Ascending cholangitis

Question 9 from the second paper of 2016, and the identical Question 21 from the second paper of 2018, presented the candidates with a scenario of an elderly woman with jaundice, confusion, hypotension, fever and abdominal pain. This describes Reynolds' Pentad, the constellation of clinical signs which is actually absent in 97% of cholangitis patients. Fortunately, the modern definitions (Tokyo Guidelines, 2013)  only require signs of infection and characteristic abdominal pain, with confirmation by imaging. Cholangitis is managed by draining the infected bile by ERCP, percutaneously, or via some sort of horrible surgical T-tube.

The notes below represent a brief summary of the information required to pass an "outline your management" question for the CICM Part II. It is not enough to "critically evaluate" anything, but it is unlikely that the college will ever expect generalist intensivists to have an in-depth knowledge of this hepatobiliary pathology. One might come to the conclusion that competent management of sepsis should give you half your marks, and some understanding of specific management (ERCP, cholecystostomy) would contribute the rest.

As far as published evidence and guidelines go, the following were useful resources in the creation of this summary:

• 2013 Tokyo (TG13)  guidelines
• The TG13 "management bundle"
• The UpToDate acute cholangitis page
• The LITFL acute cholangitis page

The majority of this summary is guided by the 2013 Tokyo (TG13)  guidelines, themselves an update of the original 2007 consensus from a conference in Tokyo. 

Causes of cholangitis

• Stones
• Parasites (eg. Clonorchis)
• Obstruction of a previously placed stent
• Reflux of infected material up into the duct during ERCP (usually, as they inject the contrast)
• Stenosis of the duct:
  • Spontaneous, benign
  • Malignant (eg. cholangiocarcinoma, pancreatic head mass)
  • Post-anastomotic (eg. following liver transplant)
  • Post-sphincterotomy (after a prior cholangitis)

Clinical manifestations

Classically, cholangitis presents with a constellation of characteristic features.

Charcot's triad:

• Fever
• Abdominal pain
• Jaundice

Reynolds pentad:

• Fever
• Abdominal pain
• Jaundice
• Confusion
• Hypotension

Charcot described the original triad in 1877. Benedict Reynolds (who got a pentad) and Everett Dargan (who got nothing) published their article in 1959, describing the addition to confusion and shock to the grouping of symptoms which mandate immediate surgery when present together with the original triad. These days these pentads and triads seem somewhat useless. In 2007 Rosing et al found that in their case series, only 43% of patients had Charcot's triad and only 3% had Reynold's pentad (all 117 patients had acute cholangitis by TG07 criteria,  almost all required ERCP and the mortality was 25%). The new TG13 guidelines  are a "duad", as they only need systemic inflammation and cholestasis:

Additionally, one may list supportive features which are not a part of the diagnostic criteria:

• Characteristic symptoms of biliary colic are the most common symptom
• In 72-93%, there is right hypochondrial and/or epigastric pain
• Nausea and vomiting are the next most frequently seen features
• Only about 30% have a fever
• Rebound tenderness is only present in about 30-50%
• Rigidity and guarding is only present in 30%

Diagnostic tests

Diagnostic biochemistry

• These diagnostic tests satisfy the TG13 criteria
• LFTs (should be raised, doesn't matter in what way - TG13 do not discriminate between "cholestatic" and "hepatototoxic" LFT patterns). The official cutoff is 150% of the normal uppermost value, in case that is of any interest to you.
• Inflammatory markers (should be raised - TG13 do not value any specific markers as superior to any of the others)

Supportive biochemistry

• These tests do not contribute directly to makign the diagnosis of acute cholangitis, but most people would agree that their results would be of interest.
• Amylase and lipase should be done, to look for co-existing pancreatitis
• Coags which is important to the guy doing the sphincterotomy, as well as prognostically interesting (if a DIC-like picture is revealed)
• Urea and creatitine which also becomes prognostically interesting, as far as organ system failure scores and prognosis of sepsis are concerned

Imaging

The purpose of imaging is to achieve a TG13-guided diagnosis, which requires two main things:

• Dilated bile duct
• Aetiology on imaging (eg. stone, a structure, a blocked stent from a previous procedure). 

TG13 recommend specific imaging:

• Ultrasonography is good because it is widely available, can give good images of the bile duct, and may reveal something about the gall bladder It can be done at the bedside and it does not involve exposure to ionising radiation.
• CT of the abdomen may be the investigation of choice if the ultrasound does not reveal any sort of obstructive pathology
• MRCP is also recommended as it "has a high sensitivity for detecting biliary calculi and malignant biliary obstruction", in particular non-calcified stones invisible to CT (Kiriyama et al, 2013)

Severity assessment

• The TG13 classify this condition pragmatically, in terms of who needs ERCP and how soon.
• Grade III (cholangitis with organ system dysfunction) needs to be ERCPed within 24hrs
• Grade II (cholangitis with ...shall we say... disturbing features, such as age over 75, temperature over 39.0°C, etc) can probably be drained after 48 hours
• Grade I (everything else) might even get away without drainage.

Management strategies

• Antibiotics: (see below; but in bief Sanford Guide recommends Tazocin or Meropenem). Of the patients with cholangitis, 70-80% will respond to conservative management (i.e. they get better with antibiotics and are clinically well by the time they get to have an ERCP).
• Drainage of the infected bile is the definitive source control measure.
• Timing of drainage is determined by severity: If the patient is sick enough to be in the ICU, some sort of drainage  should be performed within the first 24-48 hours. The severity grading system devised by the TG13 people helps separate patients into the "urgently drain" and "be patient" categories, and the Grade III patients would all inevitably end up in ICU, whereas the Grade II and I are more HDU/ward material.
• ERCP: the treatment of choice whenever feasible (stent or sphincterotomy).
• Percutaneous transhepatic cholangiography (PTCC): the bile duct can be decompressed by inserting a needle into the liver and draining the pus that way. PTC can also be used to put stents in, image the duct, extract stones, etc.
• Percutaneous cholecystostomy:  if the gall bladder is accessible, the simplest thing would be to put a drain into it (just as in the case of acalculous cholecystitis). In fact, the TG13 "bundle" recommends thi steop
• Surgical decompression by T-tube:  if ERCP is impossible, inserton of a T-tube has a lower complication rate than open cholecystectomy and exploration.
• Surgical cholecystectomy and exploration of CBD:  this is the approach which led to the mortality rates in excess of 50% during the 1960s and 70s.
• Cholecystectomy: ultimately, the gall bladder must be removed, but it should ideally happen when the patient is not falling apart from sepsis.

Microbiology

Gome et al (2013) offer the following list of organisms as a part of a lage scale recommendation bundle for antibiotics in cholangitis:. The bugs are listed along with the frequency with which they are isolated from bile cultures (not blood). The numbers don't add up to 100% because most commonly the bile is a sort of polymicrobial zoo. The blood cultures are often pointless. Sun et al (2016) report that bile cultures are positive in 59-93% of cases, whereas the blood cultures only yield something in 21-71%.

Gram-negatives		Gram-positives
E.coli	44%	Enterococcus sp.	34%
Klebsiella sp.	20%	Streptococcus sp.	10%
Enterobacter sp.	9%	Unspecified anaerobes	20%
Pseudomonas sp.	20%

Antimicrobial therapy

• For cholangitis of all levels of severity, TG13 recommend piperacillin/tazobactam. Meropenem is also appropriate and there is nothing to help you decide between them except for your own super-detailed knowledge about the local microbiome. Fluoroquinolones are out these days, because the rates of fluoroquinolone resistance are increasing. The duration of therapy is 7-10 days.

Biliary clearance issues need to be considered. Antibiotics such as meropenem and ceftriaxone achieve high biliary concentrations. However, according to van den Hazel et al (1994), this is pure fantasy. Apparently, "there is considerable laboratory and clinical evidence that as obstruction occurs, secretion of antimicrobial agents into bile stops".