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!

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!

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!

Is hyperbilirubinemia protective ?

Well..a mild increase in unconjugated bilirubin may be a good thing to have!. Iam talking about patients with Gilbert's syndrome(GS) and patients with a mild elevation in their indirect bilirubin in the absence of liver disease. GS is a benign syndrome cause by reduced activity of enzyme UDP Glucronyl Transferase. In one of the famous prospective cohort studies- The British Regional Heat Study(BRHS) there was a U shaped relationship between bilirubin level and heart disease. Men with low bilirubin levels were found to have low concentrations of HDL cholesterol, low FEV1, and low serum albumin. This led to a small study in Univ of Utah...which showed a similar inverse relationship between bilirubin & heart disease.Another prospective study from Europe called PRIME study involving 10,000 men also showed that a slightly elevated bilirubin is a marker of protection against Coronary Heart Disease. Another strong pointer towards this trend is the lesser incidence of heart disease in patients with Gilbert's syndrome compared to general population (Atherosclerosis 2002)


This benefit has been explained on the basis of the antioxidant property of Bilirubin. It might prevent oxygen radicals from damaging the endothelium, and it also prevents oxidation of LDL particles. Bot these effects can explain a lower incidence of Ischemic heart disease in this population. Well....if this idea is true....then it should protect against stoke as well. 


Stroke & bilirubin - A 30% risk reduction in incidence of carotid plaques was found in patients with their bilirubin the highest quartile compared to bilirubin in lowest quartile (Stoke 2001).  recent study published in Stroke 2009 ...studying nearly 80,000 healthy patients showed a 20% risk reduction in ISCHEMIC stroke in patients with high bilirubin levels.
Aaand...it doesnt stop here! Another study from Annals of Hepatology published in 2008 showed that a 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of peripheral vascular disease (PAD). The benefit was noticed more in men than women. Another article in JAMA 2007 comparing diabetic pts with Gilbert's syndrome to normal people...showed a a significantly lower prevalence of hypertension, HbA1c, LDLl, total cholesterol, and triglyceride,CRP and higher levels of HDL. They also had a lower incidence of proteinuria as well (have a look at the table). Very recently ,an article in Kidney International (Oct 2010) shows that in rats who had hereditary hyperbilirubnemia had lower incidence of diabetic nephropathy.


It may be difficult to prove whether high bilirubin is an effect of body's need for an antioxidant...or it does genuinely protect against atherosclerosis. But bilirubin seems to offer a definite protection, and could be used as a reasonably good marker of vascular events. The main hindrance to bilirubin's use is that we cannot modify its level...to attain any of these benefits. A level just around upper limit of normal( upto 2.5 x normal in GS) would be the level talked about in the studies.

Placebo??

I recently came across an interesting article from Annals of Internal Medicine. Placebo is a very common term we use in our day to day life...when we read articles..when we refer to a study. But I always had some curiosity about what really it has. It has also been named as 'Sugar Pill'. It can contain sugar ..or may be vegetable oil( in fact each study uses its own manufactured placebo!).Well...can it affect results of studies .


a quick example.....If its a vegetable oil,  the monounsaturated and polyunsaturated fatty acids of these 'placebos,' and their antioxidant and anti-inflammatory effects, can reduce lipid levels and heart disease." If this is used in against a lipid lowering drug...then the benefit of the drug might be blunted at the end of the study! Well...if its all sugar....and we comparing it with Metformin..then we know what to expect!!!


In this study, researchers delved into 176 studies published in reputable medical journals, such as the New England Journal of Medicine, the Journal of the American Medical Assn. and the Annals of Internal Medicine, from January 2008 to December 2009 to see if placebo contents were disclosed and if so, what they were. Only a very few number of studies did disclose what the placebo contained. The placebos are manufactured by the company running the research, and they never let the content of the placebo out! 
And to make suspicions worse...FDA does not regulate the placebos used in studies (in fact no one regulates their use...except for the drug companies)


Irrespective of what they contain....do placebos have any clinical or the so called psychological benefit. This was addressed in a review published in NEJM in 2000. The placebo did show a little benefit in studies with subjective outcomes, and for treatment of pain!


Lets hope that all studies are done in good faith...good intentions!!!!! and the researchers are willing to publish  this part of evidence as well.

A better hope for irregular hearts- Dabigatran

2 days ago  the FDA approved the first new anticoagulant in fifty years, dabigatran  for stroke prevention in patients with non-valvular atrial fibrillation. Available in 75 & 150 mg to be taken twice daily. Dabigatran showed a better side effect profile compared to warfarin in the recently published  RE-LY trial in NEJM. This was a non inferiority trial with 18000 patients. Half received Dabigatran and half..coumadin. Primary outcome was stroke. Compared with Coumadin (warfarin), patients on Dabigatran had a 9% lesser incidence of stroke, and the risk of major bleeding each year was 2.71% with dabi ..and 3.36% per year with warfarin.The risk of hemorrhagic stroke also decreased significantly. These results has pushed FDA to approve this on the market. 


On top of all these benefits.....the one advantage that stands out...is the there is NO NEED TO CHECK BLOOD LEVELS. This is a great news for patients taking warfarin....but may be a bad news for the warfarin clinics!
What is the downside of Dabigatran?  The common side effect is GI intolerance. This was not a major issue in the trial. Second..it is expected to be 7-8 times costlier than warfarin (roughly around $6 -$9 / day). But given the amount spent on blood checks, clinic visits, lost work days, money spent on patients travelling to the clinics..........plus the reduction in complications.....Dabigatran might still prove to be a cost effective medication. Well...who knows........our clever Insurance companies might think differently.     But another important group of concerns are...that there is no antidote in case of a major bleeding ( but due to short half life..stopping the drug could be adequate). Also when to stop before surgeries..and when to restart? How to monitor if needed? Well ...the most reliable means of montoring seems to be activated partial thromboplastin time(aPTT) and Thrombin clottin time (TT).


How does it work? It is a prodrug..and is immediately  converted by a serum esterase to dabigatran, a potent, direct, competitive inhibitor of thrombin. It has an absolute bioavailability of 6.5%, 80% of the given dose is excreted by the kidneys, its serum half-life is 12 to 17 hours. It is approved by FDA at a dose of 150 mg bid. Lets wait and see if this would end the story for warfarin. 


Remember....a direct thrombin inhibitor called Ximelagatran was about to be released in Europe for the same indication as Dabigatran...but had to be withdrawn because of hepatotoxicity during its trials. This was not a great problem in the RE-LY trial. But this something to be aware of especially in the first few months of treatment.

moving towards Bariatric Surgery...

Im doing my second month of ambulatory clinic rotation ...and Im getting bored with saying  " You got to lose weight" many times each day. And I ask them to follow a diet... exercise everyday ... blah.. blah.....well..they dont... and I agree ..its a tough task. So I have thought about getting surgery to help them.

In most of the studies done on weight reduction with diet &/or exercise..the drop out rate of participants has been quite high. And almost all the studies are of duration less than 2-3 years ..and weight reduction has not achieved targets.For example..in the Diabetic Prevention Program Study (NEJM 2002)..analysis of 1079 pts with ave BMI of 33 showed only a 5.6 kg reduction in weight with intensive lifestyle changes(diet & exercise ) for mean of 2.8 years. Adding Orlistat to a population similar to the above..as in XENDOS study again showed a modest 5.6 kg wt loss over 4 years. Based on UKPDS data...a reduction of 7-8% of body weight is needed to reduce a HbA1C from 8 to 6 !!   hardly achievable

With this modest effects of lifestyle and medications on weight loss ( not to mention the compliance issue), bariatric surgery seems to be a reasonable option. Bariatric surgeries are of 2 types:

1. Malabsorptive procedures - eg. jejunoileal bypass(no longer done), biliopancreatic diversion and the biliopancreatic diversion with duodenal switch. The aim is to shorten the functional length of small intestine.
2. Restrictive procedures - eg. vertical banded gastroplasty, gastric banding. simpler to perform. The aim is to make stomach smaller so you get early sateity.
3. Roux-en-Y gastric bypass -  this is the most common procedure in US. It is a combination the above two.

A meta-analysis from 2005 showed a significant 20-40 kg weight loss from bariatric surgery which persisted at 10 years. This was mostly in pts with BMI>40...which translates into a 15- 30% weight reduction. Another review in JAMA also showed extensive weight loss with surgery...and a greater proportion of reduction in obesity related complications (diabetes, OSA, Hypertension, dyslipidemia etc). The perioperative mortality(30 day) is anywhere between 0.3% to 2%. Common long term complications are gall bladder disease, GI ulcers, dumping syndromes.

So..who is eligible....

BMI>39 or BMI>34  with significant obesity-related  co morbidities (severe OSA, Cardiomyopathy, severe diabetes, interfering with work), age 16 to 65 years, acceptable operative risks, documented failure at non surgical approaches at weight loss(atleast 6 mon of supervised weight reduction programs), motivated pt, absence of active psychosis and untreated severe depression, no substance abuse.


A recent analysis of cost effectiveness(CE) of bariatric surgery showed CE ratios of $7000 - $12,000/QALY in obese pts with diabetes. Medicare in US covers the cost for the surgery....and they infact dont need patients to specifically go for all non medical interventions..to qualify! But still Insurance coverage will be a limiting factor in our 40 ish age group. Bariatric surgery at age 40 prolongs survival by 5-6 years . 

Beer potomania......

 Recently we had a gentle man who presented to us with seizures nearly 10 hours after drinking in a pub.His sodium was 115. He is someone who drinks 2-3 beers a day.Binges on weekends. Night before admission he had atleast 10 beers (as per friends). He had a low serum osmolality, and a urine osmolalty of 152 mosm/L. His Na was initially corrected with 3% NS upto 120, and then by water restriction. This guy had beer protomania.

The mechanism - Beer has a lot of water with  very low sodium and protein.Someone on a beer diet will roughly get 200 msosm/day(1L of beer has roughly 30 gm of Sodium) compared to an american diet which has 750mosm/day. Still the serum osmolaltiy is maintained.This is because ....with ingestion of so much water(in the form of beer), ADH secretion is at its lowest, and so the kidneys excrete a dilute urine.The kidneys can dilute the urine to a maximum of 50mosm/L. So for a guy who drinks 4L of beer and roughly takes 200 osmoles a day, can excrete the osmotic load in 4L of urine (50 mosm/L x 4 = 200 mosm). If he drinks a 5th litre of beer, then he would develop hyponatremia.

The Urine flow depends on the the number of osmoles excreted. So to call it beer potomania...you should have some one who has binged on a lot of beer(water) without eating anything(especially with salt). A low serum osmolality/ low urine osmolality with the above history will clinch this diagnosis. In many of these alcoholics..the situation may be complicated by the need for  5% dextrose following Vit B1 to prevent Wernicke's encephalopathy. Close monitoring and replacement is needed in those situations.

The new ACLS guidelines 2010

The concept of chest compressions and rescue breathing was first introduced exactly 50 years ago. The first CPR guidelines was developed in 1966.They had the A-B-C-D approach. A precise time frame for doing things was not there(as we ve now).But they did incorporate checking the pulse periodically and listening to breath sounds. They did not ve the 5Hs & 5Ts .The current guidelines have been altered to some extent from the previous one on 2005.Some of the salient features of the latest guidelines...
1.The A-B-C approach has been changed to C-A-B approach.( applies mostly to lone rescuer CPR...as these are done simultaneously in the hospital setting). NEJM 2010
2. More emphasis on ..not to take >10 sec checking for pulse...as compressions in someone with a pulse does not do much harm..as not doing it in some one without a pulse.(Circulation 2010). The chest compressions should be atleast 2 inches in depth.
3.Class I recommendation for adults: use of quantitative waveform capnography for confirmation andmonitoring of endotracheal tube placement.


4.Atropine is no longer recommended for routine use in the management (PEA)/asystole. Adenosine can now be considered for the diagnosis and treatment of stable undifferentiated wide-complex tachycardia when the rhythm is regular and the QRS waveform is monomorphic.


5.De emphasis on intravenous medications during CPR. Have a look at this study from JAMA 2009, which did not show a significant improvement in short or long term survival for pts with Vs without intravenous medications during CPR. iv medications did significantly improve the chances of  spontaneous circulation though.Surprisingly....epidemiological studies have shown that epinephrine is an independent predictor of poor outcome from CPR (? due to interruption with compressions!!)

6.Emphasis on therapeutic hypothermia after cardiac arrest. This has proved to benefit neurological recovery both in- & out-patient setting with both Vfib & non-Vfib rythms. Interestingly.....American Academy of Neurology in 2006, proposed predictors of poor prognosis after a cardiac arrest. These predictors....have to be carefully interpreted and may not apply these days..with the use of therapeutic hypothermia ( EEG with activity.. may help with prognostication in this setting- Ann Neuro 2010). Check these parameters 72 hours after the cardiac arrest.Have a look at this...pdf  for comparison between 2005 & 2010 guidelines.

Success!!! got my patient's LDL to 50mg/dl

First question.......What's the benefit of doing the above? We all know that lower the cholesterol..lower the cardiovascular risk. Latest evidence supports lowering it to < 70 mg/dl for the high risk patients. Well...is there a downside to overdoing this? Yes there is... at least theoretically ..for now.
The normal LDL level is 40 - 70 mg/dl. Cholesterol (mainly LDL particles) play a major role..and are the corner stone for synthesis of many steroid hormones including cortisol, tetosterone, androstenidione, Vitamin D etc. So by looking at this...obviously driving LDL to a much lower level can affect these important physiological processes.
There were a few studies done to see if reduction in LDL with statins affect endogenous steroidogenesis. In a cross sectional study of 350 type 2 diabetic patients on a statin (Diabetes care 2009) showed a significant reduction in total testosterone level with atorvastatin compared with no treatment. But the free bio available testosterone levels were normal. A pharmacology study from Holland shows the same above possibility with Statins.(British J of Clin Pharmacology )

A subgroup analysis of reproductive age group women from WISE trial showed no significant decrease in levels of estrogen or progesterone in pts with LDL < 70 Vs pts with LDL >70. (AJM 2002).
An earlier study from 1994 showed no decrease in levels of adrenal and gonadal steroids in patients with a low LDL on a statin. Most of the above studies...didnt drive down the LDL levels to < 70mg/dl.
A recent study published in 2009 comparing gonadal hormones in pts with LDL <70 with LDL <100...in pts on a statin..showed no significant difference in the sex hormone levels..over a period of 12 weeks. This may be a short duration to assess a reasonable outcome.

On the whole...driving the LDL levels to < 70 may have little or no negative effect on sex &/or adrenal hormone levels. But this possibility can be considered if a pt..with a LDL of <70 complains of decreasing libido.(these pts may also be on Spironolactone..which can make this worse).
Statins have shown some benefit in treating prostate cancer( again..may be due to their effect on lowering levels of testosterone!). Another theoretical concern with excessive lowering of cholesterol will be the possibility of a lack of adrenergic response needed during stress (especially in sepsis, ICU admissions etc) due to low cortisol production. Whether this is true remains to be answered !!

Fasting for 72 hours ..for the diagnosis?

Well..I recently admitted a patient for exactly  the same....72 hour fasting test.

A 43 yo male with 4 year history of many ER and walk in clinic visits with symptoms of sweating ..feeling of hunger and many episodes of syncope where he suddenly looses consciousness.Twice this happened while driving ..but he was also drunk at that time(so was arrested.....happened twice in jail!). Regains consciousness in minutes. Eating something just before the episode prevents it. Twice there was documented glucose levels of 45 & 50 during these episodes. His fasting glucose in clinic was 78 with a Insulin level of 78(high), and a C peptide level of 2.3 (normal).He also has a 5 year h/o abdominal pain.
The differential in this guy is 1.Insulinoma 2.Factitious hyperinsulinemia 3.Autoimmune hyperinsulinemia 4. Nesidioblastosis (islet cell hypertrophy)

The test entails admitting patient after a overnight fast ..to the hospital. Get baseline glucose, Insulin level, proinsulin level, and C peptide. Keep the pt NPO( nil per oral) with a maintenance iv fluid without glucose...or can be allowed to drink water. Monitor glucose every 4-6 hours. We are looking for hypoglycemia (glucose <45 mg/dl) or hypoglycemic symptoms. Do the same blood tests  at that point and stop the test.(for this...start checking glucose every hour once it reaches 60 mg/dl). If the above two criteria are not met...continue test until 72 hours. The idea ..is pts with Insulinoma will become hypoglycemic, and their C peptide, Insulin and proinsulin levels will be high when he has hypoglycemia. This is explained in this article from 2007. 72 hour fasting seems like..cruel..So researchers looked at options with lesser duration..and they have shown that a 48 hour fast would be enough to identify almost all patients with endogenous hyperinsulinemia(Clin Endo & Met 2000). Our patient has been on the fast for 20 hors now...without any hypoglycmeia or symptoms...

A quick look at evaluation of hypoglycemia(in absence of anti diabetic meds):
1. Whipples triad has to be satisfied( hypoglycemia, neuroglycopaenic symptoms, and prompt relief of symptoms with the administration of glucose).
 2.Then do a 72 hr formal fasting. A positive test is a glucose <50, Insulin > 3microIU/ml & C peptide >200 pmol/L. This confirms endogenous hyperinsulinemia. ( also get a drug screen for sulphonylureas...as they can mimic the same).
3. Once confirmed..then start the localisation process--- CT angiography, trans esophageal US can help. Or an experienced surgeon can go in..and find the insulinoma. If not possible...a Selective arterial calcium stimulation with hepatic venous sampling(SACST) ..where a catheter thru femoral vein lies in hepatic vein..and a 2nd catheter thru femoral artery goes into splenic/mesentric/gastroduodenal aa. and infuse Ca.This stimulates release of Insulin as picked up by the catheter in hepatic vein. ...this has a sensitivity of> 90%

Another complication of Obesity

NASH is a diagnosis showing up more and more in primary practices these days.  The main reason is the epidemic of OBESITY. NASH is on the upper end of a spectrum of disorders called Non Alcoholic Fatty Liver Disease (NAFLD). Other end of the spectrum is the relatively benign Hepatic steatosis.
NASH comprises heaptic steatosis associated with necrosis and inflammation. The main pathophysiology behind NASH is 1. Insulin resistance leading to.... 2.Hyperinsulinemia and 3. increased free fatty acids. Also implicated are oxidative injury due to induction of CYP450 in these pts. An evidence to show insulin resistance as a cause is a study comparing incidence of NASH in Type1 Vs type2 diabetics....showing a significantly higher incidence in the latter.Due to above pathophysiology..it is common to find NASH in patients with metabolic syndrome.   

Usually patients with NAFLD do not have specific symptoms from the disease. They might complain of malaise, lethargy, nausea etc. Its rare to have right upper quadrant pain or jaundice. What they will have is a slightly elevated AST /ALT (< 4 x normal..and ALT > AST). So we are not going to jump to this diagnosis straight away in this scenario. The first and important thing to exclude is the presence of alcoholic liver disease. (History..history..history!!). then we round the usual suspects(viral hepatitis, toxins, drugs etc). But its reasonable to suspect NAFLD in pts..with above characteristics without alcohol exposure...in the first place

.The risk factors are the same as for met syndrome- Obesity(prevalant in 75% of pts with body wt >10% of ideal!), Diabetes type 2, hypertriglyceridemia, equally present in males Vs females ( but likelihood of fibrosis is increased in females). Because of this association....pts with NAFLD have an increased cardiovasscular risk...have a look at this EASL statement 2008 & a latest abstract from a study on adolescents with obesity(Am J of Epi 2010)Imaging can show fatty liver.Liver biopsy is the only tool that can differentiate a benign steatosis to NASH. 8-20% of obese individuals with hepatic steatosis will have NASH..........and risk of development of fibrosis and cirrhosis from NASH is 10-50%. NASH leading to cirrhosis is the cause for 1% of liver transplantations.

Management is going to be the same as for metabolic syndrome----loosing weight, improving insulin sensitivity( Metformin & Pioglitazone are modestly effective in reducing the fat in the liver..and improving the histology in diabetic pts...and less so in non diabetic pts).Urodeoxycholic acid which was previously used as treatment...is no longer recommended..due to lack of efficacy as shown in this randomised trial ( Hepatology 2004)The latest trial published in NEJM May 2010, was on Vitamin E . Vit E @ 800 IU /day showed a significant improvement in NASH histology(mainly in no diabetics), improvement in liver enzymes..without any benefit on development of fibrosis. It will be reasonable to have these pts on Vit E (but remember that Vit E @ high doses have shown to increase mortality!).....All these measures are aimed at improving inflammation in the liver....but whether these will result in a mortality benefit..remains to be known.

A Nobel reward after 32 years!

Prof Brown in 1998

The Nobel Prize in Medicine for 2010 was announced this week. And it goes to Professor Robert Edwards of Britain for his research on Invitro fertilisation...which resulted in the first test tube baby in the history of the world. His achievement has helped bring 4 million infants into the world and raised challenging new questions about human reproduction.
Robert Edward Brown(born in 1925) was a reproductive Biologist at Cambridge University . With the help of surgeon Patrick Steptoe (died in 1988)..he pioneered conception through IVF...and the first test tube baby , Louise Brown was born on 25th July 1978. She is now aged 32 living well and gave birth to a son 3 years ago..which was a natural conception. She lives in Bristol, UK. 
The delay of 32 years in presenting this Nobel Prize....was because of the initial concern about the health of these babies. Now it has been proved beyond doubt that it is safe for the babies born. But still I think...the Nobel Prize comittee took a looooong time for this. Luckily Prof Brown is alive but  to receive this award which comes with $1.5 million. He also features as one of the TOP 100 LIVING GENIUSES published by Newyork Times (This list also has Nelson Mandela, Gary Kasparov, Steven Spielberg,Bill Gates, Steven Hawking & Mikhail Klasnikov). 


There are still many ethical issues unresolved...relating to IVF.Some of the interesting ones..
1. With IVF..a child can have upto 5 parents - the sperm donor, the egg donor, a surrogate mother who brings the child to term in her womb, and the couple intending to raise the child.In some countries..the legal mother is one who gives birth. Well this is definitely a confusion!
2.IVF clinics routinely fertilize more eggs than are implanted, at least at first. The resulting extra embryos can be frozen for storage. The parents decide about what to do with them. They might be destroyed ....for finding genetic defects, donating to someone else.
3. The child's right to access to information about his or her genetic background or mode of conception.


Whatever these ethical considerations/confusions are...Prof Brown (& Dr. Steptoe) both deserve the Nobel Prize. Prof Brown is currently admitted in his hospital in Cambridge for long term illness..but expected to be present at the ceremony. The Nobel Prize for other departments..are yet to be announced.

My chances with Polycystic Ovarian Syndrome ?

Today was endocrine clinic day...and I saw a 22 yo black female with secondary amenorrhea of 3 years duration.sought medical attention 3 weeks ago.....found to have diabetes....started on Metformin...and referred to us. She was obese & had some facial hair. Her labs are Hb- 12.8, MCV- 76, LFT- normal, Na,K, BUN, Creatinine - normal. Her TSH- Normal, LH- 6.1 mIU/ml, FSH -4.6mIU/ml, testosterone lvl- 49ng.dl (high normal is 40), DHEAS, androstenidione, 17OH progesterone - Normal. US - no ovarian cysts. She had a progesterone challenge...following which she had bleeding. She has anovulatory PCOS.
Her main concern was about her chances of getting pregnant?


Lets first look at the criteria for diagnosing PCOS. The latest criteria is from 2003..called Rotterdam Criteria ...and calls for presence of 2 of following 3 ...... a)Oligo‐ and/or anovulation b)Clinical and/or biochemical signs of hyperandrogenism c) Polycystic ovaries ...and exclusion of other causes. Our pt had 2 of the above(a & b).


There has been a good amount of evidence linking ovarian problems in PCOS to hyperinsulinemia and Insulin resistance. Insulin affects stromal proliferation etc.Have a look at this review. This forms the basis of treating these pts with Metformin......also there is more regularisation of menstrual cycle with Metformin(NEJM 2008). Other main treatment options for anovulation are Clomiphene(frequently used as first line) and lastly GnRH or lap surgery for cysts. A combination of these drugs (meformin & clomiphene) does not offer an added benefit for inducing ovulation ( Clin Endocrine 2009 & Cochrane 2009)


What are the chances of this lady getting pregnant? Well...few facts..... 
6- 10 % of fertile women satisfy criteria for PCOS. 
PCOS is the underlying cause in 70% of pts with anovulatory infertility.
In patients with anovulatory PCOS..the infertility rate is high and varies widely. Its difficult to find the exact prevalance of infertility among patients with PCOS. But ..look at this long term study (10-20 years)showing a spontaneous fertility rate of 87% in PCOS(mostly with oligomenorrhea) compared to 91% in normal controls. Also.. treatment with Clomiphene has shown pregnancy rates of 70%   just after 4 ovulatory cycles (Hum Reproduction). 
So our patient has a very good chance of getting pregnant with treatment. For now she is going to be on Metformin ( she needs to be..due to diabetes) hoping it might help with ovulation as well. If not..she will be started on Clomiphene for ovulation induction. Then we have IVF which also has good success rates.

Nutrition in ICU - a lot of calculation...can be made simple

Nutrition in ICU is an important aspect of Critical management of patients..as they are all in a catabolic state due to the high levels of circulating Catecholamines, cytokines and lymphokines. It has been emphasized that nutrition (either parenteral or enteral ) be started  as early as possible..within 24 hours of ICU admission.

Which route --Enteral Vs Parenteral - This is not a big issue...as enteral is easier and less expensive & less complicated to start......and there is some evidence that using the gut might prevent bacterial translocation. Also splanchnic circulation increases with enteral feeding..preventing mucosal breakdown. Use parenteral if contraindication to enteral feeds. e.g - GI bleed, Pancreatitis etc
What food -- In US...many types of enteral feeds are in use depending on the clinical scenario.These are pre-prepared. They can be classified according to the calorie concntration..or based on special additives. Some e.g are Osmolite- 1Kcal/ml, Jevity- 1.2Kcal/ml, Twocal-2Kcal/ml. Useful in case fluid restriction is needed!. Secondly.... use Glucerna - Diabetes, Nepro for renal disease, Oxepa for ARDS etc (we will discuss these at a later date). 
How much -- Always start low @ 20ml/hr...and increase every 4-6 hours by 20ml..upto the goal. Sooooo what is the goal?? Well here is a rough calculation.... First calculate the calories needed
Basal Energy Expenditure : 66.5+(13.8 x wt in kg) + (5 x ht in cm) - (6.8 x age in yrs)     .........for men
                                                65.5 +( 9.6 x wt in kg) + (1.8 x ht in cm) - (4.7 x age in yrs) ..........for women


Rougly for a 60 yo male 6 ft tall and 80 kg....BEE will be around 1800 Kcal/day (or if the above formula is too complicated!.....simply use 25Kcal/kg/day)
The Total Energy Expenditure will be = BEE x 1.2 x stress factor ( I add 1.5- 2.0 for being in ICU- Sepsis) (Critical Care 2003)
For our gentleman above...it will be roughly 3200 kcal/day. 
Nitrogen Balance - This is how we assess response to nutirional response. Its simply... Nitrogen intake – Nitrogen losses. 
Nitrogen intake = Calculate as 1gm of Nitrogen for each 150 Kcal of feed ( eg. for 3200 Kcal /day,it is 21 gm nitrogen)
Nitrogen losses = Urinary Urea Nitrogen (g/day) + 4g ( this is for extra renal loss of Nitrogen - stools, sweat etc)
If net nitrogen balance is > 2gm...it can be called a positive nitrogen balance........if <2 gm negative NB.To do this calculation..we need the Urine urea Nitrogen (UUN....same as BUN...but in urine) - this is done on a 24 hr collection of urine( can be done easily in a ICU setting). Do it atleast 2 days after starting tube feeds. Do this once a week...and present the Nitrogen balance to your attending!!! ( you will look more smart!)

Honey..... STOP!! I have a headache

A case that was briefly discussed in our Neurology morning report...presented by Dr.Dadu .
A 30 yo female with h/o tension headache, presented to ER with 2 episodes of headache(different than her tension headache) during sex with her boyfriend(of long time).each time it lasted for 2 hours. not associated with nausea or vomitting. Physical exam did not reveal any abnormality. Should this lady be investigated ?
Lets see....
Headache associated with sexual activity-HSA (also..orgasmic headache, beningn sexual headache, coital headache) as termed by ICHD -II, has been described as bilateral and occipital lasting anywhere between 10min to 6 hours. More common in men than women (4:1). Comorbidity with other headaches(migraine, tension etc) is common. It can be further divided into
 Preorgasmic Headache - A) Dull ache in the head and neck associated with awareness of neck and/or jaw muscle contraction and B) Occurs during sexual activity and increases with sexual excitement
C) Not attributed to another disorder
Orgasmic Headache - A) Sudden severe (‘explosive’) headache B) Occurs at orgasm
C) Not attributed to another disorder

Orgasmic headache is considered to be mostly of vascular origin.In a study done with trans cranial doppler in pts with orgasmic headache showed impaired cerebral autoregulation leading to reversible vasoconstriction. (1976) . Indomethacin seems a good treatment option...with propranolol being a good prophylactic.

But what shall we do for our patient while she is in the emergency room. Have a look at this study from Spain where they looked at 6500 pts with headache. Of these 18 pts had HSA. All patients with HSA had CT head and followed by lumbar puncture if needed. This diagnosed 2 of the 18 patients with Sub arachnoid hemorrhage. Based on this ..and some other studies..the incidence of HSA is around 1%. Of the pts presenting with HSA, sub arachnoid hemorrhage(SAH) or a aneurysm may be an underlying diagnosis in upto 10%. The rest are all benign sexual headache.
Given the risk of high mortality & successful treatment with SAH........even if the prevalence is low..it will be reasonable to image them on first presentation with CT head ..followed by lumbar puncture if needed. So our lady had these investigations..and they were negative.She has benign HSA.