Outcomes of Endoscopic Retrograde Cholangiopancreatography in Patients with Sickle Cell Disease
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.
Due to the abnormal structure of hemoglobin, red blood cells in SCD patients have a shorter life span. Chronic hemolysis leads to continuous heightened production of bilirubin, which subsequently leads to the development of pigmented gallstones. Overall, 70% of patients with sickle cell disease develop cholelithiasis during their lifetime6,7. With improving life expectancy in the disease, this number is likely to rise. An important complication of cholelithiasis is choledocholithiasis8. In the general population with known cholelithiasis, the incidence of choledocholithiasis is 10-15% (9). In SCD patients, the incidence ranges from 18-30%9,10. As a result, the need for intervention is much higher in this population. Endoscopic retrograde cholangiopancreatography (ERCP) is a valuable tool for therapeutic removal of obstructing stones both in pre- and post-cholecystectomy patients11. To date, the literature for overall safety of ERCP in patients with SCD is scarce12. Given the limited data of ERCP outcomes in patients with sickle cell disease, our study aim was to examine both ERCP-related complications and SCD-related complications in a large national cohort. This analysis was conducted to provide gastroenterologists with stronger evidence to perform ERCP in this group of patients and to provide them with anticipatory guidance about the specific risks associated with the procedure in these patients.
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.
Table 2: Sickle Cell Disease and Variant ICD-9
CM Codes
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% |
|
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.
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.
4.DISCUSSION
Overall, the risk of acute chest syndrome (5.3%), pain crisis (8.0%), infection (4%) and pneumonia (4.3%) were all significantly higher in SCD patients that underwent ERCP compared to the national average (all p>0.05). The risk of stroke, post-operative fever, bacteremia and thrombosis were similar between ERCP and non-ERCP groups.
This was a retrospective study using national
data to evaluate the safety and outcomes of ERCP in patients with
sickle cell disease. Overall, 1669 patients with sickle cell disease and its variants were included. Known
complications of ERCP were compared
between SCD patients and controls without this
disease. In order to minimize confounding, SCD-specific complications were
compared between patients that underwent ERCP and those that did not.
To
date, the largest study evaluating outcomes of ERCP in SCD patients had 54
patients12. With 1669 patients nationwide, this is currently the largest
study evaluating this specific population.
The most common indication for ERCP in SCD patients
with was choledocholithiasis (33.8%). Overall, ERCP was safe in patients
with sickle cell disease with no difference in mortality and overall complications. The rates of post-ERCP pancreatitis were comparable between groups.
There were no cases of perforation
and the risk of cholecystitis was negligible. However, the rate of post-ERCP hemorrhage was statistically
higher in the sickle cell disease group with an adjusted odds ratio of 5.06
(95% CI, 2.92 – 8.78, p<0.001). When assessing the indication for ERCP,
the risk of hemorrhage was significantly higher in patients undergoing
therapeutic ERCP for removal of stones from the bile duct,
aOR 4.52 (95% CI, 2.24 – 9.12, p<0.001). Interestingly, the risk of
hemorrhage was not associated with performing a sphincterotomy or dilation of the ampulla.
It would be expected
that patients undergoing stone retrieval would be more likely to have sphincterotomy and/or balloon
sphincteroplasty, so this discrepancy is perplexing. The reason for this increased
risk of hemorrhage is unknown,
though perhaps trauma or
size of stones removed may have played a role in the risk for bleeding, as well
as medication use such as anticoagulants and antiplatelet agents, which are
common in sickle cell disease to prevent or treat thrombosis18. Sickle Cell cholangiopathy is a rare
condition thought to arise from biliary hypoxia leading to strictures19. Whether this type of cholangiopathy
increases the risk of bleeding is unknown. Pseudoaneurysm formation and
vascular injury are other possible mechanisms to account for this increased rate of bleeding18. Unfortunately, details regarding
medications are not available through the National Inpatient Sample.
Complications related to sickle
cell disease itself were compared between patients who underwent ERCP and those
who did not. Overall, the risks of acute chest syndrome, pain crisis, infection
and pneumonia were significantly higher in the patients with sickle cell disease who underwent ERCP compared
to sickle cell patients who did not undergo ERCP during the study period.
This is important because these complications
of sickle cell disease confer
a high morbidity and mortality. A possible mechanism behind the
development of acute chest syndrome in this cohort is from hypoventilation from
sedation and gastric insufflation leading to left-sided atelectasis20. This same mechanism could also explain the
increased incidence of pneumonia. Pain crises
can be induced by hypoxia,
hypothermia, dehydration and other physiologic stressors; it is
therefore vital that in the preoperative, operative and post-operative periods,
these parameters are optimized21. Though it was not possible to elicit whether
preoperative antibiotics were given to all patients prior to ERCP in this cohort,
the risk of infection was higher amongst those undergoing ERCP, raising the
possibility that prophylactic antibiotics may be beneficial for all sickle-cell
patients before all ERCPs. A study by Cawich, et al. proposes optimal
management of sickle cell disease patients during ERCP and includes pre-procedural administration of antibiotics, management of fluids, close
monitoring of vitals including proper oxygenation and chest physiotherapy
amongst other interventions during the periods before, during and after ERCP in order
to minimize some of the comorbidities seen above12. Of
note, pre-procedural antibiotics are currently not recommended by the ASGE for routine ERCP with adequate biliary drainage, so
further studies specifically in sickle cell disease patients are warranted to
clarify if there is indeed benefit22.
Ultimately, the mortality rate in
our cohort was low and not statistically different
between the sickle cell and non-sickle cell groups, which is reassuring. The
rate of ERCP failure was also
negligible between groups ensuring that success rates are high even in this
specific population.
The conclusions of this study are limited by the retrospective nature of this study. The
data drawn upon were dependent on coders correctly billing
interventions and diagnoses encountered during the hospitalization, which introduces
inherent bias. To overcome this, matched controls were selected from the same
data set to ensure that results are not overestimated. Though rates of post-ERCP
hemorrhage were higher in the sickle cell disease
group, the severity of hemorrhage could not be adequately discerned. However,
it was clear that the rate was significantly higher amongst this cohort
when compared to matched controls and that overall mortality in the sickle
cell group was not higher. Additionally, other
helpful clinical data are not available by using the NIS database.
Factors such as severity of presentation,
laboratory values, disease course, medications (such as anticoagulation/ antiplatelet agents), anesthesia and fluids are not available, which
raises the possibility of confounding variables. Despite these limitations, the
large number of patients included makes this the largest study evaluating the outcomes of ERCP in patients with sickle cell disease.
5.Conclusion
It is also critical to be aware of the increased risk of acute chest syndrome, infection, pain crisis and pneumonia and take appropriate precautions in order to help prevent them. Further studies are warranted to develop standardized protocols to help prevent these complications which will likely include antibiotic prophylaxis in all SCD patients undergoing ERCP.
6.Contributions
All authors contributed equally to the production of this manuscript.
7.Conflicts of interest
All authors declare no relevant conflicts of interest.
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