A B S T
R A C T
Limited data exist on the
safety of endoscopic retrograde cholangiopancreatography (ERCP) in patients
with sickle cell disease (SCD). The objective of this study
is to assess ERCP outcomes
in SCD. Patients
older than 18 with SCD or its variants
undergoing ERCP 2008-2014 were identified from the National Inpatient Sample. Case-control matching based on age, sex and race was performed. Complications of ERCP were assessed against
controls; specific SCD-related outcomes were assessed
in comparison with SCD patients who did not undergo ERCP.
334 patients with SCD underwent ERCP, representing a weighted
population of 1669. Complications related
to ERCP were infrequent, though
the rate of post-ERCP bleeding
was higher in SCD
patients compared to controls (2.2% vs. 0.6%; p<0.001). When adjusted for independent factors
for post-ERCP hemorrhage including age, sex, hospital
size, hospital teaching
status and indication for ERCP, the adjusted OR for post-ERCP
hemorrhage was still higher in the SCD cohort (aOR 5.59; 95% CI, 3.63 – 8.61). Rates of post-ERCP pancreatitis were similar (5.4% vs. 4.9%;
p=0.42). Complications after ERCP specific to SCD were higher when compared to other SCD patients. The incidence of painful
crisis (8.0%), infection (4.0%), pneumonia (4.3%)
and acute chest
syndrome (5.3%) were higher in SCD patients
undergoing ERCP. Sickle cell disease
is an independent risk factor for post-ERCP hemorrhage in patients undergoing
ERCP. Additionally, the rates of SCD-related complications are higher in patients undergoing ERCP. Therefore, proper precautions must be taken prior to
ERCP to minimize the risks associated with this procedure in SCD patients.
Keywords: Endoscopic retrograde cholangiopancreatography, Hepatobiliary, Sickle cell disease.
1.Introduction
Sickle cell disease is an
autosomal recessive disorder caused by a mutation
encoding the beta-globin component of hemoglobin1. The resultant dysmorphic hemoglobin S polymerizes into
long chains under low oxygen states, leading
to the characteristic “sickle“ shape of these cells. The abnormal shape and
polymerization of the hemoglobin creates microvascular occlusion in capillary
beds. This occlusion manifests clinically as ischemia and potentially necrosis
of end organs. Patients with sickle
cell disease (SCD) suffer from both severe chronic hemolytic anemia and acute
episodes of vaso- occlusive disease due to trapping
of red blood cells (RBC)
in the microvasculature. Vaso-occlusive crises are the
hallmark of the disease and
contribute to morbidity and mortality. The disease most commonly affects individuals from Africa and is also seen
in persons of Mediterranean, Arab and Indian
descent in concert with other hemoglobinopathies,
such as hemoglobin C (HbC), hemoglobin D (HbD), hemoglobin E (HbE) and
hemoglobin S-b-thalassemia2,3. Approximately 100,000 people have sickle
cell anemia in the United States4.
This estimation is expected to
increase as newborn screening, primary stroke prevention, infection prophylaxis
and medical management improve5.
Complications of SCD can affect any part of the body, posing both diagnostic
and therapeutic dilemmas to physicians. Notably,
the biliary system is one of the most common sites affected.
2.Methods
2.1. Data source
The Nationwide Inpatient
Sample (NIS) database was used to collect data from the years 2008 to 2014. The
NIS is the largest all-payer inpatient database, comprising approximately 20%
of all inpatient admissions to nonfederal hospitals in the United States.
Patient records include information extracted from inpatient discharge data
using billing codes. It is publicly available as part of the Healthcare Cost
and Utilization Project (HCUP).
The NIS database includes
unique identifiers, demographics, primary and secondary diagnosis codes (up to
30), primary and secondary procedure codes (up to 15), hospital characteristics
and a variety of other variables related to the patient, hospital and nature of
the admission. Quality control of this database provides reliable and accurate
information pertaining to each hospital discharge. Therefore, results extracted
from this database can be used to represent the population of the United States
as a whole. Cost of hospitalization was calculated using charge ratios provided
by HCUP and each individual cost was adjusted for inflation referencing
September 2018 data.
2.2. Study population
The study population
consisted of all patients aged 18 years or older within the NIS database who
were hospitalized and underwent inpatient ERCP. Procedural coding using the
International Classification of Diseases, 9th revision, Clinical Modification
(ICD-9 CM) were used to select patients who underwent ERCP, as outlined in (Table
1). All patients with a diagnosis of SCD along with its variants were
included, as outlined in (Table 2).
Table 2: ERCP ICD-9 CM Procedure Codes.
|
Procedure Code |
Procedure Description |
|
Diagnostic ERCP Codes |
|
|
51.1 |
Endoscopic retrograde cholangiopancreatography (ERCP) |
|
51.11 |
Endoscopic retrograde cholangiography (ERC) |
|
51.14 |
Other closed (endoscopic) biopsy of biliary duct or
sphincter of Oddi |
|
52.13 |
Endoscopic retrograde pancreatography (ERP) |
|
52.14 |
Closed (endoscopic) biopsy of pancreatic duct |
|
Therapeutic ERCP Codes |
|
|
51.84 |
Endoscopic dilation of ampulla and biliary duct |
|
51.85 |
Endoscopic sphincterotomy and papillotomy |
|
51.86 |
Endoscopic insertion of nasobiliary drainage tube |
|
51.87 |
Endoscopic insertion of stent (tube) into bile duct |
|
51.88 |
Endoscopic removal of stone(s) from biliary duct |
|
52.93 |
Endoscopic insertion of stent (tube) into pancreatic duct |
|
52.94 |
Endoscopic removal of stone(s) from pancreatic duct |
|
52.97 |
Endoscopic insertion of nasopancreatic drainage tube |
|
52.98 |
Endoscopic dilation of pancreatic duct |
Table 2: Sickle Cell Disease and Variant ICD-9
CM Codes
|
Diagnosis Code |
Diagnosis Description |
|
Sickle Cell Disease |
|
|
282.6 |
Sickle-cell disease, unspecified |
|
282.61 |
Hb-SS disease without crisis |
|
282.62 |
Hb-SS disease with crisis |
|
Sickle Cell Variants |
|
|
282.41 |
Hemoglobin S – Beta thalassemia without crisis |
|
282.42 |
Hemoglobin S – Beta thalassemia with crisis |
|
282.63 |
Hemoglobin SC disease without crisis |
|
282.64 |
Hemoglobin SC disease with crisis |
The control population consisted
of non-sickle cell disease patients who underwent ERCP during the same time
period. Selection was performed using case-control matching. Patients were
selected randomly using SPSS version 25 (IBM Corp. Armonk, NY). Three non-sickle
patient controls were selected randomly for each sickle patient who underwent
ERCP. Cases and controls were matched on race, sex and age range to minimize
confounding.
2.3. Variables studied
The goal of the study was to evaluate the safety of ERCP in SCD
patients. The primary outcomes of the study were
(1) complications related to ERCP directly, which included hemorrhage,
post-ERCP pancreatitis, perforation and cholecystitis and (2) unique
complications related to sickle cell disease, which included acute chest
syndrome, pain crisis, stroke, fever, infection, bacteremia, pneumonia,
thrombosis and mortality.
Secondary outcomes evaluated included cost of hospitalization, length
of stay and procedure failure rates. Failure was defined as the need to perform
percutaneous transhepatic cholangiography (PTC) (ICD-9 code 87.51) or open bile
duct exploration (ICD-9 code 51.13) after ERCP.
Post-ERCP pancreatitis was defined using previously defined criteria
(13, 14). Bleeding after ERCP was identified by specific ICD-9 codes defining
post-ERCP hemorrhage (998.11, 909.3). Patients with a diagnosis of bleeding on
admission (primary diagnosis) were excluded to capture diagnoses related to
procedures done during the hospitalization. Cholecystitis after ERCP was
identified using ICD-9 codes 575.0 and 575.1, excluding those listed as primary
or secondary diagnosis codes. Perforation after ERCP was defined by ICD-9 code
569.83.
In order to define severity of comorbidities, the Elixhauser
comorbidity index was used. This is a well-established measure of predicting
in-patient mortality and has been validated in prior studies (15-17).
Comorbidity software created by HCUP was used to create these variables based
on known diagnosis codes.
2.4. Statistical analysis
Data analysis was performed using SPSS version 25. Individual discharge
weights provided by HCUP were used to reflect national data. Analysis for
categorical data was completed using chi-square tests and for continuous data
using the student t test. A p value of less than 0.05 was considered
statistically significant. Both univariate and bivariate analyses were
performed to assess the indications as well as complications associated with
ERCP in patients with sickle cell disease. Finally, logistic regression was
employed to determine odds ratios of complications related to ERCP.
The study was exempt from institutional review board committee review
owing to the de-identified nature of the data.
3. Results
3.1.Patient demographics
and hospital characteristics
A total of 334 patients with SCD or a disease variant were identified
who underwent ERCP during the study period from 2008 to 2014. When applying
discharge weights, this represented a national estimate of 1669 patients. Using
case- control matching in SPSS, 4884 non-sickle cell individuals were randomly
selected. These individuals were matched with the SCD cohort based on age
categories, race and sex in order to minimize confounding. Demographic
information of these cohorts is presented in (Table 3).
Table 3: Patient Demographics and Hospital Characteristics.
|
Variable |
All |
Sickle
Cell Disease (n=1669) |
Control
(n=4884) |
P-value |
|
Patient
Age (Years) |
|
|
|
0.18 |
|
Mean
(SD) |
35.23
(16.1) |
34.3
(14.3) |
35.6
(16.6) |
|
|
Sex |
|
|
|
0.904 |
|
Female |
54.50% |
54.20% |
54.60% |
|
|
Male |
45.50% |
45.80% |
45.40% |
|
|
Race |
|
|
|
0.159 |
|
White |
3.30% |
3.30% |
3.30% |
|
|
Black |
87.70% |
87.70% |
87.60% |
|
|
Hispanic |
6.30% |
5.40% |
6.60% |
|
|
Asian
or Pacific Islander |
0.90% |
0.60% |
1.00% |
|
|
Native
American |
0.80% |
0.00% |
1.00% |
|
|
Other |
1.10% |
3.00% |
0.40% |
|
|
Primary
Payer |
|
|
|
<0.001 |
|
Medicare |
16.90% |
26.90% |
13.60% |
|
|
Medicaid |
31.90% |
32.60% |
31.70% |
|
|
Private
and HMO |
32.70% |
29.60% |
33.80% |
|
|
Self-pay |
12.30% |
8.40% |
13.70% |
|
|
No
charge |
1.40% |
0.90% |
1.50% |
|
|
Other |
4.70% |
1.50% |
5.80% |
|
|
Hospital
Bed Size |
|
|
|
0.446 |
|
Small |
7.30% |
6.00% |
7.70% |
|
|
Medium |
22.10% |
21.90% |
22.20% |
|
|
Large |
70.60% |
72.20% |
70.10% |
|
|
Hospital Region |
|
|
|
<0.001 |
|
Northeast |
16.80% |
24.90% |
14.10% |
|
|
Midwest |
14.20% |
15.90% |
13.70% |
|
|
South |
45.40% |
50.30% |
43.90% |
|
|
West |
23.50% |
9.00% |
28.30% |
|
|
Hospital Teaching Status |
|
|
|
0.001 |
|
Teaching |
65.20% |
75.10% |
61.80% |
|
|
Nonteaching |
34.80% |
24.90% |
38.20% |
|
|
Weekend
Admission |
22.60% |
23.40% |
22.30% |
0.694 |
|
Elixhauser Comorbidity Index |
|
|
|
0.87 |
|
0 |
30.40% |
33.20% |
29.40% |
|
|
1 |
25.00% |
25.70% |
24.70% |
|
|
2 |
17.30% |
15.90% |
17.80% |
|
|
3+ |
27.30% |
25.20% |
28.10% |
|
The median age of all patients included in the study was 31 years. Due
to case-control matching based on race and age, there were no statistically
significant difference between groups. The majority of patients were black as
would be expected due to the higher prevalence of SCD in this population.
Patients with SCD were more likely to have Medicare or Medicaid compared to
non-sickle cell patients (p<0.001). Also, patients with SCD were more
commonly cared for in the Northeast and in teaching hospitals compared to
non-sickle cell patients (p<0.001).
There was no difference between groups with regards to Elixhauser
comorbidity index (p=0.870), as can be seen in (Table 3). The mean length of
stay was 8.7 days in the SCD group versus 7.4 days in the control group
(p=0.009). There was no significant difference (p=0.124) in the mean cost of
hospitalization between sickle cell patients ($22,813.37) and the control group
($20,583.02). However, the cost of hospitalization was higher (p<0.001) in
teaching hospitals ($23,456.11) compared to nonteaching hospitals ($16,860.75).
3.2. Indications for ERCP
The various indications for ERCP both in the sickle cell disease group
and in controls are shown in (Table 4). SCD patients had ERCP significantly
more often than non-sickle cell patients for choledocholithiasis (33.8% vs.
18.0%, p<0.001), cholangitis (18.0% vs. 10.5%, p<0.001) and jaundice
(13.2% vs. 4.1%, p<0.001). SCD patients were less likely to have ERCP for
acute pancreatitis (17.7% vs. 30.7% p<0.001), biliary strictures (8.1% vs.
13.2%, p<0.001) and abnormal liver tests (1.4% vs. 2.8%, p=0.001) when compared
to non-sickle cell patients.
Table 4: Indications for ERCP.
|
Variable |
All (n=6553) |
Sickle
Cell Disease (n=1669) |
Control (n=4884) |
P-value |
|
Choledocholithiasis
with or without gallstones |
22.00% |
33.80% |
18.20% |
<0.001 |
|
Cholangitis |
12.30% |
17.90% |
10.50% |
<0.001 |
|
Acute
Pancreatitis |
27.30% |
17.80% |
30.70% |
<0.001 |
|
Biliary
Stricture |
11.90% |
8.10% |
13.20% |
<0.001 |
|
Jaundice |
6.40% |
13.30% |
4.10% |
<0.001 |
|
Abnormal
liver tests |
2.40% |
1.40% |
2.80% |
0.001 |
3.3. ERCP related outcomes
Various ERCP-related complications were evaluated in the study
including cholecystitis, perforation, post-ERCP bleeding or hemorrhage and
post-ERCP pancreatitis (Table 5). Overall, the rates of these complications
were low in both groups. There were no perforations in either group. According
to the data user agreement, any individual count of less than 10 cannot be
reported and therefore cholecystitis was not reported. The rates of post-ERCP
pancreatitis were not significantly different between groups (5.4% in SCD vs.
4.9% in controls, p=0.42).
Table 5: Complications of ERCP.
|
|
All (n=6553) |
Sickle Cell Disease
(n=1669) |
Control (n=4884) |
|
|
Variable |
P-value |
|||
|
Cholecystitis |
IS |
IS |
IS |
0.246 |
|
Perforation |
0% |
0% |
0% |
- |
|
Post-ERCP
Hemorrhage |
1.00% |
2.20% |
0.60% |
<0.001 |
|
Post-ERCP
Pancreatitis |
5.00% |
5.40% |
4.90% |
0.42 |
The rate of post-ERCP hemorrhage was significantly higher in the SCD
group (2.2%) compared to the control group (0.6%) with p value of <0.001.
There was no statistical difference in post-ERCP hemorrhage between teaching
and non-teaching hospitals.
Independent factors associated with post-ERCP hemorrhage included sex,
hospital bed size, teaching status of the hospital, acute pancreatitis and
jaundice as the indication for ERCP. In addition, therapeutic maneuvers during
the procedure including endoscopic sphincterotomy, endoscopic dilation of the
ampulla and biliary duct and endoscopic removal of stones from the bile duct
were also associated with post-ERCP hemorrhage. When accounting for these
factors, the adjusted odds ratio (aOR) for post-ERCP hemorrhage in sickle cell
disease vs. non-sickle cell patients was 5.06 (95% CI, 2.92 – 8.78,
p<0.001). The risk was significantly higher in patients undergoing a
therapeutic ERCP for removal of stones from the bile duct, aOR 4.52 (95% CI,
2.24 – 9.12, p<0.001).
The overall
mortality rate was not statistically different between groups (1.2% in sickle
cell disease vs. 0.6% in controls; p=0.277). The failure rate of ERCP was only
0.1% for the entire cohort.
3.4.Sickle cell disease related outcomes
Sickle cell disease has inherent complications of the disease process
itself and therefore complications in this cohort undergoing ERCP were compared
to the national average for SCD patients not undergoing ERCP during the same
study period. Common complications, including acute chest syndrome, pain
crisis, stroke, post-operative fever, infection, bacteremia, pneumonia and
thrombosis, were evaluated. National estimates were based on SCD patients that
did not undergo ERCP during the study period. The findings can be seen in
(Table 6).
Table 6: Sickle Cell Disease Complications with ERCP.
|
Variable |
Sickle Cell Disease (n=1669) |
National
Estimates |
P-value |
|
Acute Chest Syndrome |
5.30% |
4.20% |
<0.001 |
|
Pain Crisis |
8.00% |
2.90% |
<0.001 |
|
Stroke |
0.00% |
0.10% |
0.579 |
|
Post-op Fever |
1.60% |
4.30% |
0.731 |
|
Infection |
4.00% |
3.10% |
<0.001 |
|
Bacteremia |
3.00% |
1.60% |
0.053 |
|
Pneumonia |
4.30% |
2.50% |
0.021 |
|
Thrombosis |
1.00% |
0.30% |
0.071 |
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