Why is there a predilection for the tricuspid valve (TV) infection among injection drug users (IDUs) with infective endocarditis (IE)?

Although right-sided IE accounts for only 9% of IE cases among non IDUs, in IDUs it accounts for over three-quarters of IE cases1.  

Several potential mechanisms have been posited to explain susceptibility of TV to infection in IDUs, including endothelial damage due to repeated inoculation of small bacterial loads, specific substances (eg talc) injected with drugs,  cocaine-induced vasospasm and thrombus formation, and drug-induced pulmonary hypertension associated with increased pressure gradients and turbulence.  In addition, facilitation of bacterial adhesion due to the deposition of immune complexes (eg antibody vs antigens in injected drugs) on the TV and coating of the injected particulate matter with bacterial adherence matrix molecules on valve surfaces may also play an important role1,2.

Add to these potential factors a higher risk nasal and cutaneous colonization with Staphylococcus aureus (a common cause of IE) among IDUs, and we have a perfect storm!

References

  1. Frontera JA, Gradon JD. Right-sided endocarditis in injection drug users: review of proposed mechanisms of pathogenesis. Clin Infect Dis 2000;30:374-9.
  2. Chahood J, Yakan AS, Saad H, et al. Right-sided infective endocarditis and pulmonary infiltrates: An update. Cardiol Rev 2016;24:230-37.
Why is there a predilection for the tricuspid valve (TV) infection among injection drug users (IDUs) with infective endocarditis (IE)?

How should I interpret high serum vitamin B12 levels in my patient with anemia?

High serum B12 levels, aka hypercobalaminemia (HC),  is not rare among hospitalized patients with 1 study reporting “high” (813-1355 pg/ml) and “very high” (>1355 pg/ml) serum B12 levels in 13 and 7% of patients, respectively1. Common causes include excess B12 intake, solid neoplasms (particularly, hepatocellular carcinoma and metastatic neoplastic liver disease), blood disorders (eg, myelodysplastic syndrome, CML, and acute leukemias, particularly AML3), and other liver diseases, including alcohol-related diseases as well as acute and chronic hepatitis.  Other inflammatory states and renal failure have also been reported2.  

Paradoxically, even in the presence of HC, a functional B12 deficiency may still exist. This may be related to poor B12 delivery to cells due to its high binding by transport proteins transcobalamin I and III in HC which may in turn cause a decrease in the binding of B12 to transcobalamin II, a key player in B12 transport to tissues2.  In this setting, elevated serum methylmalonic acid and homocysteine levels may be helpful.

References:

  1. Arendt JFB, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS ONE 2012;9:e45979.
  2. Andres E, Serraj K, Zhu J. et al. The pathophysiology of elevated vitamin B12 in clinical practice. Q J Med 2013;106:505-515.
How should I interpret high serum vitamin B12 levels in my patient with anemia?

How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?

AZ is a macrolide antibiotic which interferes with bacterial protein synthesis by binding to the 50S ribosomal subunit. It is often used to treat acute respiratory tract infections due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, as well as Mycoplasma, Chlamydia, and Legionella sp1. Although it has no in vitro activity against many aerobic gram-negative bacilli such as Pseudomonas aeruginosa, its chronic use has often been associated with a significant reduction in the frequency of disease exacerbations in patients with chronic bronchiectasis and colonization due to this organism, including patients with COPD or CF1-3.

Because P. aeruginosa is invariably macrolide-resistant, the beneficial effect of AZ in chronically infected or colonized patients must be due to factors other than its direct effect on bacterial replication.  Several mechanisms have been invoked including: 1. Inhibition of quorum-sensing dependent virulence factor and biofilm production 2.Blunting of host inflammatory response (eg, ↑IL-10, and ↓ IL-1ß, IL-6, IL-8, TNF-α, and ↓ chemotaxis); and 3. Enhanced antiviral response1.

The latter finding is quite unexpected but AZ appears to augment interferon response to rhinovirus in bronchial cells of COPD patients3.  With respiratory viruses (including rhinoviruses) causing 20-55% of all COPD exacerbations, perhaps this is another way AZ may help the host! Who would have thought!!

References

  1. Vos R, Vanaudenaerde BM, Verleden SE, et al. Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection. Transplantation 2012;94:101-109.
  2. Cochrane review. Treatment with macrolide antibiotics for people with cystic fibrosis and chronic chest infection. Nov 14, 2012. http://www.cochrane.org/CD002203/CF_treatment-with-macrolide-antibiotics-for-people-with-cystic-fibrosis-and-chronic-chest-infection
  3. Menzel M, Akbarshahi H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD. Scientific Reports 2016; 6:28698. DOI:10.1038/srep 28698.
How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?

How accurate is EKG when evaluating for left ventricular hypertrophy (LVH)?

A systematic review comparing 6 EKG criteria for LVH (including commonly used Sokolow-Lyon [defined below], Cornell voltage index or product, Gubner, and Romhilt-Estes scores 4 or 5) with echocardiography reported very low median sensitivities; “highest” sensitivity was found using the Sokolow-Lyon criteria (median 21%, 4-52%). Median specificities were  89% (53-100%) and 99% (71-100%) for Sokolow-Lyon and Romhilt-Estes criteria (5 points) (1).

More recently, MRI has become the gold standard for in-vivo LV mass measurement. In a study involving patients with aortic stenosis undergoing MRI, EKG generally had poor negative predictive value (NPV) (<70% by most criteria), but high positive predictive value (PPV) (>90% by most criteria) for LVH; for Sokolow-Lyon criteria, the NPV and PPV were 46% and 90%, respectively (2). 

In another MRI study involving patients with various cardiovascular conditions (eg hypertension, CAD), RaVL alone (>10mm) performed better than Sokolow-Lyon (AUC 0.78, specificity 95.5%) but its sensitivity was still nothing to brag about (36.5%) (3).

So, EKGs are better at ruling in than ruling out LVH!

 

LVH definition of selected EKG indexes

Sokolow-Lyon index: SV1+(RV5 or V6)>35 mm 

Cornell voltage index: men, RaVL+SV3>28 mm; women, RaVL+SV3>20 mm

Modified Cornell: RaVL>11mm (>10 mm, ref. 3)

Gubner: RI+SIII>24mm

 

References

1.Pewsner D, Juni P, Egger M, et al. Accuracy of electrocardiography in diagnosis of left ventricular hypertrophy in arterial hypertension: systematic review. BMJ 2007. doi:10.1136/bmj.39276.636354.AE  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001078

2.Buchner S, Debl K, Haimerl J, et al.  Electrocardiographic diagnosis of left ventricular hypertrophy in aortic valve disease: evaluation of ECG criteria by cardiovascular magnetic resonance. J Cardiovasc Magn Reson  2009; 11:18. https://jcmr-online.biomedcentral.com/articles/10.1186/1532-429X-11-18

3.Courand P-Y, Grandjean A, Charles P, et al. R wave in aVL lead is a robust index of left ventricular hypertrophy: a cardiac MRI study. Am J Hypertension 2015;28:1038-48. https://www.ncbi.nlm.nih.gov/pubmed/25588700

 

Contributed in part by Khin-Kyemon Aung, medical student, Harvard Medical School, Boston.

How accurate is EKG when evaluating for left ventricular hypertrophy (LVH)?

Why should I pay attention to the augmented vector right (aVR) EKG lead in my patient with chest pain?

Lead aVR is often “neglected” because of its non-adjacent location to other EKG leads (Fig 1) and poor awareness of its potential utility in detecting myocardial ischemia.

In acute coronary syndrome (ACS), ST-elevation (STE) in aVR (≥1mm) with diffuse ST depression in other leads (Fig 2) is usually a sign of severe left main coronary artery (LMCA), proximal left anterior descending (LAD), or 3-vessel coronary disease, and is associated with poor prognosis1-3.  In some patients with LMCA thrombosis, the EKG changes may be non-specific but STE in aVR should still raise suspicion for ischemia1.  Possible mechanisms for STE in aVR include diffuse anterolateral subendocardial ischemia or transmural infarction of the basal portion of the heart. 

The possibility of an anatomical variant of the Purkinje fibers leading to the absence of STE in the anterior leads in some patients with transmural anterior infarction is another reason to pay attention to aVR.

 

Fig 1. Standard EKG limb leads. Note that aVR is “in the fringes”.

ekggreatwork

Fig 2. 35 year old female with ACS due to LMCA spasm. Note STE in aVR with ST segment depression in leads V3-6, I, aVL, II, and aVF  (Courtesy National Library of Medicine)

ekgavr

 

References

  1. Kossaify A. ST segment elevation in aVR: clinical syndrome in acute coronary syndrome. Clin Med Insights: Case Reports 2013:6.
  2. Kireyev D, Arkhipov MV, Zador ST. Clinical utility of aVR-the neglected electrocardiographic lead. Ann Noninvasive Electrocardiol 2010;15:175-180.
  3. Wong –CK, Gao W, Stewart RAH, et al. aVR ST elevation: an important but neglected sign in ST elevation acute myocardial infarction. Eur Heart J 2010;31:1845-1853.
  4. De Winter RJ, Verouden NJ, Wellens HJ, et al. A new ECG sign of proximal LAD occlusion. N Engl J Med 2008;359:2071-3.

 

Why should I pay attention to the augmented vector right (aVR) EKG lead in my patient with chest pain?

When should I consider bicarbonate (BC) replacement in my patient with renal insufficiency?

Metabolic acidosis is one of the earliest complications of chronic kidney disease (CKD), with a direct correlation between the decline in glomerular filtration rate (GFR) and reduction in serum BC1.

Epidemiologic studies in patients with CKD have reported an independent association between serum BC (<22 meq/L considered low) and adverse renal outcomes and mortality1. Limited data from small interventional trials of alkali therapy supplementation and dietary interventions (eg, increased fruit and vegetable intake) have shown the benefits of raising serum BC. Specifically, 1 study involving patients with CKD stages 4 and 5 and another involving CKD stage 2 hypertensive nephropathy reported slower decline in creatinine clearance/eGFR in patients receiving BC replacement2,3.  

Less is known on the potential benefit of BC replacement in patients with acute kidney injury (AKI) with a recent Cochrane review finding no randomized controlled trials4 and national guidelines not recommending either in favor or against its use AKI5. Of note, BC therapy has also been associated with sodium and fluid overload, an increase in lactate and PCO2, and a decrease in serum ionized calcium6.

References

  1. Dobre M, Rahman M, Hostetter TH. Current status of bicarbonate in CKD. J Am Soc Nephrol 2015;26:515-523.
  2. de Brito-Ashurst I, Varagunam M, Raftery MJ, et al. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 2009; 20: 2075–2084.
  3. Mahajan A, Simoni J, Sheather SJ, et al. Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int 2010;78: 303–309.
  4. Hewitt J, Uniacke M, Hansi NK, et al. Sodium bicarbonate supplements for treating acute kidney injury. Cochrane Database of Systematic Reviews 2012; Jun 13; (6):CD009204. doi: 10.1002/14651858.
  5. Palevsky PM, Liu KD, Brophy PD, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis 2013;61:649-72.
  6. Sabatini S, Kurtzman NA. Bicarbonate therapy in severe metabolic acidosis. J Am Soc Nephrol 2009;20:692-695.

 

Contributed in part by Cynthia Cooper, MD, Mass General Hospital, Boston, MA.

When should I consider bicarbonate (BC) replacement in my patient with renal insufficiency?

How exactly do urinary tract infections (UTIs) cause delirium in my elderly patients?

 UTIs are often considered in the differential diagnosis of causes of delirium in the elderly. Though largely speculative, 2 possible pathophysiologic basis for this association are suggested:1-3

  •  Direct brain insult (eg, in the setting of sepsis/hypotension)
  • Indirect aberrant stress response, involving the hypothalamic-pituitary-adrenal [HPA] axis, sympathetic nervous system (SNS) and/or inflammatory pathways

One or both pathways can interact with the neurotransmitter and intracellular signal transduction systems underlying delirium in the brain, which may already be impaired in the elderly due to age-related or other pathologic changes.

The indirect aberrant stress pathway suggests that not only can UTI-associated circulating cytokines cause delirium but pain and discomfort (eg, from dysuria) may also contribute via the HPA axis and SNS. If true, this explanation makes it unlikely for bacteriuria or pyuria to be associated with delirium in the absence of significant systemic inflammatory response or pain and discomfort.

 

References

1.Trzepacz P, van der Mast R. The neuropathophysiology of delirium. In Lindesay J,  Rockwood K, Macdonald A (Eds.). Delirium in old age, pp. 51–90. Oxford University Press, Oxford , 2002.

2.Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol A Biol Sci Med Sci. 1999; 54: B239–B246

3. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008;65:229–38.

Contributed by Henrietta Afari MD, Mass General Hospital, Boston, MA

How exactly do urinary tract infections (UTIs) cause delirium in my elderly patients?