Tuesday, December 28, 2010

FDA warnings in 2010!!


There has been quite a few warnings ... and threat from FDA about drugs...in 2010. 


The most popular news of the year among drug warnings was a repeat FDA warning that off-label use of quinine for leg cramps may result in serious and life-threatening hematologic adverse effects.
Among other drug alerts, the FDA warned against taking 
* Long acting beta agonists (LABA) by themselves should not be taken for a long time by asthma patients, unless their symptoms are not controlled by other medications (like steroids)
*80-mg dose of simvastatin is associated with an increased risk for myopathy, including rhabdomyolysis 
*Opioid tramadol is linked to increased suicide risk
*Bisphosphonates used to treat osteoporosis have a possible increased risk for 2 types of atypical femur fractures(femoral subtrochanteric and femoral diapyseal fractures)...both of which account for <1% of all femoral/hip fractures overall.
*Rosiglitazone(Avandia) was allowed to remain available under a stringent restricted-access program, despite adverse cardiovascular effects 
* Tigecycline was linked to an increased risk for death in patients with certain severe infections.(probably because its bacteriostatic)
* A threat from FDA to withdraw Midodrine from the market....and a later "U" turn by FDA...allowing it to stay in the market (no idea what's happening!)


May be ARBs and cancer risk might be on the agenda for 2011!!

Sunday, December 26, 2010

might be useful this winter! - Frostbite

I made a big mistake of not paying attention to the local weather forecast this weekend, and I had my car stuck in the snow.I got my fingers and toes frozen! red! numb! and tender!It took a while before I got the color back in my fingers. Prolonged exposure of this kind would lead to whats called Frostbite!


Lets see what we can do! First thing is ..DONT PANIC!. and call for help....if you can!The do's & dont's according to the 2010 First Aid guidelines from American Heart Association(most of the evidence is from around 1950s) are..


1.remove wet clothing and dry and cover the victim to prevent hypothermia.
2.Do not try to rewarm the frostbite if there is any chance that it might refreeze(i.e..if you cannot avoid being continuously exposed to the cold temperature, as repeated change of temperature will worsen tissue injury due to on & off formation of ice crystals) or if you are close to a medical facility.
3.Minor or superficial frostbite (frostnip) can be treated with simple, rapid rewarming using skin-to-skin contact such as a warm hand.
4. Severe or deep frostbite should be rewarmed within 24 hours of injury and this is best accomplished by immersing the frostbitten part in warm (37° to 40°C or approximately body temperature) water for 20 to 30 minutes. THIS IS THE MOST IMPORTANT STEP IN THE MANAGEMENT/FIRST AID.
5. Do not use heating devices, stoves etc to treat frost bite..mainly because the area is numb...and there is a risk of burns.

The mechanism of injury - Exposure to low temperatures leads to ice-crystal formation, which results in damage to capillaries leading to progressive ischemia and infarction. Generation of oxygen free radicals, production of prostaglandins and thromboxane A2, release of proteolytic enzymes, and generalized inflammation are the underlying mechanical effects of these injuries. There have been studies on use of therapies aimed at reducing the production of these metabolites. (J Trauma 1983). Another study(Ann Emer Med 1987)compared use of aspirin, aloe vera, methyl prednisone and methimazole against no medications.....and showed may be a marginal benefit with these agents in reducing dermal ischemia. There may also be a role for t-PA /heparin for management of severe fostbite(after rewarming within 24 hours).J Trauma 2005. Ibuprofen(or any NSAID) can be used initially on presentation, due to their anti inflammatory properties as per this recent article from Canada. (hard to disregard as...they are probably experts in snow related issues!!)

Wednesday, December 22, 2010

Another nail in the coffin for warfarin --- Rivaroxaban

The oral factor Xa inhibitor , RIVAROXABAN is posing more threat to the existence of warfarin for management of symptomatic deep venous thrombosis and foe stroke prevention in patients with non-valvular Afib. It is a oral tablet and has excellent bioavailability...has a structure somewhat similar to Linezolid.....and has predictable anticoagulant effect across wide variations in age, weight and gender.This drug has been in use in Canada and UK since last year for DVT prophylaxis following hip and knee replacement....as it was shown to be non inferior to enoxaparin, for those indications(RECORD trials)
Rats In Peace
The latest trial on Rivaroxaban ,presented at the European Cardiology Congress ........and published in NEJM Dec 2010 is the EINSTEIN-DVT study. This is a non inferiority study involving 2449 pts with DVT randomizing them to either 15mg twice daily for 3 weeks, followed by 20mg daily of rivaroxaban Vs sc enoxaparin followed by warfarin for upto 12 months. The primary efficacy outcome was the first symptomatic VTE event, which occurred in 2.1% of those on rivaroxaban (n=1731) compared with 3% of those on usual care (n=1718), with a hazard ratio of 0.68 (95% CI 0.44-1.04).The two regimens had comparable safety profiles, with the principal safety outcome—a composite of major and nonmajor clinically relevant bleeding events—being 8.1% in both treatment groups (p=0.77). 


Its probably time for a change in the way patients are anticoagulated! and warfarin has managed to hold the fort for more than 50 years. With these new agents(rivaroxaban & dabigatran) it will be easier for patients and physicians.....as no monitoring is needed. 
But few questions still linger.......Can we reverse the bleeding due to rivaroxaban? when do we stop and restart for any surgical procedures? what are its interactions with other commonly used drugs? .....Im sure FDA will be looking into these facts before giving the final nod.

Tuesday, December 21, 2010

Testicular cancer - not as bad as I thought!

It has been a long time since I heard about testicular cancer(the most recent ..as you all know..was in relation to Tour de France!!). Today a case of metastatic choriocarcinoma was presented ...in a male in his mid twenties. He has been classified as Stage 3C and is undergoing chemotherapy ,after having had b/l orchiectomy. He has metastasis to lungs and bowels. Looking at this...his prognosis appeared grim. Lets see how grim it is??


Testicular cancer can be divided into 3 - (1) germ cell tumors, (2) non–germ cell tumors, and (3) extragonadal tumors. Germ cell tumors, which are the most common, are classified as either seminoma or nonseminoma, based on histology. Lets concentrate on non seminomatous germ cell tumors(NSGCT)...which is what our patient had. NSGCTs refer to the germ cell tumors that contain embryonal stem cells.The 4 histologic classifications of NSGCTs include (1) embryonal carcinoma, (2) teratoma, (3) choriocarcinoma and (4) yolk sac tumor.


Patients come to attention due to a hard feel to the testis or swelling of scrotum or may even present with a swollen metastatic lymph node in the supraclavicular region. 5% have gynaecomastia on presentation.
Once suspected...confirm the presence of a mass in scrotum by ultrasound. Then 3 things need to be done as part of evaluation - (as orchiectomy is the first step in treatment)
1. Tumor markers which include alpha feto protein(AFP - elevated only in NSGCT , and not in seminoma), beta hCG, and LDH( just indicates tumor burden).
2. Staging the disease with imaging.(CT scan is the choice) - its TNM staging...have a look at the AJCC staging system. Our patient had the worst staging...Stage 3C with AFP >50,000 & visceral mass >5cm.
3. Inform patient about sperm banking for future fertility concerns.


Treatment - After orchiectomy(and you have a tissue diagnosis), then next option is chemotherapy based on staging. A common regimen is bleomycin plus etoposide plus cisplatin. Other treatment options are radiotherapy(esp with brain mets), and high dose chemo with bone marrow transplant.
Prognosis -  In general terms ...testicular cancer has the best prognosis of all solid tumors ..EVEN IF THEY HAVE METASTASIZED AT THE TIME OF DIAGNOSIS !!!!! 
Patients are classified into good, intermediate & poor prognosis based on some of the above factors. Generally...none of the patients with seminoma are categorised into poor prognosis( as they usually do well). The classification can be found in National Cancer Institute webiste. Poor prognostic factors in a pt with NSGCT are 
  • Mediastinal primary, or
  • Nonpulmonary visceral metastases, or
  • For markers–any of: AFP more than 10,000 ng/mL, or hCG more than 50,000 IU/mL (10,000 ng/mL), or LDH more than 10 × the upper limit of normal
The 5 year survival of this poor prognosis group(and our patient) is around 70% !! .....and the same for good & intermediate risk groups are 94% & 83% respectively.( National Cancer Institute & Eur J of Cancer 2006). 
This gentleman to the right is a famous survivor of this cancer....as u all know!!! 

Monday, December 20, 2010

Clopidogrel- with or without PPI ??

Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.
Mechanism -  the interaction between the two is most likely due to competitive inhibition of the CYP2C19 isoenzyme trough which clopidogrel is metabolised to its active form.


A 2008 publication in JACC involving 124 pts. showed that omeprazole significantly reduced Clopidogrel's inhibitory effect on platelet P2Y12 measured by a method called Vasodilator stimulated vasoprotein(VASP) phosphorylation testing. A retrospective observational study(JAMA 2009) on 8000 patients on clopidogrel showed that concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95%confidence interval [CI],1.11-1.41)


This issue was addressed in the recent prospective randomized trial - COGENT ...published in NEJM . around 3700 patients taking clopidogrel and aspirin for cardiovascular reasons were randomly assigned to receive either omeprazole or placebo. The group on PPI showed a significant reduction in the number of GI bleed in 6 months ((1.1% with omeprazole and 2.9% with placebo (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001)). Both the groups had similar rates of adverse cardiovascular events. Also....subgroup analysis of trials like CREDO, TRITON  did not show any increase in cardiovascular event with PPI and clopidogrel. 
In spite of these data...FDA put a black box warning on the Clopidogrel-PPI interaction in Nov 2009.


The AHA/ ACC and American College of Cardiology jointly published a consensus statement 2 weeks ago based on the COGENT trial ---
 1.In patients with histories of upper GI bleeding and those at high risk for this complication (e.g., advanced age; concomitant use of warfarin, steroids, or nonsteroidal anti-inflammatory drugs; Helicobacter pylori infection), the benefits of PPI therapy probably outweigh the very small risk that PPI therapy will interfere with clopidogrel's efficacy. 
2.Patients at low risk for GI bleeding who require clopidogrel therapy should not receive concomitant PPIs.


There is some evidence that this interaction(if at all clinically significant) may not be a class effect. The authors of this study in Annals of Pharmacotherapy 2009 suggest that Omeprazole seems to interact more with clopidogrel's action in vitro..than Pantoprazole. May be ..until we get a solid answer from further trials......if PPI need to be used....lets use pantoprazole with clopidogrel (provided the insurance covers!!!!)

Friday, December 17, 2010

antiplatelets after ICH - Is it adding insult to injury??

Antiplatelets are an indispensible tool in managing atherosclerotic disease (CVS & stroke especially). The main problem with these agents have been the risk of bleeding (mostly GI bleeding & intracranial bleed). They definitely pose a bigger risk for intracerebral bleed(ICH) than patients not on antiplatelets. But since benefits outweigh this risk...we have patients on antiplatelets all the time!
This leads to 2 questions!!


1. Do patients with ICH do worse if they were on antiplatelets Vs not been on antiplatelets before the event?
It appears that patients who are on antiplatelets ,and have an ICH are 3 times more likely to die at 30 days than patients with ICH who were not on an antiplatelet.(Stroke 2007). A metanalysis of 25 studies published in (Neurology.Sept 2010) also supported the fact that prior antiplatelet use independently predicted worse mortality in case of ICH.


2. Can antiplatelets be started again in patients after an ICH. and if so..when?
The answer is YES(provided they have a compelling reason to use). The answer came up with the recent study from UK..published in Stroke.Oct 2010. 120 patients out of 417 pts who survived a ICH were prescribed antipletelet therapy. The median time from discharge to antiplatelet use was 14.8 months (range, 2 days–7.5 years).Among all survivors, there were 14 recurrent ICH, 29 subsequent ischemic strokes , and 40 subsequent ischemic strokes or myocardial infarctions .Hazard ratios associated with antiplatelet exposure were 1.07 (95% CI, 0.24–4.84) for recurrent ICH, 0.23 (95% CI, 0.03–1.68) for ischemic stroke, and 0.72 (95% CI, 0.25–2.02) for ischemic strokes or myocardial infarction. So, antiplatelet use was not associated with worse outcome.....and in fact MI & ischemic stroke were more common in this group than ICH.


A review published in Nature Neurology 2006...also concluded that antiplatelets after ICH do not increase the risk of a second ICH.
Based on this recent study....a better time to start antiplatelets would be  between 6 months to 1 year ...again ..provided there is a strong indication to restart them (coronary stents, A fib etc)

Wednesday, December 15, 2010

Latest mortality data in US - how are we doing?

The Center for Disease Control(CDC) published the National statistics report last week.....with data from 2008.
Some of the interesting data :
1. The age-adjusted death rate decreased from 760.2 deaths per 100,000 population in 2007 to
758.7 deaths per 100,000 population in 2008. Hawaii had the lowest mortality rate whereas west virginia had the highest.

2. Life expectancy went from 75.4 to 75.3 years for males in 2008, and from 80.4 to 80.3 years for females.White females have the highest life expectancy, followed by, in order, black females, white
males, and black males. This pattern has not changed from 1976 through 2008, even though life expectancy for all groups has generally increased over this time period.

3. The 10 leading causes of death are : Diseases of heart, Malignant neoplasms,chronic lower respiratory illness,Cerebrovascular diseases, Accidents (unintentional injuries),Alzheimers disease, Diabetes mellitus, pneumonia and influenza, nephritis & nephrotic syndrome, and septicemia. The only significant change in this list is that cerebrovascular disease has dropped from 3rd place(for last 5 decades) to to 4th due to a large reduction in stroke related deaths.

4. The preliminary age-adjusted death rate for the leading cause of death, Diseases of heart,
decreased by 2.2 percent. The age-adjusted death rate for Malignant neoplasms decreased by 1.6
percent . Deaths from these two diseases combined accounted for 48.0 percent of deaths in the United States in 2008 ! Other leading causes of death that showed significant decreases in 2008 relative to 2007 were:
Accidents (unintentional injuries) (3.5 percent), Diabetes mellitus (3.1 percent), and Assault (homicide)
(3.3 percent)

5. Human immunodeficiency virus (HIV) disease was not among the 15 leading causes of death in 2008.
The preliminary age-adjusted death rate for HIV disease declined by 10.8 percent from 2007 to 2008.
6. The mortality due to Clostridium difficle has been increasing steadily over the last decade.... In 2008, C. difficile ranked as the 18th leading cause of death(2.3 deaths per 100,000 population) for the population aged 65 years and older. Approximately 93% of deaths from C. difficile occurred to people 65 years and older.

These are some interesting facts .....and it looks like there has been a great progress in managing these complicated disease processes. There is still a lot of scope for improvisation in delaying the inevitable!
On the whole......a good job. Have a look at the report below........
http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_02.pdf

Tuesday, December 14, 2010

a little step towards cost effectiveness - renal US

A renal ultrasound is a very good study that gives a lot of useful information for a lot of kidney diseases. Especially...in Acute Kidney injury(AKI) , it may change the management. But ,how frequently does it change the management...and how frequently should we do it in the setting of AKI? Well.......it gets done routinely in hospitals for evaluation of AKI ..to "rule out" obstruction. 
Recently...nephrologists at Yale tried to stratify patients who might need a renal US for evaluation of cause of hospital acquired AKI. (Arch of Int Med Nov 2010)


To identify the clinical risk factors for hydronephrosis, a derivation sample of 100 patients with hydronephrosis diagnosed with ultrasonography and 100 randomly selected controls was used. The results were subsequently validated using 797 ultrasonography studies obtained over 16 months. authors were able to find 7 factors associated with risk of hydronephrosis : history of hydronephrosis; recurrent urinary tract infections; diagnosis consistent with obstruction; nonblack race; and absence of the following: exposure to nephrotoxic medications, congestive heart failure, or prerenal AKI. 1 point awarded to each risk factor (except previous h/o hydro...which was considered high risk by itself). Pts were categorised into low risk(<2 points), intermediate risk(3 points) and high risk(>3 points). The overall incidence of hydro was 10%, and hydro needing intervention was 3%. In the low risk group...223 patients had to be screened to find one case of hydro needing intervention.(thats a lot of patients!). The model had very good sensitivity & a negative predictive value of 99% for hydro needing intervention. 


So......what do we have here?? A good proportion of patients with hospital AKI( categorised as low risk by this model) who would not need a renal US as part of their work up for AKI. The authors also calculated a savings of around $42,000 (based on a 30% reduction in US requests...($200/US) with an average of 700 US procedures in 1 year)


With regards to Community acquired AKI, we dont have similar kind of data...and the one we have is from 1991(AJKD) where they found the incidence of obstruction as a cause of AKI in 17% of patients with AKI...and it was mostly due to prostatic hypertrophy. It may be reasonable to do routine US in community acquired AKI until we have any new studies......as the mortality in the above study was 24% for those with obstruction.

Wednesday, December 8, 2010

massive blood transfusion

We recently had a 35 yo guy with a massive upper GI bleed not amenable to banding of varices.He had a Sengstaken- Blakemore tube....and his TIPSS next day was not possible due to thrombosis of splenic & portal vein. He finally had a spleno-renal shunt. He was transfused 11 units of PRBCs, 12 units of FFP, and 8 units platelets before being stabilised. This can be categorized under "massive blood transfusion". There are a few complications associated with this amount of transfusion....and its important these are addressed so that our good work at resuscitation is not lost because of  these problems. Lets look at those complications.....


 Massive blood transfusion is usually defined as the need to transfuse from one to two times the patient's normal blood volume. In a "normal" adult, this is the equivalent of 10-20 units.

Coagulopathy - The most common cause of bleeding following a large volume transfusion is dilutional thrombocytopenia. This should be suspected and treated first before moving on to factor deficiencies as the cause of coagulopathy.


Citrate toxicity - results as citrate in the transfused blood can bind calcium in the patient's body. Clinically significant hypocalcemia does not usually occur unless the rate of transfusion exceeds one unit every five minutes . This is more of a risk in patients with hepatic disoprders....as citrate is metabolised in liver. Treatment is with intravenous calcium administration. So check Calcium levels every 4 hours. Hypomagnesemia can co exist with hypocalcemia...but does not affect mortality.(Transfusion 2010)


Hypothermia -  should not occur on a regular basis. Massive transfusion is an absolute indication for the warming of all blood and fluid to body temperature as it is being given.
Acid-Base balance - can be seen after massive transfusion. The most common abnormality is a metabolic alkalosis. Patients may initially be acidotic because the blood load itself is acidic and there may be a prevailing lactic acidosis from hypoperfusion. However, once normal perfusion is restored, any metabolic acidosis resolves and the citrate and lactate are then converted to bicarbonate in the liver.


Hyperkalemia - The potassium concentration in stored blood increases steadily with time. The amount of potassium is typically less than 4 milliequivalents per unit - So it needs a lot of units to raise the potassium.
Watch out for your next worse GI bleeder!!!

Tuesday, December 7, 2010

Start a statin..worry less about the liver

Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual.Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease.

With the epidemic of obesity / metabolic syndrome.....we are (and will) see obese patients with high LDL and a slightly abnormal liver function test due to ?NASH....who is in need for a statin. How safe would it be to prescribe a statin to these people?
The recently published post hoc analysis of GREACE study has some evidence to help us. In short...GREACE study is a randomised trial of 1600 pts with CHD treated with Statin to NCEP goals(i.e LDL < 100, Chol <200) Vs regular treatment. It showed a significant reduction in cardiovascular mortality if treated to NCEP targets..over a period of upto 4 years.

In the post hoc analysis in Lancet Nov 2010 ...they took 437 patients from the initial cohort..who had abnormal liver tests( AST /ALT < 3 times normal). Of them 227 were treated with a statin and 210 without a statin. All of the 227 patients on statin had improvements in their liver function whereas the 210 not on a statin showed further increase in LFTs. Also, the pts with abnormal LFTs and on a statin showed a significant decrease in CVS mortality compared to pts with abnormal LFTs and not on statin(a 68% relative risk reduction). Surprisingly...this patient group had a significant reduction in CV mortality compared to pts with normal LFTs and on a statin!
Of the 880 patients(in the whole study) who were on a statin ....< 1% stopped it due to elevation in transaminases(>3 times normal). One caution in interpreting the results of the GREACE study is that ..the average dose of Atorvastatin used was 24 mg. This may not be adequate for some ....but given the clear benefits......they can be started on a statin with monitoring LFTs. So dont hesitate to start a statin in someone with a moderate elevation in LFTs.

Monday, December 6, 2010

Dengue in India - wake up

Well...well...well.......I was little busy with my ICU rotation this month....and in the middle of it...I had to rush to India as my grandmother was taken ill to the hospital with Dengue. I should say...that people in US & Europe should be praising their government for giving them an extraordinary health system with excellent doctors and nurses. Anyway...... I wanted to write a lilttle about Dengue (this is almost non existent in Europe...and present along the mid south and south west of US)

Dengue, caused by the bite of Aedes mosquito (for some reason the worse bites are during the day) comes in three forms - 1. Dengue fever (most common type - mild symptoms lasting a week or so without any complications)  2. Dengue Hemorrhagic fever - complicated by thrombocytopenia and bleeding from mucosa.
3. Dengue shock syndrome - characterised by circulatory shock (mortality is 6 - 30% ).

A quick pathophysiology - The main pathophysiology is capillary leak and thrombocytopenia...both occuring after the fever has abated..and lasting for 2-3 days.So the critical period is those 2-3 days after fever and rigors settle down. Because of the capillary leak....there will be an increase in hematocrit(a >20% increase from baseline is significant). If supportive measures are not taken...this will proceed to circulatory shock needing careful fluid replacement.....as excessive replacement will worsen capillary leak and enhance third spacing(pleural, ascitic & pericardial)
The management is entirely supportive. Most can be managed as outpatients provided they check their platelet & hematocrit after their fever stops. Patients with thrombocytopenia need to be monitored in hospital for need for transfusions and prevention of complications including coagulopathy,bleeding into internal organs and circulatory shock. One other complication which has been reported to be present in around 40% of dengue patients is hyponatremia. The reason for this has been postulated to be hypovolemia with some SIADH. replacement with 0.9% NS would help correct it.

There have been many cases of Dengue so far...and still no action has been taken to get rid of the Aedes. Common India.......act quick.

Sunday, November 21, 2010

Long known Vitamin D ..and physiology

Of all the vitamins..Vitamin D has recently featured in almost all medical journals..given the huge prevalance(57% of hospitalised pts in US) of Vitamin D deficiency and the association of it to many important disease processes known to man! 
Vitamin D has properties of both being a hormone..and a vitamin. Lets get a quick recap of the physiology.

There are 2 main forms of vitamin D: vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Vitamin D3 is formed in the skin, after exposure to ultraviolet B radiation, from 7-dehydrocholesterol that resides in cell membranes.Vitamin D2 is obtained through irradiation of ergosterol in plants from sunlight, and enters our circulation through diet. Vitamin D3 also is available from animal sources, such as cod liver oil, salmon, mackerel, and herring. 
After vitamin D is ingested from the diet or synthesized in the skin, it is metabolized in the liver to a biologically
inactive 25-hydroxyvitamin D, 25(OH)D, which is the major circulating form of vitamin D. It is this form( 25-hydroxyvitamin D) of vitamin D that is used to determine a person’s vitamin D status. 25(OH)D is then converted into its active form 1,25 (OH)D by the kidneys. This then interacts with vitamin D receptors in the intestine and bone to augment intestinal calcium absorption and mobilize osteoclast activity. Non-calcium regulating tissues, such as the prostate,colon, and breast, locally convert 25(OH)D to 1,25(OH)2D....and this forms the basis of Vitamin D being involved in prevention of malignancy in these tissues,aas it facilitates programmed cell growth.

Although controversies exist regarding the cut off for calling deficiency( due to summer Vs winter, morning Vs evening etc)......widely accepted value of < 20ng/ml of 25(OH)D is considered deficient ....21 - 29 is considered Vit D insufficiency......and > 30 ng/ml signifies sufficiency.  Without vitamin D, only 10% to 15% of dietary calcium and approximately 60% of phosphorus will be absorbed. The efficiency of calcium absorption is increased by 30% to 40%, and phosphorus by 80%, with the interaction of 1,25(OH)2D to its receptor.
I frequently got confused with the different names vit D has! 25(OH)D is an inactive form..but this is what we measure to diagnose deficiency. 1,25(OH)D is the active form..and we dont measure it. D2 & D3 are just numbers to describe the source of VitD....D2 (cholecalciferol) from human skin, and D3(ergocalciferol) from food products. 

Monday, November 15, 2010

PCP prophylaxis in non-HIV patients

Many clinicians routinely prescribe sulfamethoxazole-trimethoprim (SMX-TMP) or another agent to prevent the development of Pneumocystis jirovecii pneumonia (PCP) in patients receiving immunosuppressive medications, with the assumption that the risks are same as some one who is immunosuppressed from HIV. Evidence justifying such a policy is sparse.
A recent study published in J Am Acad Dermatology tried to find the right way to do this. The authors of this retrospective study examined the frequency of PCP in 198 HIV-negative patients who received immunomodulatory medications for dermatologic disorders, such as psoriasis, dermatomyositis, vasculitis, and pemphigoid.
Systemic corticosteroids, methotrexate, antimalarials, and azathioprine were the most common immunosuppressive medications used by these patients; approximately 25% received a biologic agent, such as etanercept. About 25% were concurrently receiving a prophylactic medication to prevent PCP. During an average follow-up of 8 years, PCP developed in only one patient (94 years old) not receiving PCP prophylaxis (0.7% incidence). Serious reactions to the PCP-preventive medication developed in 6% of SMX-TMP recipients and 37% of dapsone recipients.
The very low risk for PCP is too small to justify routine prophylaxis. In addition to their expense, these medications are frequently associated with adverse effects. The authors sensibly recommend that clinicians avoid routine prophylaxis in patients receiving immunosuppressive agents and that we remain alert to the uncommon possibility of PCP, especially in those with apparent risk factors, which include age >60, concurrent pulmonary disease, leukopenia, hypoalbuminemia, and CD4 counts <300/dL.
This above issue was brought on by one of my colleagues, Dr.Dioverti.. during a friendly chat ...as she had a patient on bactrim prophylaxis due to chronic steroid use. This study will help those questions for now.

Thursday, November 11, 2010

Vitamin B and cognition.......doesnt work

High plasma homocysteine levels are associated with cognitive impairment in a few epidemiologic studies.In multiple clinical trials researchers have examined whether vitamin B supplementation — which lowers homocysteine levels — improves cognition or delays onset of cognitive impairment in older adults; results have been mostly negative.Have a look at the Cochrane review from 2008 .But Vitamin B deficiency has been implicated a causative factor for dementia, as it does affect the homocysteine levels.


In a new study published in Neurology 2010, Australian researchers randomized 299 community-dwelling hypertensive men (age>75) without dementia to receive either placebo or a combination of vitamin B6, vitamin B12, and folic acid.
During 2 years of treatment, no differences between groups were noted on several measures of cognition. Even in subgroups in which benefit seemed likely — men with high baseline homocysteine levels (15 ┬Ámol/L) and men with mild cognitive impairment at baseline — the investigators found no benefit from vitamin B supplementation.

The study adds more evidence to the fact that vitamin B does not improve cognition ..or prevent or improve dementia. The increased homocysteine levels may just be a marker of dementia than being a predictor of dementia. Its time to look at other things that might be important and probably stop emphasizing on Vitamin B!!

Tuesday, November 9, 2010

Linezolid or Vancomycin for nosocomial pneumonia

Nosocomial pneumonia due to MRSA is not very uncommon these days. Vancomycin is being increasingly prescribed ..keeping this in mind (atleast in my institution). Many studies have shown that Linezolid is better as it achieves higher lung epithelial lining fluid concentration which may correlate with improved efficacy.
A recent metanalysis(Crit care Sept 2010) was done to compare the efficacy /clinical outcomes of Linezolid versus Vancomycin .The theoretical advantage of Linezolid did not turn into a superior clinical benefit. The clinical cure rate, MRSA eradication rate and mortality were similar between the two antibiotics. There were significant 2 fold increased risk of thrombocytopenia and GI events in the Linezolid group compared to Vancomycin group.


Vancomycin holds its fort as the same reliable drug for MRSA nosocomial pneumonia. Teicoplanin and Linezolid will be effective alternatives to Vanco. But Linezolid will be the drug of choice for Vancomycin resistance (again...not an uncommon problem these days!!)


Generic Vancomycin is $4- $8 for a 1000mg vial(usual dose is 1g daily)
Teicoplanin is not available in USA
Linezolid(Zyvox) is $120 for a 600mg vial (usual dose is 600mg bid)

Monday, November 8, 2010

The risk of stopping antiplatelet therapy

Antiplatelets , especially Aspirin and Clopidogrel have established their importance in management of coronary artery diseases. But they also pose a bleeding risk. This risk is high if a procedure needing tissue sample is done. We had a 66 yo male ..4 months after a STEMI for which he received a drug eluting stent , and was started on Aspirin and clopidogrel. This clinic visit he is complaining of 6 month h/o early satiety, loss of apetite..and our records show a weight loss of 15lb in last 3 months.He needed a upper GI endoscopy ..with a possible biopsy. What do we do with his antiplatelets? ....Lets look at some facts from AHA
· Cessation of all antiplatelet therapies after PCI, at any time, for any stent, is associated with an increased risk of thrombotic events, including late stent thrombosis. These events are likely to occur within 7 to 30 days of drug discontinuation. 

·Cessation of clopidogrel (alone) during the early period after PCI (within 30 days of either DES or BMS placement) is associated with an increased risk of events. 

·Cessation of clopidogrel (alone) beyond 30 days from the time of BMS placement is common in clinical practice and does not confer increased risk of thrombosis over a brief period of time. 
·Cessation of clopidogrel (alone) upon completion of 6 months of treatment after DES placement is controversial (in terms of long-term risk) but does not seem to confer a significant short-term risk(within the subsequent 30 days) in a majority of patients if aspirin is continued. 

 The importance of continuing aspirin in the above scenarios was shown by a review in JACC 2005, where the median duration of stent thrombosis when both drugs were stopped, was 7 days...compared to 122 days when only clopidogrel was stopped and aspirin was continued.In addition, many retrospective studies have shown safety of continuing aspirin during GI procedures. The GI prcedures have been classified into high & low risk based on the risk of bleeding.
Considering the urgent need for endoscopy, the fact that UGI endoscopy is a low risk for bleeding, and the STEMI 4 months ago....we had our patient continue Aspirin, but stop Clopidogrel 5 days before procedure. He will continue his dual antiplatelet therapy the day after his procedure. As always.....the befits & risks were, and have to be discussed with the patient!

Thursday, November 4, 2010

I forgot to apply my brakes !!

The population with dementia is increasing ...and will probably increase for ever! An interesting article from Alzheimers association showed that the health care cost for managing dementia is almost thrice the profit of Walmart! Anyway our topic is not that. I had a patient today brought by his son, who takes care of dad's finances. His Mini mental state exam(MMSE) was 22, and the question of driving came up. Can this patient drive with this MMSE score? or will he forget to apply his brakes one day ?!!

First of all ......MMSE alone cannot be used to assess driving. It has a low sensitivity when used alone ..to assess suitability of driving. A score of <25 is possibly useful in this aspect according to the latest guidelines from American Academy of Neurologist(AAN April 2010). If its not MMSE ..what predicts safety of driving?

Based on a number of studies Clinical Dementia Rating (CDR)scale appears to be useful for predicting unsafe driving. CDR mainly relies on memory ,but also has other factors like orientation, judgement, personal care, home& hobbies etc(altogether memory is the major category...with other 5 as secondary categories). A score of  0.5 to 1 may predict unsafe driving ....but it has a wide confidence interval....as many pts with that score passed the on road driving test(which is best at predicting unsafe driving........unfortunately can't be done in the office!!!)
The Academy of Neurology has the following as recommendations...

The CDR scale (Level A)
• A caregiver’s rating of a patient’s driving ability as marginal or unsafe (Level B)
• A history of traffic citations (Level C)
• A history of crashes (Level C)
• Reduced driving mileage (Level C)
• Self-reported situational avoidance (Level C)
• MMSE scores of 24 (Level C)
• Aggressive or impulsive personality characteristics (Level C)

Factors not useful in assessing safe driving are

• A patient’s self-rating of safe driving ability (Level A)
• Lack of situational avoidance (Level C)



Our gentleman had CDR score of 1, with a marginal caregiver rating, situational avoidance. He was advised to stop driving. Hope he doesn't forget this advice!

Tuesday, November 2, 2010

Plumbing paradigm might work!

I recently presented a morning report in my Clinic about preventive Cardiology...and I had mentioned about 'plumbing paradigm' ( relieving coronary blockage whenever we find one) does not make things better compared to a medical & lifestyle approach. I based this on two studies done on patients with stable coronary artery disease -

1.COURAGE trial - 2200 patients with stable CAD(ST depression or T wave inversion on resting ECG, inducible ischemia with exercise, or at least one coronary artery stenosis of at least 80% and angina. EF <30were excluded ). 2/3rds of pts had multivessel disease. Pts were randomised to PCI with bare metal stent Vs medical therapy. Over a period of nearly 5 years..there was no difference in primary outcome of all cause mortality, non fatal MI between 2 groups. Angina relief , stroke, hospitalisation for MI did not differ as well. But..a subgroup(n=314) were further enrolled to undergo nuclear study at baseline and after 1 year. PCI did show a significant reduction in ischemic myocardium compared to medical therapy.
2. BARI 2 trial - 2300 patients with type 2 diabetes and CAD(>50% stenosis of major coronary artery with +ve stress test or >70% stenosis with classic angina. Class 3 & 4 heart failure, creatinine>2 were excluded).Over a period of 5 years there was no significant difference between PCI/CABG  Vs medical therapy alone ...in terms of survival, MI, and angina. 


But ..recently ..the MASS 2 trial was published in Circulation -  a randomised controlled trial of 611 patients with CAD ( with proximal multivessel stenosis .70%, stable class 2 or 3 CHF, HTN or diabetes). Pts were randomised to either CABG or PCI with BMS or medical therapy alone. Follow up for 10 years showed a significant improvement in cardiovascular mortality, recurrent MI, angina ...compared to medical therapy.PCI was associated with an increased need for further revascularization, a higher incidence of myocardial infarction, and a 1.46-fold increased risk of combined events compared with CABG. A thing to note..is that majority of patients in this study had aither triple vessel disease or proximal LAD disease....and this is likely why CABG showed a great benefit. 


So.....based on these studies.....PCI /CABG may be superior to medical therapy in patients with stable multivessel disease( and the plumbing paradigm seems to work). But this cannot be generalized for others with stable and mild CAD ..where medical therapy has equal mortality and antianginal benefit as intervention...provided the disease is stable.

Monday, November 1, 2010

Multiple sclerosis- a few pearls

As we all know MS is an inflammatory, demyelinating disease affecting the central nervous system. MS is a dynamic disease with constant formation of new lesions and a progressive clinical course resulting in disability. 


 *For every 8-10 new lesions detected on magnetic resonance imaging (MRI), only one clinical manifestation typically can be demonstrated.
*Patients with relapsing remitting MS have an average of 5-10 new lesions per year and 1 or 2 clinical exacerbations
*no etiologic agent for MS has been identified


*MRI of head and spine with and without gadolinium shows the lesions(plaques). Enhancement of a lesion on T2 weighted image is indicative of an active lesion. Lesions that dont enhance are chronic lesions. Usually its a mixture of both. One differential here in a patient with 10 or more enhancing lesion on first presentation is Acute Disseminated Encephalomyelitis(ADEM). A history of recent vaccination/viral illness points more towards ADEM than MS in this scenario.
*CSF oligoclonal bands (which are IgG) is elevated in nearly 85 -90% of patients and serves as a good test with high sensitivity. So if negative....the likelihood of MS is low. IgG Index, which is calculated as follows (IgGCSF/albuminCSF)/(IgGserum/albuminserum) is usually elevated. ( Normal is < 0.77)
*Management is usually a multidisciplinary approach( as it is with most of the neurological illness)


* An acute exacerbation, if it is severly disabling should be treated with 1mg/kg/day of i.v methylprednisone for 3-5 days with a taper over next 2-4 weeks. This has shown to reduce the duration of disability, but does not improve the degree of resulting disability. (Neurology 1998 )
* Options for reducing relapses are many. interferon beta-1a IM (Avonex), interferon beta-1b SC (Betaseron and Extavia), glatiramer acetate SC (Copaxone), & interferon beta-1a SC are immunomodulators used in this aspect. In general these agents reduce the relapses by one third...with efficacy being high for high dose high frequency(HDHF) interferon  Betaseron (34), Rebif (33%), Copaxone (29%). But on the whole ...studies had shown variable results. for eg. INCOMIN study in 2002 showed benefit with HDHF interferon compared to low dose....which was later disproved by Danish MS study in 2006.
* The latest drug approved by FDA is Fingolimod...based on the recent TRANSFORMS study in NEJM 2010 which showed fewer relapses compared to interferon 1a over 1 year period. One advantage of fingolimod id that it is a oral medication...as opposed to all other meds(either im or sc).
*Modafanil or amantadine can be used effectively for symptoms of fatigue ...in pts with MS.


Its not much to choose in between the medications..in terms of efficacy. So therapy can be guided by patient profile and side effect profile of the drug.

Sunday, October 31, 2010

Evaluating hypoxia - not that tough!

I had a few queries from you guys about the calculation of partial pressure of Oxygen in alveoli (PA02) , in my previous post.
Thanks for those who brought this up
This is what I mentioned for calculation of A-a gradient
A-a = (713 x FiO2) - PaO2-PaCO2-PaCO2/4

where PAO2 = (760-47) x FiO2 - PaCO2 /0.8
          here 760 is the atmospheric pressure...and 47 is water vapour pressure....and 0.8 is the respiratory quotient assuming we have the stipulated proportion of fat,CHO & protein in the diet.
This is how I got 713.   I have simplified the PaCO2 /0.8 portion of this equation into PaCO2 - PaCO2 /4  just because I find this easier than having a 0.8 in the denominator.

Usually A-a gradiesnt is calculated by PAO2 - PaO2 , .....and PAO2 is taken as 150 . This value of 150 is only applicable if the patient is breathing room air i.e 0.21.  If not then we have to substitute that value and arrive at the PAO2 appropriate for that FiO2. This is the reason I didnt mention the value 150 in the equation.
Hope this clarifies!

Friday, October 29, 2010

Evaluating hypoxia - not that tough!

This is one of the most common finding for ICU transfer/admission. And there are many ways to evaluate hypoxia. Lets try and do  a simple way which would cover the common problems causing hypoxia in clinical practice. 
OK……the usual situation will be that you are called to see a patient with reduced O2 saturations on the wards….and an ABG, chest xray has been done and pt is on O2. (If not done, you need these to make a good decision ). While waiting for these to be done ….we can do the most important thing..taking a SHORT focused history and exam (many times this will give us the clue and we can use the test to confirm them). If not..then lets go through the tests

First thing to assess is that whether this hypoxia is due to pulmonary or extrapulmonary causes( sedatives, neuromuscular weakness, central hypoventilation). The A – a gradient will help. It can be  calculated by the formula  PAO2 (  713 x FiO2 ) – PaO2 – PaCo2 – PaCo2/4 .  Normal gradient is <12 and differs with age…so use age/ 4 +4 to correct for age. Ok..back to the evaluation- If A-a gradient is normal then its likely extrapulmonary cause(usually they have resp acidosis). If it is normal then look at PaCo2. If high..that will suggest airway obstructive disease ie. COPD/asthma. If PaCo2 id normal then have a look at the Chest Xray(CXR). If the CXR is normal then its likely to be a Pulmonary embolism (if the history correlates…..give a shot of heparin(Fondaparinux or Enoxaparin) and send the patient for CTA of chest).  If CXR is abnormal and shows a focal infiltrate then its likely to be pneumonia or atelectasis. If  infiltrates are diffuse then there are 2 possibilities – cardiogenic pulmonary edema or non cardiogenic pulmonary edema(ARDS). The ideal way to distinguish them is to do a Pulmonary artery wedge pressure. But this is not done in recent days as it does not seem to improve mortality. So …we have to rely on factors like ECHO(if done already), EKG, CVP and History.  We can try giving a bolus of Frusemide  to see if it helps. Both may get better, but usually patients with CHF might find a quicker relief.  One other  point here….is to always compare this CXR to a previous one(esp when pt. was stable)

Throughout this evaluation ..history will be helpful. I have found it useful ..to go back to the history(mainly the presenting symptoms) when Iam stuck in the process of evaluating these numbers( any numbers!).                      
So to summarise…the order with which we can look at the numbers ..
1.      1. A-a gradient   2. PaCo2   3. Chest Xray  4. EKG,ECHO,JVD,CVP etc
     Whenever  we are stuck….always get back to the history!

Wednesday, October 27, 2010

Hyperammonemia - if not Liver...what is it?

I have an interesting 50ish  patient in the Clinic with a history of 3 -4 admissions in the last 6 months due to episodes of altered mental status, confusion, lethargy which has made her stop driving(school bus) on one occasion. Her imaging was normal and her EEG showed diffuse slowing suggestive of a metabolic cause. Her ammonia(NH3) level was 110 with a normal liver function test and no clinical signs of chronic liver disease. She improved in 24-48 hours with lactulose. She is not an alcoholic or smoker. Her BMI is 30, and she had bariatric surgery done 4 years ago. So what can we do for her? Well....first will continue on lactulose while we investigate....and advise to stop driving.


How to approach . Well it is tough when we have some one with symptomatic high ammonia levels with a normal Liver function. These are the differentials in this case ---


1.Medications - Sodium valproate ( by inhibiting carbamoyl phosphate synthetase in the urea cycle. can happen both in acute & chronic setting. Some of these patients do have an underlying enzyme defect which is now unmasked by valproate). Chemotherapy drugs are also implicated esp 5- Flurouracil. But the underlying malignancy can also cause high NH3 levels. So interpretation might be difficult in that situation.
2.Digestive & Urinary tract infections - Proteus, H.pylori, Corynebacterium, Klebsiella are urea splitting bacteria and can cause hyperammonemia.
3. Surgical procedures - Ureterosigmoidostomy(due to diffusion of NH3 into circulation), portosystemic shunts, lung & bone marrow transplant (mostly due to GI bleeding, total parenteral nutrition), and bariatric surgery( again due to unmasking of underlying enzyme defect due to a high protein diet)
4. Late onset enzymatic defeciency - The most common in adults would be Ornithine transcarbamoylase(OTCM) defeciency(X-linked), but other urea cycle defects can occur. Best way to start investigating is to get a Citrulline & arginine level. If citrulline is low.... its a defect of either Carbamoyl phosphate(CP) or Ornithine TCM. If high.....its a defect in arginosuccinate synthase. If normal go with arginine( check the diagram). 
5. Small bowel bacterial overgrowth(SBBO) -  more bacteria in the gut breaks down more protein and releases more NH3 . This is possible in patients with bariatric surgery(esp if its a bypass with a blind loop).


So...in our patient..we think it is related to her bariatric surgery. Going through the above list......2 possible mechanism could contribute. Underlying enzyme defect Vs SBBO. I have scheduled her for a Hydrogen breath test with Lactulose(for SBBO) and awaiting her citrulline levels. Hopefully we would be able to nail the culprit. In case its SBBO..she would need to go on antibiotics preferred one being Metronidazole or Rifaximin. Lets see!