 mg/dl > 80% is strongly associated with survival in critically ill patients without diabetes, while no difference was found in mortality between groups among diabetic patients. Lanspa et al[22]found that TIR 70–139 mg/dl༞80% was independently associated with mortality in critically ill patients, particularly those with HbA1c ༜6.5% that represented well controlled glucose level before admission. Hiromu Naraba et al [10] chose a less stringent 70-180mg/dl as time in range ,which was the same range we selected according to the guidelines from the Society of Critical Care Medicine and American Diabetes Association[23], and reported that lower TIR was associated with higher 28-day mortality in critically ill patients with HbA1c < 6.5%, whereas there was no consistent association in patients with HbA1c ≥ 6.5%. Furthermore, similar association could be found during the first three days in their study. Despite the slight difference in chosen target range, our research further supported the idea that tight glycemic control might benefit the patients without diabetic history or with well-controlled glucose level in patients with AP.

One of the possible explanations is the hyperglycemia adaption[24].Chronic hyperglycemia could lead to reactive oxygen species (ROS)[25], which may also play a key role in the progress of pancreatic inflammation. For patients with poor long-term blood glucose control, they have already adapted the adverse consequences induced by chronic hyperglycemia. While for patients with well-controlled blood glucose, they have poor tolerance of the oxidative stress-related tissue injury induced by acute hyperglycemia and inflammations during AP, resulting in more severe status. Patients with DM could also withstand relatively low glucose values better due to the mechanism of cellular adaptation to recurrent hypoglycemia[26, 27]. Since the in-hospital hypoglycemic incidences occurred in our study was extremely low, the effects beyond the target range were mainly from hyperglycemia. These results remind us that antecedent control of AP patients should be taken into consideration when setting blood glucose targets. Further intervention study should be warranted into the appropriate management in acute pancreatitis patients with different blood glucose levels.

Regardless of whether TIR in an early stage was independently associated with the occurrence of SAP or MSAP ,it was not a powerful predictor of such outcome, for the area under roc curve of TIR was not large enough in all groups(from 0.641 to 0.668).In other words, the extent of the deterioration of AP prognosis should not be entirely attributed to blood glucose. Indeed, it seems impossible for one single biochemical variable to prognosticate in the outcome of AP.

To our knowledge, this is the first study demonstrating the effect of TIR in early stage on the outcome of AP. Strength as it had ,there were also some limitations we should note. First, for the retrospective nature of the study, we could not formulate plans for the timing and frequency of blood glucose measurement in advance. Second, owing to the characteristics of single-center observational study, the conclusion may not be extended to all AP patients. Third, TIR in this study is not generated by continuous glucose monitoring system (CGMS), and that may reduce the accuracy, though we’ve selected patients with relatively high frequency measurement as far as possible. Hence, prospective studies with large sample sizes are warranted to provide further evidence for the optimal blood glucose control.

We demonstrated that higher TIR 70–180 mg/dL in early stage of AP was associated with a lower risk of developing in SAP or MSAP. Patients maintained blood glucose levels between 70 and 180 mg/dL at least 70% of the time had decreased possibility of developing into SAP or MSAP compared with those who were not. All these findings were also found in patients with good antecedent control while not present in patients with poor antecedent control, suggesting that patients with previously well controlled blood glucose might benefit from early tight blood glucose management. Further interventional trials are needed to investigate the optimal blood glucose control target for patients with pancreatitis.

Conflict of interest： The authors declare that they have no conflict of interest.

Ethical approval: The study was approved and informed consent from all subjects of our study was waived by the Ethics Committee of The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University. All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication : Not applicable.

Availability of data and materials: The data generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions : Conceptualization: Chuchen Meng ,Shaohua Zhuang and Xinhua Ye; Investigation: Chuchen Meng, Jie Zhang , Ying Wang , Xinhua Ye and Shaohua Zhuang; Methodology: Chuchen Meng and Shaohua Zhuang; Clinical data collection: Chuchen Meng, Jie Zhang; Writing - original draft: Chuchen Meng; Writing - review editing: Xinhua Ye; Supervision: Shaohua zhuang. All authors read and approved the final manuscript.

Acknowledgments：The authors acknowledge the contribution of all the staff who participated in this study .

Funding : None

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Table1:Characteristics of patients who developed more severe pancreatitis or not.
		Total (N=298)	MAP(N=263)	SAP or MSAP(N=35)	p
	BMI(Kg/m²)	25.79±4.39	25.73±4.35	26.25±4.77	0.540
	Age(year)	48.67±15.72	48.16±15.14	52.49±19.44	0.211
	Sex(male%)	207(69.46)	181（68.82%）	26（74.29%）	0.510
HbA1C(%)		7.12±2.27	7.03±2.22	7.81±2.51	0.054
TG（mmol/L）		2.27（0.99，5.81）	2.22（0.98-5.21）	4.07（1.30-8.90）	0.041
	CRP max(mg/L)	79.75（25.93，160.98）	74.30（20.75，146.9）	183.17（88.03,309.99）	＜0.01
	Diabetes n(%)	102（34.22）	83（31.56）	19（54.29）	＜0.01
	Heart failure n(%)	24（8.05）	4（1.52）	20（57.14）	＜0.01
	Kidney failure n(%)	30（10.07）	15（5.70）	15（52.86）	＜0.01
	Respiratory failure n(%)	15（5.03）	1（0.38）	14（40.00）	＜0.01
	Etiology
	Biliary n(%)	129（43.29）	114（43.45）	15（42.86）
	HTG n(%)	79（26.51）	64（24.33）	15（42.86）
	Alcohol n(%)	37（12.41）	33（12.55）	4（11.43）	0.029
	Combined n(%)	53（30.20）	52（19.77）	1（2.86）
	Glucose control
	Mean median (IQR)	8.76（7.56,10.99）	8.61（7.48,10.71）	10.35（8.38,13.04）	＜0.01
	Hypoglycemia n(%)	11(3.69)	7(2.66)	4(11.43)	0.029
	CV % median (IQR)	27.44（21.37，33.44）	27.69（21.53，33.67）	24.02（20.51，30.55）	0.145
	TIR median (IQR)	70.19（40.88，85.71）	71.43（44.62，86.67）	55.41（12.82，77.78）	＜0.01
	TIR≥70% n(%)	112（37.58）	105（39.93）	7（20.00）	0.022
	CV＞36% n(%)	53(17.79)	47(17.87)	6(17.14)	0.600
MAP mild pancreatitis; MSAP moderately severe acute pancreatitis; SAP severe acute pancreatitis. TIR: time in range; BMI body mass index TG triglyceride; HbA1C hemoglobin A1C; CV coefficient of variation; CRP C-reaction protein; IQR interquartile range.

Table 2: Association of TIR 70-180mg/dl in first 72 hours with MAP or SMAP by logistic regression analyses
	Models	OR	95%CI	p
ALL	crude	0.981	0.969-0.993	0.001
	Model1	0.968	0.953-0.983	＜0.001
	Model2	0.962	0.941-0.983	0.001
HbA1C＜6.5%	crude	0.952	0.925-0.981	0.001
	Model1	0.936	0.905-0.969	＜0.001
	Model2*	0.928	0.888-0.969	0.001
HbA1C ≥6.5%	crude	0.986	0.964-1.008	0.212
	Model1	0.967	0.941-0.995	0.019
	Model2*	0.971	0.942-1.000	0.053
Model1:is adjusted for age, sex and body mass index;
Model2:includes all variables in Model 1 plus HAb1C,TG,Diabetes and etiology of AP
Model2*:includes all variables in Model 1 plus TG, Diabetes and etiology of AP

Table 3: Association of TIR 70-180mg/dl≥70% in first 72 hours with MAP or SMAP by logistic regression analyses
	Models	OR	95%CI	p
ALL	crude	0.409	0.192-0.869	0.020
	Model1	0.289	0.122-0.684	0.005
	Model2	0.418	0.146-1.195	0.103
HbA1C＜6.5%	crude	0.319	0.115-0.886	0.028
	Model1	0.231	0.077-0.699	0.010
	Model2*	0.238	0.071-0.802	0.020
HbA1C ≥6.5%	crude	0.917	0.187-4.490	0.915
	Model1	0.605	0.103-3.568	0.579
	Model2*	1.207	0.157-9.280	0.856
Model1:is adjusted for age, sex and body mass index;
Model2:includes all variables in Model 1 plus HAb1C,TG and etiology of AP
Model2*:includes all variables in Model 1 plus TG, Diabetes and etiology of AP

No competing interests reported.

Association between time in range 70-180mg/dl in early stage and severity in patients with acute pancreatitis

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