Gastrointestinal disease

“My patient with severe Crohn’s disease is found to have an elevated serum lipase without other supportive evidence of pancreatitis. What other sources of elevated lipase should I consider?” 

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , Leave a comment

Over 20 different conditions have been linked to elevated serum lipase levels or hyperlipasemia associated with conditions other than pancreatitis. The most common causes are sepsis and acute kidney injury, but less common causes include gastrointestinal bleeding, liver disease, and type 2 diabetes mellitus, and inflammatory bowel disease.1   More specifically, up to 9% of patients with Crohn’s disease may have hyperlipasemia, often associated with a more extensive and active disease.2  

Recall that hyperlipasemia is one of the hallmarks of acute pancreatitis (serum lipase greater than 3-5x the upper limit of normal) but, as noted above, it is not 100% specific for this condition.  Although pancreatic tissue has a 50-to-100-fold greater lipase activity than other organs in the gastrointestinal tract,3 serum amylase may also be elevated in diseases involving salivary glands, stomach, heart, skeletal muscle, white and brown adipose tissue, and even the brain.1 This finding should come as no surprise since, as an enzyme, lipase metabolizes triglycerides into glycerol and free fatty acids and plays a key role in the metabolism and transport of lipids into peripheral tissues. 4   

Last, despite potential extra-pancreatic sources, serum lipase is still preferred over amylase in diagnosing pancreatitis due to its higher specificity and sensitivity. 5  

Bonus Pearl: Did you know that increased intracranial pressure, including intracerebral hemorrhage, edema, and tumors may also be associated with elevated serum lipase levels? 6 

Contributed by Charles Hurth, D.O., Mercy Hospital, St. Louis, Missouri

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References: 

  1. Feher KE, Tornai D, Vitalis Z, Davida L, Sipeki N, Papp M. Non-pancreatic hyperlipasemia: A puzzling clinical entity. World J Gastroenterol. 2024 May 21;30(19):2538-2552. doi: 10.3748/v30.i19.2538. PMID: 38817657; PMCID: PMC11135416. https://pmc.ncbi.nlm.nih.gov/articles/PMC11135416/#B33  
  2. Heikius B, Niemelä S, Lehtola J, Karttunen TJ. Elevated pancreatic enzymes in inflammatory bowel disease are associated with extensive disease. Am J Gastroenterol. 1999 Apr;94(4):1062-9. doi: 10.1111/j.1572-0241.1999.x. PMID: 10201484. https://pubmed.ncbi.nlm.nih.gov/10201484/ 
  3. Tetrault GA. Lipase activity in serum measured with Ektachem is often increased in nonpancreatic disorders. Clin Chem. 1991 Mar;37(3):447-51. PMID: 1706233. https://pubmed.ncbi.nlm.nih.gov/1706233/
  4. Wang H, Eckel RH. Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr. 2012 Aug 21;32:147-60. doi: 10.1146/annurev-nutr-071811-150703. Epub 2012 Apr 23. PMID: 22540257; PMCID: PMC4065112. https://pmc.ncbi.nlm.nih.gov/articles/PMC4065112/
  5. Tenner S, Vege SS, Sheth SG, Sauer B, Yang A, Conwell DL, Yadlapati RH, Gardner TB. American College of Gastroenterology Guidelines: Management of Acute Pancreatitis. Am J Gastroenterol. 2024 Mar 1;119(3):419-437. doi: 10.14309/ajg.0000000000002645. Epub 2023 Nov 7. PMID: 38857482. https://pubmed.ncbi.nlm.nih.gov/38857482/
  6. Larson GM, Koch S, O’Dorisio TM, Osadchey B, McGraw P, Richardson JD. Gastric response to severe head injury. Am J Surg. 1984 Jan;147(1):97-105. doi: 10.1016/0002-9610(84)90041-2. PMID: 6691557. https://pubmed.ncbi.nlm.nih.gov/6691557/

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

“My patient with severe Crohn’s disease is found to have an elevated serum lipase without other supportive evidence of pancreatitis. What other sources of elevated lipase should I consider?” 

Should I discontinue the glucagon-like peptide-1 receptor agonist (GLP-1RA) perioperatively in my patient with an upcoming elective surgery?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

Despite initial concerns, GLP-1RAs need not be categorically discontinued in patients undergoing surgery and, in fact, may be continued safely in most patients.

A December 2024 clinical practice “guidance”—not “guidelines” due to lack of firm evidence—involving several professional societies, including the American Society of Anesthesiologists (ASA) and the American Gastroenterological Association suggests that GLP-1RA therapy may be continued perioperatively in the absence of the following high risk factors: escalation phase of GLP-1RA (vs maintenance phase),1 higher dose, weekly dosing, presence of GI symptoms suggestive of delayed gastric emptying (eg, nausea, vomiting, abdominal pain, dyspepsia, constipation) and medical conditions associated with delayed gastric emptying (eg, gastroparesis, Parkinson’s disease).2

In the presence of one or more of the above risk factors that may contribute to delayed gastric and aspiration perioperatively, withholding GLP-1RAs should be considered.  When balancing the risks and benefits of withholding these drugs, shared decision making involving the patient and members of the care team including the procedural, anesthesia and prescribing providers is prudent.  For example, with discontinuation of GLP-1RAs, one should also consider the possibility of hyperglycemia in patients with diabetes with its potential adverse effects on surgical outcome .1

As far as the timing of discontinuation of GLP1-RAs, ASA recommends holding such drugs on the day of surgery for daily formulations and a week prior to surgery for weekly formulations while maintaining glycemic control. The above “guidance” also recommends assessment for symptoms of delayed gastric emptying on the day of surgery with use of point of care ultrasound (POCUS), if available, to assess degree of delayed gastric emptying.1

It’s worth noting that despite early case reports of pulmonary aspiration of gastric contents in patients on GLP-1RAs undergoing procedural sedation and/or general anesthesia, (3,4) recent larger studies have not substantiated such claims. Interestingly, a 2024 retrospective observational cohort of over 13,000 adults with diabetes found a lower risk of perioperative and postoperative delayed gastric emptying and antiemetic use among patients treated with GLP1-RA compared to non-users; aspiration/pneumonitis and ileus risks within 7 days were not significantly different between the 2 groups. 5

Bonus Pearl: Did you know that scintigraphy via ingestion of a radio-labelled meal is the gold standard for diagnosis of gastroparesis with the 13 C breath test using a solid meal as an acceptable alternative?6

Contributed by Shirley Joo, MD, Internal Medicine Associate Program Director, Mercy Hospital, St. Louis, Missouri

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References

  1. van Zuylen ML, Siegelaar SE, Plummer MP, et al. Perioperative management of long-acting glucagon-like peptide-1 (GLP-1) receptor agonists: concerns for delayed gastric emptying and pulmonary aspiration. Br J Anaesth. 2024;132:644-648. Perioperative management of long-acting glucagon-like peptide-1 (GLP-1) receptor agonists: concerns for delayed gastric emptying and pulmonary aspiration – PubMed
  2. Kindell TL, Wang AY, Wadhwa A, et al. Multisociety clinical practice guidance for the safe use of glucagon-like peptide-1 receptor agonists in the perioperative period. Surgery for Obesity and Related Diseases 2024;20:1183-1186. Multisociety clinical practice guidance for the safe use of glucagon-like peptide-1 receptor agonists in the perioperative period
  3. Klein SR, Hobai    Semaglutide, delayed gastric emptying, and intraoperative pulmonary aspiration: a case report.   Can J Anaesth. 2023;70(8):1394-1396.  Semaglutide, delayed gastric emptying, and intraoperative pulmonary aspiration: a case report – PubMed
  4. Silveira SQ, da Silva  LM, de Campos Vieira Abib  A,  et al.  Relationship between perioperative semaglutide use and residual gastric content: a retrospective analysis of patients undergoing elective upper endoscopy.   J Clin Anesth. 2023;87:111091.  Relationship between perioperative semaglutide use and residual gastric content: A retrospective analysis of patients undergoing elective upper endoscopy – PubMed
  5. Klonoff DC, Kim SH, Galindo RJ, et al. Risks of peri- and postoperative complications with glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab 2024; 26:3128-3138. Risks of peri- and postoperative complications with glucagon-like peptide-1 receptor agonists – PubMed
  6. Ghazanfar H, Allena N, Javed N, Ponnachan D, Narasimhadevara S, Komadur T, et al. Diagnostic Modalities Used in Diagnosing Gastroparesis: A Clinical Review. Cureus. 2022 Oct 21;14(10):e30540. https://pmc.ncbi.nlm.nih.gov/articles/PMC9675943/ 

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should I discontinue the glucagon-like peptide-1 receptor agonist (GLP-1RA) perioperatively in my patient with an upcoming elective surgery?

Do proton pump inhibitors (PPIs) reduce the risk of bleeding from lower gastrointestinal tract?

FA Manian MD, MPH, , , , , , , , , , , , , , Leave a comment

The short answer is “No”!  Although proton pump inhibitors (PPIs) are effective in reducing the risk of upper gastrointestinal bleed (GIB) in high-risk patients, they do not protect against lower GIB. 1 In fact, their use has been associated with an increased risk of small bowel injury related to non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin.2,3

A 2015 case-control study involving over 1,000 patients hospitalized for GIB found that although concomitant use of PPI in patients on NSAIDs, low-dose aspirin, other antiplatelet agents or anticoagulants was associated with a reduced risk of UGIB, it was not associated with reduced risk of lower GIB.  Interestingly, in this study, PPIs were associated with higher risk of lower GIB which might have been related to confounding factors and not necessarily a direct causal effect.4 Lack of an impact of PPIs on lower GIB among patients on aspirin or NSAIDS has also been supported by others. 5-7

The fact that PPIs don’t seem to reduce the risk of GIB distal to the duodenum should not be surprising given their primary mechanism of action through inhibition of acid production by gastric parietal cells. 8  What is perhaps more intriguing is how they may potentially increase the risk of small intestinal injury while still protecting the gastro-duodenum from NSAID-induced mucosal damage.

In a cool laboratory study involving rats, treatment with a PPI was associated with exacerbation of NSAID-induced intestinal ulceration and bleeding; by itself treatment with PPI was not associated with intestinal mucosa injury.9 Interestingly, in this study, a marked shifts in numbers and types of enteric bacteria with a significant reduction in jejunal Bifidobacteria spp was noted with PPI therapy. Restoration of small intestine Bifididobacteria during treatment with a PPI along with an NSAID prevented intestinal ulceration/bleeding. The investigators concluded that when used along with an NSAID, PPIs may cause small intestinal injury through alteration in the microbiome of the gut.  Fascinating!

Bonus Pearl: Did you know that the 2022 American Gastroenterological Association (AGA) clinical practice update on de-prescribing of PPIs lists several conditions for which acute/short term use of PPIs are NOT indicated, such as isolated lower GI symptomatology, acute nausea and vomiting not believed to be related to GERD/esophagitis, acute undifferentiated abdominal pain, and empiric treatment of laryngopharyngeal symptomatology? 10 

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References

  1. Lue A, Lanas A. Proton pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits. World J Gastroenterol 2016;22:10477-10481. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192259/#:~:text=PPIs%20do%20not%20prevent%20NSAID,and%20the%20risk%20of%20LGB.
  2. Endo H, Sakai E, Taniguchi L, et al. Risk factors for small-bowel mucosal breaks in chronic low-dose aspirin users: data from a prospective multicenter capsule endoscopy registry. Gastrointes Endosc 2014;80:826-34. https://pubmed.ncbi.nlm.nih.gov/24830581/
  3. Washio E, Esaki M, Maehata Y, et al. Proton pump inhibitors increase incidence of nonsteroidal anti-inflammatory drug-induced small bowel injury: A randomized, placebo-controlled trial. Clin Gastroenterol Hepatol 2016;14:809-815. https://pubmed.ncbi.nlm.nih.gov/26538205/
  4. Lanas A, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015;13:906-12. https://pubmed.ncbi.nlm.nih.gov/25460554/
  5. Nagata N, Niikura R, Aoki T, et al. Effect of proton-pump inhibitors on the risk of lower gastrointestinal bleeding associated with NSAIDs, aspirin, clopidogrel, and warfarin. J Gastroenterol 2015;50:1079-1086. https://pubmed.ncbi.nlm.nih.gov/25700638/
  6. Garcia Rodriguez LA, Lanas A, Soriano-Gabarro M, et al. Effect of proton pump inhibitors on risks of upper and lower gastrointestinal bleeding among users of low-dose aspirin: A population-based observational study. J Clin Med 2020;9:928. https://www.mdpi.com/2077-0383/9/4/928
  7. Casado Arroyo R, Polo-Tomas M, Roncales MP, et al. Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of a patients commonly using PPI co-therapy. Heart 2012;98:718-723. https://pubmed.ncbi.nlm.nih.gov/22523056/
  8. Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell. Physiol Rev 2020;100:573-602. The Physiology of the Gastric Parietal Cell – PMC (nih.gov)
  9. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology 2011;141:1314-22. https://www.gastrojournal.org/action/showPdf?pii=S0016-5085%2811%2900926-7
  10. Targownik LE, Fisher DA, Saini SD. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review. Gastroenterology 2022;162:1334-1342. https://www.gastrojournal.org/article/S0016-5085(21)04083-X/fulltext

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Do proton pump inhibitors (PPIs) reduce the risk of bleeding from lower gastrointestinal tract?

Is there any evidence that proton pump inhibitors (PPIs) benefit patients with acute pancreatitis?

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

Despite their widespread use, there is no firm evidence that PPIs should be routinely prescribed in the treatment of acute pancreatitis (AP).1   In fact, current guidelines do not include the use of PPIs as standard therapy in  AP. 1-3

Although a 2023 systematic review and meta-analysis involving 6 randomized controlled trials and 3 cohort studies of patients with AP found a significant decrease in the rate of pancreatic pseudocyst formation in patients who received PPI, no significant difference in the rates of 7-day mortality, length of hospital stay, or acute respiratory distress syndrome was found when compared to control groups.3

Theoretically, PPIs may improve the course of AP through reduction in the incidence of stress-related upper GI hemorrhagic complications.  However, the incidence of such complications in AP is quite low, ranging from 1.2% to 14.5%, with great majority of cases (>85%) unrelated to peptic ulcer disease. 3,4  These findings may help explain why it has been difficult to show any benefit for use of PPIs in reducing the incidence of GI bleed in AP.3,5

Similarly, although PPIs have been shown to reduce secretin-stimulated bicarbonate secretion by the pancreas, the clinical significance of this finding in the overall course of AP—except perhaps a lower risk of pseudocysts—remains unclear.3 Parenthetically, experimental studies have reported contradictory results regarding the inhibition of pancreatic enzyme production by PPIs,  with omeprazole failing to suppress amylase release in isolated pancreatic acini while pantoprazole showing reduced amylase secretion in rats.3

It is also unclear how the reported anti-inflammatory effects of PPIs may benefit the clinical course of AP.3,6 What is clear is that any potential benefits of PPIs in AP should be weighed against their potential adverse effects, including the risk of nosocomial pneumonia, Clostridiodes difficile infection, and spontaneous bacterial peritonitis.7,8 

Bonus Pearl: Did you know that PPIs may not only inhibit acid production by gastric parietal cells but also interfere with bactericidal activity of neutrophils?  One potential mechanism is interference with proton pump-dependent H202 generation within lysosomes necessary to create a highly acidic and bactericidal environment. 9  Fascinating!

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References

  1. Arvanitakis M, Dumonceau JM, Albert J, et al. Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) evidence-based multidisciplinary guideline. Endoscopy 2018; 50:524-46. Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) evidence-based multidisciplinary guideline – European Society of Gastrointestinal Endoscopy (ESGE)
  2. Crocket SD, Wani S, Gardner TB, et al. American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis. Gastroenterology 2018;154:1096-1101. American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis (gastrojournal.org)
  3. Horvath IL, Bunduc S, Hanko B , et al. No evidence for the benefit of PPIs in the treatment of acute pancreatitis: a systematic review and meta-analysis. Scientific Reports 2023;13:2791. https://doi.org/10.1038/s41598-023-29939-S
  4. Rana SS, Sharma V, Bhasin Dk, et al. Gastrointestinal bleeding in acute pancreatitis: etiology, clinical features, risk factors and outcome. Tropical Gastroenterology 2015;36:31-35. http://www.tropicalgastro.com/articles/36/1/gastrointestinal-bleeding-in-acute.html
  5. Demcsak A, Soos A, Kincses L, et al. Acid suppression therapy, gastrointestinal bleeding and infection in acute pancreatitis-An international cohort study. Pancreatology 2020;20:1323-31.lyso https://www.sciencedirect.com/science/article/pii/S142439032030658X?via%3Dihub
  6. Hackert T, Tudor S, Felix K, et al. Effects of pantoprazole in experimental acute pancreatitis. Comparative Study 2010;8:551-7. https://pubmed.ncbi.nlm.nih.gov/20851132/
  7. Elzouki AB, Neffati N, Rasoul FA, et al. Increased risk of spontaneous bacterial peritonitis in cirrhotic patients using proton pump inhibitors. GE Port J Gastroenterol 2019; 26:83-89. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454390/#:~:text=The%20result%20showed%20that%20PPI,medical%20literature%20confirm%20this%20association.
  8. Yibirin M, De Oliveira D, Valera R, et al. Cureus 2021;13:e12759/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887997/#:~:text=The%20most%20likely%20explanation%20for,incidence%20of%20pneumonia%20%5B2%5D
  9. Ozatik O, Ozatik EY, Tesen Y, et al. Research into the effect of proton pump inhibitors on lungs and leukocytes. Turk J Gastroenterol 2021;32:1003-1011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975296/

 

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Is there any evidence that proton pump inhibitors (PPIs) benefit patients with acute pancreatitis?

Why do we often prescribe ceftriaxone in preference to fluoroquinolones for prophylaxis of infections in patients with cirrhosis and upper GI bleed?

FA Manian MD, MPH, , , , , , , , , , , Leave a comment

Preference of ceftriaxone over fluoroquinolones (FQs) for prophylaxis of infection in patients with cirrhosis and upper GI bleed (UGIB) can often be traced back to a small 2006 Spanish randomized controlled trial (RCT)1 which found a significantly lower rate of proved or possible bacterial infection and lower rate of fermentative Gram-negative bacilli infection in the ceftriaxone group (vs norfloxacin) over a 10-day period (11% vs 33% and 0% vs 11%, respectively). There was no significant difference in the incidence of proved bacterial infection (spontaneous bacterial peritonitis or bacteremia, P=0.07) or 10-day mortality between the 2 groups.   

It’s worth emphasizing that the primary impetus for this study was evaluation of the efficacy of ceftriaxone in patients with cirrhosis and UGIB in a setting where FQ Gram-negative bacilli was thought to be highly prevalent. Parenthetically, a similar RCT performed where the prevalence of FQ resistance was considered low failed to find a significant difference in breakthrough bacterial infection, rebleeding or mortality when ceftriaxone was compared to IV ciprofloxacin.2

Another caveat of the 2006 study was that an IV antibiotic (ceftriaxone) was compared to a oral antibiotic (norfloxacin) which, in the setting of active UGIB, may be problematic.

Despite these limitations, its favorable safety profile compared to FQs coupled with its ease of administration has often made ceftriaxone the drug of choice for prophylaxis of infections in patients with cirrhosis and UGIB. The 2016 Practice Guidance by the American Association for the Study of Liver Diseases considers ceftriaxone as the first choice in patients with advanced cirrhosis, on FQ prophylaxis, and in hospital settings with high prevalence of FQ resistant bacterial infection.3

Bonus Pearl: Did you know that the prevalence of FQ resistant in Enterobacteriaceae may be as high as 30% in certain regions of U.S. and >50% in certain regions of the world? 4

Also see related 2 P4P pearls (1, 2) on the association of UGIB bleed with infections in patients with cirrhosis.

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References

  1. Fernandez J, Del Arbol LR, Gomez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterol 2006;131:1049-1056. https://pubmed.ncbi.nlm.nih.gov/17030175/
  2. Pittayanon R, Reknimir R, Kullavanijaya P, et al. Intravenous ciprofloxacin vs ceftriaxone for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding:A randomized controlled trial. Thai J Gastroenterol 2016;17:24-30. http://www.thaigastro.com/books.php?act=content&content_id=476&book_id=61
  3. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive bleeding in cirrhosis:risk stratification, diagnosis and management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65:310-335. https://pubmed.ncbi.nlm.nih.gov/27786365/
  4. Spellberg B, Doi Y. The rise of fluoroquinolone-resistant Escherichia coli in the community:scarier than we thought. J Infect Dis 2015;212:1853-1855. https://pubmed.ncbi.nlm.nih.gov/25969562/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why do we often prescribe ceftriaxone in preference to fluoroquinolones for prophylaxis of infections in patients with cirrhosis and upper GI bleed?

Why might Lactated Ringer’s (LR) solution be preferred over normal saline (NS) for fluid resuscitation in acute pancreatitis?

FA Manian MD, MPH, , , , , , Leave a comment

Although the data is limited, fluid resuscitation with lactated Ringer’s (LR) solution in acute pancreatitis has been associated with lower risk of persistent systemic inflammatory response syndrome (SIRS) compared to normal saline (NS),  with an additional trend toward lower mortality.1-3

A 2018 meta-analysis of 3 randomized-controlled trials (RCTs) and 2 retrospective studies involving 428 patients found a significantly lower odds of developing SIRS at 24 hours (OR 0.38, CI 0.15-0.98).   Mortality was also lower in the LR group (OR 0.61, 95% CI 0.28-1.29), though it did not reach statistical significance. 1

A small 2011 RCT was the first to suggest the “protective” effect of LR in acute pancreatitis, reporting significant reduction in the prevalence of SIRS after 24 hours when compared to NS (84% vs 0%);  patients on LR also had a significantly lower C-reactive protein (CRP) (104 mg/L vs 51.4 mg/L) at 24 hours. 2   Significantly lower CRP levels were also reported at 48 and 72 hours when LR was compared to NS in another RCT in acute pancreatitis.3

As for potential mechanisms for the observed beneficial effects of LR on the pancreatic tissue in acute pancreatitis, hyperchloremic metabolic acidosis (with its attendant low extracellular pH) often seen in large volume NS resuscitation was initially thought to contribute to pancreatic injury.2  A more plausible explanation, however, may relate to the direct anti-inflammatory effect of lactate itself.  Of interest, lactate has been shown to inhibit macrophage induction invitro 4  and suppress innate immunity in experimental models of pancreatitis. 3 Who would have guessed!

Bonus Pearl: Did you know that Ringer’s solution gets its name from Sydney Ringer, a 19th century physician who demonstrated the importance of salts of sodium, potassium, calcium and chloride in precise proportions for cellular function?  LR solution was actually concocted in the 1930s by a St. Louis pediatrician, Alexis Hartmann, and was also known as the “Hartmann’s solution”. 4

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References

  1. Iqbal U, Anwar H, Scribani M. Ringer’s lactate versus normal saline in acute pancreatitis: A systematic review and meta-analysis. J Dig Dis 208;19:335-341. https://onlinelibrary.wiley.com/doi/epdf/10.1111/1751-2980.12606
  2. Wu BU, Hwang JQ, Gardner TH, et al. Clin Gastroenterol Hepatol 2011;9:710-17. https://www.cghjournal.org/article/S1542-3565(11)00454-X/abstract
  3. de-Madaria E, Herrera-Marante I, Gonzalez-Camacho V, et al. Fluid resuscitation with lactated Ringer’s solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial. UEG J 2017;6:63-72. file:///C:/Users/manifa/OneDrive%20-%20Mercy%20Online/pancreatitis%20LR2spain.pdf
  4. Lee JA. Sydney Ringer (1834-1910) and Alexis Hartmann (1898-1964). Anaesthesia 1981;36:1115-21. https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2044.1981.tb08698.x

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Why might Lactated Ringer’s (LR) solution be preferred over normal saline (NS) for fluid resuscitation in acute pancreatitis?

My patient with diverticular bleed has now developed signs of bowel ischemia with abdominal pain and sepsis after transcatheter colic artery embolization. Is bowel ischemia common after embolization of lower gastrointestinal (GI) arteries?

FA Manian MD, MPH, , , , , , , , Leave a comment

It may be more common than we think! Reported rates of bowel ischemia following lower GI artery embolization have been as high as 22% (1,2). For this reason, it is prudent to closely monitor for signs of bowel ischemia and infection in patients who undergo embolization to control lower GI bleeding.

In some cases, ischemia of the bowel appears to be mild enough to be treated conservatively, while in other cases bowel infarction with surgical intervention has been necessary (1).  One case report described signs of infection (including fever, abdominal tenderness and leukocytosis) 2 days after arterial embolization in a patient who was treated conservatively (3), while another described “sepsis” 6 days post procedure with bowel wall ischemia requiring surgical resection (1). 

Bowel injury leading to a septic picture following embolization of lower GI arteries should not be surprising given the expected capillary hypoperfusion and risk of tissue hypoxia.  Compared to embolization for upper GI bleed, lower GI embolization may place the patient at higher risk of bowel ischemia bowel ischemia due to lack of a rich collateral blood supply (1).  Older patients may also have mesenteric artery atherosclerotic disease or low cardiac output,  further compromising the collateral blood flow (3).  

At a more molecular level, hypoxia leads to the activation of hypoxia-inducible factor (HIF-1), which plays an important role in inducing gut injury. In fact, deletion of HIF-1a in mice prevented shock-induced intestinal permeability and bacterial translocation that ultimately led to bacteremia (4). 

As for preventing embolization-induced bacteremia, although antibiotics are used for liver and spleen embolization prophylaxis, their role in colic angioembolization is unclear (5).  

Bonus Pearl: Did you know that some of the earliest angioembolizations were performed during the Vietnam War to stop bleeding from bullet injuries? (6)

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References:

  1. Gady, J, Reynolds, H., & Blum, A. Selective arterial embolization for control of lower gastrointestinal bleeding: Recommendations for a clinical management pathway. Current Surg 2003; 60: 344-347. https://www.sciencedirect.com/science/article/abs/pii/S0149794402007493
  2. Rossetti A, Buchs NC, Breguet R, et al. Transarterial embolization in acute colonic bleeding: review of 11 years of experience and long-term results. Int J Colo Dis 2013;28:777-782. https://link.springer.com/article/10.1007/s00384-012-1621-5
  3. Shenoy, S, Satchidanand, S, & Wesp S. Colonic ischemic necrosis following therapeutic embolization. Gastrointest Radiol 1981, 6: 235-237. https://link.springer.com/article/10.1007/BF01890256
  4. Vollmar, B., & Menger, M. Intestinal ischemia/reperfusion: Microcirculatory pathology and functional consequences. Langenbeck Arch Surg 2011; 396: 13-29 https://link.springer.com/article/10.1007%2Fs00423-010-0727-x 
  5. Ryan, J. Mark, Ryan, Barbara M, & Smith, Tony P. Antibiotic prophylaxis in interventional radiology. JVIR 2004; 15: 547-556. https://www.sciencedirect.com/science/article/pii/S1051044307603248
  6. Nolan, T, Phan H, Hardy A, et al. Bullet embolization: Multidisciplinary approach by interventional radiology and surgery. Semin Interven Radiol 2012, 29: 192-6. https://www.ncbi.nlm.nih.gov/pubmed/23997411 

Contributed by Hannah Ananda Bougleux Gomes, Medical Student, Harvard Medical School, Boston, MA.

My patient with diverticular bleed has now developed signs of bowel ischemia with abdominal pain and sepsis after transcatheter colic artery embolization. Is bowel ischemia common after embolization of lower gastrointestinal (GI) arteries?

I am admitting a patient with diabetes mellitus (DM) due to chronic pancreatitis. Should I manage her diabetes any differently than my other patients with DM?

FA Manian MD, MPH, , , , , , , , Leave a comment

You may have to!  That’s because patients with DM due to pancreatic disease (also known as “pancreatogenic [Type 3C] diabetes”) tend to have more labile blood glucoses with particular predisposition to severe hypoglycemic episodes due to the impairment of glucagon production by pancreatic alpha-cells. 1-3

This observation dates back to a 1977 study where a high rate of hypoglycemic episodes was found among 59 patients with chronic pancreatitis (most with insulin-dependent DM), including 3 deaths and 2 suffering from severe brain damage following hypoglycemic coma. Interestingly, low basal glucagon levels were found in the latter patients, supporting impairment in glucagon synthesis. Of note, while hypoglycemia is a serious problem in these patients, they are not spared from complications of chronic hyperglycemia, including retinopathy and kidney disease.2

As for the blood glucose management in type 3C DM, since the principle endocrine defect is insulin deficiency, insulin therapy is preferred for most patients, particularly those who are acutely ill or are hospitalized. For otherwise more stable patients with mild hyperglycemia, metformin is an ideal agent as it enhances hepatic insulin sensitivity without the risk of hypoglycemia. As a bonus, metformin may also decrease the risk of pancreatic cancer in chronic pancreatitis, based on observational studies. 4

Also, don’t forget that concurrent pancreatic exocrine insufficiency is common in patients with type 3C DM and requires oral pancreatic enzyme requirement with meals.

Fascinating Pearl: Did you know that in patients with type 3C DM, hyperglycemia is mediated not only by decreased production of insulin, but also by decreased synthesis of pancreatic polypeptide, a peptide that mediates hepatic insulin sensitivity and glucose production? 5

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References

  1. Linde, J, Nilsson LH, Barany FR. Diabetes and hypoglycemia in chronic pancreatitis. Scand J Gastroenterol. 2012;12, 369–373. https://www.ncbi.nlm.nih.gov/pubmed/867001
  2. Andersen D. The practical importance of recognizing pancreatogenic or type 3c diabetes. Diabetes Metab Res Rev. 2012;28:326-328. https://onlinelibrary.wiley.com/doi/abs/10.1002/dmrr.2285
  3. Cui YF, Andersen DK. Pancreatogenic diabetes: Special considerations for management. Pancreatology. 2011;11(3):279-294. doi:10.1159/000329188. https://jhu.pure.elsevier.com/en/publications/pancreatogenic-diabetes-special-considerations-for-management-4
  4. Evans J, Donnelly L, Emsley-Smith A. Metformin and reduced risk of cancer in diabetic patients. Br Med J. 2005;330:1304-1305. https://www.researchgate.net/publication/7888859_Metformin_and_reduced_risk_of_cancer_in_diabetic_patients
  5. Rabiee A. Gafiatsatos P, Salas-Carnillo R. Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patents on insulin pump therapy. J Diabetes Sci Technol 2011;5:1521-28.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262724/

Contributed by Hugo Torres, MD, MPH, Hospital Medicine Unit, Mass General Hospital, Boston, Massachusetts

I am admitting a patient with diabetes mellitus (DM) due to chronic pancreatitis. Should I manage her diabetes any differently than my other patients with DM?

Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Short answer: Yes! Although we usually associate acute acalculous cholecystitis (AAC) with critically ill patients (eg, with sepsis, trauma, shock, major burns) in ICUs, AAC is not as rare as we might think in ambulatory patients. In fact, a 7 year study of AAC involving multiple centers reported that AAC among outpatients was increasing in prevalence and accounted for 77% of all cases (1)!

 
Although the pathophysiology of ACC is not fully understood, bile stasis and ischemia of the gallbladder either due to microvascular or macrovascular pathology have been implicated as potential causes (2). One study found that 72% of outpatients who developed ACC had atherosclerotic disease associated with hypertension, coronary, peripheral or cerebral vascular disease, diabetes or congestive heart failure (1). Interestingly, in contrast to calculous cholecystitis, “multiple arterial occlusions” have been observed on pathological examination of the gallbladder in at least some patients with ACC and accordingly a name change to “acute ischemic cholecystitis” has been proposed (3).

 
AAC can also complicate acute mesenteric ischemia and may herald critical ischemia and mesenteric infarction (3). The fact that cystic artery is a terminal branch artery probably doesn’t help and leaves the gallbladder more vulnerable to ischemia when arterial blood flow is compromised irrespective of the cause (4).

 
Of course, besides vascular ischemia there are numerous other causes of ACC, including infectious (eg, viral hepatitis, cytomegalovirus, Epstein-Barr virus, Salmonella, brucellosis, malaria, Rickettsia and enteroviruses), as well as many non-infectious causes such as vasculitides and, more recently, check-point inhibitor toxicity (1,5-8).

 
Bonus Pearl: Did you know that in contrast to cholecystitis associated with gallstones (where females and 4th and 5th decade age groups predominate), ACC in ambulatory patients is generally more common among males and older age groups (mean age 65 y) (1)?

 

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References
1. Savoca PE, Longo WE, Zucker KA, et al. The increasing prevalence of acalculous cholecystitis in outpatients: Result of a 7-year study. Ann Surg 1990;211: 433-37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1358029/pdf/annsurg00170-0061.pdf
2. Huffman JL, Schenker S. Acute acalculous cholecystitis: A review. Clin Gastroenterol Hepatol 2010;8:15-22. https://www.cghjournal.org/article/S1542-3565(09)00880-5/pdf
3. Hakala T, Nuutinene PJO, Ruokonen ET, et al. Microangiopathy in acute acalculous cholecystitis Br J Surg 1997;84:1249-52. https://bjssjournals.onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2168.1997.02775.x?sid=nlm%3Apubmed
4. Melo R, Pedro LM, Silvestre L, et al. Acute acalculous cholecystitis as a rare manifestation of chronic mesenteric ischemia. A case report. Int J Surg Case Rep 2016;25:207-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941110/
5. Aguilera-Alonso D, Median EVL, Del Rosal T, et al. Acalculous cholecystitis in a pediatric patient with Plasmodium falciparum infection: A case report and literature review. Ped Infect Dis J 2018;37: e43-e45. https://journals.lww.com/pidj/pages/articleviewer.aspx?year=2018&issue=02000&article=00020&type=Fulltext  
6. Kaya S, Eskazan AE, Ay N, et al. Acute acalculous cholecystitis due to viral hepatitis A. Case Rep Infect Dis 2013;Article ID 407182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784234/pdf/CRIM.ID2013-407182.pdf
7. Simoes AS, Marinhas A, Coelho P, et al. Acalculous acute cholecystitis during the course of an enteroviral infection. BMJ Case Rep 2013;12. https://casereports.bmj.com/content/12/4/e228306
8. Abu-Sbeih H, Tran CN, Ge PS, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J ImmunoTherapy of Cancer 2019;7:118. https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0604-2

 

 

Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

My elderly patient with abdominal pain has a negative Murphy’s sign on physical exam. How accurate is Murphy’s sign in diagnosing cholecystitis?

FA Manian MD, MPH, , , , , , Leave a comment

Not as accurate as we might like! In fact, no single clinical finding has been found to carry sufficient weight in ruling in or excluding cholecystitis and Murphy’s sign (inability to take a deep breath due to pain upon palpation of the right upper quadrant) is no exception. 1

A meta-analysis of patients with Murphy’s sign reported a sensitivity of 65% and a specificity of 87% (positive LR 2.8, negative LR 0.4, with 95% C.I. including 1.0 in both). 1,2  However, among the elderly (mean age 79 y), the sensitivity may be as slow as 48% 2 and in patients with gangrenous cholecystitis as low as 33%.3  

In contrast, Murphy’ s sign elicited at the time of ultrasound of the gallbladder (ie,“sonographic Murphy’s) is generally thought to very sensitive  (>90%) for acute cholecystitis;3,4 1 study reported a sensitivity of 63%, however (specificity 94%).5  Remember that altered mental status may also mask sonographic Murphy’s sign. 

Indirect fist percussion of the liver has been suggested by some authors as a more sensitive alternative to Murphy’s sign (100% vs 80%) in a small series of patients with cholecystitis.2

Bonus pearl: Did you know that another technique originally described by the famed American surgeon, John Murphy, to diagnose acute cholecystitis consisted of the “hammer stroke maneuver” in which percussion of the right midsubcostal region with the bent middle finger of the left hand was performed using the right hand to strike the dorsum of the left hand with hammer-like blows? 6

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References

  1. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient have acute cholecystitis. JAMA 2003;289:80-86. https://jamanetwork.com/journals/jama/article-abstract/195707
  2. Ueda T, Ishida E. Indirect fist percussion of the liver is a more sensitive technique for detecting hepatobiliary infections than Murphy’s sign. Current Gerontol Geriat Res, Volume 2015, Article ID 431638. https://www.hindawi.com/journals/cggr/2015/431638/
  3. Simeone JF, Brink JA, Mueller PR, et al. The sonographic diagnosis of acute gangrenous cholecystitis. The importance of the Murphy sign. AJR 1989;152:289-90. https://www.ncbi.nlm.nih.gov/pubmed/2643262
  4. O’Connor OJ, Maher MM. Imaging of cholecystitis. AJR 2011;196:W36774. https://www.ajronline.org/doi/full/10.2214/AJR.10.4340
  5. Rallis PW, Lapin SA, Quinn MF, et al. Prospective evaluation of the sonographic Murphy sign in suspected acute cholecystitis. J Clin Ultrasound 1982;10:113-5. https://www.ncbi.nlm.nih.gov/pubmed/6804512
  6. Salati SA, al Kadi A. Murphy’s sign of cholecystitis-a brief revisit. Journal of Signs and Symptoms 2012;1:53-6. https://www.researchgate.net/publication/230820198_Murphy’s_sign_of_cholecystitis-_a_brief_revisit

 

 

My elderly patient with abdominal pain has a negative Murphy’s sign on physical exam. How accurate is Murphy’s sign in diagnosing cholecystitis?