Cyanosis without hypoxia

Clinically evident cyanosis is often due to increased levels of reduced hemoglobin in the blood caused by cardiac or pulmonary diseases. Recently a 23 year old woman presented with cyanosis of the tongue and finger tips. She was not anemic or icteric. She did not have any cardiac or pulmonary disease. Her capillary oxygen saturation was 93 percent. When a few drops of her blood (dark brown in colour) were spilled on a white filter paper, no change in colour was noted after adequate exposure to the atmosphere.

This provoked a discussion on the causes of cyanosis without hypoxia.

We discussed methaemoglobinemia as a possible cause. Methaemoglobinemia is a condition where the hemoglobin molecule has a ferric iron instead of the normal ferrous iron. This condition can occur following exposure to drugs like nitrites, sulphonamides and some chemical dyes. When iron is in the ferric state, hemoglobin does not easily release its oxygen to tissues. Methaemoglobinemia can also be due to inherited disorders: deficiency of the enzyme within red cells that normally converts iron from a ferric state to a ferrous state - an enzyme called methaemoglobin reductase - can result in methaemoglobinemia. Another reason is the presence of an abnormal hemoglobin called Hemoglobin M.

Our patient however did not have methaemoglobin reductase deficiency. Her hemoglobin electrophoresis showed the presence of the hemoglobin variant called Hemoglobin M. And that explained why she had cyanosis without hypoxia.

The Mantoux tuberculin skin test - interesting facts

The Mantoux test or the Tuberculin Skin Test (TST) is one of those tests that most doctors will do when faced with a patient who is suspected of having tuberculosis. The test involves the intradermal injection of 0.1ml of a protein called tuberculin purified protein derivative. The test is interpreted as positive or negative according to the size of induration on the skin (not erythema), measured perpendicular to the long axis of injection, between 48 and 72 hours after the injection.

The TST is not a very sensitive test. In those who are not suffering from any kind of disease that compromises their immunity, the test has a sensitivity of about 95 percent. This means that this test may miss one out of every twenty previously healthy people who develop tuberculosis. The sensitivity of the TST drops to 80 percent when an immunocompromised person develops tuberculosis. This means that for people with HIV, the TST is not reliable in excluding tuberculosis because it can be negative in 1 in 5 people with HIV infection who develop tuberculosis.

The size of induration required for a positive TST depends on who is being tested. An induration of 5mm is adequate if the person is immunocompromised in any way through disease or from medication. Otherwise an induration of 10mm is required for the test to be regarded as positive.

We would regard a person as being newly infected with tuberculosis when the tuberculin skin test was negative earlier but is positive now. If such a person has no signs of active tuberculosis (after being investigated), the person will be labelled as having latent tuberculosis.

There are situations where a positive TST is not due to latent tuberculosis or to active tuberculosis. BCG vaccination in childhood can result in a positive test for 3 to 5 years after the vaccination. The test can also remain positive for many years after a person has been successfully treated for tuberculosis in the past.

There is a peculiar phenomenon known as the booster phenomenon where a person may develop a positive test simply because of a tuberculin skin test done earlier within the past one year. This phenomenon is because the TST boosts cell mediated immunity that had previously waned. It occurs in people who had tuberculosis earlier. The danger in not being aware of this phenomenon is that we may label such patients as having latent tuberculosis because of the recent conversion in the TST.

To overcome the problem of misinterpreting the TST in people (like health care workers) who may undergo annual tuberculin skin testing, we can do the two-step tuberculin skin test. The details of how this test is done is given in the reference below.

References:
1. The two-step tuberculin skin test
2. Tuberculin skin testing

The 2013 Nobel Prize in Physiology or Medicine

 Some genetic diseases are caused by defects in the transport of proteins within cells.  An understanding of the mechanisms involving transport of proteins via vesicles was the research work that led to the 2013 Nobel Prize in Medicine / Physiology. (Read about it).  

Genetic diseases can be caused by single gene abnormalities, chromosomal abnormalities or by a combination of genetic and environmental factors. Abnormalities in genes cause diseases in various ways:

1. Excess production of proteins. An example is the fragile X syndrome which shows itself as learning disability or mental retardation and autistic behaviour. This is caused by excess production of a protein that is used in synapses of the brain.

2. Insufficient production of proteins. An example is the group of diseases called glycogen storage disorders which can present with hypoglycaemia, hepatomegaly and/or muscle weakness.

3. Production of an abnormal protein. An example is phenylketonuria which is due to production of an inactive form of the enzyme that hydrolyses the amino acid phenylalanine. This leads to delayed milestones in childhood, seizures, learning disabilities and mental retardation as well as reduced or absent pigmentation of skin, hair and eyes. 

4. Defective transport of proteins. Genetic diseases involving abnormalities in protein transport can manifest in patients as hypopigmentation of skin, defects in cell mediated immunity and/or neurological defects. Bardet-Biedl syndrome where the affected person has mental retardation, retinopathy and is of small stature with poorly developed external genitalia, Charcot Marie Tooth disease and Spinocerebellar ataxias where those affected have ataxic gait along with other neurological abnormalities, Hereditary Spastic paraplegia which causes a pure motor paraplegia, are examples of neurological conditions where the genetic defect affects protein transport within cells. Alzheimer’s disease and Type 2 diabetes mellitus may also have defects in the transport of proteins. The transport of amyloid precursor protein by vesicles has been noted to be defective in the early stages of Alzheimer’s disease.  

Reference: Insights into vesicular transport in inherited diseases

Managing patients with shock

A beautiful review about circulatory shock in the NewEngland Journal of Medicine gives us practical advice for dealing with patients in shock. I summarise here three important learning points from that article. 

1. Diagnosing circulatory shock

Do not define shock only by the presence of arterial hypotension even though a blood pressure lower than 90mm Hg systolic and a mean blood pressure less than 70mm Hg are often present. This is because in those with chronic hypertension, the fall in blood pressure may not reflect the degree of shock. Also, the blood pressure alone may be misleading as it can be low in people who have chronic hypotension or have just suffered a transient episode of vasovagal syncope. The diagnosis of shock needs signs of poor perfusion to tissues and organs. The article tells us to consider the diagnosis of shock when there is tachycardia and signs of poor tissue perfusion as seen through three windows in the body:

                a. The skin: Cold and clammy

                b. The brain: Confusion, disorientation or other signs of altered mental status

                c. The kidney: A urine output of less than 0.5ml per kg per hour.

2. The VIP rule for resuscitation

This is the Ventilate, Infuse and Pump rule.  Ventilate (when needed) to ensure adequate oxygen intake. In this context we must remember that pulse oximetry is unreliable as a measure of adequate oxygen in the blood when there is peripheral vasoconstriction. So blood gases must be measured for this purpose. 

Fluids must always be infused in patients with shock since even those with cardiogenic shock can benefit from fluid resuscitation. However infusion of fluids must be carefully monitored. A fluid challenge refers to the infusion of 300 to 500ml of fluids (usually crystalloids) over a period of 20 to 30 minutes in order to see whether there is any improvement in one or more of the parameters of circulatory shock. The results of such a fluid challenge can then guide decisions for further infusion of fluids. 

Inotropic agents need to be used when the hypotension is severe or when the response to fluid resuscitation is slow or insufficient.

3. Using inotropic agents in circulatory shock

The authors consider norepinephrine to be the agent of first choice in those with shock whose cardiac output is not decreased. This will be seen in conditions like the early stages of septic shock (distributive shock). In the dose range of 0.5 to 2ug per kg per minute, norepinephrine elevates mean blood pressure without increasing the heart rate. Dobutamine is considered the agent of first choice in those with shock who need an increase in cardiac output. Both dobutamine and norepinephrine can be used together when needed. The authors do not recommend either dopamine or epinephrine as agents of first choice. Dopamine increases the risk of arrhythmias and increases mortality in the acute stage when given to patients with cardiogenic shock. Epinephrine increases the risk of arrhythmias and reduces splanchnic blood flow. These agents can be used as second line agents if necessary. Low dose vasopressin is an agent that can be added to norepinephrine for those with septic shock who have an adequate cardiac output.

Prolonging life and the futility of medical care

We see and interpret the world according to our individual beliefs and values. This difference in interpretation can be seen in the way doctors and lay people make decisions regarding how patients, who are seriously ill and without a chance of cure, have to be managed. When doctors have exhausted all that they have in their therapeutic armamentarium, they speak of poor prognosis and of futility in prolonging life with the use of technology. It sometimes comes as an unpleasant surprise to the doctors when close family members hear them but insist on continuing whatever life-sustaining measures are in place for their loved ones. Doctors tend to feel that such people are in denial of the reality that should be readily apparent to everyone.  In this NEJM article, the author gives us a reason why the loved ones of critically ill patients may differ in their views from doctors. The author tells us that doctors base their reasoning on outcomes for deciding what is important: can the patient be cured or not, is the question for them. For family members, what they do for their loved ones (the process of providing care) is what matters most.  The process of providing care to a loved one can be therapeutic in itself, irrespective of the outcome.  Doctors have outcome-based ethical reasoning on prolonging life while the loved ones of a patient may have process-based ethical reasoning. Doctors need to understand that this is the reason for family members often insisting on continuing futile medical interventions for their loved ones. Instead of labeling such requests as unreasonable and such people as being in denial of reality, doctors should give them time to feel that they have done all that they need to do before letting go of their loved ones.  

Angiotensin receptor blockers: the story continues................

Angiotensin receptors are protein molecules that mediate the effect of the hormone angiotensin 2. These receptors are found in various parts of the body. The existence of angiotensin in the body was recognised by the work of people like Tigerstedt, Bergman and Goldblatt who, in different experiments in the late nineteenth and early twentieth centuries, showed the presence of a vasoconstrictor substance released by the kidneys¹. This substance was named renin and it was soon determined that renin led to the formation of angiotensin 1 and that angiotensin 1 had to be changed to angiotensin 2 in order to be effective. The conversion of angiotensin 1 to angiotensin 2 is facilitated by the enzyme called angiotensin – converting enzyme. Angiotensin 2 exerts its effects on blood vessels and other tissues through receptors called angiotensin receptors. These receptors are also of two types: angiotensin receptor 1 (AT1) and angiotensin receptor 2(AT2). The vasoconstrictor effect of angiotensin 2 is mediated through the AT1 receptor and the angiotensin receptor blockers used clinically are all AT1 receptor blockers.

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) are both used in medicine for patients with hypertension, cardiac failure, ischemic heart disease and proteinuric-renal disease. Angiotensin receptor blockers score over angiotensin converting enzyme inhibitors in a few ways: they provide a more comprehensive blockade of the renin angiotensin system and they do not affect the serum levels of bradykinin. Hence the effect of angiotensin receptor blockers is more consistent with dose, and bradykinin-related side effects – like cough and angioedema – are not seen².

Angiotensin Receptor Blockers have been shown to protect against myocardial infarctions and strokes in patients who are at high risk for these vascular events. A study reported in 2008 showed the benefit of these drugs in preventing cardiovascular events in patients undergoing long-term hemodialysis ³. A meta-analysis had also shown that ARB can prevent the development of atrial fibrillation in patients with heart failure⁴ and another meta-analysis had shown that these drugs could prevent new onset diabetes in patients who are predisposed to developing diabetes⁵. Hence angiotensin receptor blockers not only reduce blood pressure but also favourably influence cardiovascular risk factors.

There may however be differences in clinical benefit between various angiotensin receptor blockers. A study comparing Losartan, Irbesartan, Valsartan, Candesartan and Telmisartan in patients with heart failure found that Losartan showed poorer survival rates in elderly people with heart failure compared to the other drugs⁶.

Alzheimer’s disease is a common cause of dementia. A pathological finding in this disease is amyloid deposition in the brain.  There is very new evidence, based on autopsies, that those who take angiotensin receptor blockers for hypertension have less amyloid deposition in their brains than those who are on other kinds of antihypertensive drugs⁷ and this actually confirms some earlier anecdotal reports that treatment with angiotensin receptor blockers reduces the likelihood of developing Alzheimer’s disease.  It appears that angiotensin receptor blockers are able to reduce amyloid deposition in the brain by reducing inflammation within the brain.

In conclusion, we have learnt a great deal about the clinical benefits of blocking the renin-angiotensin-aldosterone system (RAAS) in the last decade. Since the ARB class of drugs are more expensive than the ACEI class of drugs, doctors are encouraged to use angiotensin-converting enzyme inhibitors wherever RAAS inhibition is needed and to use angiotensin receptor blockers only when patients are intolerant to ACEI. However, if the recent evidence of the possible benefit of angiotensin receptor blockers in preventing dementia can be verified through other studies, then the drugs in this class will have a distinct edge over their first cousins – the ACE inhibitors.

References:

1. Discovery and development of angiotensin receptor blockers, Wikipedia: http://en.wikipedia.org/wiki/Discovery_and_development_of_angiotensin_receptor_blockers

2. Amy Barreras, et al.Angiotensin 2 receptor blockers. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200815/

3. Effect of angiotensin receptor blockers in patients undergoing hemodialysis http://www.ajkd.org/article/S0272-6386(08)00955-4/abstract

4. Prevention of atrial fibrillation with angiotensin converting enzyme inhibitors and angiotensin receptor blockers http://content.onlinejacc.org/article.aspx?articleid=1136655

5. Angiotensin converting enzyme inhibitors or angiotensin receptor blockers for prevention of Type 2 diabetes http://content.onlinejacc.org/article.aspx?articleid=1136856

6. Angiotensin 2 receptors for the treatment of heart failure http://www.ncbi.nlm.nih.gov/pubmed/17381379

7. Ihab Hajjar, et al. Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol 2012; Published online Sept 2012. http://archneur.jamanetwork.com/article.aspx?articleid=1356776#METHODS

Flushing out excess glucose from the blood

There are many kinds of oral drugs used for reducing high blood sugar in diabetes. Drugs like metformin, the sulphonylureas, the glinides, the dipeptidyl peptidase 4 inhibitors and the thiazolidinediones promote entry of glucose into body cells by different mechanisms - by reducing insulin resistance (metformin, thiazolidinediones), by increasing secretion of endogenous insulin (sulphonylureas, glinides) and by increasing levels of glucagon-like peptide 1(DPP4 inhibitors). Now we have a new class of oral drugs that reduces blood sugar by flushing out the excess glucose in the urine. By reducing reabsorption of glucose from the proximal tubules of the kidney, these drugs (called the sodium glucose co-transporter 2 inhibitors) lower blood sugar by allowing more glucose to be excreted in the urine. In effect, it reduces the renal threshold for glucose excretion. An advantage of this method is that by flushing out the excess glucose, instead of storing it inside cells, patients will lose weight. The disadvantage is that osmotic diuresis (by the glucose in the urine) can cause intravascular volume depletion and postural hypotension. Excess glucose in the perineal region can also predispose to candida infection in women. Whether this class of drugs will improve the morbidity and mortality associated with diabetes and whether it will be safe for all diabetics will be seen in the next few years.

Ref.: Canagliflozin, a new drug for diabetes

Good in one situation but not in another

In September 2009, the New England Journal of Medicine informed its readers that the RE-LY study showed evidence of the thrombin inhibitor Dabigatran being as effective as, if not better than, Warfarin for the prevention of thromboembolic events in patients with atrial fibrillation. Those patients with atrial fibrillation who took Dabigatran in a dose of 110 mg twice daily had the same rates of stroke as those who took Warfarin but had significantly lower rates of major hemorrhage. Those patients who took Dabigatran in a higher dose of 150 mg twice daily had the same rates of major hemorrhage as Warfarin but with lower rates of stroke. So, either way, we see a benefit of Dabigatran over Warfarin.

Can we conclude that Dabigatran is at least as good as Warfarin in preventing undesired thrombosis and thromboembolic phenomena in the body?

The RE-ALIGN study published in the New England Journal of Medicine in September 2013 tells us that we cannot make that generalisation. It appears that a drug that is good in one situation is not necessarily good in all situations. In this RE-ALIGN study, the investigators report that Dabigatran was not as effective as Warfarin in preventing thromboembolic complications in patients who had mechanical heart valves. Furthermore, it was associated with an increased risk of bleeding. The message they send us is: use Warfarin, not Dabigatran, for preventing thromboembolism in patients with mechanical heart valves.

What is the reason for this paradox? The authors of the RE-ALIGN study tell us that this could be because the mechanisms involved in the clotting of blood are different in atrial fibrillation and in mechanical heart valves. Stasis of blood in the atria is the cause of thrombosis in atrial fibrillation while contact of blood with the mechanical valve and the release of tissue factor after surgery are the mechanisms of thrombosis in those with mechanical heart valves. These differences make Dabigatran good in one situation but not in the other. This reminds me of something else which is good in one situation but not not in another: the combination of aspirin and clopidogrel is good in acute coronary syndromes but not in chronic stable angina.

Chronic stable angina and the ST segment deviation vector in ECG

Coronary artery disease, as all physicians know, presents in different ways in different people. We have anecdotes of people who die suddenly without ever being aware that their coronary arteries were blocked. On the other end of this coronary artery disease spectrum we have the condition called chronic stable angina where patients experience chest pain only on exertion. And in between these two extremes lie the various categories of acute coronary syndrome. Intuitively we might believe that the milder manifestation of chronic stable angina represents the benign end of the spectrum where the coronary arteries are only minimally involved. This is not always true because we have learnt that even in patients with chronic stable angina there can be extensive coronary involvement.

What matters in coronary artery disease are the answers to three questions: Which artery is blocked? Is that artery blocked proximally or distally? What is the degree to which it is blocked? And of the two coronary arteries and their branches, high grade blocks in the left main coronary artery and in the proximal portion of the left anterior descending artery are the most dangerous. So when faced with patients who have chronic stable angina, one of the important things I want to know is whether they have involvement of the left main coronary artery or the proximal portion of the left anterior descending artery. Determining the ST segment deviation vector from the ECG is an attempt to answer this question without a coronary angiogram.

The ST segment deviation vector is determined in much the same way as the cardiac axis is determined from the QRS complexes. We use the limb leads and look at the ST segments in them. Wherever ST segments are depressed, the vector is moving away from those leads and wherever ST segments are elevated, the vector is moving towards those leads. And the vector is perpendicular to any lead whose ST segment is neither elevated nor depressed. With these basic electrophysiological principles, we can proceed to determine the ST segment deviation vector, if any, in patients with chest pain. A general rule is that when the ST segment deviation vector is in the quadrant between minus 90 degrees and minus 180 degrees (the "aVR quadrant"), there is a high probability of significant stenosis in either the left main or the proximal left anterior descending coronary arteries.

I use this information as a guide in deciding which patients with chronic stable angina should be referred for a coronary angiogram after an exercise stress test.

For an understanding of how ST segment deviations will look like in patient with significant blocks in the left main coronary and proximal left anterior descending coronary arteries, please see:
Proximal left anterior descending artery block
Left main coronary artery block

A patient with blepharospasm

The patient, a man in his early sixties, had been diagnosed as suffering from diabetes, hypertension and chronic renal failure. The notes in the patient's case record had however failed to record something that was very obvious. He had bilateral blepharospasm and used his hand to keep his eyes open when talking to me. He told me that he had seen a couple of doctors in various parts of the country for this disorder but nothing had helped. I listened sympathetically and, after the usual review of his various medical problems, prescribed him treatment for diabetes, hypertension and renal failure.

Later, I read an article on benign essential blepharospasm.

I realised that this condition, which was initially considered a psychiatric disorder, is now regarded as a form of focal dystonia affecting the orbicularis oculi and other muscles around the eyeball. No one knows where exactly the lesion is but it is generally regarded as a disorder of neural circuits that regulate blinking. The sensory component of this circuit is triggered by a variety of stimuli ranging from light, sensory stimuli from the trigeminal nerve, and strong emotions. The motor component is mediated by the facial nerve. Blepharospasm disappears when the patient is asleep and when deeply relaxed. Hence, there have been treatments designed to promote such relaxation using pharmacological and non-pharmacological methods. The results have been variable and no one method has been shown to be consistently better. Currently, the most effective treatment for benign essential blepharospasm is injection of Botox into the muscles around the eye. Botox is Botulinum A toxin. It inhibits the release of acetylcholine from presynaptic nerve terminals. The effect Botox injections can last from one to five months.

Ref: Medscape article

Nitrites in the urine of people without any urinary symptoms

Recently I tested the urine of  a male patient who had fever for 4 days with no localising symptoms and signs. The urine showed a trace of protein, some leukocytes and red blood cells (less than 10 cells per high power field). The urine nitrite test was positive. I wondered if this patient really had urinary infection because, if not for the positive urinary nitrite, I might have considered the urine protein and cellular abnormalities as being the result of the fever and not the cause of the fever. This led me to read an article in the American Family Physician which gave me some information as to why the urinary nitrite test may be falsely positive. I have quoted the relevant extract below:

Nitrites normally are not found in urine but result when bacteria reduce urinary nitrates to nitrites. Many gram-negative and some gram-positive organisms are capable of this conversion, and a positive dipstick nitrite test indicates that these organisms are present in significant numbers (i.e., more than 10,000 per mL). This test is specific but not highly sensitive. Thus, a positive result is helpful, but a negative result does not rule out UTI.⁶ The nitrite dipstick reagent is sensitive to air exposure, so containers should be closed immediately after removing a strip. After one week of exposure, one third of strips give false-positive results, and after two weeks, three fourths give false-positive results.³⁶ 

Diseases and "casual parentheses"

Wilfred Trotter, an English surgeon, once said: "Disease often tells its secrets in casual parentheses." This implies that we need to observe and listen carefully, often over a period of time, without prematurely concluding that we know what the problem is, if we are keen to make a correct diagnosis. In the Malaysian Family Physician there is a report of a young patient who presented with mild arthritis of the ankle joints after a short febrile illness.
I asked myself what I would have diagnosed at that point. I think I would have considered it to be part of a viral syndrome but would look carefully for evidence of septic arthritis.
A few days later this patient developed erythema nodosum - a localised painful inflammation of the subcutaneous tissue. Since erythema nodosum is the result of an immune response, I would at this stage have considered the possibility of a reactive arthritis and looked for infections in the urinary tract, gastrointestinal tract and also for streptococcal infections in the throat.
This case report in the Malaysian Family Physician has made me realise that the disease the patient really has is not what I am thinking about. The correct diagnosis revealed itself to the doctors only after yet more time. This appears to validate what Wilfred Trotter said.

Read the case report in the Malaysian Family Physician

Thrombolytic therapy in a patient with thrombocytopenia

A middle aged man was admitted to the hospital with dengue fever. He had a low platelet count of 60,000/cu.mm on admission. In the ward he developed chest pain and an acute anterior wall ST elevation myocardial infarction. The specialist in charge of the patient decided to administer Streptokinase believing that salvaging the ischemic myocardium outweighed the risk of bleeding. The patient had no bleeding complications from the Streptokinase even though his platelet count continued to fall to a level of 20000/cu.mm over the next few days.

This made me wonder if it was safe to administer thrombolytic therapy to people with pre-existing thrombocytopenia.

The evidence I found in the literature says that, if patients have no bleeding manifestations, it is relatively safe to administer thrombolytic therapy. Heparin, because of its potential to reduce platelet counts, may be more dangerous than Streptokinase. Even though this patient that I described above did not suffer any bleeding complications from thrombolysis, my intuitive feeling is that it is prudent to transfuse platelets if the platelet count is very low when thrombolytic therapy is contemplated.

Reference: An editorial in Clinical Cardiology

Reflections on an elderly man with breathlessness

When a 68 year old man, a smoker, presents with breathlessness and rhonchi in the lungs, with an x-ray chest showing emphysema (increased air trapping), the most obvious clinical diagnosis is COPD. 

Since bronchial asthma is also a disease with rhonchi in the lungs, one may be asked whether this patient has bronchial asthma. As a rule of thumb, one can say that COPD is more likely in older individuals with wheezing while bronchial asthma is more likely in younger people. Having said this, we must not forget that late onset bronchial asthma is possible and COPD can occur in younger individuals with, say, alpha one antitrypsin deficiency. So age is not an absolute differentiating criteria. 

What are the more reliable differentiating points between COPD and bronchial asthma? In the history, an episodic nature of breathlessness or a diurnal variation in breathlessness, with completely asymptomatic periods in between, are strong points in favour of bronchial asthma. Based on spirometry, one can say that if the FEV1: FVC ratio remains below 0.7 after adequate bronchodilator therapy, the diagnosis is COPD. It is important to know that the reversibility of the bronchial tree should be used diagnostically only in the stable phase, not during a time when the patient is having an acute exacerbation.

Rhonchi in the lungs indicate bronchial narrowing. The typical physical sign of obstructive lung disease is rhonchi on auscultation but the absence of rhonchi does not rule out an obstructive lung disease. 

The clinical context in which one detects rhonchi is very important. In elderly people and in those with cardiovascular risk factors, the possibility of heart failure must always be considered as a differential diagnosis when they have rhonchi and crepitations in the lungs. When in doubt, treat with diuretics and bronchodilators until the diagnosis is clear. Based on the proverb "All that glitters is not gold" we have the clinical saying: All that wheezes is not asthma. This implies that wheezing need not always be due to bronchospasm but can also be due to extrinsic compression by edema or a mass.

The PEFR is a useful tool for managing patients with obstructive lung diseases because it gives us an objective parameter to measure the degree of bronchospasm. In this context, I wish to emphasise that even in COPD there is always an element of bronchospasm. The PEFR has both diagnostic and therapeutic implications. With the PEFR we can diagnose asthma and differentiate between asthma and COPD based on the degree of reversibility in readings. With the PEFR, we can also titrate medication in bronchial asthma. We know, for example, that we must prescribe oral steroids to a patient with bronchial asthma whose PEFR remains persistently below 50 percent of expected.

Crepitations in the lungs can indicate a number of possibilities according to the clinical situation. Consolidation of the lung, bronchiectasis, interstitial lung disease and left heart failure are some of the conditions that must come to mind when crepitations are detected in the lungs.

A low PaO2 alone or in combination with a high PaCO2 signify respiratory failure in a patient with COPD. What does a normal PaCO2 in a patient with acute exacerbation of asthma or COPD indicate? It indicates that there is insufficient alveolar ventilation and is a red flag. This is the rule of thumb: In all people who are hyperventilating, the PaCO2 must be low. If it is not low, it means there is insufficient alveolar ventilation. A danger sign.

Hyperinflation of the lungs is generally said to be present when we see that the domes of the diaphragm are flat and the right dome of the diagphram is below the anterior end of the 6th rib. In lungs with hyperinflation, the cardiac show will appear smaller than usual. If it appears normal or enlarged, cor pulmonale or some other form of heart disease must be suspected. 

In patients with COPD, pay particular attention to the pulmonary arteries. The main pulmonary artery is the convexity below the aortic knuckle on the left heart border. It is normally smaller than the aortic knuckle. When the main pulmonary artery is as big as or bigger than the aortic knuckle, one can suspect that it is enlarged because of pulmonary hypertension. Remember: Perihilar shadows in COPD can be due to enlarged pulmonary vessels.

An opacity in the lungs on chest x-ray only means that the air in the alveoli has been replaced by something else. Opacities in the lungs occur in consolidation (inflammatory fluid), pulmonary edema (non-inflammatory fluid), fibrosis and collapse as well as mass lesions. You will need to evaluate the nature of an opacity by looking for associated signs in the x-ray and by knowing the clinical features of the patient. Some opacities have characteristic associations - like consolidation in the upper lobes of the lungs strongly suggest tuberculosis infection. But these are not absolute and therefore not diagnostic. Upper lobe opacities for example can be due to silicosis, malignancies, granulomatous diseases, and Klebsiella pneumonia.

The perspective gap

In the book 'Give and Take' by Adam Grant, psychologist and professor at Wharton Business School, there is a term called the perspective gap. This refers to our inability to fully appreciate another person's distress when we ourselves are not experiencing a similar kind of distress. The perspective gap explains why physicians often underestimate the severity of the pain that their patients report. In this context, the author of the book gives an account of an incident that occurred in a San Francisco hospital where a respected oncologist wanted a spinal tap done for a patient with advanced metastatic cancer because he wanted to determine if the reason for that patient's deteriorating level of consciousness was meningitis.

The neurologist, who was requested to do the spinal tap, however had his doubts about the need for such a procedure because, not only would the procedure be painful for the patient, he believed it would not result in any significant clinical improvement. The patient and his relatives too did not want the procedure. However, after repeated explanations and much persuasion by the oncologist, the patient and family members agreed to the procedure believing that the oncologist could not be wrong. The neurologist finally did the spinal tap. Soon after that, the patient developed a pounding headache, slipped into a coma and died three days later from the cancer.

The neurologist goes on to say that this incident showed him how the oncologist uncritically accepted the notion that he was doing good. This is the perspective gap that we, as doctors, must always be aware of. The only way to avoid it is to always look at the advice we give to our patients from the point of view of the patients themselves. We should remember the perspective gap when we advice our patients about diabetic diets and also when our prescriptions contain too many medications.

Treating acute ischemic strokes with antidepressants

Depression is common after strokes. This is something that we can all relate to intuitively because a catastrophic event like a stroke is bound to affect one's emotions. A study published in the Medical Journal of Malaysia (April 2, 2013) reinforces this point and made me look up an article that had caught my attention a few months ago. In February 2011, the Lancet Neurology had published a study involving 113 patients with ischemic strokes and hemiplegia / hemiparesis, 57 of whom were treated with 20mg of Fluoxetine daily within five to eleven days of the stroke. At the end of three months, the researchers noted that those who had been treated with Fluoxetine (and physiotherapy) showed better motor recovery than those who received only physiotherapy.

When patients are depressed, they are unlikely to be motivated to do the post-stroke exercises that will help them recover motor function. While this may be a good reason to diagnose and treat depression after a stroke, the authors of this study also postulate that fluoxetine may have direct beneficial effects on neurons. It may turn out that antidepressants like fluoxetine are good for stroke recovery irrespective of whether the affected person is clinically depressed or not.


References:
1. Prevalence of depression in stroke patients with vascular dementia in University Kebangsaan Malaysia Medical Centre.

2. Fluoxetine for motor recovery after acute ischemic stroke (FLAME): a randomised placebo-controlled trial. 

Atypical pneumonia

Atypical pneumonia is often due to Mycoplasma or Chlamydia infections when the pneumonia is community-acquired. This type of atypical pneumonia responds well to macrolide antibiotics. In this week's issue of the New England Journal of Medicine (article), there is a report about a healthy young woman who developed a form of atypical pneumonia that rapidly progressed to respiratory failure. Hence this is a good opportunity to discuss some clinical aspects of severe atypical pneumonia acquired from the community.

Atypical pneumonia - other than Mycoplasma and Chlamydia - should be suspected when the respiratory illness does not respond to treatment with the usual antibiotics for community acquired pneumonia.

1. Think of Legionella pneumophilia when there are associated symptoms and signs of involvement of the CNS and / or gastrointestinal tract.

2. Think of Leptospiral infection when there is associated severe myalgia, headache or neck pain. Involvement of the liver and kidney and the presence of a skin rash are further points in favour of suspecting this condition.

3. Think of fungal pneumonia if the patient is immunocompromised and if there is exposure to an enviroment where fungi are likely - mouldy and damp places like caves, for example.  

4. Think of Toxoplasma and Pasteurella infections if there is close exposure to cats.

5. Think of Lyme disease, Rickettsial infections and Tularemia if there is a history or physical evidence of tick bites.

A woman with diarrhoea

A patient without a pituitary gland?

"Please see my MRI. Something is very wrong," my patient, Ms L. said to me.

I looked at her carefully. She appeared to be close to tears. Then I opened the large folder containing her MRI scan pictures and looked at the radiologist's report first. It read: Empty sella syndrome. There was no other abnormality in the scan.

"Who sent you for this scan?" I asked.

She looked embarrassed when she told me that she had been referred for the scan by a doctor in a private hospital because of her headaches. Of course I knew that she had been suffering from headaches because she had been my patient for over 2 years and I was treating her for migraine.

"I went to this doctor because some of friends told me that I should get a second opinion for my headaches," she explained.
"So, what did the doctor say after seeing this scan?"
"He said that I did not have a pituitary gland. He said I needed tests for different kinds of hormones." After a pause, she continued, "I cannot afford the costs of all those tests."

It was a familiar story. Patients are often attracted to doctors who "scan them" believing that scanned images of their bodies are better than clinical judgement.

I looked sympathetically at Ms L. How should I start explaining to her that she could not have lived all these years if she did not have a pituitary gland? Then I told her that the empty sella syndrome is a radiological diagnosis only. It simply means that the pituitary gland is not seen on MRI scans. Just because it is not seen on the scan, does not mean it is not there. Many people with the empty sella syndrome have normal pituitary function.

I ordered the tests for the relevant anterior pituitary hormones - TSH, FSH, LH, ACTH and Prolactin - and spent time reassuring her that her headaches were not due to a brain tumour. Two weeks later, I reviewed the results of these tests and found them all to be normal. Ms L was relieved.

"I wonder where my pituitary gland is hiding," she murmured.
With a straight face I told her, "We will not search for it with any more scans."

Even after she left, her question kept haunting me. Where was the gland if it was not in the sella tursica? I must find the answer to that.

When a doctor prescribes a drug with uncomfortable side effects.....

A 35 year old woman came to my clinic in the hospital because she had noticed discharge of milk from both her breasts. Her last pregnancy was more than 4 years ago. Her physical examination was normal. I wondered if she had hyperprolactinemia and I requested a test for the same.  I also asked her about her menstrual cycles and whether she experienced any hot flushes because I was aware that increased prolactin levels diminished secretion of estrogen from the ovaries. She said that her menstrual cycles were erratic. She did not have any hot flushes. I should have discussed about libido but I did not. Anyway, the serum prolactin levels were high in her and that made me suspect that she had a prolactin secreting tumour in the pituitary. I examined her cranial nerves, pupils, optic disc and visual acuity and field of vision. Nothing abnormal was detected.

The patient was worried when she realised that she might have a tumour in the brain. I explained to her that such tumours were never malignant and that, in most cases, it was so small that we did not even call it a tumour. Instead we called it a microadenoma. She wanted to know how small it was. I told her that a microadenoma is, by definition, something that is less than 10mm in diameter and I showed her how small it looked on paper.

An MRI was then done for her. It confirmed a microadenoma of the pituitary. I then tested her thyroid function and her serum cortisol level because, even though it was only a microadenoma, I wanted to make sure that it was not impinging on the function of the adjacent parts of the pituitary gland. These tests were normal.

In consultation with an endocrinologist she was then offered treatment with a dopamine agonist. We offered her bromocriptine because that was the only drug available with us in the hospital. I knew though that the best dopamine agonist for reducing serum prolactin was cabergoline. Dopamine agonists are also used to treat Parkinsonism and my patient had an uncomfortable moment when the pharmacist who dispensed her medication told her that she had Parkinsonism. It took me awhile to reassure her that she did not have that neurological disease.

When she began to suffer nausea and vomiting because of the bromocriptine, she consulted another doctor in a different hospital. Following the advice there, she underwent transsphenoidal resection of the microadenoma. This is a technique where the tumour is excised through an incision in the nose so that the lesion can be approached through the sphenoid sinus.

She came back to see me after the surgery, happy that she did not have to take the bromocriptine anymore. I learnt something useful from this encounter: when a doctor prescribes a drug that causes uncomfortable side effects, the patient blames the doctor, not the drug!

IMEC 2013

A report on some aspects of the International Medical Education Conference (IMEC) held in the International Medical University, Bukit Jalil, in March 2013.

The keynote address by Ronald Hardin was about excellent teachers for the 21^st century. He spoke on the type of teachers that we needed - comparing the different types of teachers to Carps, Sharks and Dolphins. Carps, he said, just muddled along without drawing attention to what they were doing, being interested only in maintaining the status quo. Sharks were aggressive and always wanted to win. They saw the world as filled with either winners or losers. The teacher of the 21^st century, Ron Hardin said, should be neither of these types. Instead they should be like the Dolphins who have good strategies and learn from previous experience. Dolphins like to win but they do want others to lose. Such teachers, he said, are unyielding on their principles unless those principles no longer make sense and they act on the big picture while being aware of the small details.

Cees van der Vleuten from Maastricht University, The Netherlands, spoke on how assessment should be used in medical schools for learning instead of being a mere tool for measuring learning.

A debate on whether professionalism can only be instilled by role modelling was held between Trudie Roberts from the University of Leeds and Dato’ Sivalingam from IMU. The debate was lively and filled with humour and references to people in music, arts and literature. The conclusion was that, while role models are important, professionalism should also be actively promoted as a goal in medical education.

A few of the research papers that I liked…..

1. A study looked at the awareness of palliative care among final year medical students and found that these students were aware of, and had interest in, this field.

2. A paper was presented on the adverse health effects of using Facebook. The authors found increasing social isolation from family and community as well as other adverse changes in health and behaviour occurred in medical students who used Facebook for an average of 2.5 hours or more per day.

3. A paper on plagiarism by medical students found that when students who indulged in plagiarism were counselled by mentors and peers, instead of being summarily punished, they showed improvement.  

4. A study looked at the role of nurses in the training of medical students and found that nurses do make significant contributions in this regard.

5. How do pre-clinical students view problem-based learning? A study found that while students generally like the PBL method of learning, their learning through PBL sessions can be improved by having smaller groups, by using better triggers, and by having content experts as facilitators.

6. A paper presented findings on how students are better able to understand illnesses from patients’ point of view when they are encouraged to write, and share, their own experiences during the time when they themselves were ill.

7. Google search is a useful tool for medical students when they wish to analyse clinical information and make diagnoses, according to a paper which studied the ability of fourth year medical students to make an appropriate diagnosis from clinical data.

8. End of life attitudes among final year medical students were surveyed in a study. The study showed that most medical students feel that decisions regarding life-prolonging treatment should be made by groups of doctors, nurses and other involved parties and not individually by anyone.

9. Do students use printed books or electronic books for study? A paper from University Technology Mara found that, for Pathology, medical students still use printed textbooks even though they have access to the Internet. Another study from Monash University found that second year medical students used mainly online resources instead of printed books.

10. A study on peer assisted learning found that when final year students are given the opportunity to teach medicine to third year students, both groups benefit from the program.

How clinical reasoning works

In a recent examination, students were given a scenario and then asked a few questions about it. Their answers show me how they interpreted the evidence.

A man suffers a pulmonary fat embolism and hypoxia after trauma to his legs from a motor vehicle accident. He is intubated and ventilated. His blood pressure is normal and stable. Subsequently he develops elevated levels of urea and creatinine in his blood. His serum potassium is also elevated (6.5mmol/L). His urine output is recorded as 450ml/day. His ECG shows sinus rhythm with frequent ventricular premature beats. His serum creatine phosphokinase (CPK) level in the blood is significantly elevated. His ABG shows signs of metabolic acidosis. His blood counts show a haemoglobin value of 10.5gm/dL, an elevated white cell count and a slightly low platelet count (130000/uL). His PT and PTT are normal. 

The students were asked:

What is the complication (apart from fat embolism) that is seen in him?

Some answered 'Acute myocardial infarction'.
Comment: These students got this response by looking at the ventricular ectopic beats in the ECG and the elevated CPK level in the blood. However they failed to take into account the lack of ST segment or T wave changes in the ECG. 

Some answered 'Sepsis with multi-organ failure'
Comment: These students looked at the elevated white cell count and the abnormalities in the lung and kidney to come up with this answer. They did not realise that elevated WBC count can be due to inflammation after trauma and that the lung abnormality is due to fat embolism. Sepsis is a possibility in this situation but, with the available evidence, we have no unequivocal evidence of sepsis yet. 

What is the correct way to reason and answer this question?
The rising urea and creatinine within a short period of time along with a lower than expected urine output suggests acute kidney injury. What could be the cause of the kidney injury? There is trauma and a raised CPK level. These suggest severe damage to muscles. Hence rhabdomyolysis could be a cause. It is also possible that he has hypovolemia due to loss of blood and that has contributed to the acute kidney injury but the evidence for this is not seen in the scenario. So, the answer to the question should be: The complication that he has now developed is acute kidney injury secondary to rhabdomyolysis. 

How will the ventricular ectopics be explained? The logical explanation for it will be: hypoxia from the fat embolism is the cause of the myocardial irritability.  

Evidence based medicine and Black Swans

Evidence based medicine tells us that
a) beta blockers are useful for those with atrial fibrillation (1),
b) that beta blockers are useful for those in heart failure with systolic dysfunction (2).

Can we extrapolate and say that beta blockers will therefore be useful for those suffering from atrial fibrillation and heart failure with systolic dysfunction? Will we prescribe beta blockers for those with atrial fibrillation and heart failure based on evidence? I am sure most of us will answer “yes” to both questions.

Unfortunately this view turns out to be incorrect as new evidence from a meta-analysis of beta blockers in patients with atrial fibrillation and heart failure with systolic dysfunction shows. The authors of this analysis, published in JACC Heart Failure in February 2013, say: The main finding of the present meta-analysis indicates that the effect of beta-blockers in patients with Heart Failure (HF) and Atrial Fibrillation (AF) is significantly different from the effect of these drugs in patients with HF and sinus rhythm. Indeed, beta-blockers were not found to have a favourable effect on HF hospitalizations or mortality in 1,677 AF patients who had been enrolled in placebo-controlled, randomized studies (3).

Unexpected results or events are what the author and Dean’s Professor in the Sciences of Uncertainty at the University of Massachusetts, Nasim Nicholas Taleb, calls Black Swans. The term arises from the once-held conviction that all swans are white because no one had ever seen a black swan for hundreds of years. A Black Swan, by definition, is a rare event that cannot be predicted by existing knowledge but which, when it occurs, can have tremendous impact on our lives or radically change our thinking. We make ourselves open to Black Swans when we allow our knowledge to blind us by making us believe that we know everything. Black Swans remind us that we must never be too confident that we know everything simply because we know a lot of stuff.

Evidence based medicine is a great repository of knowledge. When a form of treatment is proposed, we often ask the question: Is it evidence based? The assumption is that, if it is evidence based, we can be sure of the kind of effect the proposed treatment will have. Black Swans tell us that evidence based medicine should be used for predicting results only after being aware of variations in clinical situations between the past and the present. There is a subtle randomness about reality, and variations between individuals, that should make us aware of possible errors in extrapolating data from the past.

Intellectual humility is a mark of wisdom because it makes doctors aware that there are many things they do not know. Only through wisdom can we avoid being struck by Black Swans.

References: 
1. Rodney H. Falk. Atrial Fibrillation. N Engl J Med 2001; 344:1067-1078 
2. Wilson S. Colucci. Use of beta blockers in heart failure due to systolic dysfunction. Uptodate.
3. Rienstra M, Damman K, Mulder BA, et al. Beta-Blockers and Outcome in Heart Failure and Atrial Fibrillation: A Meta-Analysis. JCHF. 2013;1(1):21-28.