EUH Morning Report: How should we reduce the risk of Clostridium difficile-associated diarrhea (CDAD) in hospitalized patients who require antibiotics?

The Bottom Line: Moderate-quality evidence supports a significant protective effect of probiotics against CDAD, and higher-risk patients (e.g. patients with prior history of CDAD) stand to benefit more from prevention. Probiotics should not be given to patients who are immunocompromised, are pregnant, are in intensive care, or have prosthetic heart valves or certain preexisting gastrointestinal disorders (e.g., inflammatory bowel disease, ostomy). For most other hospitalized patients who receive antibiotics during hospitalization, prescribing 20 to 50 billion colony forming units of probiotics daily (starting within 24–48 hours of antibiotic initiation) can prevent CDAD (Dressler, 2017).

References: Dressler DD. Do probiotics prevent C. difficile-associated diarrhea in patients receiving antibiotics? NEJM Journal Watch. 2018 Mar 13.

Goldenberg JZ, Yap C, Lytvyn L, Lo CK, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Datbase Syst Rev. 2017 Dec 19;12:CD006095.

Summary: In summarizing their systematic review, Goldenberg et al (2017) state:

“This review includes 39 randomized trials with a total of 9955 participants. Thirty-one studies (8672 participants) assessed the effectiveness of probiotics for preventing CDAD among those taking antibiotics. Our results suggest that when probiotics are given with antibiotics the risk of developing CDAD is reduced by 60% on average. Among trials enrolling participants at high risk of developing CDAD (>5%), the potential benefit of probiotics is more pronounced with a 70% risk reduction on average. Side effects were assessed in 32 studies (8305 participants) and our results suggest that taking probiotics does not increase the risk of developing side effects. The most common side effects reported in these studies include abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance.”

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EUH Morning Report: Do specific blood pressure medications lead to higher prevalence of Orthostatic Hypotension syncope or recurring syncope in older adults with dementia?

The Bottom Line: In older adults with dementia, nitrates and alpha-blockers alone and the combinations of ACE-Is and diuretics, alpha-blockers and diuretics, and ACE-Is and nitrates are more frequent in patients with syncope due to OH than in those without (Testa et al, 2018).

References: Testa G, Ceccofiglio A, Mussi C, Bellelli G, et al. Hypotenstive drugs and syncope due to orthostatic hypotension in older adults with dementia (syncope and dementia study). J Am Geriatr Soc. 2018 Aug;66(8):1532-1537. Doi:10/1111/jgs.15421.

Ungar A, Mussi C, Nicosia F, et al. Etiology of syncope and unexplained falls in elderly adults with dementia: Syncope and Dementia (SYD) Study. J Am Geriatr Soc. 2016 Aug;64(8):1567-1573. Doi:10.1111/jgs.14225.

Summary: The recent Syncope and Dementia (SYD) Study found that syncope due to OH was the most common type (50%) of syncope in a population of older adults with dementia and recurrent syncope. Additionally, in nearly half of the study’s participants, dementia was vascular in origin (Unger et al, 2016). Aggressive blood pressure treatment has been related to OH, although the role of specific drugs and combinations is unclear (Testa et al, 2018).

Testa et al (2018) found that the number of drugs administered and particular hypotensive drugs, specifically nitrates alone and combinations of ACE-Is and diuretics and of ACE-Is and nitrates, significantly increase the risk of syncope due to OH. Testa et al (2018) recommend using extreme caution when using these drugs in older adults with dementia.

EUH Morning Report: Should lasix (furosemide) be considered in the setting of hypercalcemia?

The Bottom Line: Avoid loop diuretics in the setting of acute hypercalcemia, except may be considered for patients with concomitant volume overload.

Loop Diuretic:

  • inhibits calcium resorption in distal renal tubule
  • may worsen volume depletion and electrolyte derangements and should be used with caution
  • no evidence to support use in acute hypercalcemia
    • may be used to control volume overload
    • associated with hypokalemia and possibly contributes to dehydration

(DynaMed Plus, 2016)

References: DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. 116018, Hypercalcemia; [updated 2016 Dec 27, cited 2018 Jul 19]; [about 10 screens]. Emory login required.

LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Annals of Internal Medicine. 2008;149(4):259-263.

Saitz R. Furosemide for hypercalcemia: Neither proven nor recommended. NEJM Journal Watch. 2008 Sept 25.

Summary: In his review of LeGrand et al (2008), Dr. Richard Saitz provides the following summary and comment.

A literature review found little support for the use of the diuretic furosemide to treat hypercalcemia.

Many textbooks recommend saline and furosemide as first-line management for hypercalcemia. Investigators searched the literature since 1950 for studies of furosemide or bisphosphonate use for hypercalcemia in people.

They identified nine reports — the most recent from 1983 — involving 37 patients treated with furosemide for hypercalcemia; doses ranged from 240 mg to 2400 mg. Calcium normalized in 14 of 39 episodes, and within 12 hours in only two cases. Intensive monitoring was accompanied by replacement of fluid and electrolyte losses. Complications included hypernatremia, coma, metabolic acidosis, hypophosphatemia and hypomagnesemia, altered mental status, and tetany.

Investigators identified 56 clinical studies of bisphosphonates — 34 were randomized and included more than 1000 patients. In a systematic review of 26 studies of bisphosphonate use in hypercalcemia of cancer, calcium levels normalized in more than 70% of patients. The authors conclude that volume repletion and bisphosphonate therapy should be the standard management strategy for hypercalcemia, with furosemide used only for managing fluid overload.

COMMENT

Forced saline diuresis for hypercalcemia is a long-standing practice that persists, even in authoritative texts, despite the absence of evidence for its efficacy, the existence of known risks, and the availability of other proven treatments. Saline and bisphosphonates, with or without calcitonin, are the standard of care for hypercalcemia.

(Saitz, 2008)

EUH Hunt Conference: What are the benefits of tamoxifen in treating encapsulating peritoneal sclerosis (EPS)?

The Bottom Line: Tamoxifen appears to exert its effect through inhibition and modulation of TGF-β. In vitro and animal models showed that Tamoxifen treatment blocked EMT induced by TGF-β, preserved the fibrinolytic activity and reduced the migration capacity of mesothelial cells leading to reduced fibrosis and reduced PD effluent levels of VEGF leading to reduced angiogenesis in the peritoneum. However, Tamoxifen has almost always been used in combination with corticosteroids, therefore the efficacy and safety of Tamoxifen alone in the treatment of EPS still remains to be evaluated.

Reference: Moinuddin Z, Summers A, Van Dellen D, Augustine T, et al. Encapsulating peritoneal sclerosis – a rare but devastating peritoneal disease. Frontiers in Physiology. 2014;5:470. Doi:10.3389/fphysi.2014.00470

Summary:  Encapsulating peritoneal sclerosis (EPS) is a devastating but rare complication of long-term peritoneal dialysis. The disease is associated with extensive thickening and fibrosis of the peritoneum resulting in the formation of a fibrous cocoon encapsulating the bowel leading to intestinal obstruction. The incidence of EPS ranges between 0.7 and 3.3% and increases with duration of peritoneal dialysis therapy.
Tamoxifen is a Selective Estrogen Receptor Modulator (SERM) with antifibrotic properties and has been used in the treatment of various fibrotic disorders like retroperitoenal fibrosis, fibrosing mediastinitis, fibrosing cerivicitis, and desmoid tumors

A large retrospective Dutch study demonstrated significantly reduced mortality in EPS patients that were treated with Tamoxifen (45.8%) when compared to those that were not treated with Tamoxifen (74.4%).The potential side-effects of Tamoxifen (deep vein thrombosis, endometrial cancer, and calciphylaxis) also need to be considered.

Grady Morning Report: What are the current guidelines concerning the management of acute pulmonary embolism (PE)?

The Bottom Line:

Only one of the phase 3 clinical trials investigating the use of new direct oral anticoagulants in patients with VTE reported efficacy results for the subgroup of patients with acute PE and RV dysfunction. Among patients with elevated NT‐proBNP levels, recurrent VTE occurred in 15 of 454 patients in the edoxaban cohort and in 30 of 484 patients in the warfarin group.

A new trial, the Pulmonary Embolism International Trial (PEITHO‐II) will focus on the safety, efficacy and cost‐effectiveness of dabigatran in the treatment of patients with acute intermediate‐risk PE. Patients will be treated with low molecular weight heparin for at least 72 hours followed by dabigatran treatment for 6 months.

References: Klock FA et al. Management of intermediaterisk pulmonary embolism: uncertainties and challenges. Eur J Haematol. 2015 Dec;95(6):489-97. doi: 10.1111/ejh.12612. Epub 2015 Jul 15.

Link to current trial (still recruiting patients): https://www.escardio.org/Working-groups/Working-Group-on-Pulmonary-Circulation-and-Right-Ventricular-Function/Education/peitho-2

Summary:

Reperfusion Treatment

A. The Pulmonary Embolism Thrombolysis Trial (PEITHO) compared, in a double‐blind manner, fibrinolysis with tenecteplase plus heparin vs. placebo plus heparin in 1005 patients with acute PE. Eligible patients had RV dysfunction, plus myocardial injury; that is, they were at intermediate‐high risk of an adverse early outcome. The primary outcome, a composite of all‐cause death or hemodynamic decompensation/collapse, was significantly reduced with tenecteplase. On the other hand, there was an increased incidence of hemorrhagic stroke after fibrinolytic treatment with tenecteplase; major non‐intracranial bleeding events were also increased in the tenecteplase group compared with placebo. This study strongly argues against the standard application of thrombolysis in hemodynamically stable PE patients.

B. Catheter‐directed techniques are considered an alternative to surgery. The safety and efficacy of pharmacomechanical fibrinolysis is supported by the results of a recent trial which enrolled 150 patients with submassive (intermediate‐risk) or massive (high‐risk) PE. Due to the lack of high‐quality studies in patients with PE in general as well as in patients with intermediate‐risk PE specifically, the safety and efficacy of these interventions remain unknown.

Anticoagulation Treatment

New non‐vitamin K‐dependent oral anticoagulants (NOACs), in particular direct factor IIa (thrombin) and factor Xa inhibitors, were developed and tested in large phase‐3 randomized clinical trials. A meta‐analysis of the phase III clinical trials on VTE showed that new oral anticoagulants were associated with a significantly lower risk of major as well as fatal hemorrhage compared to VKA treatment. The experience with NOACs in current trials on intermediate risk PE is limited.

 

 

EUH Morning Report: Should lasix (furosemide) be considered in the setting of hypercalcemia?

The Bottom Line: Avoid loop diuretics in the setting of acute hypercalcemia, except it may be considered for patients with concomitant volume overload.

DynaMed Plus provides the following information on loop diuretics:

  • inhibits calcium resorption in distal renal tubule
  • may worsen volume depletion and electrolyte derangements and should be used with caution
  • no evidence to support use in acute hypercalcemia
    • may be used to control volume overload
    • associated with hypokalemia and possibly contributes to dehydration

References: DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. 116018, Hypercalcemia; [updated 2016 Dec 27, cited 2018 Jul 19]; [about 10 screens]. Emory login required.

LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Annals of Internal Medicine. 2008;149(4):259-263.

Summary: The following is a review of LeGrand et al’s 2008 article (NEJM Journal Watch):

A literature review found little support for the use of the diuretic furosemide to treat hypercalcemia.

Many textbooks recommend saline and furosemide as first-line management for hypercalcemia. Investigators searched the literature since 1950 for studies of furosemide or bisphosphonate use for hypercalcemia in people.

They identified nine reports — the most recent from 1983 — involving 37 patients treated with furosemide for hypercalcemia; doses ranged from 240 mg to 2400 mg. Calcium normalized in 14 of 39 episodes, and within 12 hours in only two cases. Intensive monitoring was accompanied by replacement of fluid and electrolyte losses. Complications included hypernatremia, coma, metabolic acidosis, hypophosphatemia and hypomagnesemia, altered mental status, and tetany.

Investigators identified 56 clinical studies of bisphosphonates — 34 were randomized and included more than 1000 patients. In a systematic review of 26 studies of bisphosphonate use in hypercalcemia of cancer, calcium levels normalized in more than 70% of patients. The authors conclude that volume repletion and bisphosphonate therapy should be the standard management strategy for hypercalcemia, with furosemide used only for managing fluid overload.

COMMENT

Forced saline diuresis for hypercalcemia is a long-standing practice that persists, even in authoritative texts, despite the absence of evidence for its efficacy, the existence of known risks, and the availability of other proven treatments. Saline and bisphosphonates, with or without calcitonin, are the standard of care for hypercalcemia.

EUH Morning Report: What is the criteria for liver transplantion in patients with hepatocellular carcinoma?

The Bottom Line: Liver transplant is recommended for patients with potentially resectable or transplantable disease according to performance status or lack of severe comorbidity, or in patients with unresectable disease who meet Milan or United Network for Organ Sharing (UNOS) criteria. Controversy exists over liver transplantation in patients with tumors marginally outside Milan or UNOS criteria, but some institutions may still consider it (DynaMed Plus, 2017).

  • Milan criteria for liver transplantation for hepatocellular carcinoma includes either of:
    • single lesion ≤ 5 cm in diameter
    • 2-3 lesions all ≤ 3 cm in diameter
  • UNOS criteria for liver transplantation for hepatocellular carcinoma includes both of:
    • Milan criteria
    • no evidence of macrovascular involvement or extrahepatic disease

Reference: DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. 909499, Management of early hepatocellular carcinoma / Liver Transplant; [updated 2017 May 31, cited 2018 June 28]; [about 24 screens]. Emory login required.

Summary: 

(DynaMed Plus, 2017)

EUH Krakow Conference: Review of Kikuchi-Fujimoto Disease

Bottom line: “Kikuchi–Fujimoto disease, or Kikuchi’s disease, also known as histiocytic necrotizing lymphadenitis, is a rare, benign, self‐limiting condition characterized by cervical lymphadenopathy and fever….symptoms usually resolve spontaneously within 1–4 months. However, cervical lymphadenopathy can persist for up to 6 months and even 1 year. There is a possibility of recurrence, yet rates of only 3–4% have been reported. The treatment of Kikuchi’s disease is primarily supportive and aims to facilitate the relief of symptoms with the use of analgesics, antipyretics, and rest. In a more severe or protracted disease course, short‐duration oral corticosteroid therapy is the treatment of choice. There are no specific guidelines regarding the dosage or length of treatment. Hydroxychloroquine is another therapeutic option that has been used to achieve rapid clinical improvement in Kikuchi’s disease. The safety profile of hydroxychloroquine may make it a better alternative to long‐term, high‐dose corticosteroids as it has fewer adverse effects. Despite a lack of recommendation, intravenous immunoglobulin, given its immunomodulatory nature, has also been used successfully in patients with severe disease. The mortality rate with Kikuchi’s disease was calculated to be 2.1%. Patients diagnosed with Kikuchi’s disease should be subject to close long‐term monitoring for the possible development of SLE [systemic lupus erythematosus]. Kikuchi’s disease can precede the onset of SLE by years.”1 Review articles provides several histopathological and dermatological images of patients with the condition.

ReferenceMathew LM, Kapila R, Schwartz RA. Kikuchi-Fujimoto disease: a diagnostic dilemmaInt J Dermatol. 2016 Oct;55(10):1069-75. doi: 10.1111/ijd.13314. Epub 2016 May 21. 

EUH Krakow Conference: Review of Lemierre’s Syndrome

Bottom Line: Vijay and Fattah1 state that Lemierre’s syndrome typically presents in young adults who were previously healthy. In a case series of 222 patients who fit the “Lemierre’s syndrome case presentation, the median age was 19 years and 89% of patients were aged 10 to 35 years.”2 Its four key elements are “primary oropharyngeal infection within 4 weeks, suppurative thrombophlebitis of the internal jugular (IJ) vein, metastatic septic emboli, and [a] causal association with F necrophorum.” It should be “suspected in those with a recent history of oropharyngeal infection presenting with fever and rigors, with or without evidence of metastatic lesions, particularly respiratory symptoms (pleuritic chest pain, dyspnoea, haemoptysis).” Penicillin/beta-lactamase inhibitor, penicillin plus metronidazole, and carbapenem” are “appropriate empirical antibiotic regimens….There are no controlled trials to guide management, but most sources recommend between 2–6 weeks of antibiotics in total.” Review article provides four computed tomography pulmonary angiogram (CTPA) images with red arrows that indicate locations of multiple peripheral nodular lesions.

References:

1. Vijay V, Fattah Z. Lesson of the month 1: Lemierre‘s syndrome: a reminder of the ‘forgotten disease.’ Clin Med (Lond). 2018 Feb;18(1):100-102. doi:10.7861/clinmedicine.18-1-100.

2. Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focuson Lemierre’s syndrome. Clin Microbiol Rev. 2007 Oct;20(4):622-59. doi:10.1128/CMR.00011-07.

EUH Morning Report: Review of microscopic colitis

Bottom Line: “Microscopic colitis is a common cause of chronic watery diarrhea, particularly in the elderly. The accompanying symptoms, which include abdominal pain and fatigue, can markedly impair patients’ quality of life. Diagnosis is based upon characteristic histologic findings of the colonic mucosa….Two recent randomized studies have confirmed the effectiveness of oral budesonide for both induction and maintenance treatment of microscopic colitis and is now endorsed by the American Gastroenterological Association as first-line treatment.”

Reference: Cotter TG, Pardi DS. Current approach to the evaluation and management of microscopic colitis. Curr Gastroenterol Rep. 2017 Feb;19(2):8.