My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Assuming no recent changes in the dose of warfarin, one potential culprit may be her recent antibiotic exposure. Of the long list of antibiotics associated with elevated INR, quinolones (e.g. ciprofloxacin, levofloxacin), trimethoprim-sulfamethoxazole, macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are generally thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk. 1-3

Other drugs such as amiodarone (Did she have atrial fibrillation during her recent hospitalization?), acetaminophen (Has she been receiving at least 2 g/day for several consecutive days?), and increasing dose of levothyroxine (Was she thought to be hypothyroid recently?) should also be considered.3,4

Also remember to ask about herbal supplements (eg, boldo-fenugreek, dong quai, danshen) that may potentiate the effect of warfarin. 3 Of course, poor nutrition in the setting of recent illness might have also played a role.5

As far as the mechanisms for drug interaction with warfarin, some drugs act as cytochrome p450 inhibitors (thus reducing the metabolism of warfarin), while others influence the pharmacodynamics of warfarin by inhibiting the synthesis or increasing the clearance of vitamin K-2 dependent coagulation factors.3

Antibiotics may increase the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Check out a related pearl on P4P: https://pearls4peers.com/2015/06/25/is-there-anyway-to-predict-a-significant-rise-in-inr-from-antibiotic-use-in-patients-who-are-also-on-warfarin  

 

References

  1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622
  2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf
  3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. doi:10.1378/chest.11-2292.  https://www.ncbi.nlm.nih.gov/pubmed/22315269
  4. Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy 2011;31:591-7. https://www.ncbi.nlm.nih.gov/pubmed/21923443
  5. Kumar S, Gupta D, Rau SS. Supratherapeutic international normalized ratio: an indicator of chronic malnutrition due to severely debilitating gastrointestinal disease. Clin Pract. 2011;1:e21. doi:10.4081/cp.2011.e21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981245

 

Contributed by Rachel Weitzman, Medical Student, Harvard Medical School, Boston, MA.

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Which non-pharmacological approaches may help symptoms of orthostatic hypotension in my patient with autonomic insufficiency?

A number of simple measures to help reduce the symptoms of neurogenic orthostatic hypotension (nOH) in susceptible patients have been recommended.1

  • Blood volume repletion (a minimum of 64 oz or 2L of water intake daily), depending on cardiac status. In addition, rapid consumption (within 5 min) of 16 oz or 500 ml of water can raise blood pressure by 30 mmHg for about an hour. It’s worth noting that liquids other than water (eg, water plus salt) do not provide the same BP response, likely due to water-induced hypo-osmolar reflex in the portal circulation.2,3
  • Increase salt intake if possible (eg, add 1-2 teaspoons or 2.3-4.6 g of salt per day), as many patients with nOH have an inadequate salt intake.
  • Improve physical conditioning that is not gravitationally challenging (eg, stationary recumbent bicyle, rowing machine).
  • Avoid increased core body temperature (eg hot tubs, prolonged hot showers).
  • Head-up position while sleeping through use of a wedge under the mattress or blocks under the head of the bed so that the head is 6-9 inches (15-23 cm) higher than the feet. This is to minimize nocturnal supine hypertension which can cause pressure diuresis and volume depletion.
  • Compressive garments, preferably either an abdominal binder or thigh high stockings when erect; knee high stocking are not likely to be effective.
  • Smaller, more frequent,  meals not high in carbohydrates in patients with postprandial hypotension.
  • Dietary supplementation with B12 or iron, if deficient.

 

References

  1. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017;264:1567-1582. https://www.ncbi.nlm.nih.gov/pubmed/28050656
  2. Jordan J, Shannon JR, Black BK, et al. The pressor response to water drinking in humans: a sympathetic reflex? Circulation 101:504-9. http://circ.ahajournals.org/content/101/5/504.long
  3. Raj SR, Biaggioni I, Black BK, et al. Sodium paradoxically reduces the gastropressor response in patients with orthostatic hypotension. Hypertension 2007;48:329-334. https://www.ncbi.nlm.nih.gov/pubmed/16785332
Which non-pharmacological approaches may help symptoms of orthostatic hypotension in my patient with autonomic insufficiency?

My middle age patient complains of night sweats for several months, but she has had no weight loss and does not appear ill. What could I be missing?

Night sweats (NS) is a common patient complaint, affecting about a third of hospitalized patients on medical wards1.  Despite its long list of potential causes, direct relationship between the often- cited conditions and NS is usually unclear2, its cause may remain elusive In about a third to half of cases in the primary care setting, and its prognosis, at least in those >65 y of age, does not appear to be unfavorable 2,3.

Selected commonly and less frequently cited conditions associated with NS are listed (Table)2-9.  Although tuberculosis is one of the first conditions we think of when faced with a patient with NS, it should be emphasized that NS is not common in this disease (unless advanced) and is rare among hospitalized patients as a cause of their NS1,9.

In one of the larger study of adult patients seen in primary care setting, 23% reported pure NS and an additional 18% reported night and day sweats5; the prevalence of NS in both men and women was highest in 41-55 y age group. In multivariate analyses, factors associated with pure NS in women were hot flashes and panic attacks; in men, sleep disorders. 

Table. Selected causes of night sweats

Commonly cited Less frequently cited
Neoplastic/hematologic (eg, lymphoma, leukemia, myelofibrosis)

Infections (eg, HIV, tuberculosis, endocarditis)

Endocrine (eg, ovarian failure, hyperthyroidism, orchiectomy, carcinoid tumor, diabetes mellitus [nocturnal hypoglycemia], pheochromocytoma)

Rheumatologic (eg, giant cell arteritis)

Gastroesophageal reflux disease

B-12 deficiency

Pulmonary embolism

Drugs (eg, anti-depressants, SSRIs, donepezil [Aricept], tacatuzumab)

Sleep disturbances (eg, obstructive sleep apnea)

Panic attacks/anxiety disorder

Obesity

Hemachromatosis

Diabetes insipidus

References

  1. Lea MJ, Aber RC, Descriptive epidemiology of night sweats upon admission to a university hospital. South Med J 1985;78:1065-67.
  2. Mold JW, Holtzclaw BJ, McCarthy L. Night sweats: A systematic review of the literature. J Am Board Fam Med 2012; 25-878-893.
  3. Mold JW, Lawler F. The prognostic implications of night sweats in two cohorts of older patients. J Am Board Fam Med 2010;23:97-103.
  4. Mold JW, Holtzclaw BJ. Selective serotonin reuptake inhibitors and night sweats in a primary care population. Drugs-Real World Outcomes 2015;2:29-33.
  5. Mold JW, Mathew MK, Belgore S, et al. Prevalence of night sweats in primary care patients: An OKPRN and TAFP-Net collaborative study. J Fam Pract 2002; 31:452-56.
  6. Feher A, Muhsin SA, Maw AM. Night sweats as a prominent symptom of a patient presenting with pulmonary embolism. Case reports in Pulmonology 2015. http://dx.doi.org/10.1155/2015/841272
  7. Rehman HU. Vitamin B12 deficiency causing night sweats. Scottish Med J 2014;59:e8-11.
  8. Murday HK, Rusli FD, Blandy C, et al. Night sweats: it may be hemochromatosis. Climacteric 2016;19:406-8.
  9. Fred HL. Night sweats. Hosp Pract 1993 (Aug 15):88.
My middle age patient complains of night sweats for several months, but she has had no weight loss and does not appear ill. What could I be missing?

My 35 year old patient with chronic alcoholism blames benign prostatic hypertrophy for his difficulty voiding. Could his bladder dysfunction be related to his alcoholism?

Several case reports in the literature have stressed the association of bladder dysfunction (BD) with chronic alcohol abuse1,2.  Although some cases may be associated with concurrent thiamine deficiency (with its attendant neuropathy), other cases of BD do not appear to be. The mechanism of BD in this setting may be related to the toxic effect of alcohol on peripheral, autonomic and/or central nervous systems2,3.

Binge drinking may also be associated with urinary retention, with spontaneous atraumatic urinary bladder rupture having been reported on several occasions4. Lastly, alcohol withdrawal alone may precipitate urinary retention5.  

Unfortunately, many cases of abdominal pain due to urinary retention in the setting of alcohol abuse or withdrawal may be mistakenly attributed to ascites or other causes5.  High index of suspicion for BD is essential to minimize its complications.

In our patient, given the low prevalence of benign prostatic hypertrophy in men less than 40 years of age, urinary retention due to alcohol-related BD is more likely.

 

References

  1. Yuan R, Carcciolo VJ, Kulaga M. Chronic abdominal distension secondary to urinary retention in a patient with alcoholism. JAMA 2002;287;318-19.
  2. Sheremata WA, Sherwin I. Alcoholic myelopathy with spastic urinary bladder. Dis Nerv Syst 1972;33:136-139.
  3. Mellion M, Gilchrist JM, De La Monte S. Alcohol-related peripheral neuropathy: nutritional, toxic or both? Muscle Nerve 2011;43:309-16.
  4. Muneer M, Abdelrahman H, El-Menyar A, et al. Spontaneous atraumatic urinary bladder rupture secondary to alcohol intoxication: a case report and review of literature. Am J Case Rep 2015;16:778-81.
  5. Iga J-I, Taniguchi T, Ohmori T. Acute abdominal distension secondary to urinary retention in a patient after alcohol withdrawal. Alcohol Alcoholism 2005;40:86-87.
My 35 year old patient with chronic alcoholism blames benign prostatic hypertrophy for his difficulty voiding. Could his bladder dysfunction be related to his alcoholism?

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?

My patient with a recent fall has a low serum 25 (OH) D level. Can vitamin D (VD) deficiency be associated with falls?

Short answer: Yes! Although the essential role of VD in calcium homeostasis and bone health is widely recognized, the extra-skeletal impact of its deficiency is often overlooked, including its effect on muscle function.  In fact, in 30% of patients, VD deficiency may present as proximal muscle weakness before any biochemical signs develop (eg, hypocalcemia, high alkaline phosphatase), likely mediated through VD receptors in muscle tissue 1,2. 

A recent meta-analysis of fall prevention with supplemental vitamin D concluded that at a dose of 700-1000 IU, supplemental vitamin D reduced falls by 19% within 2-3 months of treatment initiation among patients 65 y or older2; this benefit was not affected by type of supplemental VD, gender, age, or level of independence, and may be independent of additional calcium supplementation.  No fall reduction was observed with a daily dose < 700 IU or achieved serum 25 (OH)D levels below 60 nmol. 

References 

  1. Rasheed K, Sethi P, Bixby E. Severe vitamin D deficiency induced myopathy associated with rhabdomyolysis. N Am J Med Sci 2013;5:334-336.
  2. Bischoff-Ferrari HA, Dawson-Hughes B, Orav JE, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. BMJ 2009;339:b3692.
My patient with a recent fall has a low serum 25 (OH) D level. Can vitamin D (VD) deficiency be associated with falls?