Hypertriglyceridemia-associated acute pancreatitis: Response to continuous insulin infusion.

OBJECTIVE: To assess the response of serum triglycerides (TG) to continuous insulin infusion (CII) in adults with hypertriglyceridemia-associated acute pancreatitis (HTGP).
METHODS: Retrospective analysis of TG response to standardized CII therapy in 77 adults admitted to intensive care with TG >1000 mg/dL and HTGP.
RESULTS: Participants had initial TG 3869.0 [2713.5, 5443.5] mg/dL and were 39.3 ± 9.7 years old, 66.2% males, 58.4% Hispanic, BMI 30.2 [27.0, 34.8] kg/m2, 74.0% with diabetes mellitus (DM) and 50.6% with excess alcohol use. TG-goal, defined as ≤1,000 ± 100 mg/dL, was achieved in 95%. Among the 73 TG-goal achievers (responders), 53.4% reached TG-goal in <36 hours after CII initiation (rapid responders). When compared to slow responders taking≥36 hours, rapid responders had lower initial TG (2862.0 [1965.0, 4519.0] vs 4814.5 [3368.8, 6900.0] mg/dL), BMI (29.4 [25.9, 32.8] vs 31.9 [28.2, 38.3] kg/m2), DM prevalence (56.4 vs 94.1%), and reached TG-50% (half of respective initial TG) faster (12.0 [6.0, 17.0] vs 18.5 [13.0, 32.8] hours). Those with DM (n = 57) vs non-DM (n = 20) were obese (31.4 [28.0, 35.6] vs 27.8 [23.6, 30.3] kg/m2), took longer to reach TG-final (41.0 [25.0, 60.5] vs 14.5 [12.5, 25.5] hours) and used more daily insulin (1.7 [1.3, 2.1] vs 1.1 [0.5, 1.9] U/kg/day). Among those with DM, the rapid responders had higher daily use of insulin vs slow responders 1.9 [1.4, 2.3] vs 1.6 [1.1, 1.8] U/kg/day. All results significant. In multivariable analysis, predictors of faster TG response were absence of DM, lower BMI and initial TG.
CONCLUSION: CII was effective in reaching TG-goal in 95% of patients with HTGP. Half achieved TG-goal within 36 hours. Presence of DM, higher BMI and initial TG slowed the time to reach TG-goal. These baseline parameters and rate of decline to TG-50% may be real-time indicators to initiate and adjust the CII for quicker response.

Introduction

Hypertriglyceridemia-associated acute pancreatitis (HTGP) is a serious and common disorder with no consensus on most effective management approach to mitigate the disease. Hypertriglyceridemia (HTG) is the third most common cause of acute pancreatitis (AP), accounting for approximately 10% of cases, after gallstones and alcohol [1]. The pathogenesis of HTGP is unclear but the most accepted mechanism suggests hydrolysis of TG by pancreatic lipase, in and around the pancreas, leading to the production of free fatty acids (FA) in pancreatic capillaries. These FAs accumulate in capillaries leading to pancreatic ischemia with acidosis, trypsinogen activation, and the initiation of AP [2].

The management of HTGP includes an aggressive reduction of TG to at least <1000 mg/dL using either continuous insulin infusion (CII) or plasmapheresis (PEX) based on clinical severity at presentation. The reduction of TG to less than 1000 mg/dL showed a decrease in the risk of further AP episodes [3]. Once the TG is at goal and the patient can tolerate oral intake, dietary modifications (diet low in refined carbohydrates and saturated and trans fat as well as no alcohol) and lipid-lowering medications (such as fibrates, omega-3 fatty acids and selected statins) are added to achieve long-term TG control [4].

CII is an effective modality of therapy to reduce TG levels rapidly. Insulin reduces TG levels by promoting the synthesis of lipoprotein lipase that hydrolyzes plasma TG and facilitates the storage of fatty acids in adipocytes [5]. In the currently available literature, there are only limited studies looking at the duration required for CII to reduce TG to <1000 mg/dL and no studies that measured the quantity of insulin required for reducing TG [6-8]. Our study aimed to fill these gaps.

Methods

Study design

This retrospective study examined adults admitted to the intensive care unit (ICU) of John H Stroger Jr Hospital of Cook County, in Chicago, Illinois from January 2011 to June 2019 with a TG >1000 mg/dL and HTGP requiring CII. Patients received a standardized 0.1 U/kg regular insulin bolus followed by the ICU adjustable insulin infusion protocol based on the serum glucose levels. The target glucose range was a 110–150 mg/dL with glucose levels checked hourly. The amount of insulin adjustment was depending upon the hourly infusion rates and the levels of glucose above or below the target range. Fluid management, using either 0.9% or 0.45% saline, was consistent for all ICU patients based on hydration parameters. We aimed to investigate the rate of the HTG response to CII in patients with HTGP and to identify the predictive factors that affected the response. The study, which analyzed de-identified data, was approved with a consent waiver by the Institutional Review Board of John H Stroger Jr Hospital of Cook County, Chicago, Illinois.

Inclusion/Exclusion criteria

Inclusion criteria were adult patients (age ≥18 years) admitted to the ICU with the diagnosis of AP, admission serum TG level >1000 mg/dL, and who received treatment with CII. AP was defined per 2012 Atlanta classification of acute pancreatitis as any two of the three following criteria: abdominal pain (acute onset, persistent, severe, epigastric pain often radiating to the back), pancreatic enzymes (serum lipase or amylase) level at least 3 times greater than the upper limit of normal, and/or computed tomography (CT) or magnetic resonance imaging (MRI) evidence of acute pancreatitis [9]. Exclusion criteria included pregnancy, patients who underwent therapeutic plasma exchange (TPE) procedure, and those who did not receive a bolus prior to CII. Data were obtained from a detailed electronic medical chart review.

Outcomes

The primary outcome was the achievement of the TG goal ≤1,000 ± 100 mg/dL. Secondary outcomes were time durations to achieve TG-50% (half of the respective initial TG) and TG-goal.

Variables

Data collected included baseline demographic and clinical information such as age, gender, race, body mass index (BMI), excess alcohol use, history of gallbladder disease, DM, hypothyroidism, and serum TG level on admission. Gallbladder sludge and gallstones were considered present if documented at admission or noted in any abdominal imaging (ultrasound or CT) during the hospital stay. Excess alcohol use was identified by self-report per Center for Disease Control (CDC) definition criteria [10]. DM was defined per the American Diabetes Association (ADA) criteria as HbA1C ≥6.5% or documented diagnosis of any type of DM [11]. Per World Health Organization (WHO) and CDC criteria, obesity was defined as BMI >30 kg/m2 [12]. To evaluate the response of HTG to CII, other pertinent variables collected included documentation if the patient was placed on bowel rest (NPO or nothing per mouth) after admission, time of CII initiation, time of initiation of oral TG-lowering medications (such as fibrates, statins, fish oil) administered during hospitalization.

Serum TG levels while on CII used for analysis were three major reference points: 1) Initial TG, serum TG level at the start of CII, 2) TG-50%, serum TG level at the time of reaching half of respective initial serum TG, 3) TG-goal defined as reaching TG ≤1000 ± 100 mg/dL. For patients who did not reach the TG-goal, the lowest serum TG was defined as TG-final. Accordingly, two time durations were defined in hours: 1) time to reach TG-50% from initiation of CII and 2) time to reach TG-goal from initiation of CII. The CII was analyzed as 1) total dose of insulin used from the start of CII to TG-goal and 2) total daily insulin use per kilogram body weight (U/Kg/day). Frequency of TG checks of patients in the ICU was a minimum of every 6–12 hours until TG was at goal.

Statistical analysis

Continuous variables were reported as mean ± standard deviation for parametric data and as median [25th, 75th percentile] for non-parametric data. Differences between continuous variables were measured by independent-samples t-test for parametric data and Mann-Whitney U tests for non-parametric data. Categorical variables were reported as n (sample size) and percentages. The association (or relationship) between categorical variables was measured by the chi-square (χ2) test. A 2-tailed P <0.05 was considered statistically significant. Binomial logistic regression was used to estimate confidence intervals, odds ratios (OR), and P values. The multivariate regression analysis was used to measure the degree of the linear relationship between independent variables (predictors) and dependent variables (responses). IBM SPSS, version 26 software (SPSS Inc, Chicago, Illinois) was used for all statistical analyses.

Results

Based on the inclusion criteria, a total of 204 patients were identified for the study (Fig 1). Out of those patients, 117 patients were excluded from the study due to insufficient medication administration record (MAR) data during the hospital stay. After chart review, another 10 patients were excluded as they received TPE during the hospital stay. A total of 77 patients were identified for the final analysis: 75 patients received CII only, the other 2 patients received CII and subsequent TPE due to poor response to CII. For the two patients included in the final analysis who received CII and TPE, only the data while on CII was included.

Fig 1

Consort chart.

The baseline characteristics of the 77 patients who received CII are shown in Table 1. The initial TG was 3869.0 [2713.5, 5443.5] mg/dL. The average age was 39.3 ± 9.7 years, 66.2% were males, 58.4% Hispanic, BMI was 30.2 [27.0, 34.8] kg/m2, 50.6% reported excess alcohol use, and 74% had DM. All patients were placed NPO after admission.

Table 1

Baseline characteristics of the study population.

Baseline Characteristics	n = 77
Age (years)	39.3 ± 9.7
Male, n (%)	51 (66.2)
Ethnicity, n (%)
Hispanic	45 (58.4)
African American	15 (19.5)
White	15 (19.5)
Other	2 (2.6)
BMI (kg/m2)	30.2 [27.0, 34.8]
DM, n (%)	57 (74.0)
HbA1C%	9.6 ± 3.4
History of excess alcohol use, n (%)	39 (50.6)
Gall stone disease, n (%)	1 (1.3)
Overt hypothyroidism, n (%)	2 (2.6)
Initial serum TG (mg/dL)	3869.0 [2713.5, 5443.5]

TG-goal was achieved in 73 patients (95%) (RP, responders). One patient with initial TG of 7035.0 mg/dL was classified as a responder with TG final of 1191.0 mg/dL since the CII was stopped at that level. The four patients who did not reach TG-goal (NR, non-responders) did not differ significantly at baseline from responders. Among the four NR, two underwent TPE and two were transitioned to oral fibrates as they clinically improved.

The time course to reach TG-goal in RP is shown in Fig 2. The time to reach the TG-50% and the TG-goal varied widely from 25th percentile to 75th percentile, 8.0 to 24.5 hours and 16.0 to 52.0 hours respectively. Among the 73 RP, patients were further divided per time taken to reach TG-goal as <36 hours (RRP, rapid responders, n = 39) vs ≥36 hours (SRP, slow responders, n = 34) as shown in Table 2. The SRP vs RRP were more obese (31.9 [28.2, 38.3] vs 29.4 [25.9, 32.8] kg/m2, p = 0.028), more likely to have DM (94.1 vs 56.4%, p = 0.000), had higher initial serum TG (4814.5 [3368.8, 6900.0] vs 2862.0 [1965.0, 4519.0] mg/dL, p = 0.000), and took longer to reach TG-50% (18.5 [13.0, 32.8] vs 12.0 [6.0, 17.0] hours, p = 0.001).

Fig 2

Reduction in serum triglyceride levels over time after insulin initiation in the 73 responders.

TG0 and T0-Intial TG and time, TG1 and T1-TG and time as insulin initiation, TG2 and T2-TG and time for reduction by 50% or less, TG3 and T3-TG goal and time at insulin drip discontinuation.

Table 2

Clinical and laboratory characteristics among the 73 responders who reached TG goal in less than 36 hours vs 36 hours or more.

	Responders (n = 73)	Less than 36 hours (n = 39)	36 hours or more (n = 34)	P value#
Demographics:
Age (years)	39.1 ± 9.7	39.3 ± 8.6	38.9 ± 11.0	0.881
Males, n (%)	49 (67.1)	27 (69.2)	22 (64.7)	0.80
Ethnicity, n (%)				0.36
Hispanic	45 (61.6)	25 (64.1)	20 (58.8)
African American	14 (19.2)	6 (15.4)	8 (23.5)
White	12 (16.4)	8 (20.5)	4 (11.8)
Other	2 (2.7)	0 (0.0)	2 (5.9)
BMI (kg/m2)	30.2 [27.0, 34.8]	29.4 [25.9, 32.8]	31.9 [28.2, 38.3]	0.028*
Excess alcohol use, n (%)	37 (50.7)	24 (61.5)	13 (38.2)	0.062
DM, n (%)	54 (74.0)	22 (56.4)	32 (94.1)	0.000*
Baseline:
HbA1C%	9.6 ± 3.5	8.4 ± 3.2	10.9 ± 3.3	0.002*
Initial serum TG (mg/dL)	3874.0 [2701.0, 5443.5]	2862.0 [1965.0, 4519.0]	4814.5 [3368.8, 6900.0]	0.000*
Serum TG at the start of CII (mg/dL)	3427.0 [2383.0, 4938.5]	2701.0 [1770.0, 3992.0]	4122.0 [3248.5, 6543.0]	0.000*
Time from initial TG to start of CII (hours)	3.0 [0.0, 5.5]	4.0 [0.0, 5.0]	3.0 [0.0, 6.0]	0.848
Midpoint:
TG-50% (mg/dL)	1367.0 [862.5, 2053.5]	974.0 [692.0, 1367.0]	1753.0 [1378.0, 2656.5]	0.000*
Time from start of CII to TG-50% (hours)	15.0 [8.0, 24.5]	12.0 [6.0, 17.0]	18.5 [13.0, 32.8]	0.001*
Total insulin used to reach TG-50% (units)	85.6 [38.3, 145.4]	56.0 [29.3, 111.0]	110.3 [78.5, 221.8]	0.004*
Final:
TG final (mg/dL)	820.0 [634.5, 940.0]	752.0 [547.0, 889.0]	898.0 [668.0, 966.3]	0.013*
Time from start of CII to TG goal (hours)	30.0 [16.0, 52.0]	17.0 [12.0, 26.0]	54.0 [43.5, 67.5]	0.000*
Total insulin used to reach TG goal (units)	171.0 [82.0, 266.9]	87.0 [41.3, 175.0]	266.9 [191.7, 469.3]	0.000*
Total daily insulin used to reach TG goal (units/kg/day)	1.6 [1.0, 2.1]	1.8 [1.0, 2.3]	1.5 [1.0, 1.8]	0.169

*Statistically significant P <0.05.

#The p value pertinent to <36 hours vs ≥ 36 hours.

Among the total 77 patients, 57 had DM and 20 did not have DM as shown in Table 3. Among the patients with DM, 35.1% were on subcutaneous insulin before hospitalization. Compared to non-DM, patients with DM were obese (31.4 [28.0, 35.6] vs 27.8 [23.6, 30.3] kg/m2, p = 0.003), took longer time to reach TG-50% (16.0 [10.5, 27.0] vs 9.5 [5.3, 14.8] hours, p = 0.004) and TG-goal (41.0 [25.0, 60.5] vs 14.5 [12.5, 25.5] hours, p = 0.000) since starting CII and had higher daily insulin need (1.7 [1.3, 2.1] vs 1.1 [0.5, 1.9] U/kg/day, p = 0.041).

Table 3

Differences between patients with and without diabetes.

	Patients with DM (n = 57)	Patients without DM (n = 20)	P value
Demographics:
Age (years)	38.6 ± 9.9	41.3 ± 9.0	0.279
Males, n (%)	38 (66.7)	13 (65.0)	0.892
Ethnicity, n (%)			0.028*
Hispanic	35 (61.4)	10 (50.0)
African American	14 (24.6)	1 (5.0)
White	7 (12.3)	8 (40.0)
Other	1 (1.8)	1 (5.0)
Excess alcohol use, n (%)	26 (45.6)	13 (65.0)	0.136
BMI (kg/m2)	31.4 [28.0, 35.6]	27.8 [23.6, 30.3]	0.003*
Baseline:
Initial serum TG (mg/dL)	3987.0 [2905.5, 6246.5]	3426.5 [2186.5, 4519.0]	0.099
Serum TG at the start of CII (mg/dL)	3427.0 [2520.0, 5539.0]	2837.5 [2171.0, 4519.0]	0.205
Time from initial TG to start of CII (hours)	3.0 [0.0, 5.0]	4.0 [1.0, 6.7]	0.136
Midpoint:
TG-50% (mg/dL)	1470.0 [977.0, 2260.5]	1157.0 [791.0, 1537.8]	0.038*
Time from start of CII to TG-50% (hours)	16.0 [10.5, 27.0]	9.5 [5.3, 14.8]	0.004*
Total insulin used to reach TG-50% (units)	101.9 [63.5, 191.5]	38.3 [18.6, 54.8]	0.000*
Final:
TG final (mg/dL)	847.0 [641.5, 962.5]	791.0 [586.0, 970.8]	0.440
Time from start of CII to TG goal (hours)	41.0 [25.0, 60.5]	14.5 [12.5, 25.5]	0.000*
Required ≥36 hours to reach TG goal, n (%)	35 (61.4)	2 (10.0)	0.000*
Total insulin used to reach TG goal (units)	249.4 [129.9, 408.7]	60.5 [30.5, 106.4]	0.000*
Total daily insulin used to reach TG goal (units/kg/day)	1.7 [1.3, 2.1]	1.1 [0.5, 1.9]	0.041*

*Statistically significant P <0.05.

In bivariate analysis, the factors at baseline associated with faster TG response (TG-goal in <36 hours since starting CII) were the absence of DM, lower HbA1C, BMI, and initial TG. In binomial logistic regression analysis, only the absence of DM (OR 18.9, CI 3.02–119.2, p = 0.002) and higher daily insulin dose per kg (OR 3.11, CI 1.19–8.15, p = 0.02) were related to faster TG response.

Among those with DM, the patients were divided into RRP and SRP (Table 4). In bivariate analysis and binary logistic regression, compared to SRP with DM, RRP with DM showed higher total daily insulin use (U/kg/day) (1.9 [1.4, 2.3] vs 1.6 [1.1, 1.8], OR 4.6, CI 1.4–15.3, p = 0.019).

Table 4

Clinical and laboratory characteristics among the 54 patients with diabetes in the responder group who reached TG goal in less than 36 hours vs 36 hours or more.

	Less than 36 hours (n = 22)	36 hours or More (n = 32)	P value
Demographics:
Age (years)	37.2 ± 7.7	39.3 ± 11.2	0.45
Males, n (%)	17 (77.3)	20 (62.5)	0.25
Ethnicity, n (%)			0.85
Hispanic	15 (68.2)	20 (62.5)
African American	5 (22.7)	8 (25.0)
White	2 (9.1)	3 (9.4)
Other	0 (0.0)	1 (3.1)
BMI (kg/m2)	31.4 [27.0, 35.1]	31.9 [28.3, 37.4]	0.470
Excess alcohol use, n (%)	14 (63.6)	11 (34.4)	0.034*
Baseline:
HbA1C%	10.5 ± 2.6	11.2 ± 3.1	0.43
Initial serum TG (mg/dL)	2855.5 [1722.0, 4171.3]	4814.5 [3403.8, 6990.0]	0.001*
Serum TG at the start of CII (mg/dL)	2493.0 [1527.5, 3902.3]	4122.0 [3275.0, 6751.0]	0.000*
Time from initial TG to start of CII (hours)	3.0 [0.0. 5.3]	2.5 [0.0, 5.0]	0.813
Midpoint:
TG-50% (mg/dL)	954.0 [585.5, 1305.8]	1837.0 [1378.0, 2681.5]	0.000*
Time from start of CII to TG-50% (hours)	15.0 [6.0, 20.0]	22.5 [13.3, 34.3]	0.017*
Total insulin used to reach TG-50% (units)	90.0 [45.8, 143.4]	117.3 [81.6, 227.3]	0.117
Final:
TG final (mg/dL)	732.0 [546.8, 884.5]	898.0 [674.0, 962.8]	0.032*
Time from start of CII to TG goal (hours)	23.5 [10.8, 28.5]	54.0 [42.5, 72.5]	0.000*
Total insulin used to reach TG goal (units)	125.8 [64.3, 214.5]	279.2 [234.0, 469.8]	0.000*
Total daily insulin units used to reach TG goal (units/kg/day)	1.9 [1.4, 2.3]	1.6 [1.1, 1.8]	0.019*

*statistically significant P <0.05.

After completion of CII therapy, 70.1% were converted to subcutaneous insulin. During the hospital stay, 92.2% received fibrates after 27.0 [9.0, 43.0] hours and 29.9% received statins 53.6 ± 36.6 hours after initiation of CII. Among the 73 RP, the use of fibrates <36 hours vs ≥36 hours from the start of CII did not show a significant difference (p = 0.325) in the time taken from initiation of CII to TG-goal. All patients were discharged from the hospital indicating that there was a resolution of acute pancreatitis.

Discussion

Currently, there is no consensus concerning the most effective management of HTGP. Therapeutic options for acute HTGP management include supportive management for acute pancreatitis (including intravenous hydration, analgesics, bowel rest), CII, and, in select cases, PEX [13]. Only a few studies compared CII against supportive management. In one study, there was no difference between the two groups and subcutaneous insulin was used in some participants of the conservative treatment group [6]. In Berberich et al., a subgroup analysis of conservative therapy only (n = 10) vs. those who concurrently received CII (n = 12), there was no difference in the rate of TG decline with the limitation of this conclusion being the small sample size [14].

PEX is an effective but cumbersome and expensive process that removes TG from circulation, reserved for select patients with severe life-threatening HTGP. After one session, PEX can decrease TG by approximately 70% [15]. Potential complications of PEX include urticaria, risk of infections, allergic reaction to donor plasma, hypotension, and central catheter-associated complications such as hemorrhage, thrombosis, and injury to blood vessels [13].

There are few head-to-head studies comparing the efficacy of CII and PEX in acute HTGP management [16, 17].

Growing evidence consistently demonstrates CII to be an effective, safe, economic, and minimally invasive therapeutic option in patients with HTGP with or without DM [7, 16–19]. CII is effective and non-inferior to PEX in achieving a rapid reduction in TG levels [16, 17] and is more feasible and easier to use than PEX.

Our retrospective study is unique in evaluating the predictors as well as the rate of response of HTG to CII in a multi-ethnic population with HTGP. In our study, the time to reach the TG-goal was widely variable. The faster response of serum TG to CII was strongly associated with absence of DM, lower BMI, initial TG, and higher daily insulin use per kg body weight. In those without DM, the time to reach the TG-goal was about one day. Among those with DM, RRP had higher daily insulin use per kg body weight, lower initial TG and they reached the TG-goal within one day. In a literature review of 34 patients who received CII, patients with HTGP took three to five days to decrease serum TG to less than 500mg/dL [8]. In a study of 106 patients with HTGP receiving conservative management or CII, both groups reached TG <1000 mg/dL by day 3 [6]. This study did not find any statistical difference in TG response between the two groups. However, one of the notable limitations of that study is the use of subcutaneous insulin among the patients managed conservatively.

This study may suggest some practical management approaches to treating HTGP. In patients who have DM, we showed that much higher insulin/kg dose should be considered at initiation, at least 1.9 units/kg/day. As the management progresses, the time to reach TG-50% from initiation of CII can be utilized. At least half of the RRP reached TG-50% in 15 hours from initiation of CII compared to the much longer time taken by the SRP. Hence, an increase of insulin rate should be actively considered if, at approximately 15 hours after initiation of CII, TG did not decrease by 50%. In these circumstances, especially when some of the patients may not have DM, one should consider precautions for avoiding hypoglycemia. If TG is used as basis for insulin adjustment, a parallel infusion of dextrose may be needed to maintain euglycemia with cautious monitoring.

The limitations of our study include that it was retrospective, was not randomized and without comparison to other treatments modalities. However, this was not the scope of this study. Additionally, the CII dose was adjusted based on blood glucose levels and not primarily determined by the TG response.

Conclusion

CII was effective in reaching TG-goal in 95% of patients with HTGP. Half achieved TG-goal within 36 hours. Presence of DM, higher BMI and initial TG slowed the time to reach TG-goal. These baseline parameters and the rate of decline to TG-50% may be real-time indicators to initiate and adjust the CII for quicker response. Prospective studies are needed to establish more precise management protocols with emphasis on insulin dosing.

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14 Sep 2021

PONE-D-21-25261Hypertriglyceridemia-Associated Acute Pancreatitis: Response to Continuous Insulin InfusionPLOS ONE

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Whilst you may use any professional scientific editing service of your choice, PLOS has partnered with both American Journal Experts (AJE) and Editage to provide discounted services to PLOS authors. Both organizations have experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. To take advantage of our partnership with AJE, visit the AJE website (http://learn.aje.com/plos/) for a 15% discount off AJE services. To take advantage of our partnership with Editage, visit the Editage website (www.editage.com) and enter referral code PLOSEDIT for a 15% discount off Editage services.  If the PLOS editorial team finds any language issues in text that either AJE or Editage has edited, the service provider will re-edit the text for free.

Upon resubmission, please provide the following:

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● A clean copy of the edited manuscript (uploaded as the new *manuscript* file)

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The aim of this retrospective case series is to analyze the outcome of to continuous insulin infusion in hypertriglyceridemia-associated acute pancreatitis. It was concluded that continuous insulin infusion was effective in reducing serum triglyceride level in the majority of patients. Presence of diabetes, higher BMI and initial triglyceride slowed the time needed to effectively reduce serum triglyceride level.

There are many case reports and series demonstrating the effectiveness of insulin in lowering triglyceride level. This study provides data about the quantity of insulin and the duration required to reduce effectively the serum triglyceride level.

Criticisms:

1. Fasting and intravenous hydration applied in the treatment of acute pancreatitis rapidly and greatly reduces serum triglyceride level and can be as effective as intravenous insulin. Provide data about the applied intravenous fluid therapy in the first days of your patients. Intravenous hydration can be a confounding factor in this study. Please, discuss it.

2. Was dextrose infusion applied as part of the parenteral fluid therapy in the study? Please, provide details in the Methods.

3. Could you give data about the severity and outcome of acute pancreatitis especially in the RP and NR, SRP and RRP group, respectively?

4. What is the 75th percentile in this data from table 2? 4 [0.5]

5. Page 12: ‘Figure 1: Consort Table’. Some contradiction: is it a figure or table? ‘Patient’s flow chart’ is suggested to be used.

6. Page 22: ‘Figure 1’ is supposed to be Figure 2. What is the meaning of gosl? Please use the word time/Time, insulin/Insulin consistently.

7. The style of references does not follow the requirements of the journal.

8. There are many typos in the manuscript. Some of them:

Abstract: kg/m2…instead of …kg/m 2…

Abstract: …HbA1c… instead of …HbA1C…

Page 10: …abdominal pain… instead of…. pain abdomen…

Repeatedly:…. p = 0.130… instead of …p 0.130…

Table 2 title: …. less than 36 hours vs 36 hours …instead of … less than vs 36 hours …

Table 2:… 36 hours or more… instead of … 36 hours or More …

Table 2: … (hours) … instead of … hours)…

Reviewer #2: 1. Please review abstract. Currently not able to be interpreted easily.

2. "CII is an effective modality of therapy to reduce acutely the TG levels" - please review syntax

3. "AP was defined per Atlanta classification of acute

pancreatitis 2012 as any two of the three following criteria: pain abdomen (acute onset, persistent, severe, epigastric pain often radiating to the back), pancreatic enzymes (serum lipase or amylase) level at least 3 times greater than the upper limit of normal, computed tomography (CT) or magnetic resonance imaging (MRI) evidence of acute pancreatitis" - please correct to abdominal pain

4. Why were pregnant women excluded from this study?

5. "Secondary outcomes were time durations to achieve TG-50% (half of the respective initial TG) and time durations to achieve TG-goal" - please take out durations

6. What is your institution's protocol about rate and concentration of dextrose delivery? This will affect insulin doses

7. "The four patients who did not reach TG-goal (NR, non-responders) had a long time to initiation of CII (3 [0, 5.5] vs 10 [2.2, 37.2] hr, p 0.130) but otherwise did not differ from RP" - p value suggests this is not significant

Reviewer #3: In this manuscript authors investigated efficacy of continuous insulin insfusion on lowering triglyceride levels in patients with hypertriglyceridemic pancreatitis. They also search for the factors that can predict treatment success. This study gives a new insight how insulin, as a triglyceride lowering agent, could be used in patients with hypertriglyceridemic pancreatitis and which parameters could help in titration of therapy. In the current literature this kind of data are lacking so this manuscript is of great importance from the clinical and research points of view.

Introduction provides good and concise background of the topic. The objective is clearly defined.

Methodology of the study is well designed but continuous insulin infusion protocol could be explained in a more detailed way (quantity of insulin in infusion, type and volume of solution, frequency of glucose checks, goal glucose levels and adjustment of infusion rate). Other components of methodology, inclusion/exclusion criteria and outcomes are thoroughly written.

Results are well presented. Tables and figures are clear, informative and easy to follow. The data provide enough evidence to make a conclusions.

Discussion gives good perspective of current knowledge and how findings of this study can upgrade clinical practice. Conclusions are well presented and supported by the data.

The literature cited is relevant to the study.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

22 Oct 2021

Journal Requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Data included as Supplemental Materials

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

Information about de-identified data added to Methods section, page 4.

3. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service.

Whilst you may use any professional scientific editing service of your choice, PLOS has partnered with both American Journal Experts (AJE) and Editage to provide discounted services to PLOS authors. Both organizations have experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. To take advantage of our partnership with AJE, visit the AJE website (http://learn.aje.com/plos/) for a 15% discount off AJE services. To take advantage of our partnership with Editage, visit the Editage website (www.editage.com) and enter referral code PLOSEDIT for a 15% discount off Editage services. If the PLOS editorial team finds any language issues in text that either AJE or Editage has edited, the service provider will re-edit the text for free.

Upon resubmission, please provide the following:

● The name of the colleague or the details of the professional service that edited your manuscript

● A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a *supporting information* file)

● A clean copy of the edited manuscript (uploaded as the new *manuscript* file)

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The aim of this retrospective case series is to analyze the outcome of to continuous insulin infusion in hypertriglyceridemia-associated acute pancreatitis. It was concluded that continuous insulin infusion was effective in reducing serum triglyceride level in the majority of patients. Presence of diabetes, higher BMI and initial triglyceride slowed the time needed to effectively reduce serum triglyceride level.

There are many case reports and series demonstrating the effectiveness of insulin in lowering triglyceride level. This study provides data about the quantity of insulin and the duration required to reduce effectively the serum triglyceride level.

Criticisms:

1. Fasting and intravenous hydration applied in the treatment of acute pancreatitis rapidly and greatly reduces serum triglyceride level and can be as effective as intravenous insulin. Provide data about the applied intravenous fluid therapy in the first days of your patients. Intravenous hydration can be a confounding factor in this study. Please, discuss it.

In our ICUs, such patients would receive IV fluids (either 0.9% or 0.45% saline) based on hydration parameters. We did not include these data since the IV fluid therapy is consistently implemented with hydration information added in the Methods section, page 4.

2. Was dextrose infusion applied as part of the parenteral fluid therapy in the study? Please, provide details in the Methods.

There were no indications in the blood glucose data that any patients would have required dextrose infusions, therefore not mentioned in the Method section.

3. Could you give data about the severity and outcome of acute pancreatitis especially in the RP and NR, SRP and RRP group, respectively?

This study was focused on the impact of CII on HTG reduction. Data to assess severity of AP were not collected. However, based on admission and discharge dates, all patients survived and were discharged home. Sentence added in Results, page 10.

4. What is the 75th percentile in this data from table 2? 4 [0.5]

Fixed typo – 4 [0, 5]

5. Page 12: ‘Figure 1: Consort Table’. Some contradiction: is it a figure or table? ‘Patient’s flow chart’ is suggested to be used.

Figure 1 title changed to Consort Chart

6. Page 22: ‘Figure 1’ is supposed to be Figure 2. What is the meaning of gosl? Please use the word time/Time, insulin/Insulin consistently.

Figure 1 changed to Figure 2 and typos/inconsistencies fixed.

7. The style of references does not follow the requirements of the journal.

Reference style updated.

8. There are many typos in the manuscript. Some of them:

Abstract: kg/m2…instead of …kg/m 2…

Abstract: …HbA1c… instead of …HbA1C…

Page 10: …abdominal pain… instead of…. pain abdomen…

Repeatedly:…. p = 0.130… instead of …p 0.130…

Table 2 title: …. less than 36 hours vs 36 hours …instead of … less than vs 36 hours …

Table 2:… 36 hours or more… instead of … 36 hours or More …

Table 2: … (hours) … instead of … hours)…

Typos corrected.

Reviewer #2: 1. Please review abstract. Currently not able to be interpreted easily.

Abstract revised.

2. "CII is an effective modality of therapy to reduce acutely the TG levels" - please review syntax

Sentence on page 3 revised to: CII is an effective modality of therapy to reduce TG levels rapidly.

3. "AP was defined per Atlanta classification of acute

pancreatitis 2012 as any two of the three following criteria: pain abdomen (acute onset, persistent, severe, epigastric pain often radiating to the back), pancreatic enzymes (serum lipase or amylase) level at least 3 times greater than the upper limit of normal, computed tomography (CT) or magnetic resonance imaging (MRI) evidence of acute pancreatitis" - please correct to abdominal pain

Corrected.

4. Why were pregnant women excluded from this study?

Pregnant women were excluded to eliminate pregnancy as a confounding variable. At the same time, no patients with pregnancy were in the initial study group prior to exclusion. In this study of acute pancreatitis, no pregnant patients with acute pancreatitis presented.

5. "Secondary outcomes were time durations to achieve TG-50% (half of the respective initial TG) and time durations to achieve TG-goal" - please take out durations

Corrected.

6. What is your institution's protocol about rate and concentration of dextrose delivery? This will affect insulin doses

No information about rate and concentration of dextrose delivery is needed so there were no indications in the blood glucose data that any patients would have required dextrose infusions.

7. "The four patients who did not reach TG-goal (NR, non-responders) had a long time to initiation of CII (3 [0, 5.5] vs 10 [2.2, 37.2] hr, p 0.130) but otherwise did not differ from RP" - p value suggests this is not significant

As suggested, this statement was deleted.

Reviewer #3: In this manuscript authors investigated efficacy of continuous insulin insfusion on lowering triglyceride levels in patients with hypertriglyceridemic pancreatitis. They also search for the factors that can predict treatment success. This study gives a new insight how insulin, as a triglyceride lowering agent, could be used in patients with hypertriglyceridemic pancreatitis and which parameters could help in titration of therapy. In the current literature this kind of data are lacking so this manuscript is of great importance from the clinical and research points of view.

Introduction provides good and concise background of the topic. The objective is clearly defined.

Methodology of the study is well designed but continuous insulin infusion protocol could be explained in a more detailed way (quantity of insulin in infusion, type and volume of solution, frequency of glucose checks, goal glucose levels and adjustment of infusion rate).

More details were added to the Methods section, page 4.

Other components of methodology, inclusion/exclusion criteria and outcomes are thoroughly written.

Results are well presented. Tables and figures are clear, informative and easy to follow. The data provide enough evidence to make a conclusions.

Discussion gives good perspective of current knowledge and how findings of this study can upgrade clinical practice. Conclusions are well presented and supported by the data.

The literature cited is relevant to the study.

________________________________________

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Submitted filename: PLOS One Reviewer Responses 10-22-21.docx

Click here for additional data file.

11 Nov 2021

Hypertriglyceridemia-Associated Acute Pancreatitis: Response to Continuous Insulin Infusion

PONE-D-21-25261R1

Dear Dr. Amblee,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Zoltán Rakonczay Jr., M.D., Ph.D., D.Sc.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #3: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All required questions have been answered.

All required questions have been answered.

All required questions have been answered.

All required questions have been answered.

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

18 Nov 2021

PONE-D-21-25261R1

Hypertriglyceridemia-Associated Acute Pancreatitis: Response to Continuous Insulin Infusion

Dear Dr. Amblee:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Zoltán Rakonczay Jr.

Academic Editor

PLOS ONE