Chlorthalidone.......what a miss!

Chlorthalidone is a diuretic acting on the distal convoluted tubule...same as Hydrochlorthiazide. It is a 'thiazide like diuretic'....as it has a different structure than thiazide diuretics, but acts on the same Na-Cl symporter in the DCT. Chlorthalidone first came to light ..when used in the MRFIT trial in the 1970s. Since then chlorthalidone has been the diuretic of choice in the major hypertension trials - ALLHAT, Hypertension Detection and Follow-up Program (HDFP), Systolic Hypertension in the Elderly Program (SHEP). And chlorthalidone was the only antihypertensive showing some mortality benefit in the ALLHAT trial. 
Inspite of these data, im surprised that we still chose HCTZ on top of chlorthalidone. I cant figure out a valid reason for this swap.(If anyone knows ...let me know)

Studies done to compare Chlorthalidone with HCTZ in the past(1976)..were very small..but they all showed that  chlorthalidone once a day is equally efficacious to HCTZ twice a day....in fact with a trend towards even better blood pressure control and a slightly lesser incidence of hypokalemia. A recent study from Iowa showed a superior antihypertensive effect of chlorthalidone than HCTZ. (again ...small study- 30 pts....short duration-8wks.....no hard outcomes.....but hard to discard!)


So......Chlorthalidone seems to have a definite edge over HCTZ both in reducing BP and in preventing adverse cardiac events..with a similar or may be a better side effect profile.
Why is this difference between the two ? Well...we know the answer to some extent. 
1. Chlorthalidone has a longer elimination half life (50 hrs Vs 10 hrs for HCTZ) -- this means more sustained antihypertensive effects. This has been nicely shown in the above study from Iowa.
2. Bioavailability is the same as HCTZ, but it is 99% protein bound..which helps limit glomerular filtration and excellent delivery to action sites thru secretion. HCTZ is 40% protein bound.
3. Chlorthalidone is 99% bound to RBC carbonic anhydrase ...which forms a reservoir for continued action. 
4.Chlorthalidone is a stronger inhibitor of Carbonic anhydrase than HCTZ.....adding to its diuretic effect.
5. Recently..it has been found that Chlorthalidone decreases platelet aggregation and promotes angiogenesis. 
(Hypertension .July 2010)
6. Finally ..COST . 30 tabs of 50mg Chlorthalidone - $20.00 (12.5 mg starting dose....once a day)
                              100 tabs of 50 mg HCTZ          - $ 16.00 (12.5 starting dose......twice a day)


So..if some one is on HCTZ and doing well...it will be reasonable to leave it. Other wise Im changing to Chlorthalidone. And this is easily the first choice thiazide for me!!
Anyone has an argument?!

combination of Aspirin,Plavix & Warfarin - how bad or how good?

I am sure you had come across those patients who had been on aspirin & warfarin ..or...plavix & warfarin...or rarely all three (either intentionally or by mistake!!). Well...a patient with CAD might benefit more from a antiplatelet...but may need warfarin for A.fib ....will he benefit from both? A recent article from Arch of Int Medicine tried to address these issues by calculating the risk of bleeding associated with each combination.
Lets look at the risk of stoke with A fib at 1 year...so the numbers from the above study would make more sense.

Risk of stroke with A fib - commonly assessed with CHADS2 score
CHADS score of 0,1,2,3,4,5 & 6 carries a 1 year stroke risk of ..roughly 2%,3%, 4%, 6%, 8%, 12% & 18% respectively.So we usually start treatment to prevent this thromboembolic risk by starting them on either antiplatelets or warfarin. This question about warfarin or no warfarin always pops up when we see a patient with A fib.

Now lets see the numbers from the above study where they looked at a cohort of 82,000 patients discharged with a diagnosis of Atrial fibrillation. During a follow up period of 3 years ..11%(13,000 pts) had a fatal or non-fatal bleeding.Having warfarin as the standard ..the hazard ratio for the above end point is as follows
For Aspirin alone - 0.93
for plavix alone - 1.06
for aspirin + plavix - 1.66
for aspirin + warfarin - 1.83
for plavix + warfarin - 3.08
for aspirin +plavix+warfarin - 3.70

Clearly this was something that was expected ..based on previous studies. The crude incidence rate of bleeding was 13% for plavix +warfarin, and 15% for triple therapy. So having these numbers ...gives a better idea for making a risk-benefit decision !! ...So ..whoever your pt is....aspirin+plavix+warfarin seems to be a bad combination!

Urine test can help pulmonologists too!

This is a urine test done to find the presence of the pneumococcal polysaccharide capsule(the antigen) for diagnosing Community acquired pneumonia caused by Streptococcus pneumoniae. The advantage is that the test can be done in 15 min, and so you have a result  quickly.This may help narrow antibiotics quickly. The next question is ..how far is it reliable. Lets see...

In a study done in Newzealand(but urine antigen was tested in Duke Univ, NC!!) urine antigen was checked in pts with pneumonia along with blood and sputum samples.Subjects without pneumonia served as controls. The most important finding was that antigen testing was negative in all the controls. This gives the test....a very high specificity (so if it is positive..then pt is more likely to have pneomococcal pneumonia). It can also be positive in patients with strep throat, urine having strep mitis.

A study from Spain, in 2001, showed that the positivity of the urine antigen test does not differ much between bacteremic and non-bacteremic patients with Strep Pneumo pneumonia. Have to note...that the test was not reliable in pts who had only a presumptive diagnosis of pneumonia.again specificity was 98%.
The next study from Germany compared the urine test in pts with infiltrate Vs those without infiltrate (what we call as exacerbation of COPD!). The detection rate in pts without an infiltrate (i.e COPD exacerbation) was very low..suggesting its not useful in those group of patients. This has been incorporated in the latest ATS guidelines on CAP. (Just peek at page S40 regarding where its useful).
This recent study from Arch of Int Med also showed the usefulness of urine antigen testing. To be more creative and quick..you can even do the rapid antigen test in a blood culture bottle sample with good detection rates.(Clin Micro 2005)

Whats the downside! - Well..not many. We are trying to diagnose the etiology of only a 3rd of CAP. And even in those found to be positive...there is a possibility of another infection(especially in ICU admits).
 The test can be positive upto 5 days after a pneumococcal vaccine.
 Also ...once had a pneumococcal pneumonia...the urine test will be positive for weeks.(so..not useful if pt is readmitted within 3-5 weeks).
Watch out for false positives with Strep mitis (a cause of endocarditis).

Doc...We can't run the Complete Blood Count !!

We recently had an interesting patient admitted to our ICU. So I thought I will share this with you all.
64 yo male with h/o hypertension admitted with left hemiparesis with the CT head showing a right parietal intracerebral bleed. His BP was managed and on 3rd day was transferred to the rehab unit.
On his day of admission, the hematology laboratory called me saying that they could not run his Complete (Full) blood count due to some interference with the analyser and the blood. It wasnt a problem with the analyser, as it could run  other samples. So we sent 2 more samples. The white cell count(WCC) was 130,000 /cmm and platelet count was >1,000,000/cmm. Both were way above normal. This led to the suspicion of a bone marrow proliferative disorder.So we examined the peripheral smear...which surprisingly was normal with normal looking WCC and platelets. There were some faint bluish appearing strands in the smear. At the same time, the serum sample appeared grossly cloudy with some precipitation at the bottom.

Hematologist was called, and we decided to warm the sample to 37 C. What a surprise!!....his serum became clear (his warmed (clear looking) and unwarmed samples in the figure). We immediately ran it on the analyser..and it gave a normal WCC and platelets. So...the above phenomenon is what is called Cryoprecipitation. The gentleman had further tests done ..which showed massively elevated IgM cryoglobulins with negative rheumatoid factor (which will make it Type 1 Cryoglobulenemia). Search for a cause for Cryoglobulenemia led to a positive lambda light chain spike in his protein electrophoresis. He is awaiting a bone marrow biopsy. His most likely diagnosis would be Monoclonal Gammopathy of Unknown significance (due to absence of end organ damage) with Type 1 cryoglobulenemia.

Pseudothrombocytosis and pseudoleucocytosis have been reported in the past ..with cryoglobulins. A spurious count this high has not been documented before. Keep this in mind if your lab calls with this kind of problem. This scenario may not happen  in your lifetime...but ..if it does ask the lab to heat the sample.....You will look like a GENIUS!!
Just a word about cryoglobulins - they are immunoglobulins which precipitate at temperatures below 37 C. Depending on the type of Ig they are classified into
Type 1 - Monoclonal .contains only one type of Ig. Either IgM or IgG. rhematoid factor negative. usually associated with paraprotenemias (Multiple myeloma, MGUS, waldenstorms)
Type 2 - can be monoclonal or polyclonal. rheumatoid factor positive. usually associated with infection(commonly Hepatitis C).

A recap of basics - Pulse oximetry

Pulse oximetry - This is easily one of  the most common and most useful tool in everyday Medicine to manage in hospital, nursing home, clinic patients etc.
It tells us what percentage of hemoglobin is saturated with Oxygen- SO2. When measured in arterial blood, we call it SaO2.
Mechanism - Every pulse oximeter has 3 components - 1. a source emitting 2 wavelengths of light- red & infrared   2. receiver receiving these lights after after passing through the finger or ear lobe   3. a unit processing this information.
The Hemoglobin (Hb) in circulation is mostly in the oxidised form(OxyHb) ..and some in reduced form(deoxyHb). OxyHb absorbs red light and deoxy Hb absorbs infrared light. When the oximeter probe is clipped on the finger, the emitter sends the red & infrared signals. These are absorbed by the respective Hbs (OxyHb - red ,& deoxyHb- infrared). The receiver receives the remaining light. The processing unit then calculates the SaO2 by the following formula...

SaO2(SpO2) = Oxy Hb / OxyHb + deoxyHb x 100

Carboxyhb & MetHb - In case of suspected carboxy or meth hemoglobenemia....the calculation is done by adding them to the denominator. CarboxyHb is bright red in color, and absorbs red light(as OxyHb). Now we can understand the reason behind normal SaO2 in patients with high CarboxyHb (poisoning & low levels in smokers). This can be corrected by using an oximeter emitting 4 wavelengths of light instead of two. But its not usually done...due to the rarity of these disorders. 

Venous Vs arterial sats - Well...venous circulation on the finger tip also has oxyHb & deoxyHb. So how does the oximeter differentiate? ...It is designed to pick up signals only from pulsatile wave forms. So we only get a SaO2....not a SvO2. Because of this...it may not be reliable in people with peripheral vascular disease or in patients with severe tricuspid regurgitation (pulsatile veins).

Anemia - Low Hb does not affect SaO2, as it does not measure the amount of Oxygen in Hb, but the percentage of Hb saturated with Oxygen. i.e occupying the Fe-protporphyrin complexes. So even if Hb is 5g/dl,but all 5 g is well saturated with Oxygen..the oximeter will read 100% SaO2. Another point here....anemia also does not affect partial pressure of O2(PaO2). The only parameter anemia..affects is the Oxygen content of blood.(which we dont need in clinical practice!)

Lastly...anyhting that interferes mechanically with the light wavelengths (e.g red nail polish, sometime dark skin)will affect the oximeter reading.

Hyperkalemia with beta blockers!

I recently had a Chronic kidney diesease patient on low dose Ramipril with a stable potassium level for many months, got admitted to the hospital for an hypertensive urgency.Her renal function & K were stable on admission. She was started on a Labetalol infusion overnight.Next day her potassium level was 6.9mEq/L, and she needed two Insulin dextrose treatment( couple of hours apart) to get that back to normal. Her TTKG(transtubular potassium gradient) was 4. This is hyperkalemia due to Labetalol.

Lets see how........ There are 2 mechanisms by which betablockers can cause hyperkalemia.
1. Beta blockers suppress catecholamine-stimulated renin release, thereby decreasing aldosterone synthesis.
2. More importantly nonselective beta blockers decrease cellular uptake of potassium.(NEJM )
                          
The primary mechanism for handling an acute potassium load is by redistribution into the cells.Normally, agonist binding to the beta2-adrenergic receptor stimulates the formation of cyclic AMP, which acts through protein kinase A to phosphorylate and activate the Na-K-ATPase pump, leading to the influx of potassium into cells. Competitive inhibition of the beta2 receptor by beta blockers decreases Na-K-ATPase function and reduces potassium uptake by cells.
So..this seems to happen only with non-selective beta blockers(Labetalol, Propranolol, Carvedilol, Nadolol).
Based on some retrospective studies, nonselective beta blockers have caused or contributed to hyperkalemia in 4% to 17% of hospitalized patients studied.
Have a look at this study on renal transplant patients receiving Labetalol, ended up having hyperkalemia more frequently than patients treated with agents other than labetalol.(AJNephrology 2002). The fact that hyperkalemia developed immediately after Labetalol infusion strengthens the hypothesis of blocking cellular intake of potassium than catecholamine suppression as the primary cause of Hyperkalemia with non selective betablockers.

So...just add nonselective betablockers to your differential for Hyperkalemia ......especially in patients who cannot excrete potassium properly (renal failure, on ace-i or ARD, spironolactone etc)
Sorry guys...I could not get full text of articles...will update once I get access to them!

Etomidate in ICU....comes with a price

This is a common scenario in Intensive Care Unit. For those not practicing in US....The ICU is managed by Internal Medicine residents with the help of Anaesthesiologists(only for intubations).
We have had many patients transferred to the ICU for management of Sepsis/Septic shock who would need intubation. A commonly used induction anaesthetic for intubation is Etomidate.It is preferred for its rapid onset action, and a low cardiovascular risk profile! In many of these patients there has been a substantial drop in blood pressure after intubation with Etomidate, which needed fluid boluses &/or vasopressor supprt.


The mechanism behind this is as follows -  Etomidate inhibits 11-beta hydroxylase in the synthesis of corticosteroids. This enzyme converts 11-deoxy cortisol to active cortisol. This was shown in a prospective, observational cohort study of 40 critically ill pt’s without sepsis given etomidate during intubation.ACTH stimultation testing done at 1, 12, 48 and 72 hrs after etomidate.Authors found a reversible adrenal insufficiency following etomidate administration that persisted no longer than 48 hours.80% of patients tested (32) had evidence of adrenal inhibition at 12 hours.(Int Care Med 2008). 
Since Etomidate blocks 11-beta hydroxylase, it can block aldosterone synthesis as well. So a theoretical possibility of Hyperkalemia is on the cards as well.
To add to this problem.....patients on concomitant benzodiazepines and /or opioids (in opioid naive pts) can add to the cortisol suppression by etomidate. BZD inhibits 21 & 17- hydroxylases, and opioid suppresses stress related cortisol production.(Int Care Med 2008)


Based on this..it would be reasonable to administer stress dose steroids (Hydrocortisone 50mg 6th hourly) to patients who have received etomidate. Based on the above observation...give hydrocortisone for atleast 48 hours after etomidate. Also try to minimise use of BZD and opioids in these patients. 
Also try to avoid etomidate in patients with hyperkalemia.

Not everyone likes it...but has a lot to offer!

As one of the most commonly spoken/advised diet in the clinics...lets have a peek into it.
Dietary Approach to Stop Hypertension(DASH) - Initiated by the NIH, studies were done on specific dietary patterns on the influence of Hypertension. The first study was published in NEJM 1995 ..done on 459 pts with BP <160 systolic ,& diastolic between 80-95. Three type of diets were studied- a control diet (typical american diet), control diet with fruits & vegetables(F/V), and DASH diet. Hypertensives showed a significant 11 & 5 mm Hg drop in their sys & dias BP resp,while on DASH diet. Improvements were noticed as early as in 2 weeks. All 3dietary patterns were taking 3g /day of Sodium.


The next study,DASH-sodium study was done on DASH  Vs the Control diet,each with three levels of Sodium intake(3gm/day, 2.4gm/day, 1.5gm/day of Na) .About 400 pts with BP between 120 - 160 systolic & 80-95 diastolic with 50% blacks were included. The DASH diet, as compared with the control diet,resulted in a significantly lower systolic blood pressure at every sodium level. The combination of DASH +low sodium showed a greater reduction than either agents alone.
So....nowadays you can see ads about DASH diet in many places. This has been taken as a serious issue by the US government recently...given the spreading epidemic of Obesity which is most often associated with Hypertension. 
What does DASH diet consist of - lots of fruits & vegetables,low-fat dairy products, whole grains, poultry, fish, and nuts, while reducing intake of fats, red meat, sweets, and sugar-containing beverages. 

Total fat 27% of calories ,Sodium 2,300 mg (1.5gm is even better), Saturated fat 6% of calories ,Protein 18% of calories,  Carbohydrate 55% of calories, Cholesterol 150 mg,Potassium 4,700 mg, Magnesium 500 mg,  Fiber 30 g.
.Also see this......u can print and give this to your patient for a sample menu.


Latest on DASH trials - A study of Framingham CHD risk score among participants from the DASH trial published in Circulation Aug 2010, showed that..... Compared with control  and F/V diet, the DASH diet reduced estimated 10yr CHD risk by 18% & 11% respectively.There was a significant improvement in LDL veles with DASH, but not with glucose levels. DASH has also shown a 37% reduction in incidence of heart failure in women (Arch of Int Med 2009) 48 - 83 yrs age without a h/o diabetes or heart failure. Only 20% of women had hypertension. What this shows..is that the diet can be of benefit even in people without hypertension, diabetes or CAD.


A common question patients have asked is...If the diet reduces weight? Well...it is not designed to make you loose weight. Added with exercise..then it might(thats another topic !!)

Update on ' Preventing the first variceal bleed'

Previously ..on 08/16/2010, I posted about the prevention of first variceal bleed in patients with cirrhosis, and discussed about benefit of non selective betablockers (NSBB) across the whole spectrum of varices, and compared them with Endoscopic variceal ligation (EVL).
I came across a recent study published in Hepatology published online on Feb 2010, which is a randomised study of NSBB Vs EVL + NSBB for the prevention of first variceal bleed.
They studied around 300 patients with a diagnosis of Cirrhosis mainly due to Hep B/ Hep C(around 60%) & alcohol . They were assigned to one of the two treatment group, and followed for 2 years. There was no statistically significant difference in incidence of first variceal bleed or mortality. But the EVL + NSBB group had to have EVL every 4 weeks in the beginning ..until the obliteration of varices. This met with more complication rates than patients on betablockers alone.
The authors concluded that The addition of ligation to nadolol may increase adverse events and did not enhance effectiveness in the prophylaxis of first variceal bleeding.

A problem that most studies on this subject encountered ..has been the non compliance with medications in this group of people. The authors in this study did mention about some participants abusing alcohol.....and this could have had an effect on the results. In my opinion ....patients non compliant with taking daily medications or in whom NSBB causes side effects might benefit from EVL.

Intra-aortic baloon pump - some useful tips

IABP  was first tried in humans in 1968 by Dr. Kantrowitz (also did the first Cardiac transplant in USA).
Basic principle - Counterpulsation -It is balloon inflation in diastole and deflation in early systole. Balloon inflation causes 'volume displacement' of blood within the aorta, both proximally and distally. This leads to a potential increase in coronary blood flow and potential improvements in systemic perfusion.


Physiological effects -  The primary aim is to improve the LV function by augmenting the coronary blood flow.  IABP inflates at the onset of diastole, thereby increasing diastolic pressure and deflates just before systole, thus reducing LV afterload. The magnitude of these effects depends upon:
        1.Balloon volume: the amount of blood displaced is proportional to the volume of the balloon.
        2.Heart rate: LV and aortic diastolic filling times are inversely proportional to heart rate; shorter diastolic time produces lesser balloon augmentation per unit time.
        3.Aortic compliance: as aortic compliance increases (or SVR decreases), the magnitude of diastolic augmentation decreases.( so beneficial in elderly with stiff arteries than a young elastic aorta)


Indications are... where you need an increase in coronary flow to augment LV function. Its more important to know the absolute contraindications -  Aortic regurgitation, aortic dissection, aortic or popliteal stents, very poor prognosis. Also be careful in pts with peripheral vascular disease.


 Waveform -  The balloon is inflated with Helium so that it quickly travels from pump to balloon...and also gets absorbed in blood incase of balloon rupture. The console uses the EKG waveform &/or systemic arterial waveform as a trigger for inflating the balloon. The balloon inflates with the onset of diastole, which corresponds with the middle of the T-wave(dicrotic notch on arterial wave). The balloon deflates at the onset of LV systole and this corresponds to the peak of the R-wave. Since the distal aortic pressure drops with inflation, you can see a slight dip at the dicrotic notch followed by a second peak due to augmentation of the diastolic pressure ( which should be more than the pts systolic pressure denoted by the peak before the dip @ dicrotic notch). Have a look at the figure.


Monitoring - Depending on hemodynamic status..the inflation can happen with each beat (1:1) or every other beat(1:2) & so on. Keep all these patients on heparin anticoagulation. And importantly monitor their Urine output. If it drops suddenly...confirm the position of the tip of balloon (2cm above carina) with an Xray..as the balloon may be adjacent to the renal artery. Once patient's pressor needs have gone down..start weaning them from IABP by reducing the rate of augmentation 1:2 to 1:3 and so on. 
Hope this helps!!

The Incretins and Diabetes

 Way back in 1964 investigators found a greater insulin release from pancreas to an oral glucose load than to an intravenous load. This was recently termed 'the Incretin effect' .  This effect is due to two incretin hormones-  glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]. They are  released by intestinal cells in response to a glucose load. They bind to beta cells and increase insulin secretion. The above said Incretin effect is defective in Type 2 diabetics mainly as a consequence of Diabetes than a primary event..as shown in this study from Denmark. 
The physiologic effects of GLP-1 occur by multiple mechanisms, including stimulation of  insulin secretion, reduced inappropriate glucagon secretion, slowing of gastric emptying, induce satiety,positive effects on β-cell prolif-eration, β-cell differentiation, and inhibition of β-cell apoptosis in animal and in vitro models.(Diab,Obesity & Metabolism 2009)
But GLP gets rapidly degraded in the body by Dipeptidyl peptidase-4 (DPP-4), an enzyme secreted from cell surface of lymphocytes..and also by kidneys, liver, bone marrow.
Given this physiology..now we have two types of medications to enhance the Incretin system. 
1. GLP agonists - Exenatide(Byetta), Liraglutide.
2. DPP 4 inhibitors - Sitagliptin(Januvia), Saxagliptin, Vidagliptin.


In AMIGO trials 1,2,&3 ...addition of Exenatide to Metformin, to sulphonylurea, & to combination of metformin and sulphonylurea respectively showed a significant decrease in HbA1C at 30 weeks compared to placebo. Also more people reached HbA1C targets in Exenatide group compared to placebo. Liraglutide has also shown similar effects .Eventhough these drugs increase insulin secretion ..there is no increase in incidence of hypoglycemia, and,they are weight neutral.(Lira has been associated with medullary ca of thyroid in rats)


In studies where Sitagliptin has been added to Metformin or to pioglitazone showed greater number of people reaching HbA1C targets compared to addition of placebo over a period of 6 months.(Diabetes Care 2006 & C Ther)The other DPP4 inhibitors also showed similar results. The main side effects noted were increase in white cell count, nasopharyngeal infections.(likely due to the fact that DPP4 is secreted from lymphocytes)


Based on the above..these 2 types of medications have started to be used widely. As you can see..they are promising..but these are still early days for them...as we would like to know if these reductions in HbA1C with them will turn out into a reduction or delay in micro or macrovascular complications. (we dont want another Rosiglitazone! -  refer to my post on Aug 3rd 2010)

what is it with Cranberry juice and warfarin!

Anticoagulation clinic!! - a place to advice patients about diet, and monitoring treatment closely. Today..I had a patient ask me about Cranberry and products ..and taking them with warfarin. Well..I didnt know the right answer. She has an aunt diagnosed with cancer..and she would like to take cranberry for its antioxidant/anticancer property. So ..I delved into some evidence.....
What does FDA say -  In 2006, FDA issued warning about a potential interaction between the two in raising the INR. This was based on a UK health committee's warning about the same interaction. The warning came after 12 reports of a suspected interaction!! (Just 12 reports...without any base??)


What is the mechanism of interaction - Warfarin  is a racemic mixture of the R- and S-enantiomers, with the S-enantiomer having 2-5 times more anticoagulant activity.It was proposed that some Flavinoids in Cranberry products might inhibit cytochrome P450 (CYP) 2C9, the enzyme responsible for the hepatic elimination of S-warfarin. But many studies have shown  no effect on CYP2C9(J of Exp Pharm 2010), although some questionable effect on the less important enzyme, CYP3A4(Drug Met & Dis 2009)


What does evidence say -  The same year as FDA put up the warning...the first randomised trial on this was published( J of Amer Diet Asssoc,2006). Just with 7 patients...taking 250cc of Cranberry juice /day......no difference in INR was found during 3 months duration. Another study in Clin Pharm in 2009 showed no difference in INR among warfarin pts taking 240cc/day of cranberry juice Vs placebo for 2 weeks.
A recent review in Amer J of Medicine concluded that no interaction exists between warfain and Cranberry products consumed in moderation (around 250cc/day). We don't know about excessive consumption though.
So, thats pretty much it......... SAFE to tahe warfarin and Cranberry products (may be < 300 cc/day). Anticoagulants like Dabigatran are on the horizon...which might have less interaction...and would be the way forward.

Does Influenza vaccine help?

Since the winter is coming lets have a quick look into the vaccine and its usefulness....as we are going to be asked about this by almost all our patients!

In 2006, the US Advisory Committee on Immunization Practices  published a document where 11 categories of people were listed as being at high risk of complications from influenza. These include healthy adults, 50 to 65 years of age, and healthcare workers.

A recent Cochrane review involving 40 clinical trials which included a total of 70,000 healthy patients < 65 yrs age given either live, inactivated(commonly used in our clinic) or killed vaccines showed the following-

1... In studies where the vaccine strain matched the actual virus (by chance), 1% of pts who had the vaccine developed illness compared to 4% in pts who received placebo.

2... In places where the vaccine strain didnt match the actual disease virus...the corresponding figures were 1% & 2%.

3... Vaccination had a modest effect on time off work( by less than a day) but had no effect on hospital admissions or complication rates. The risk of Gullian Barre that can be attributed to the vaccine is around 1 case per 100,000 vaccinations.

And...what about patients age>65 years? In a study in JAMA 2004, elderly people >65 yrs of age formed the majority of hospital admissions due to influenza. Also ..a study(EPIVAC study) on 1400 community dwelling people age>65 ,with chronic heart disease showed reduction in influenza related mortality with the vaccine.

So in Dec 2009, FDA approved an inactivated vaccine...called Fluzone High Dose, an injectable vaccine that contains 4 times the amount of antigen found in a regular shot. Whether this will translate into a better clinical outcome remains to be seen.
Bottom line - vaccine seems to benefit older patients >65 years and with chronic cardiac or respiratory illness.The use in healthy adults may not have a big benefit.

Isosorbide mononitrate Vs dinitrate - what to use?

This post is due to the question asked by one of my clever interns. What is the difference between the nitrates, and how can we apply that in practice based on the evidence we have.
We use three intrates- nitroglycerine, isosorbide mononitrate(ISMN), isosorbidedinitrate(ISDN). They are used widely for stable & unstable angine , heartfailure, and acute MI.  ISMN & ISDN both have to be denitrified to nitric oxide and cause vasodilation of venules and arteioles.

ISDN - has extensive first pass metabolism in the liver, and its half life is 40 min. Its major metabolites are isosorbide 2 mononitrate & isosorbide 5 mononitrate with half lives of 2 & 4 hrs respectively.
In a study done on pts with tid dose of ISDN with a 14 hr drug free interval, the excercise capacity improved after the first dose. Another study with same dose showed antianginal effects decreased progressively after the 2nd & 3rd dose likely due to tolerance. There is a sustained release ISDN when used at the max dose of 80mg bid ..causes tolerence,but when administered less than 12 hrs apart with a long drug free period...the antianginal effect was ok. One of the major studies of black pts with heart failure A-HEFT trial showed mortality benefit in adding ISDN with hydralazine.This made ACC to include ISDN in their 2009 guidelines for heart failure.

ISMN - doesn't undergo first pass hepatic metabolism.half life is around 4-6 hrs.It is primarily used in the management of chronic stable angina. It is not FDA-approved for treating heart failure. Standard formulations are 20 & 40 mg ..and again when given in an eccentric fashion(less than 12 hrs between daytime doses)...tolerance seems to be less.There is an extended release ISMN given once a day which also gives antianginal efect.

Soooo...... ISMN is preferred for angina as its once daily administration, and does better with compliance. Its better to give the drug in the morning during the time pts are active..and leave them drug free during sleep.
ISDN is recommended for heart failure (especially useful in black people..along with hydralazine), and has to be given in n eccentric fashion ( 8 hrs apart i.e- at 9am & 5pm...and so a 16hr drug free interval) to prevent tolerance. If adherence is an issue..then ISMN can be used in an off label fashion.
Also its safe to taper slowly ..when stopping nitrates..to prevent rebound.

Child pugh score - has drawbacks...still good.....but out of favour

CG Child
1908-1991

CTP- easily one of the most commonly heard score from medical school!
Child(in photo) & Turcotte came up with  a classification to assess the operative risk in cirrhotic patients undergoing  shunt surgery,which was modified by Pugh in 1973.It has 5 variables-  ascites, encephalopathy, PT  and serum bilirubin and albumin, classifying patients in class A, B or C. This classification was subsequently used to predict the outcome of surgery in cirrhotic patients in general, and more recently, to stratify patients on the waiting list for liver transplantation (LT). 


Drawbacks with CTP - The common problem is that,the degree of both ascites and hepatic encephalopathy are subjective assessments and so can vary widely.Also patients may be on diuretics, lactulose etc which may alter their severity( and there is no consensus on whether to grade them at their best or their worst)

Then lets take the bilirubin grading. The cut offs are arbitrary. For example...someone with a bilirubin of 4mg/dl will be in the same severity score as someone with a bilirubin of 15mg/dl. This is called 'the ceiling effect'. Albumin grading also has a similar kind of problem- someone with an albumin of 2.5mg/dl will have the same severity score as someone with a albumin of 1 mg/dl. This is called 'the floor effect'. Prothrombin time (PT) can vary between labs due to the difference in the thromboplastin agent used in each lab. So INR can overcome this problem...as it is standardised by WHO. But it should be remembered that INR was designed to standardize the anticoagulation effect of warfarin and not to evaluate the severity of liver disease. 


In spite of these drawbacks recent studies comparing CTP with MELD  has shown that both scores predict3,12 & 36 month mortality equally well in cirrhotic patients undergoing elective or emergency TIPS.
In a study(correspondence in Hepatology) comparing the two scores in predicting mortality in cirrhotic patients with acute variceal bleed,both scores predicted in-hospital and 1 year mortality without any significant difference between them. Both scores were able to predict short and medium term mortality in pts with chronic liver disease as well.


But MELD is being preferred these days because it is objective, and includes creatinine(which we all know...is an independent predictor of mortality).And importantly MELD has been found to be better at organ allocation than CTP.We can discuss about MELD at a later date!

Trouble shooting vents - to initiate

Managing your patient on a ventilator can be a big and at stressful task for someone starting their residency.....an intern! Eventhough it is easy to get help from the resident or the attending or the respiratory therapists....its better to go through some of the basic stuffs. We will try to keep this simple and easy to use .....especially with algorithms.So this is not going to be fully explanatory...but will serve the purpose.

Lets start with initiating ventilators.The first thing to be chosen is the mode of ventilation. The common mode used in most of the hospitals is assist control ventilation, whereby we set the desired tidal volume...and is delivered to the pt irrespective of whether the ventilator or the pt initiates the breath.
The parameters we determine (or we set on the ventilator) are
1. Tidal volume (usually around 8-10cc/kg or less in case of ARDS)
2. Respiratory rate (usually these pts were tachypneic before intubation..so start with 5-10breaths less than what they were doing...and then titrate)
3. FiO2 - start with 100% FiO2
4. Positive end expiratory pressure(PEEP) - start with 5 cm of H2O

Common types of waveforms that you may want for your patient when setting the ventilator- Square waveform( more exhalation time...useful for eaxmple in status asthmaticus) and decelerating waveform (useful in ARDS).

Now you have initiated the ventilation/oxygenation for the patient. Do a chest Xray immediately to look for ETT placement and expansion of both lungs (which you should have checked by auscultation beforehand)

Get an ABG in 15 - 30 min to determine if any change is needed with regards to the oxygenation(FiO2 & PEEP) or ventilation (Tidal volume & respiratory rate) or both. You are all set. Have a look at this nice algorithm from Cleveland clinic.(This is available in your Mass Gen hand book or Washington Manual).
Hope this helps...and we will discuss about some common issues in ventilator management, subsequently.

non HDL , LDL and cardiovascular risk

We all know that LDL is a calculated value from triglycerides and HDL(Freidwald formula),and is not a measured value. But it still holds good in terms of predicting atherosclerosis burden. The formula becomes less accurate as triglyceride(TG) level increases, and once TG is > 400, it is inaccurate.That is the reason for treating TG first if its >500 before treating LDL.But patients do have CAD and end up with an Acute Coronary Syndrome, even after LDL levels are at target. This is what we call "residual risk".

To address this risk, there has been a good deal of studies in this aspect. In the ATP 3 NCEP guidelines, non-HDL cholesterol is the second targey after LDL cholesterol. non-HDL includes all the cholesterol particles apart from HDL, and is obtained simply by subtracting total cholesterol from HDL.It comprises of VLDL, LDL,& IDL. In a study comparing non HDL to LDL and their risk of CVD, an increase that an increase of 30 mg/dL in non–HDL-C,and LDL-C levels would result in increases in CVD risk of 19%, and 11%, respectively. Authors concluded that non-HDL is a better prdictor of CVD than LDL.

In the TNT trial(first trial to show that reducing LDL to <100 mg/dl would further reduce CV mortality), even in those who reached LDL < 70, CHD risk was still strongly influenced by low levels of HDL. 

The group of patients in whom this would apply a lot will be those with diabetes and metabolic syndrome, who typically have a high triglyceride level and a low HDL level, which would make their non HDL levels high. There is a nice small review article from Mayo Clinic Proceedings which discusses this...and also about apo-B levels(which can be expensive and may not confer more information than non HDL)

There are some other studies like ARBITER trial, niacin and statin therapy increased HDL-C levels, reduced
carotid intima media thickness,and lowered CV events compared with statin and ezetimibe therapy.And there are large trials going on to address the issue with non HDL cholesterol and CV risk. For now...based on studies so far...the non HDL cholesterol targets need to be roughly within 30mg/dl more than the LDL targets. adding Niacin to a statin ..to bring up the HDL..and in this way reduce the non HDL cholesterol is an acceptable option for now.

Midodrine may not be there!

The latest medication which has come under FDA's radar in the last month...is the drug that has been increasingly used by nephrologists and heaptologists--- MIDODRINE .
On Aug 17th 2010 FDA issued a proposal to withdraw midodrine from the market within 30 days. 
So I decided to look into the evidence behind using Midodrine. 
Let me start with a little background on Midodrine---- It is a alpha agonist, and acts on venous and arteriolar vasculature producing increased vascular tone. It increases sitting, standing and lying BP.So the most common side effect reported is supine hypertension.


It is surprising that there is very scarce data on the clinical effectiveness of Midodrine. So far 3 randomised trials have been done. One is 3 weeks duration, and the other two are of 1-2 days duration!!! All studies were done on patients with orthostatic hypotension .
In the 3 week trial(JAMA 1997), pts on Midodrine(10 mg tid) had significantly higher (by about 20 mmHg) 1-minute standing systolic pressure 1 hour after dosing (blood pressures were not measured at other times) for all 3 weeks.They also had a similar increase in supine and sitting BP. And 25% of the 82 pts on Midodrine  dropped out of the study(due to pilomotor reactions, supine HTN, urinary retention)
The 1 & 2 day study also showed similar improvements in standing BP.In 1 day study the supine BP was >200 systolic in 22% pts on 10mg and 45% pts on 20mg. This elevated BP lasted for 6 hours after the dose. 


The only indication midodrine is approved is for Orthostatic hypotension. This has been extrapolated, and has been commonly used in one other setting...which is for treating hypotension during dialysis. There are nearly 10 studies on this..but again..the largest of these studies had 21 participants, and with short follow up. Have a look at this review from 2004. 


So there seems to be no real convincing data to support Midodrine. The Shire pharmaceuticals agreed to perform post marketing trials..but failed to do any. And thats the reason for FDA's proposal. It seems unlikely that Midodrine will be available in the near future(as early as this month).So what this means is..that physicians and patients on Midodrine have to be prepared to find an alternated  drug pretty soon!

Natriuretic peptides - Physiology & Variations

 Studies conducted in the 1950s, revealed that dilatation of the cardiac atria could induce natriuresis. In 1964, electron microscopy revealed the presence of secretory granules in the atrial myocyte.In 1981 de Bold and colleagues demonstrated that extracts from atrial myocytes injected into rats led to brisk natriuresis and diuresis. These atrial hormones were subsequently named atrial natriuretic peptides(ANP)
The Brain natriuretic peptide (BNP) was discovered from porcine brain in 1988. BNP is first synthesized as prepro-BNP, which is then cleaved to pro-BNP(108 aa) and finally to BNP (32 aa). The remaining 76 aa N terminal unit is called the NT-pro BNP. Both BNP and NT-pro BNP are sensitive diagnostic markers for heart failure.




Eventhough both of them can be used for diagnosing heart failure, they have different ranges, cut off values and certain physiological differences.  
BNP is a biologically active neurohormone whereas NT-pro BNP circulates as a inert substance.The clearance mechanisms and half-lives of BNP and NT-proBNP are also different. BNP is degraded by endopeptidases and has a half-life of 5–10 min, whereas NT-proBNP is cleared passively primarily by the kidney and has a half-life of 25–120 min.Despite these notable differences, the two hormones share many similarities in terms of their utility for diagnosis and risk stratification.


Variations in levels : Natriuretic peptide levels have been shown to fluctuate on a day-to-day basis and are correlated with a variety of characteristics. In a study including 911 healthy subjects(with normal LVEF) from the Framingham Heart study cohort, the strongest predictor of a high BNP/NT-pro BNP were older age and female sex. Other predictors for high peptide levels were lower diastolic blood pressure, lower BMI, and a large left atrial size.

As we all know, obesity is associated with higher incidence of Hypertension.The mechanism is likely due to sodium/water retention. If this is true then they might have an inherent low BNP level( also called natriuretic handicap). This was shown nicely...again in a group of Framingham patients that healthy! people who are obese have a low BNP/NT pro BNP. Also patients with Diabetes have a low peptide level. Obesity and Diabetes together have an additive effect on lowering BNP levels.


when intrepreting peptide levels, we should have these physiological variations in mind before making decisions based on BNP/NT-pro BNP levels.