Friday, January 28, 2011

Fondaparinux(Arixtra) and a word of caution

Fondaparinux is being used widely for anticoagulating patients in the acute setting (MI, PE,DVT etc). It has quite a few advantages over heparin and other low molecular weight heparins. Lets quickly see how it works.
Fondaparinux is a completely synthetic pentasaccharide. It is an indirect ,selective Factor Xa inhibitor. It inhibits factor Xa activity indirectly through binding and activating antithrombin III. Fondaparinux is not consumed in this reaction but instead is released from the inhibitory complex once binding of antithrombin III to factor Xa has occurred. In this way , by binding to 1 ATIII molecule,it can inhibit nearly 50 factor Xa molecules. It does not bind to other plasma proteins.predictable dose response that is independent of age or sex.It does not bind with platelet factor 4(PF4) , and hence doesnt cause thrombocytopenia (as caused by heparin- HIT).


Fondaparinux has nearly complete bioavailability after subcutaneous injection. The pharmacokinetics of fondaparinux appears predictable and consistent independent of age or sex. The peak plasma level is obtained about 2 h after the subcutaneous injection, indicating that a rapid onset of antithrombotic activity is obtained on initiation of treatment. The elimination half-life is about 17 h and it is dose-independent, which allows a convenient once-daily dosing regimen. Fondaparinux is eliminated exclusively by the kidneys.


This last property of being excreted by kidneys makes it a riskier agent in patients with renal failure...and it is contraindicated for patients with GFR < 30ml/hr(as risk of bleeding in this group is around 7.5%,compared to 0.1-0.4% in pts with GFR>80ml/hr). This is for patients with stable kidney function. A considerable proportion of patients for whom we prescribe Fondaparinux (until we confirm or refute the diagnosis of PE/DVT or NSTEMI) also have acute renal failure. In these instances the kidney's actual GFR is less than the reported GFR from the MDRD formula(as the production and excretion of creatinine is not in a steady state any more). So its possible to have a MDRD GFR as>30ml/min.....but with an actual GFR lot less than 30ml/min.......in which case giving Fondaparinux might be a disaster (because of a 17hr half life.....it lasts for 2-4 days in normal individuals. looonger in pts with AKI!) It would be reasonable to first think twice..whether this patient needs acute anticoagulation...and if yes..then to consider unfractionated heparin in someone with acute renal failure. 

Monday, January 24, 2011

Does Cranberry Juice Prevent Recurrent UTI ?


As we all know....cranberry juice has been thought to prevent UTIs. No we have a randomised controlled trial to answer the above question. Reasearchersa at Michigan conducted a double blind trial on women 18 - 40 years of age who presented with with UTIs over a 2 year period.


There were 319 participants who were randomized to receive 8 ounces twice daily of placebo juice or of low-calorie cranberry juice cocktail standardized for its concentration of proanthocyanidin (the active ingredient). A clean-catch urine sample was collected for culture at baseline, 3 months, and 6 months, and at visits associated with UTI episodes. During the 6-month follow up, 54 culture-confirmed recurrent UTI episodes were observed. The recurrence rate — 16.9% overall — was 19.3% in the cranberry juice group and 14.6% in the placebo group (P=0.21).

These findings and the don't show any reduction in the recurrence of UTI among reproductive age group females. However, as the authors point out, something other than proanthocyanidin might be the active factor, and the placebo might inadvertently have contained this ingredient. Therefore, this study is probably not the last nail on cranberry juice and UTI prevention.In fact the 2008 cochrane review 
showed a small reduction in UTI over a 12 month period.


After an initial urinary tract infection (UTI), 24% of otherwise healthy women aged 18 to 39 experience a recurrence within 6 months, and 5% of women have multiple recurrences within 1 year. Cranberry juice is a well-known folk remedy for preventing UTI, and in vitro experiments have suggested that cranberries decrease the adherence of Escherichia coli to the uroepithelium.

All this study shows is that proanthocyanidin may not be the active ingredient behind UTI prevention ! Given the inability to prove or disprove this theory........it will be ok to take cranberry juice....as it doesnt cause any harm.

Tuesday, January 18, 2011

angioedema risk with ace-inhibitors

We recently had an african american male presenting with swollen tongue, lips and a stridor. was intubated for airway compromise..given epinephrine im, benadryl, ranitidine, hydrocortisone. Was extubated the next day after resolution of edema. This gentleman was started on Lisinopril 2 weeks ago for hypertension. This is likely...to be Angioedema due to ace-i!!


The pathophysiologic mechanism of angioedema with regard to ACE inhibitor therapy is believed to relate to the kallikrein-kinin plasma effector system. Bradykinin, which is normally degraded by kininase II/ACE, accumulates in tissues pts on ace-i.  Plasma bradykinin has been shown to increase up to 12-fold during acute angioedema attacks in patients with hereditary or acquired forms of angioedema. A case control study from 1997 showed consistently decreased levels of carboxypeptidase N(kininase1) and C1 esterase inhibitor in pts with angioedema secondary to ace-i Vs pts without angioedema on ace-i.

Another interesting theory has been the association of low levels of dipeptidyl peptidase 4( known to catabolise bradykinin) in pts with ace-i associated angioedema. (Hypertension 2002). The reason this is interesting is because ..... the recent DPP-4 inhibitors(Sitagliptin, Saxagliptin) that we use for diabetes work by inhibiting DPP-4. So if the above theory is true..then we might see an increased risk of angioedema in patients on these medications along with ace-i(as most diabetics need ace-i). Lets wait and see!!!!


Several risk factors for development of angioedema with ace-i have been proposed.The most important predisposing risk factor, evidenced by case-control studies, appears to be ethnic differences.The risk of angioedema with ACE inhibitors is higher in blacks and appears not to be related to dose, specific ACE inhibitors, or concomitant medications...as shown in this nice case control study(Clin Pharm & Ther 1996). Other risk factors are a history of idiopathic angioedema, head and neck surgery, and seafood allergy. 


This study from 1988 ...which looked at 3 studies...each with 12,0000 patients.....showed that the incidence of angioedema is high in the first week of starting Enalapril...and then declined. But previous tolerance to an ACE inhibitor does not exclude the risk for angioedema when therapy is modified to a different ACE inhibitor. Finally...the oberall incidence of angioedema with ace-i is around 0.1 - 0.6% over a period of 6 months (a rough estimate based on studies like OCTAVE  (again showing a higher incidence among African americans than other races)

Monday, January 10, 2011

Amiodarone and hyperthyroidism

Amiodarone therapy causes thyroid dysfunction in 14 to 18% of the involved patients. Therefore, before initiation of such therapy, patients should have a baseline TSH measurement, and then they should be monitored at 6-month intervals during treatment.
In patients receiving amiodarone, either hypothyroidism, which is treated with levothyroxine replacement, or hyperthyroidism may develop.

Amiodarone-induced hyperthyroidism is of two types.
Type 1 is similar to iodine-induced hyperthyroidism (jodbasedow phenomenon) and manifests with a low TSH level, a high free T4or T3estimate, and a low radioiodine uptake. Doppler ultrasonography shows increased vascularity of thyroid tissue, similar to that in Graves’ disease. Because of low radioiodine uptake,  131I treatment cannot be used, and use of antithyroid drugs has yielded only varied success. Although mild cases have resolved even when amiodarone therapy has been continued, consideration of ceasing this drug treatment is recommended. Restoration of euthyroidism may take months after cessation of amiodarone therapy.

Type 2 amiodarone-induced hyperthyroidism resembles a destructive thyroiditis. Laboratory values and radioiodine uptake are similar to the findings in type 1; however, Doppler ultrasonography shows decreased vascularity of the thyroid tissue. Corticosteroid treatment is recommended, and patients sometimes require surgical removal of the thyroid.

Wherever possible its better to avoid ..than to treat this complication!!

Thursday, January 6, 2011

CT scan for lung cancer screening

The National Lung Cancer Screening trial (NSLT) ..comparing two ways of detecting lung cancer- low dose helical CT Vs regular chest xray was stopped in Nov 2010 , after the results showed a dramatic reduction in mortality!


The trial began in 2002 and involved more than 53,000 current and former heavy smokers(quit within last 15 years) 55 to 74 years of age. Individuals were randomized to undergo screening annually for 3 years with either CT or chest x-rays, and were then followed for another 5 years.
The results, which were reviewed by the trial's Data and Safety Monitoring Board on October 20, show a statistically significant difference in lung cancer mortality in the 2 groups, which led to the trial being halted. There were 354 lung cancer deaths among those who underwent CT screening and 442 among those who underwent chest x-ray.This is a 20% reduction in mortality in patients who underwent screening with CT scan. This is an impressive finding....but the study has not been published yet. Questions do remain......who is at high risk? and who needs CT scan? There will also be a problem with false positivies, as with any other screening test. So will be interesting to see the cut off criteria for doing a screening CT scan.


Thus far, there has been no recommendation for lung cancer screening from any authority, but these new data might be a turning point.  Keeping in mind that Lung cancer is the leading cause of cancer mortality in US  and worldwide....screening will help reduce the associated mortality. But the most important intervention that will reduce mortality will be staying away from Tobacco!!

Tuesday, January 4, 2011

urinary calcium and renal stones

Calcium oxalate stones are the most common type of renal stone.(around 75%). 3 types of stones can be caused by calcium- calcium oxalate, CaCO3, or CaHPO4


Calcium oxalate crystals can form at any pH and have various microscopic morphologies. It is estimated that about half of the oxalate in urine comes from ascorbic acid (vitamin C), which is a precursor to oxalate. Calcium oxalate crystals are also associated with ethylene glycol ingestion, another oxalate precursor. Calcium carbonate (CaCO3), the main component of marine shells and egg shells, can be found as small granular crystals in alkaline urine. Calcium carbonate crystals are not common in urine but when present can be mistaken for bacteria. Calcium phosphate (CaHPO4 or Ca[H2PO4]2) crystals can have different morphologies depending on their state of hydration and can be present in the urine sediment of neutral or slightly alkaline or acidic urine.


Eventhough calcium is involved in majority of stones....its measurement in urine is of limited value in predicting/diagnosing renal stones.This is because of a lot of other factors involved in stone formation( citrate, oxalate, urine Ph etc). Risk assessment using ratios such as the calcium/magnesium ratio, the calcium/citrate ratio, and the (calcium * oxalate)/(magnesium * citrate) ratio have met with little success, and are regarded to play a supplementary role in evaluation of renal stones.( Ped Nephrol 2009)


But Urine calcium can be used in assessing patients with primary hyperparathyroidism. A study done comparing biochemical parameters and treatment outcomes in stone formers with hyperparathyroidism Vs those without systemic disease...found ..a greater amount of calcium excretion in urine of stone formers with hperparathyroidism than in stone formers without systemic disease.(Brit J of Urol 2009) .Thus high Calcium creatinine clearance rate(or calcium creatinine ratio > 0.20) can be helpful in patients with hyperparathyroidism in predicting/assessing risk for stone formation. Interestingly, parathyroidectomy did not reverse the hypercalciuria or hypophosphatemia in these patients.


Increased Urinary calcium - > 300mg/24 hours
Increased calcium creatinine ratio - > 0.2 
A quick word about diet in calcium stones---- is reducing calcium in diet doesnt help( again because of multiple factors involved in stone formation). But reducing oxalate consumption prevents crystal formation and reduces stone formation.Have a look at this article from NEJM 2002 (hope u all have access)

Sunday, January 2, 2011

Red flags in evaluation of syncope

Syncope is one of the commonest presentation to the ERs....and would require substantial spending if everyone gets a complete work up to diagnose or rule out the causes. It would be reasonable to risk stratify patients and investigate. The first step would be to get the definition of syncope right! ----- It is a transient loss of consciousness due to transient global hypoperfusion of brain. 


Not everyone needs admission or specialist referralUrgent referral or hospital admission for investigation is needed for patients who have chest pain, breathlessness, a history of cardiac disease, family history of sudden death, signs of heart failure, or abnormalities on electrocardiography. The electrocardiography features that suggest cardiac arrhythmias include ventricular tachycardia, a widened QRS complex (>120 ms), sinus bradycardia (<50 beats/min), prolonged or excessively shortened corrected QT interval (>450 ms and < 300 ms, respectively), T wave inversion leads V1–V3, epsilon waves or ventricular late potentials (arrhythmogenic right ventricular dysplasia), and right bundle branch block with ST elevation and T wave inversion in V1–V3 (Brugada syndrome). Patients who report a history of syncope with no warning symptoms (Stokes-Adams attack), syncope during exercise, palpitations preceding syncope, and syncope in the supine position should be investigated by a specialist. People with frequent or injurious syncope or implications for driving also warrant specialist input. Prolonged unconsciousness, confusion after the event, or neurological signs and lateral tongue biting suggest a non-syncopal event, and this should prompt neurological evaluation


To simplify the above, San Fransisco Syncope Rule was developed .SFSR  uses the presence of an abnormal electrocardiogram(any new rythm changes or presence of an abnormal rythm), heart failure(or a c/o shortness of breath), anaemia (haematocrit < 30%), or systolic hypotension (< 90 mm Hg) to identify patients who require urgent action. In the original derivation study, the SFSR had 96% (92% to 100%) sensitivity and 62% (58% to 6%) specificity in identifying patients with short term adverse outcomes. In the study where the SFSR score was validated, it showed a 98% sensitivity and 58% specificity in identifying patients with short term (1 month) mortality. And it had the ability to decrease overall admissions by 7%. A thing to remember in this study..was that the rule was applied after the ER physician has evaluated the patient. So would be optimal for an Internal medicine resident seeing a ER consult.


The reason behind paying special attention to cardiac causes are...cardiac syncope carries a high mortality in all age groups. The Framingham study cohort's age and sex adjusted hazard ratios for death over a mean follow-up of 8.6 years was 2.4 (95% confidence interval 1.78 to 3.26) for cardiac syncope compared with 1.17 (0.95 to 1.44) in the "vasovagal group," which included orthostatic hypotension. 
Have a look at the American College of Cardiology recommendations on evaluation of syncope.