Journal of the Pancreas Open Access

Keywords

Cholangitis; Cholangiopancreatography, Endoscopic Retrograde

Abbreviations

ERCP Endoscopic Retrograde Cholangiopancreatography

INTRODUCTION

Ascending cholangitis is a life threatening condition that occurs in the presence of biliary obstruction. It can present with variable severity with symptoms being fever, abdominal pain and jaundice. Initial treatment includes adequate fluid resuscitation and administration of broadspectrum antibiotics. Early stabilization followed by decompression of the biliary system is required. It has been observed that surgical management of acute cholangitis is associated with substantial morbidity and mortality [1]. On the contrary, non-surgical drainage seems to be effective in relieving the biliary obstruction. This is most frequently achieved through Endoscopic Retrograde Cholangiopancreatography (ERCP).

Severity of acute cholangitis is based on the initial response to antibiotics and presence of organ dysfunction [2] (Table 1). Timing of ERCP depends on the presence of organ dysfunction, response to antibiotics and other comorbid conditions [3]. In patients presenting with acute cholangitis, ERCP could be delayed because of initial resuscitation efforts, coagulation abnormalities and other comorbid conditions [4]. In our experience, unavailability of consent accounted for delays in performing ERCP. Studies have also shown that outcomes of acute cholangitis not only depend on the time taken to decompress the biliary system but also on etiology, presence of organ dysfunction and comorbid conditions [5].

Table 1. Characteristics including demographic variables, etiologies, comorbid medical conditions, ’Door to ERCP times’ and ERCP findings in patients stratified by varying severity of cholangitis.

We investigated the outcomes amongst patients with cholangitis of varying degrees of severity, based on ‘Door to ERCP’ time. The primary objective of the study was to observe the correlation between in-hospital mortality and ‘Door to ERCP time’, after controlling for severity of acute cholangitis. Secondary objectives included analyzingthe factors affecting the severity of cholangitis and the correlation between length of hospital stay and ‘Door to ERCP time’.

METHODS

Study Population: Inclusion and Exclusion Criteria

Our study was a retrospective review of patients who underwent ERCP for cholangitis during the study period between January 2009 and August 2012. The parameters included within the Tokyo Consensus for Cholangitis (2007) [2] were assessed for all the study subjects. Only those patients who fulfilled the criteria towards the diagnosis of cholangitis were included in the study. The patient with cholangitis who did not undergo ERCP were excluded from the study. The protocol for the study was reviewed and approved by the Institutional Review Board (IRB) at Bronx Lebanon Hospital Center.

Data Extraction and Tabulation

Demographic data including age, gender and ethnicity were extracted from medical records. Routine laboratory parameters including serum liver chemistry, complete blood count and coagulation profile were reviewed for all the patients. The medical charts were reviewed for symptoms, vital signs, physical examination findings, etiology of cholangitis and other comorbid medical conditions. The time (in hours) that elapsed between the presentation to Emergency Room (ER) and completion of ERCP was defined as ‘Door to ERCP time’. It was calculated from review of electronic medical records. Death during the index admission for acute cholangitis was considered as in-hospital mortality. Length of hospital stay was defined as the time period (in days) between presentation to ER and hospital discharge. Lengths of hospitalization in patients who expired were not included towards calculation of this variable. Recovery period for a patient was defined as the number of days of hospitalization after ERCP was performed. Patients were stratified into three different groups based upon ‘Door to ERCP time’ - patients who underwent ERCP within 24 hours, between 24 to 48 hours, and more than 48 hours respectively. Mortality was assessed in these three groups after controlling for severity of presentation. The lengths of stay amongst these three groups were also observed.

STATISTICAL ANALYSIS

Unpaired student t-test was used for continuous variables that were normally distributed. Non-parametric rank (Wilcoxon) sum was used for continuous variables that were not normally distributed. The association between two variables with removal of the set of random controlling variable was achieved by the Partial correlation test. SPSS version 20 was used for performing all statistical analyses.

RESULTS

A total of 301 patients underwent ERCP procedures during the study period. Amongst these, only 69 patients were diagnosed as having acute cholangitis as per the diagnostic criteria included within the Tokyo Guidelines. All patients who underwent ERCP had successful biliary cannulation. The mean age of patients with cholangitis was 54 years (20±SD). 68% (n= 47) of the study population were of Hispanic ethnicity while 16% (n=11) was of African American ethnicity. Underlying etiology of cholangitis was choledocholithiasis in 63.8%, malignant stricture in 15.9%, benign stricture in 14.5% and stent occlusion in 4%. 68% (n=46) of patients presented with grade-I severity (without end organ dysfunction and responded to initial resuscitation), 19% (n=13) with grade-II severity (without end organ dysfunction and but did not respond to initial resuscitation) and 13% (n=10) with grade–III severity (with organ dysfunction).

Older individuals were more likely to present with increased severity of cholangitis. The mean age of individuals presenting with grade-III severity was 73(±17) years which was significantly higher than those presenting with less severe disease (p=0.002). Univariate analysis revealed that both mortality and length of stay were not significantly different across groups with varying severity of cholangitis. Patients with benign strictures were more likely to have severe cholangitis (grade-III) while those with malignant strictures were more likely to present with grade–I cholangitis. Patients with peri-ampullary diverticulae had more severe presentation (grade-III). The ‘Door to ERCP time’ was not significantly different amongst the three groups. 50% (n=5) of patients with the Grade–III cholangitis underwent ERCP within 24 hours of presentation, whereas the rest (n=5) had delayed ERCP (beyond 48 hours from the time of presentation) (Table 1). Of the five patients with delayed ERCP, three patients had to wait until compensation of an underlying cardiac condition, one had to be resuscitated from severe shock and one patient underwent Interventional Radiology guided cholecystectomy as first line of therapy as per family’s wishes.

Thirty three percent (n=23) of study population underwent ERCP within 24 hours of presentation, 18% (n=12) underwent ERCP between 24 hours and 48 hours of presentation and 49% (n=34) had ERCP after 48 hours of presentation. Presentation on a particular day of the week (weekend including Friday or weekday) was not a deciding factor in ‘Door to ERCP time’. All the three study groups were similar in terms of age, gender, laboratory parameters and comorbid conditions (Table 2).

Table 2. Characteristics including demographic variables, etiologies, day of presentation, comorbid medical conditions, laboratory parameters and ERCP interventions/findings in patients stratified by ’Door to ERCP times’.

Forty Nine percent (n=34) of patients included in the study, underwent endoscopic biliary decompression after 48 hours of initial presentation. The delays for ERCP were multifactorial including- time taken for management of the comorbid conditions, early interventional radiology assisted decompression, time taken for correction of coagulopathy, time taken for management of shock, refusal of consent and initial resuscitation with antibiotics. These factors however differed amongst patients with varying severity of cholangitis (Table 3).

Table 3: Factors affecting the ’Door to ERCP times’ in patients stratified by varying severity of cholangitis.

The all cause in hospital mortality for patients with acute cholangitis include in this study was 11% (n=8). Mortality did not correlate with ‘Door to ERCP time’, even after controlling for the severity of the acute cholangitis at the time of presentation (Table 4). Fifty percent (n=4) of these patients died from cholangitis related complications, one patient died from end stage liver disease with Hepatocellular carcinoma while the remaining died from hospital acquired infections . Patient with grade-III cholangitis who expired and had the ERCP after 48 hours of presentation- underwent an early cholecystostomy.

Table 4: Mortality among patients stratified by severity of cholangitis and timing of ERCP.

The mean lengths of stay for patients with ‘door to ERCP time’ of less than 24 hours, between 24 to 48 hours and more than 48 hours was 7 days, 6 days and 14 days respectively. The difference in the lengths of stay was statistically significant amongst these groups (Figure 1a). Recovery time, as calculated by the number of days of hospitalization after ERCP, was not significantly different amongst the three groups (Figure 1b).

Figure 1a. Box-plot comparing the means of lengths of hospital stay (in days) amongst the three study groups stratified by timing of ERCP.

Figure 1b. Box-plot comparing the means of recovery times (in days) amongst the three study groups stratified by timing of ERCP.

DISCUSSION

Acute cholangitis is infection arising from the hepatobiliary system due to biliary obstruction and bactibilia. Severity of cholangitis helps in guiding the management and predict the outcomes. Based on review of literature and expert opinion, a severity grading for the acute cholangitis was proposed in 2007 at the Tokyo consensus [2]. The stratification of severity of acute cholangitis was done based upon presence of organ dysfunction and response to initial resuscitation. This severity grading was revised in the 2013 Tokyo consensus to include laboratory parameters. This aided in triaging the patients who require urgent biliary intervention [6]. In view of the retrospective nature of the study, all the patients in the study were graded for severity as per the Tokyo classification of 2007.

Cholangitis in elderly tends to be severe and have poor outcomes due to presence of other comorbid conditions and atypical clinical presentation [7]. In our study, the patients with grade-III cholangitis were significantly older (mean age of 73 years) than patients with grade-1 (mean age of 50 years) and grade-II (mean age of 50 years) cholangitis (p=0.002). There was no significant difference in the distribution of etiologies, barring biliary strictures, across the three groups with varying severity of cholangitis. Multiple sources [8, 9] have reported that malignant strictures tend to present with severe acute cholangitis. However, we noticed in our study population that patients with malignant strictures presented with lower grade of severity. Majority of these patients were already aware of their diagnosis of a hepatobiliary malignancy and hence were more likely to seek early medical intervention. Patients who had a periampullary diverticulum were more likely to fail initial resuscitative measures (70% in grade-III cholangitis). Impaired sphincter of Oddi [10] with resultant increase in retrograde biliary infection [11] has been reported in patients with duodenal diverticulae.

The timing of the ERCP for decompression of the biliary system has been controversial [12, 13]. The mortality was reported to be high (17%-40%) if ERCP was delayed due to advanced age or underlying comorbid conditions [14]. The presence of comorbid conditions had been proposed for usage towards grading the severity of cholangitis but was deemed impractical due to the complexity [6]. However, in patients with cholangitis the ‘Door to ERCP time’ may be prolonged for management of decompensated comorbid conditions [4]. We observed that 49% of our study population had ERCP performed after 48 hours. There was no difference in mortality between the groups which had biliary decompression within 24 hours, between 24 to 48 hours and beyond 48 hours. There were no difference in the baseline characteristics such as age, gender, etiology of cholangitis, clinical presentation, laboratory parameters, ERCP findings and interventions performed amongst these groups. As seen in other studies [15] we did not observer any weekday versus weekend variation.

The severity of cholangitis does affect mortality and other outcomes such as length of stay [4]. Good predictive models have been designed to triage the patients who need earlier intervention [6, 16]. Despite severe presentation of cholangitis, decompensated comorbid conditions often curtail an early ERCP. This was demonstrated in our study when almost half of patients with severe cholangitis, who constituted up to 11% of total study population, ended up getting ERCP beyond 48 hours of presentation. There was no observed difference in mortality amongst the three groups stratified as per the ‘Door to ERCP time’ even after controlling for the severity of cholangitis. The length of stay was prolonged in patients with delayed ERCP but the recovery time, as noted by number of days of hospitalization after ERCP was not different amongst the three groups. The prolonged length of stay in patients with delayed ERCP could be attributed to the time spent for management of underlying decompensated medication condition.

In conclusion, decompression of biliary tract should be attempted on expedited basis in every patient with acute cholangitis. However, we noted no difference in mortality for patients who underwent delayed ERCP. We did observe that the delay in ERCP contributed to increase in the length of hospital stay and thereby could possible lead to increased morbidity.

Conflict of Interest

The authors declare that there is no conflict of interests.

References

1. Lai EC, Mok FP, Tan ES, Lo CM, Fan ST, You KT, Wong J. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med 1992; 326:1582-1586. [PMID: 1584258]
2. Wada K, Takada T, Kawarada Y, Nimura Y, Miura F, Yoshida M, Mayumi T, et al. Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg 2007; 14:52-58. [PMID: 17252297]
3. Bornman PC, van Beljon JI, Krige JE. Management of cholangitis. J Hepatobiliary Pancreat Surg 2003; 10:406-414. [PMID: 14714159]
4. Navaneethan U, Gutierrez NG, Jegadeesan R, Venkatesh PG, Sanaka MR, Vargo JJ, Parsi MA. Factors predicting adverse short-term outcomes in patients with acute cholangitis undergoing ERCP: A single center experience. World J Gastrointest Endosc 2014; 6: 74-81. [PMID: 24634711]
5. Gigot JF, Leese T, Dereme T, Coutinho J, Castaing D, Bismuth H. Acute cholangitis. Multivariate analysis of risk factors. Ann Surg 1989; 209:435-438. [PMID:2930289]
6. Kiriyama S, Takada T, Strasberg SM, Solomkin JS, Mayumi T, Pitt HA, Gouma DJ, et al. New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo Guidelines. J Hepatobiliary Pancreat Sci 2012; 19:548-556. [PMID: 22825491]
7. Sugiyama M, Atomi Y. Treatment of acute cholangitis due to choledocholithiasis in elderly and younger patients. Arch Surg 1997; 132:1129-1133. [PMID: 9336514]
8. Lee CC, Chang IJ, Lai YC, Chen SY, Chen SC. Epidemiology and prognostic determinants of patients with bacteremic cholecystitis or cholangitis. Am J Gastroenterol 2007; 102:563-569. [PMID: 17335448]
9. Boey JH, Way LW. Acute cholangitis. Ann Surg 1980; 191:264-270 [PMID: 7362292]
10. Lotveit T, Osnes M, Aune S. Bacteriological studies of common duct bile in patients with gallstone disease and juxta-papillary duodenal diverticula. Scand J Gastroenterol 1978; 13:93-95. [PMID: 416486]
11. Lotveit T, Osnes M, Aune S, Larsen S. Studies of the choledocho-duodenal sphincter in patients with and without juxta-papillary duodenal diverticula. Scand J Gastroenterol 1980; 15:875-880. [PMID: 6782650]
12. Mosler P. Diagnosis and management of acute cholangitis. Curr Gastroenterol Rep 2011; 13: 166-172. [PMID: 21207254]
13. Tokyo Guidelines for the management of acute cholangitis and cholecystitis. Proceedings of a consensus meeting, April 2006, Tokyo, Japan. J Hepatobiliary Pancreat Surg 2007; 14:1-121. [PMID: 17590902]
14. Buyukasik K, Toros AB, Bektas H, Ari A, Deniz MM. Diagnostic and therapeutic value of ERCP in acute cholangitis. ISRN Gastroenterol 2013; 2013: 191729. [PMID: 23997958]
15. Kostis WJ, Demissie K, Marcella SW, Shao YH, Wilson AC, Moreyra AE, Myocardial Infarction Data Acquisition System Study G. Weekend versus weekday admission and mortality from myocardial infarction. N Engl J Med 2007; 356:1099-1109. [PMID: 17360988]
16. Salek J, Livote E, Sideridis K, Bank S. Analysis of risk factors predictive of early mortality and urgent ERCP in acute cholangitis. J Clin Gastroenterol 2009; 43:171-175. [PMID:18769362]