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!!

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!!)

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.

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!!! 

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!!!!)

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)

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

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.

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!!!

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.

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.