Abstract
The study involved hospitalizations with a diagnosis of hypertriglyceridemia-induced acute pancreatitis (HTGAP). This cohort was grouped into plasmapheresis and nonplasmapheresis groups using ICD-10 codes (6A550Z3 and 6A551Z3). Information was obtained on inpatient mortality, length of stay, total hospital charges, as well as the occurrence of comorbid systemic immune response syndrome, sepsis, septic shock, acute respiratory failure, acute respiratory distress syndrome, kidney failure, hypocalcemia, and need for transfusion of blood products. The study identified independent predictors of plasmapheresis. The plasmapheresis group had a higher proportion of patients with diabetes mellitus and obesity. Inpatient mortality was higher in the plasmapheresis group (0.86% vs 0.57%), and plasmapheresis was also associated with longer length of stay and higher total hospital charges. Overall, plasmapheresis was associated with higher proportions of inpatient complications. Patients with HTGAP had higher odds of undergoing plasmapheresis if they were in an urban location (adjusted odds ratio [aOR] 6.14, 95% confidence Interval [CI] 1.86–20.28, P = 0.003), larger hospital (aOR 3.37, 95% CI 2.14–5.29, P < 0.001), and teaching hospital (aOR 2.01, 95% CI 1.39–2.92, P < 0.001). Black patients were less likely to undergo plasmapheresis than white patients (aOR 0.42, 95% CI 0.23–0.78, P = 0.006). Patients with HTGAP who receive plasmapheresis may be at higher risk of numerous in-hospital complications, including death, compared to those who do not receive plasmapheresis. Black and older patients were less likely to undergo plasmapheresis.
Keywords: Acute pancreatitis, hypertriglyceridemia, outcomes, plasmapheresis
Hypertriglyceridemia-induced acute pancreatitis (HTGAP) is a known complication of hypertriglyceridemia that can be fatal.1 Hypertriglyceridemia is reported to be the third leading cause of acute pancreatitis.2 HTGAP is characterized by the clinical syndrome of acute pancreatitis in the presence of severe hypertriglyceridemia (>1000 mg/dL) and the absence of other causes.3 Pancreatitis tends to be more severe in patients with HTGAP compared with other causes.4,5 The mainstay of management of acute pancreatitis is pancreatic rest, pain control, and fluid administration. In the subset of patients with HTGAP, insulin drip, and in select patients, plasmapheresis may be used as adjuvant therapy.6 There is a lack of randomized controlled studies investigating the benefit of plasmapheresis over other treatment modalities.1,2,7 In this study, we used 3 years of data from a national database to identify the demographic characteristics and outcomes of patients admitted with HTGAP who received plasmapheresis to obtain predictors of plasmapheresis in the national population. This study aimed to identify any factors that predict the choice of the procedure in these patients.
METHODS
This was a retrospective observational study involving adult hospitalizations with HTGAP in the US between January 1, 2016, and December 31, 2018. We sourced data from the Nationwide Inpatient Sample (NIS) database for 2016, 2017, and 2018. The NIS is a database of hospital inpatient stays derived from billing data submitted by hospitals to statewide data organizations across the US.8 This dataset is weighted to obtain national estimates.9 The databases were coded using the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS). The study involved hospitalizations with a diagnosis of HTGAP. There is no specific diagnostic code for HTGAP. This cohort was obtained following a literature review of prior studies and guidelines that combined a clinical diagnosis of acute pancreatitis, hypertriglyceridemia, and exclusion of biliary disease, alcohol, and drug-induced acute pancreatitis.10,11 Hence, patients with a principal diagnosis of unspecified acute pancreatitis and a secondary diagnosis of hypertriglyceridemia were included. Patients <18 years or with a secondary diagnosis of cholelithiasis or cholecystitis were excluded. Hospitalizations with plasmapheresis were identified with ICD-10 procedure codes 6A550Z3 and 6A551Z3.
The study outlined the sociodemographic and hospital characteristics of HTGAP hospitalizations with plasmapheresis. We calculated inpatient mortality, length of stay (LOS), total hospital charges (THC), as well as the proportions of hospitalizations with comorbid systemic immune response syndrome, sepsis, septic shock, acute respiratory failure, acute respiratory distress syndrome, renal failure, hypocalcemia, and need for transfusion of blood products. We identified independent predictors of undergoing plasmapheresis in patients with HTGAP.
We analyzed the data using Stata® Version 16 software (StataCorp, College Station, TX). All analyses were conducted using the weighted samples for national estimates under the Healthcare Cost and Utilization Project regulations for use of the NIS database. Age was grouped as 18 to 39 years representing young adults, 40 to 64 years representing middle-aged adults, and 65 years and above representing the elderly. To obtain independent predictors of plasmapheresis, a univariable prescreening model was employed to identify variables associated with undergoing plasmapheresis. Thus, age categories, sex, Charlson comorbidity index (CCI), race, hospital location, hospital teaching status, hospital bed size, mean household income, and comorbidities were screened, with variables with P < 0.2 included in the final multivariable regression analysis. Age categories, sex, race, CCI, hospital location, hospital teaching status, hospital bed size, hypertension, diabetes, chronic kidney disease, obesity, anemia, and smoking history were included in the final model. P < 0.05 was the threshold for statistical significance.
The NIS database is a retrospective dataset and lacks patient, state-level, and hospital identifiers. This study, therefore, did not require Cook County Health institutional review board approval. The NIS is a large publicly available all-payer inpatient care database in the US from the Healthcare Cost and Utilization Project central distributor.
RESULTS
We analyzed 1155 hospitalizations over the 3 years. The mean age of hospitalized patients with plasmapheresis was 39.8 years; 38.5% were women, and 22.9% were Hispanic. These hospitalizations had a higher proportion of comorbid diabetes mellitus and obesity but a lower proportion of comorbid congestive heart failure and chronic kidney disease. The plasmapheresis group was significantly more likely to be in large-bed, urban, teaching hospitals (Table 1). Inpatient mortality was 0.86% in the plasmapheresis group and 0.57% in the nonplasmapheresis group. The plasmapheresis group had longer LOS and higher THC. Overall, plasmapheresis was associated with higher proportions of complications (Table 2).
Table 1.
Patient and hospital characteristics of 1155 hospitalizations for hypertriglyceridemia-induced acute pancreatitis with plasmapheresis
| Variable | Proportion |
|---|---|
| Mean age ± SE (years) | 39.8 ± 0.4 |
| Age range | |
| 18–39 | 65.8% |
| 40–64 | 33.3% |
| ≥65 | 0.9% |
| Women | 38.5% |
| Racial distribution | |
| White | 58.5% |
| Black | 6.5% |
| Hispanic | 22.9% |
| Others | 12.1% |
| Charlson Comorbidity Index score | |
| 0 | 3.4% |
| 1 | 15.6% |
| 2 | 7.8% |
| ≥3 | 73.2% |
| Insurance type | |
| Medicare | 9.4% |
| Medicaid | 27.2% |
| Private | 47.8% |
| Uninsured | 15.6% |
| Median annual income in patient’s zip code, 2017 | |
| ≤$43,999 | 26.0% |
| $44,000–$55,999 | 30.0% |
| $56,000–$73,999 | 22.9% |
| ≥$74,000 | 21.1% |
| Comorbidities | |
| Diabetes | 68.8% |
| Hypothyroidism | 6.5% |
| Hypertension | 46.3% |
| Smoking history | 39.4% |
| Congestive heart failure | 3.0% |
| Chronic kidney disease | 6.1% |
| Coronary artery disease | 6.9% |
| Prior cerebrovascular accident | 0.4% |
| Obesity | 38.1% |
| Chronic obstructive pulmonary disease | 2.6% |
| History of anemia | 30.3% |
| Hospital characteristics | |
| Hospital region | |
| Northeast | 14.7% |
| Midwest | 30.8% |
| South | 37.2% |
| West | 17.3% |
| Hospital bed size | |
| Small | 10.8% |
| Medium | 23.8% |
| Large | 65.4% |
| Urban location | 98.7% |
| Teaching hospital | 80.1% |
Table 2.
Clinical outcomes of 1155 hospitalizations for hypertriglyceridemia-induced acute pancreatitis and plasmapheresis
| Outcome | Value |
|---|---|
| Primary outcome | |
| In hospital mortality | 0.86% |
| Secondary outcomes | |
| Mean length of stay (days) | 8.5 |
| Mean total hospital charges | $92,391 |
| Systemic immune response syndrome | 14.7% |
| Sepsis | 6.9% |
| Septic shock | 3.5% |
| Hypocalcemia | 36.8% |
| Blood transfusion | 6.5% |
| Acute respiratory failure | 15.2% |
| Acute respiratory distress syndrome | 0.9% |
| Acute renal failure | 29.0% |
Patients with HTGAP had higher odds of undergoing plasmapheresis if they were in urban-located (adjusted odds ratio [aOR] 6.14, 95% confidence interval [CI] 1.86–20.28, P = 0.003), large-bed-size (aOR 3.37, 95% CI 2.14–5.29, P < 0.001), and teaching hospitals (aOR 2.01, 95% CI 1.39–2.92, P < 0.001). The CCI was not significantly associated with a change in odds of plasmapheresis. Black patients were less likely to undergo plasmapheresis compared to white patients (aOR 0.42, 95% CI 0.23–0.78, P = 0.006). Older age was associated with a lower odds ratio of undergoing plasmapheresis, with elderly patients having only a 2% odds of getting plasmapheresis compared to young adults (aOR 0.02, 95% CI 0.01–0.10, P < 0.001) (Table 3).
Table 3.
Independent factors associated with plasmapheresis in hospitalizations for hypertriglyceridemia-induced acute pancreatitis
| Variable | Adjusted OR | 95% CI | P value* |
|---|---|---|---|
| Urban hospitals | 6.14 | 1.86–20.28 | 0.003 |
| Large hospital bed sizea | 3.37 | 2.14–5.29 | <0.001 |
| Anemia | 2.61 | 1.88–3.64 | <0.001 |
| Teaching hospital | 2.01 | 1.39–2.92 | <0.001 |
| Charlson index ≥3 | 1.85 | 0.84–4.05 | 0.124 |
| Medium hospital bed sizea | 1.69 | 1.01–2.80 | 0.044 |
| Diabetes | 1.66 | 1.20–2.31 | 0.002 |
| Obesity | 1.25 | 0.93–1.67 | 0.135 |
| Women | 0.83 | 0.62–1.12 | 0.226 |
| Hypertension | 0.64 | 0.47–0.87 | 0.005 |
| Blacksb | 0.42 | 0.23–0.78 | 0.006 |
| Age 40–64 yearsc | 0.41 | 0.30–0.57 | <0.001 |
| Age ≥65 yearsc | 0.02 | 0.01–0.10 | <0.001 |
aCompared to small hospital by bed size.
bCompared to Whites.
cCompared to age 18–39.
CI indicates confidence interval; OR, odds ratio.
DISCUSSION
The mean age of hospitalizations for patients with HTGAP who had plasmapheresis was significantly lower than the overall mean age for patients with HTGAP. A 3-year retrospective study based in a tertiary care center in India found that the mean age of patients undergoing plasmapheresis was 37.5, with a range of 15 to 79 years.12 This was similar to the findings from our study. Older patients are reported to have higher risks of complications following plasmapheresis, with some reports showing a risk of complications of 11.5% in patients >65 years old vs 3.9% in younger patients.13 Plasmapheresis is rarely used in older adults and may come with the risk of numerous adverse effects including clotting, blood access difficulty, and allergic reactions (13). Our findings reflect this lower use of plasmapheresis in older adults.
Patients with HTGAP had higher odds of undergoing plasmapheresis if they were in urban-located, large-bed, and teaching hospitals. This is possibly due to the availability of the technology and expertise in these large urban hospitals and teaching hospitals. Black patients were less likely to undergo plasmapheresis compared to white patients. It is unclear why this racial discrepancy exists. Overall, the findings reflect that those in larger, urban teaching hospitals were more likely to undergo plasmapheresis while black and older patients were less likely to undergo plasmapheresis.
The plasmapheresis group had a higher proportion of patients with diabetes mellitus and obesity, which are known causes of secondary hypertriglyceridemia (4). Plasmapheresis has been reportedly implemented in patients with HTGAP following failure in conventional management such as pain control, fluid resuscitation, pancreas rest, and insulin therapy.14 Insulin resistance in diabetes has been linked with worse outcomes in acute pancreatitis.15 Additionally, obesity is known to be linked with insulin resistance, which may put these patients at a higher risk of being refractory to treatments like insulin therapy.16
In our study, patients who underwent plasmapheresis had higher mortality, increased LOS, and increased rate of complications compared to patients who did not receive plasmapheresis. This is discordant with other case reports and observational studies, which found plasmapheresis to have both mortality and morbidity benefits.17–20 A retrospective study involving 862 patients in China did not show any statistically significant difference in mortality between HTGAP patients who underwent plasmapheresis compared to those without plasmapheresis.21 Despite the absence of observed statistical significance in mortality in the study done in China, they recorded an absolute increase in mortality in patients treated with plasmapheresis. Our study found numerous complications that were more common in plasmapheresis patients, including sepsis, septic shock, hypocalcemia, need for blood transfusions, and acute renal failure. In a study involving 17 patients treated with plasmapheresis for HTGAP in a hospital in Taiwan, 13 patients showed complete recovery while two patients died from septic shock and multiorgan failure and two other patients developed intra-abdominal abscesses that necessitated surgical drainage.22 The presence of complications like septic shock and organ failure may result in increased mortality in patients undergoing plasmapheresis. Reported side effects associated with plasmapheresis include hypotension, arrhythmias, sensations of cold associated with paresthesia, temporarily elevated temperatures, and shock, among others.23 Thus, noninvasive treatment is initiated before plasmapheresis, especially considering the noninferiority, safety, and efficacy of these treatment modalities, such as insulin therapy.24,25 Sicker patients and patients who fail conservative management are more likely to receive plasmapheresis, making the plasmapheresis group more likely to be associated with worse outcomes compared to patients treated without plasmapheresis.
Plasma exchange was also associated with longer LOS and higher THC. The cost of plasmapheresis is reported to be higher than other triglyceride-lowering therapies for HTGAP, which may contribute to the higher THC associated with plasmapheresis therapy.24 This increased healthcare cost utilization has not consistently translated to improvement in clinical outcomes. The greater LOS may reflect the increased prevalence of complications in these patients and the need for continued monitoring.
In a subset of patients who receive double-filtration plasmapheresis, recent studies have demonstrated no beneficial effects in improving clinical outcomes in HTGAP patients despite rapid and effective reductions in triglyceride levels compared to those without double-filtration plasmapheresis.26 Double-filtration plasmapheresis has, however, been shown to help stabilize patients with severe hypertriglyceridemia and related recurrent pancreatitis who are refractory to dietary and drug therapies that are conventionally used.27
This study has some limitations. The NIS database does not include information regarding the severity of hypertriglyceridemia or HTGAP. The database reports information on hospitalizations and not on individual patients. The data from the NIS are subject to nonrandomization, and only a small proportion of hospitalizations with HTGAP involved plasmapheresis.
In conclusion, we noted an increase in mortality and complications among patients who received plasmapheresis. We are, however, unable to make any firm recommendation against the use of plasmapheresis due to the limitations of this retrospective observational study. We recommend the implementation of conservative management before using plasmapheresis, considering the noninferiority and safety profile of conservative management. The uncertainty regarding the use of plasmapheresis further emphasizes the need for large, randomized controlled studies on the use of plasmapheresis in patients with HTGAP.
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