Wednesday, December 30, 2009

Thanks for returning to the NH blog again! We are witnessing the historical development of some of the drugs used in contemporary pediatric cardiology. Hitherto, we have seen histories of Digoxin, Diuretics, Beta-blockers, ACE inhibitors, Prostaglandins and Sildenafil. Let us witness some history of drugs that set our rhythm right: The Antiarrhythmics!

The first victory on the war against malaria came from natives of Peru. The Cinchona bark, also known as Peruvian bark, Jesuits’ powder, or Devil’s bark was probably the first ever medication to be effective against malaria. This medical remedy from the New World (the American continent) caught the attention of Europe around AD 1650s and very soon ended up being the fancy of medical world. This also started an indiscriminate use there on. It did not take much time for the unscrupulous to realise the potential profit making in the Peruvian bark. To beat the competition, many used fake bitter tasting preparations to mimic the Cinchona bark. Worse were the people who used larger doses imagining faster and more effective recovery. This started the downfall of cinchona bark when cases of dangerous relapses (due to fake medicines) and sudden deaths (due to overdose) appeared.

Soon after the introduction of cinchona bark, the German physician Georg Stahl had recognised its action on the heart and subsequently sporadic attempts were made to exploit this. When the side effects of cinchona bark continued to dominate, further attempts to delineate its effect on heart stopped. Celebrity physician of the time, Thomas Sydenham did an extremely careful study on the Cinchona bark. The prevalent belief of the time was a “Peruvian curse” on the cinchona bark. Sydenham argued vehemently against the “curse hypothesis” and proved that the drug was a safe one, provided the discipline of dosage, timing, and duration of treatment were properly taken care of. Despite the best efforts by Sydenham, the scepticism on Cinchona bark continued.

Around 1820, the purified form of quinine was extracted from Cinchona bark and within the next decade, quinine in its purified form was used all over. This gave the opportunity to few physicians around 1850s to prescribe quinine in supranormal doses for management of heart problems, albeit without any scientific evidence. This practice went on for a few years in a selected group of physicians.

As the Dutch had dominated the Cinchona plantations worldwide, availability of Quinine was the best in Netherlands. Not surprisingly, a patient of atrial fibrillations, who visited the famous Dutch cardiologist Karl Wenckebach in 1912, boasted that he himself can control the fibrillations. The surprised cardiologist asked the patient to prove himself. When the patient returned the next day, to the surprise of Wenckebach, his heart rate was well in control.

On enquiry, the patient revealed the secret. He had simply taken quinine to bring his atrial fibrillation under control! What’s missed was the dose the patient had taken which Wenckebach had forgotten to ask. He presumed the regular dose and tried quinine on about a dozen patients. To his annoyance, only one responded favourably. In 1914, Wenckebach brought out his book on cardiac arrhythmias (please note the year: ECG was yet to be used in clinical practice!!)in which he referred to the matter of Quinine’s anti-arrhythmic action just in passing.

Walter Frey was a busy practicing physician in Berlin, Germany. In 1918, he reported about the use of Quinidine in controlling atrial arrhythmias in a prominent Viennese medical journal. He claimed that quinidine was the most effective of the four principal cinchona alkaloids when it came to anti-arrhythmic action. Although Quinidine was supposed to be the least toxic of all the four components it was still a pretty hazardous drug. That made the medical supervision mandatory.

Quinidine was not a new drug. When the cinchona bark was getting purified, many isomers were isolated. Quinidine was one of these isomers that was isolated in 1833 by Henry and Delondre. When tested as antimalarial, it nowhere matched the effect of quinine. The anit-arrhythmic action gave a new lease of life for the once discarded quinidine. From then on, it has never looked back. It can still be used for treatment of supraventricular and ventricular arrhythmias in many occasions.

Procainamide and Its Analogues

A renowned cardiac surgeon of Cleveland, Ohio, Frederick Mautz was a worried man due to the recurrent per and post operative arrhythmias. He had set out to investigate drugs that could be applied directly to the heart surface prevent these arrhythmias. He was logical in assuming that application of local anaesthetics, like procaine, could act as prophylactic medication against these arrhythmias. Added to this, Procaine had already shown to have similar effect on heart.

With this, the animal experiments started. To the excitement of Mautz, procaine indeed showed highly effective action.
With the success of animal experiments, Mautz proposed the use of intrapericardial instillation of procaine for irregular beats of the heart during surgery. Till then, the only option was the use of quinidine which itself had a temperamental action. Procaine was found to be superior to the effects of quinidine.

The problem with procaine was its short duration of action. Added to this, if used repeatedly, the cumulative effect was dangerous to central nervous system. To overcome this, procaine was researched extensively to improve the duration of action, reduce CNS side effects and to improve the cardio-specificity. The result was Procainamide, which is useful till today to treat ventricular arrhythmias on acute basis. When efforts were made to use the drug for long-term, the risk of inducing systemic lupuserythematosus appeared. Hence, it is not for long term therapy.

Efforts were made to improvise the molecule for long term use. In this bargain, the team of French scientists headed by Laville and Justin-Besanc of Laboratoires Delagrange tested 2-chloroprocainamide. Although it had negligible anti-arrhythmic action, it was found to be a very effective antiemetic on oral administration. This was further improved to create metoclopramide.

In the next post, we shall see the development of another group of drugs. Just before that, let me tell you that I am about to finish this series on the “developmental history” of drugs used in Pediatric Cardiology. I need some ideas for the new series. If anyone can give me some ideas for the new series, it would be very helpful. Please note that the responsibility of the research on your ideas would be entirely mine! I would not disturb you for any further help, unless you wish to provide me some. However, the credit for the idea will be fully acknowledged in the blog with the full name of the contributor!!

On a personal note, the New Year is fast approaching. Our team is depleted as of now! Consumption of remaining leaves or the wretched climate of Bangalore causing respiratory problems has taken the toll on the rest!! With half the team doing more than full work, the time available for decent academics and discussions get progressively shorter. Hope, we shall get back to full strength soon.

VENTRICULIZATION OF PAs
What if the cath tracing of PA mimic that of RV? We had a 4-year-old who had undergone ICR for TOF with transannular patching a couple of years back. He came back with an aneurysmally dilated RVOT. On cath, PA tracing was as described above. Unless we see the location of catheter on screen, we cannot make out the PA entry on tracing. Traditionally, homograft repair is considered as the surgical option. However, our surgical team felt that a reduction plasty of RVOT can be done. Is the impingement of this dilated RVOT on LPA very common? If any data with anyone, please let me know.

AMPULLA Vs DUCTAL CONSTRICTION
What should be the ideal device for a bizarre PDA? We used a regular PDA device in a bizarre PDA in a 34-year-old. The larger side of device sat nicely in the ampulla and before the release, it slipped into the duct and found its home at one of the constrictions of the duct. Before we could make any other change, the device seemed to settle well there. We decided to leave the device as it is. What might be the possible complications? Is the muscular duct as good as the ampulla for accommodating the device? Any experiences in this regard? Please comment your ideas on it.

NOT HOLMES’, NOT JOUBERT’S
The DILV with NRGA would be a Holmes’ heart; the same with malposed GA would be a Joubert’s heart. How about a DILV with side-by-side great arteries? We happened to see one like this. This baby had a classical DILV, but with PA from LV and Aorta from OC. On short axis, they had a side-by- side relationship. Is there a name for such a combo? How common are these entities? If you have seen one, please tell me.

EBSTEINS IN CTGA
Is the TV anatomy in Ebsteins with AV concordance any different from Ebsteins with AV-VA discordance? We know that physiologically, they connect to different great arteries and different pressures. But, anatomically, is the displacement or histology any different? Does it translate to any difference in surgical approach and outcome? What does the surgical team opine about this? We had one of our senior surgeons mentioning the practical difficulties of treating a CTGA with Ebsteins. If there are issues, can we take any measures to ensure better outcome in the post-surgical period? If any research has been made on this which you have come across, please send it to us.

SINGLE DILEMMA
We often come across infants with Single Ventricle physiology with a moderate PS. Many times these babies saturate around 75-80% on baseline. What can be done for them? The PS would not be sufficient to enable BD Glenn. The saturations do not allow PA tightening. BT shunt would be negative for future Glenn. How should we be going about? Please drop in your suggestions.

TRANSITIONAL CYANOSIS
We saw a 2-year-old with Transitional AVCD with common atrium and uncertain pulmonary venous drainage. The pulmonary veins were draining into the roof of common atrium all around. The IVC was interrupted and there was bilateral SVC. There was an inevitable mixing at the atrial level, as for any other common atrium. However, this baby had mild cyanosis and clubbing with the saturation of 80%. Such picture does not occur in regular cases of common atria. How does the streaming affect the situation? We are planning to establish the correct anatomy of pulmonary veins in this baby with a cardiac CT. Can the interrupted IVC explain this picture? If you have come across such a picture, please tell me about your observations.

Pen in your comments. Use my email drkiranvs@gmail.com if you find any problem posting your comments.

Happy, prosperous and eventful 2010 to all of you

Regards

Kiran

Friday, December 25, 2009

Hearty welcome to the NH blog again! We are witnessing the historical development of some of the drugs used in contemporary pediatric cardiology. Hitherto, we have seen histories of Digoxin, Diuretics, Beta-blockers, ACE inhibitors and Prostaglandins. It is time to raise to the history of something exciting; the story of Viagra AKA Sildenafil!

In the year 1985, the research team of Pfizer in UK took a step that literally changed its fortune. It was serendipity at its best. The research team headed by Simon Campbell and David Roberts decided to target Atrial Natriuretic Peptide (ANP). Their intention was to develop a compound that could lower blood pressure by enhancing the activity of ANP.

ANP had found its place in the human physiology by that time. It was a vasodilator which increased the excretion of sodium and water by kidneys. It was logical to conclude that elevating its level would reduce blood pressure. The biochemistry of ANP had revealed that the peptide worked by stimulating guanylate cyclase to increase the synthesis of cGMP.

The Pfizer research team decided to formulate a phosphodiesterase inhibitor which would destroy the cGMP in the renal tissue. Their superior technology allowed them to isolate known isoenzymes totally uncontaminated. Yet, these isoenzymes failed to show any desired response.

In the pharmacopeia, there were no known potent selective inhibitors of the Phosphodiesterases till then. This prompted the team of Nicholas Terrett to seek the help of contemporary research. They sought out the data from any other research team working on the same issue and compounds, irrespective of the success they have produced for their respective teams.

In their hot pursuit, they tripped on the research team of Rhone-Poulenc. The mighty organization had its UK division named May and Baker. Their team had come up with a compound called zaprinast, which was yet to be marketed. Surprisingly, it was meant to be an anti-allergy drug. Being a xanthine analogue, Zaprinast was designed to deliver an anti-anaphylactic and anti-inflammatory effect. In the trails, it not only turned out to be a weak inhibitor of the Phosphodiesterase, it also lowered blood pressure in vitro. This had put in the molecule in the back seat.

The Pfizer team took it from there. They did a detailed comparison between zaprinast and cGMP. An elaborate computer graphic application was made to compare the finer aspects of the stereochemistry and the quarternary structures.

With Zaprinast as the base molecule, various variations in the heterocyclic ring system of it were prepared. Out of hundreds of variations, a pyrazolopyrimidinone was found to be most promising. Its potency was about ten times that of zaprinast.

The development of this intermediate molecule encouraged the team. The stereochemistry of the new molecule gave them the idea on the direction to proceed and enhance its potential further. The phosphodiesterase against which it was potential was found to be a subset called PDE5.

With the new molecular structure in their kitty and the detailed structure of cGMP, the next generation of molecular development was clearly on its way. Finally, two further modifications in the intermediate molecule led to the development of sildenafil as a specific PDE5 inhibitor in the year 1989. Not only the molecule of sildenafil was about 100 times more potent than zaprinast, it was also very highly specific in its site of action.

The initial objective of Pfizer to produce an effective anti-hypertensive was met with a disappointment when the phase III trials of Sildenafil did not meet the target levels of end points. Never before in its history, had Pfizer chased about 1600 compounds to come to a compound of this target value. The drug neither proved to be a good antihypertensive, nor a good coronary vasodilator for angina as a secondary effect. The initial lab reports were no way matchable to the outcome of phase III human trials. Pfizer research team had a lost product after such gruelling effort. The trial had lost its battle and the Pfizer team decided to call it a day. They recalled all the remaining drugs from the human volunteers in 1992. To their surprise, none of the 30 men who participated in the sildenafil trial returned unused tablets even on repeated requests from the research team.

The progress in this effect enraged the physician in charge. He decided to have a personal talk to all these participants. On repeated questioning and assurance to continue the supply of the said tablets for some more time, the male volunteers revealed that the tablets were increasing their erectile function.

The research team did not initially realise the mountain of gold they were sitting on. After the initial reluctance of the team to continue the trial, they decided to investigate the drug for the confirmation of side effects. The continuation of the trial not only confirmed the same effect in healthy volunteers, it also showed the benefit in patients of erectile dysfunction.

The research team was perplexed by these serendipitous effects. At the same time, there were advances in understanding the role of nitric oxide as a signalling molecule. The bottom-line was simple; it stimulated guanylate cyclase and formed cGMP. The same mechanism occurred during sexual stimulation, in which Nitric Oxide was released, raising the cGMP levels in the corpus cavernosum in the penile apparatus, letting the blood to fill the area and cause a sustained erection.

Although the Pfizer research team did not realise, the marketing team immediately knew where to strike! Pfizer marketing team used their influence in the media to raise an awareness campaign about the erectile dysfunction. Series of articles were written in the major newspapers and journals. Once the awareness about this sensitive issue was created in the general public and the inhibition about talking on the issue thinned out, Pfizer decided to launch Sildenafil under the name Viagra in 1998. It did not speak of hypertension or angina, but only as a treatment for erectile dysfunction! The molecule changed the financial graph of Pfizer and changed its fortunes forever. So much for the serendipity and patience for investigating any issue without any bias! Further research is in progress for improving the molecule further so as to take away the possible adverse effects and improve the area of its present action!!

On a personal note, it was time for new faces and new blood. We had selections for the RGUHS fellowship in Pediatric cardiology for the session 2010-11 recently. There were 5 aspirants for 2 seats. Finally, after a theory and Viva test, Dr Prashanth Patil and Dr Hemanth were selected. We extend our happiness in welcoming the new members to the team. I sincerely hope at least they would contribute something to this blog!

I had been to the fort city of Karnataka – Chitradurga. There was a conference on Critical care in Pediatrics. I had to do an arrhythmia quiz there. Due to some constraints from other speakers, I ended up consuming the stage for about 90 minutes and covered the topics on ICU management of Blue neonate and management of CHF also. The response from the post-graduate students was good, but the attendance of the practicing Pediatric community was disappointing. Anyway, the experience was worth the effort.

“REVERESE” PVRI
High PVRI can be caused by increased Qp or due to long standing high pulmonary venous pressure. In the latter, how would one evaluate the reversibility of high PVRI if the cause is treated? Our data on the high PVRI and the decision making on reversibility are based on high antegrade flow. Is there any data on reversibility in the setting on high pulmonary venous pressure? If there is a case of cor-triatriatum or supramitral membrane with high PVRI, how operable are these lesions? If we operate, can the PVRI fall? Can the Heath-Edward classification of histological changes applicable to such situations too? If there is a combined lesion involving high Qp and pulmonary venous hypertension, is there any way of calculating the PVRI contributed by either of them separately? How to estimate the reversibility in such cases? If not, is there any use of doing a diagnostic cath study in such situations? If you have any reference or personal experience in handling these scenarios, please let me know.

BLOCKING BRONCHUS AS TREATMENT
In cases of pulmonary bleeding in a Post-BD Glenn physiology, should we do a diagnostic bronchoscopy to find out the source of bleed? We had an unfortunate incident in which a 7-year-old who had undergone a single lung BD Glenn few years back (due to single branch PA anatomy) came back with severe hemoptysis. We could initially control his hemoptysis, transfused and as the first part of diagnostic modality, did a cath study with the idea of blocking the bleeding vessel if found. We could not find any such vessel on cath and patient was shifted to ICU. Late night, the patient had a massive bout of hemoptysis and passed away. One “ever-alert” member of our surgical team pointed towards the possibility of using bronchoscopy to find out the source of bleeding. On the side of utility of bronchoscopy, he suggested the idea of blocking the bronchus of the bleeding lung to limit the bleeding to the same side, thereby avoiding the flooding of the other lung with the bleed. This would buy us some time for therapeutic intervention and prevent the sudden death of the patient. The idea is innovative and looks life-saving. I remembered the suggestion of one of the Pediatric Surgeons who taught us to push the tracheal foreign body to one bronchus if it cannot be removed in a choking patient, which is really life saving. Are there any caveats to this? Please let me know your views.

PATCHY COMPROMISE
We often come across “Canal Tets” – The complete AV canal defects with subaortic extension of VSD and severe PS. Do such cases always require transannular patch correction? We have seen that in such cases even if the size of pulmonary valve annulus is in an acceptable Z score range, surgeons still prefer to do transannular patching. The argument is that the VSD patch involving inlet and subaortic regions would inevitably narrow the RVOT. Any experience in this regard? Please send it to me or post it in comments.

CONGENITAL NON-EBSTEIN HUGE RIGHT ATRIUM
We came across a 3-month-old with huge RA. It was so big that it had compressed all the other chambers to a negligee! The AV valves were at normal levels, ruling out an Ebstein anomaly. There was a functional TR due to non-coaptation, which could not have been a primary lesion. What is this condition called? Does the term Idiopathic Dilatation of RA exist? What may be the etiology of such a lesion? How to manage these? Is there an option of surgical reduction? If you have come across any such lesion, please tell me.

TO CLOSE OR NOT TO?
I came across a 10-year-old boy with a perimembranous VSD which was restricted by prolapsing RCC. The effective VSD was small and the AR was trivial. Technically, neither of the lesions by themselves would warrant any surgical intervention. How should we go about this combination in that age? Should we wait for the AR to progress? I don’t see any reason why the VSD would enlarge in size from here on. A previous echo report showed the VSD to be a moderate one earlier and there on, the boy was lost for follow-up as the family thought that nothing was much wrong with him. Should we just go about operating such a scenario or wait for the progress of AR? Can we trust the family to be alert to bring him for timely follow-ups? Should we make any decisions that may sound unscientific, as the patient’s family cannot be trusted on follow ups? This is another of “third-world” problems! Any inputs?

Pen in your inputs. Use my email drkiranvs@gmail.com for sending your questions or comments. It will be of great use to our readership.

Regards

KIran

Friday, December 18, 2009

Welcome back to the NH Pediatric Cardiology blog. We are in the process of exploring the developmental history of drugs used in the Pediatric Cardiology.

Birth of a child and the process of labour had always been a matter of philosophical and scientific interest for human race from time immemorial. However, the chemical interest in the process of childbirth began around 1930. The men who thought of this novelty were Dr Raphael Kurzrok and Dr Charles Lieb working in the Department of Obstetrics and Gynecology at Columbia University in New York. It was the time when artificial insemination in humans was thought of. In this process, the animal experiments were going in full swing. In one of the earliest human trails, they had an interesting observation. The uteri of women undergoing artificial insemination sometimes contracted violently and on other occasions relaxed! They failed to determine the cause of the phenomenon but documented that such behaviour was common and unpredictable in their series.

Before their report was forgotten, about 5 years later, Ulf von Euler was working with the chemical nature of seminal fluids of animals at the Karolinska Institute in Stockholm, Sweden. In the seminal contents of monkey, sheep and goat, he detected an acid that lowered blood pressure and caused smooth muscle contraction. His initial presumption for the acidic nature of this substance was the contribution from Prostate. Unable to think of any other name, He named it ‘prostaglandin’ and conveniently forgot!

Sune Bergstrom was a student of von Euler. Bergstrom’s area of interest was the utility of Craig countercurrent extraction apparatus purifying the extracts. For his work, he was able to obtain a $100 000 grant from the Upjohn Company in the mid-1950s. Recalling the work of von Euler, he decided to go with the analysis of Prostaglandins and was successful in isolating small amounts of several different highly potent prostaglandins. He also elucidated their structures. They were subsequently classified as types A to F. Each type was being given a subscript indicating the number of unsaturated centres in the side chains.

Bergstrom’s work paid off well. In 1957, he isolated crystals of alprostadil (the original prostaglandin E1) from sheep prostate glands. In next five years, the structures of alprostadil, dinoprost (the prostaglandin F2a) and dinoprostone (prostaglandin E2) were determined.

Although Dinoprostone is one of the most commonly occurring and most potent of the mammalian prostaglandins, it proved to be unstable due to its chemical structure. The same effect was found in all prostaglandins of E series. The stability factor became a major issue for Upjohn and the bosses decided to recruit more scientists on this job. In this process, Phillip Beal and his colleagues could achieve laboratory synthesis of a naturally occurring prostaglandin in 1965. Inspired by their success, they also synthesised alprostadil in 1969.

At the same time, some of the Harvard scientists took interest in this problem and started working on it. Elias Corey not only synthesised dinoprostone in 1970, he also succeeded in modifying the structure to obtain dinoprost.

The availability of synthetic prostaglandins opened a new door of opportunity. The volumes could allow a decent clinical trial. Upjohn decided to supply prostaglandins free of cost to any research team for understanding the therapeutic advances. But, out of the sixteen naturally occurring prostaglandins only three were proved to be of any clinical value.

In 1967, a research team discovered the link between the prostaglandin inhibition and Peptic Ulcer. Some of the Prostaglandins of E series inhibited gastric acid secretion. This led to the hope that prostaglandins could be used in the treatment of peptic ulcer. However the therapeutic effects could not be evaluated because none of them were active by mouth. Although an injectable formulation was prepared, it had a very brief duration of action. Also, the prostaglandins of the E series lacked any site specificity of action and ended up producing more unwanted effects than therapeutic ones. Adverse effects were mainly due to vasodilation, which caused facial flushing, headache and hypotension.

The vasodilating properties of alprostadil led to a new avenue of therapeutic use that has saved thousands of newborns. The use of prostaglandins to dilate the ductus arteriosus in neonates with duct dependent congenital heart diseases gave a new lease of life to such newborns. It also added a new drug to the limited list of drugs used in Pediatric Cardiology.

Slowly, but steadily, Prostaglandins found a formidable place in the Pharmacopeia. Due to its proven ability to induce contraction of the uterus, intravenous infusion of dinoprostone found its place in inducing labour. It is now given by the vaginal route, either as pessaries, tablets or gels. In 1972, it was also being used for the induction of abortion after the first trimester of pregnancy.

Chemical modification of prostaglandin was the new objective for research scientists. In this way, John Vane of Burroughs Wellcome could isolate a prostaglandin-like substance (prostanoid ) called Epoprostenol which was found to be a prostacyclin. These naturally occur in the walls of blood vessels, and are responsible for producing vasodilation. It also prevents clotting. As for any prostaglandins, it is rapidly metabolised. The half life is being three minutes when given by injection.
Later generation of prostacyclins are being developed now and is one of the most promising therapeutic options for the treatment of PPHN.

In the next post, we shall see the development of one more class of cardiac drugs.

On a personal note, the delay in the present post was largely due to the sudden CMEs I had to attend for a couple of guest lectures. The one on previous Sunday was in the heritage city of Mysore, a beautiful place located 3 hours from Bangalore. The JSS medical college in Mysore is presently celebrating its Silver Jubilee. To commemorate the event, the dynamic team of JSS Pediatricians have arranged a monthly CME of all pediatric sub-specialties. This time, it was the turn of Cardiology and Endocrinology.

I am feeling a bit philosophical off late. Life poses multiple problems and one among them is to stand up against your own people. We often find ourselves in such a situation and wonder what the right course of action is. I must have read the holy “Bhagavad Gita” good number of times. This is exactly what the mighty Arjuna had faced in the epic Mahabharata. What lord Krishna preached him might be for the entire universe, wherein every human being is confronted with a similar situation at least once in a life-time. Tackling a stranger doing wrong things might be easier. But, tacking the people whom you respect when they are deliberately erring is one of the toughest jobs. And, when that error affects you directly, then the tackling becomes inevitable. Is the matter you are fighting for is more important than the relationship? If the other party had respected the relationship, then they would not have committed the deliberate error. The expression of error from their side shows how meagre a respect they have for your regard, respect and relationship. In this scenario, is it better to express your discomfort with the situation and accept the ensuing wrath or continue respecting the relationship and accept the changes with a perpetual grinding of teeth? Is there a via-media solution? I felt it might be better to voluntarily give up your right and make them feel guilty of their motives and actions. But one should be ready for the losses if the other party does not feel guilty at all!!

Also, it may be OK if it is an individual decision. But, if a number of people are involved in the sufferers group, this individual decision would find no place. “Fight for the Right” would be the only solution left. The ancient wisdom seldom changes and is aptly called the “roots” of culture!

What is the best indicator of the Pre-op assessment of PA anatomy in TOF? We use the McGoon ratio. Nakata index is an equally popular modality. However, we often see the surgeon disagreeing on the data provided by cath and echo on PA sizes. They quote the “underfilling” concept and accept low McGoons for total correction. Is there any way of “fool-proofing” the measurements? They whole idea of subjecting a patient to a semi-invasive procedure becomes redundant if the data obtained is uncertain. What is the current trend? Even the CT scan cannot escape this “underfilled” hypothesis. If anyone is using a better modality, please let me know.

We often see adult population with TOF physiology. We had a man in his 30s, presenting with cyanosis and hemoptysis. Echo revealed TOF physiology and the cath showed fairly large collaterals. However, his chest radiograph also had a lesion which looked cavitatory. Pulmonary Kochs is a common problem in the developing world and commoner in TOF. Eventually, we relearned an important lesson: Not all patients with hemoptysis in TOF are due to collaterals!
We saw an 11-year-old boy with single ventricle physiology, saturating 73% in room air. His mean PA pressures were 15mmHg and ventricular EDP was 14mmHg. Although the McGoon’s was 2.3, the same underfilled hypothesis came up. This time, it was in the opposite direction! When this boy has PA pressure of 15mmHg on controlled conditions of anesthesia, how much would the PA pressures be on regular wakeful state? Should we consider a simultaneous PA tightening? Would ACEI help? If BD Glenn is not feasible, can we simply add a BTT shunt and call it a final palliation? With complete Fontan repair not an option due to criteria, should we address the cyanosis with only BD Glenn in an 11-year-old or leave him for his natural history? Some problems of third-world do not even find a place in the regular text books!!

We see some of the older children, who at the current era look OK for 2-pump repair. However, few years back, they have undergone a Glenn repair, putting them on single pump pathway. It is likely that the expertise available at that time might have led to the plan. With the learning curves for this young field getting better, those kids (who are adolescents now) look good for 2-pump. But, how practical is it? Is taking down a Glenn which is almost a decade old is easy? When their SVC looks quite dilated, re-attaching it to RA would be a real task in the process. How difficult is the task? What is the surgical experience in this regard? It is worth discussing. Any inputs from the surgical fraternity?

What should be the ideal management for an obstructed homograft conduit with ventricular dysfunction? We had a26-year-old man who has undergone a classical repair for cTGA VSD PS (VSD closure with LV to PA homograft) at UK about 10 years back. At present, his homograft conduit is heavily calcified leading to LV dysfunction. RV has started to fail as a part of natural history. His PA pressure was a mean of 45mmHg. Is there a role of re-doing the conduit repair? One suggestion was to undo the original repair and redo a Senning with Rastelli (definitive repair). How practical is it with a biventricular dysfunction? Is there a role of heart transplantation with a PA mean of 45mmHg? Is heart-lung transplantation an option? If anyone had an experience in this regard, please let me know.

We had an ethical issue to address. This 17-year-old girl with TOF physiology had severe cyanosis and small branch PAs. McGoon was <1. Our obvious thinking was a BTT shunt as the final palliation. But our surgical team came up with a practical issue. They argued that the addition of BTT shunt may not contribute to major relief in quality of life. It may add on to the existing load on the ventricle. More so, the family can never understand the palliative nature of the procedure, despite best of your efforts to make them understand. They seek a certain degree of respite from the surgery, which they will never get from the addition of BTT shunt in this age. This actually increases their burden. So, the argument was to accept the natural history than making the social scenario worse for a small improvement in cyanosis. The eventual cost-benefit may not be worth it. However, some of us refused to accept this hypothesis. Since all the people who disagreed with the principle were young, the balance favoured the experience. “You are yet to burn your fingers on it” was the comment! The people who were neutral and did not raise their hand for either of the opinion bothered. What is your take on it? Please let me know.

Come up with your opinions in the comments. You can also send in your opinions and your experiences to my email: drkiranvs@gmail.com I shall post them on your behalf with full credits to the contributor!

Regards

Kiran

Thursday, December 3, 2009

Welcome back to NH blog. We are in witness of “developmental history” of Cardiac medications pertinent to Pediatric Cardiology.

In the last 3 posts, we have seen the historical aspects in the development of Digoxin, Diuretics and Beta-blockers. This post will see another class of drugs, termed as “the most useful class of cardiac drugs” by contemporary Cardiologists: the ACE inhibitors.

The advent of beta-blockers was an epoch making event in the field of cardiology. It inspired a generation of scientists to undertake research in the crucial field of drug development. When the beta-blockers were found to be successful as anyi-hypertensives also, many a minds drifted their attention towards achieving the anti-hypertensive effect with other compounds.

John Vane was one of the researchers working on this issue. In 1960, after witnessing the beta-blocker saga, he shifted his attention towards anti-hypertensives. He was a man of extremely sound fundamentals and true to his nature, he started his research investigating the causes of hypertension. At that period, he was working in the Institute of Basic Medical Sciences at the Royal College of Surgeons of England.

One of his Brazilian post-doctoral students, Sergio Ferreira, brought an extract of the venom of Brazilian arrowhead viper, (Bothrops jararaca), to London. As a matter of interest, they evaluated it. To his surprise, he discovered its capability in blocking the formation of angiotensin II from angiotensin I. This conversion reaction was mediated through an enzyme called Angiotensin Converting Enzyme.

Vane could immediately sense the possible effects of this in the human body. He expressed the findings of his research with some of the leading clinicians. He was disappointed to see the reaction of them. The clinicians were not trained in understanding the developmental research of drugs. They would start with a possible clinical trial, but nothing less than that.

Vane’s initial disappointment could not stop him. His ability to trace something new was impeccable. He had solid belief in his findings and its possible impact on the future of medicine. He decided to approach scientists instead of physicians this time. He made a trip to the famous Squibb Institute for Medical Research in New Jersey and was able to convince the researcher team on the novel concept called “The use of ACE inhibitor in controlling high blood pressure”.

Vane’s honesty, belief and commitment impressed the chief scientist of Squibb, Miguel Ondetti. Ondetti gave the responsibility of fractionating the viper venom to his colleagues. His team did a wonderful job and could elucidate the structure of several peptides from the venom. This confirmed the existence of a very active peptide inhibiting ACE. Vane had already reached this point and had called this compound teprotide. After coinciding with Vane’s observation, Squibb scientists went a step ahead. They could now synthesise the compound and start an animal trial.

Teprotide was administered intravenously in patients with elevated plasma renin levels as a part of first clinical trial. It sure proved to be an effective hypotensive agent. However in the control group with hypertension but normal rennin levels also showed a similar and comparable hypotensive effect. Since it was a peptide, teprotide was obviously inactive orally. So, the next step was an attempt to synthesise an orally active analogue of teprotide.

The Squibb research team started a massive mission for this. They ended up screening about 2000 non-peptides, but all these were in a vain. The team head thought that a new approach would be more worthwhile. At the same time, publication of a scientific paper caught their attention. This paper by Byers and Wolfenden dealt with inhibition of digestive enzyme carboxypeptidase A by benzylsuccinic acid. The authors had found the site called C-terminal phenylalanine residue of of carboxypeptidase A to which substrates were bound. As benzylsuccinic acid had a similar enough structure it could competitively inhibit it.

The Squibb researchers made use of this fact and used numerous techniques for quite some time to finally create a compound which was one-thousand-fold strong in inhibitory activity. This was called captopril which was the first non-peptide ACE inhibitor suitable for oral use and thereby introduction into the clinical use. The scepticism prevailed. To add on to this chaos, an early clinical trial showed captopril with renal damage or granulocytopenia. The Committee on Safety of Medicines of United Kingdom put up the clause of “to be limited for the use only in patients with severe hypertension who had not responded to standard therapy” for captopril when it was marketed.

The scepticism was short lived. An intensive postmarketing surveillance was enough to prove the minor nature of side effects with low incidence for captopril. This led to the extension of licence in 1985 for use in mild to moderate hypertension. Newer modifications of Captopril led to the development of other ACE inhibitors. All these are now firmly established in the treatment of heart failure and in hypertension and are considered as the treatment of choice.

In the next post, we shall see the development of one more class of drugs.

On a personal note, with the advent of December, the numbers of people taking leaves are increasing! The foolish rules of “You cannot carry over your leaves to next session” would leave every unfortunate soul who is “not on leave” strangled! Anyway, life goes on and it is time to realise that pain is an integral part of human suffering!

Many centres wake up in December and start conducting their mandatory quota of CMEs. Hence, we people are in demand. This adds on to the woes of consulatants who are at the hospital working. On the other hand, most of the CMEs happen on a Sunday and pain of losing a precious Sunday increases with this. We can neither refuse nor whole heartedly accept these invitations. Overall, December ends up being “pain, pain”!

Last year, we reported a case of Truncus with Tricuspid Atresia in the Indian Heart Journal. It is a rare combination indeed. We had another boy aged 14 years with this combination. He had a Tricuspid atresia with the common arterial trunk committed more to RV. The age precluded us from defining his PA anatomy on Echo. On cath, we found a Type 2 Truncus with the origin of LPA stenosed. RPA pressures were systemic. No further management options exist in him. How frequent are such combinations? What is the embryological basis of such lesions? Is a single lung with more than normal pressure tide over such a lesion for such a long time? Are there any other protective issues that we are missing? If so, how to detect them with the available technology? Some questions lead to more questions and minimal answers. Any data, please transfer!

We saw a 6-year-old boy with history of Kawasaki disease. He was treated with Immunoglobulins on day 14 of illness in the past. He is otherwise asymptomatic. On follow up echo, we found an echogenic mass in the dilated LAD along with some aneurysms. His effort tolerance on a treadmill was normal. On the cath study, we found a near complete occlusion of LAD. Some collaterals and retrograde filling of RCA was seen. Since the child was asymptomatic, it was decided to have a close follow up. Is the treadmill a good idea? Can we do it with less invasive methods like Stress thalium instead of TMT? Are there any guidelines for the timing of cath? What are the guidelines for the surgical intervention in such scenarios? AHA has come out with guidelines for Kawasaki disease. Are they pertinent for Developing countries also? Any data with anyone?

What determines the shunt in ASD? Looks like an exam question! It is the RV EDP obviously. We had a 4-year-old girl with ASD R to L, Smallish muscle bound RV, with SO2 of 85%. The desaturation led to cath study. The RV EDP was 12mmHg, which was lesser than LV EDP. Are the EDPs dynamic? Can the RV EDP keep fluctuating? Can it be severe enough to cause cyanosis? Can repairing the ASD a good option? It was decided to go for a BDG with fenestrated ASD closure? Can we follow the same strategy for other instances with high RV EDPs also? Let me know your take on this.

Is there a linear relationship between the AV valve Z score and 2-pump repair? Till what Z scores do we accept the 2-pump repair? We had a 5-year-old with intact IAS, moderate VSD, moderate PS and TV Z score of minus 3. The RV was reasonably sized and reached apex. The RA was not dilated much. It was decided to go for VSD closure, pulmonary valvotomy and PFO open. How would such lesions behave post surgery? The surgical team felt that since the RA was not dilated, the impact of TV narrowing was not much and hence the surgical repair was acceptable. Are there any criteria for 2-pump repair in such instances? Pen your opinions.

We had an interesting coincidence during our cath study. Although it was a shock for the surgeons on the table, their efficiency could tackle the situation. This 4-year-old was operated outside with a right sided BTT shunt 2 years for pulmonary atresia. On echo, the windows were very compromised and we could not see the PA confluence. In the cath study, the arch injection filled both LPA and RPA. We presumed confluence and went ahead. On the table, we found that the PAs were non-confluent. The LPA originated from ascending aorta posteriorly and the RPA filled though the PDA. No doubt that both the PAs filled on the aortic injection simultaneously! We relearned a precious lesson of not presuming without considering the alternatives!! What could have been a surgical disaster was managed by superior surgical skills of our experienced surgical team.

What is the impact of a severe Shone physiology on PDA? We had a 6-year-old girl with severe subvalvar MS, bicuspid aortic valve with severe AS and a large PDA shunting bidirectional. With the aortic pressures being low due to severe MS and AS, and PA pressures being high due to MS, can we decide operability of PDA by the direction of shunt? The child saturated 94% on upper limb and 86% on lower limbs, would it suggest Eisenmengarization? Should we cath the child? The surgical team opined that the child should be cathed for operability. It is again the question of sequential lesions that we had discussed few posts back. We had some surgical success in such lesions in the past, but the patient then was a toddler. The age is against us this time. Is there any way of clinical decision making? Please let me know if you have any experience in this regard.

Pen in your opinions in the comments. You can also send in your opinions and your experiences to my email: drkiranvs@gmail.com I shall post them on your behalf with full credits to the contributor!

Regards

Kiran

Saturday, November 28, 2009

Welcome back to the NH Pediatric Cardiology blog.

We saw the historical development of Digoxin and Diuretics in the last 2 posts. In this post, we shall see the development of another important class of cardiac drugs: the Beta Blockers.

The huge laboratory of Eli Lilly in Indianapolis is a place for innovation. The recordings of events are so meticulous that serendipities are not unusual. In this lab, Irwin Slater was working on the analogues of isoprenaline to create long-acting bronchodilators. The agents were screened for their ability to relax tracheal strips contracted by pilocarpine to simulate the asthmatic bronchoconstriction. Adrenaline was used on these strips to ensure their responsiveness between the tests. Some strips were by chance got exposed to dichloroisoprenaline. Surprisingly, these strips did not relax when the adrenaline was added. For the first time, an antagonism to adrenaline was noted. In 1957, at a scientific meeting, Slater reported the phenomenon of dichloroisoprenaline antagonism.

This finding got the keen attention of Neil Moran, at Emory University in Atlanta. He requested Eli Lilly to provide samples of the new drug to investigate its effects on the heart. He was surprised to find that dichloroisoprenaline not only antagonised the changes in heart rate and muscle tension produced by adrenaline, it also mimicked the activity of the adrenaline to a certain extent. He reported his findings in a prominent journal.

It was the time when ICI Pharmaceuticals Division (now incorporated in AstraZeneca) had decided to make it big in the market. For this, they had caught a big man – James Black (Knighted in future, after winning the Nobel) Moran’s report caught the attention of James Black. The equipped Lab of ICI at Alderley Park in Cheshire was seeking a major breakthrough and had funded Black with a grant to further diversify his investigations into coronary artery disease.

Black had a phenomenal sense of first principles. He had for long believed that there exists an alternative way of treating angina. It would simply be to find a drug to reduce the oxygen demand of the heart. Black did not believe in merely increasing blood supply by vasodilators such as the nitrates. He sensed that treating a patient just symptomatically would not solve the issue. Black was in pursuit of a medication with longer, better and sustained effect that could increase the life span of the patient.

Black, by then, had realised the relationship between the heart rate and the oxygen demand. The influence of catecholamines on heart rate was well established. He was logical enough to correlate the effects of suppressing adrenaline and noradrenaline on heart rate and thereby the oxygen demand. But, his experiments along these lines till then had no gain.

On reading Moran’s paper a new wave of thought occurred to Black. He immediately realised the potential of this paper. His team had done extensive work on receptors which Raymond Ahlquist had described as beta-adrenoceptors. It should be possible to find an analogue of dichloroisoprenaline devoid of intrinsic action. This molecule can bind to the beta receptors in the heart.

Black entrusted his colleague John Stephenson to synthesise the drug of his ideas. The first effective beta-adrenoceptor blocker was synthesised in February 1960, by replacing the bulky chlorine atoms of dichloroisoprenaline with a second benzene ring to form pronethalol. The drug was orally active but short-acting. A small clinical trial on 30 patients confirmed the anticipated actions pronethalol in angina. The side effects noted were mild. It also gave pleasant surprises to the research team when its action went beyond the angina. Black had anticipated prevention of atrial fibrillation and atrial or ventricular tachycardias through diminution of the response to emotional or exercise-induced
sympathomimetic activity. This was confirmed in the trail. The drug also showed a marked hypotensive effect when taken for several months. This was totally unexpected but well desired. This led to the development of another trail in hypertensive patients. Pronethalol proved its value in reducing blood pressure also. Finally, the research team thought, the wonder drug was born!

But their happiness was short lived. Long-term toxicity testing in mice was received within few month of the trail of the drug and showed the association of pronethalol with cancer of the thymus gland. But such a big breakthrough could not be left alone. ICI decided to launch the drug late in 1963. Its use was limited to patients whose lives were seriously at risk. Today, the drug has become only a historical reference, but it started a new era in cardiac management.

No sooner the thymus carcinoma report arrived, the ICI research team started to improvise the drug. As a result, within a short time of the launch of pronethalol, the new drug propranolol was launched by ICI in 1964. It was found to be non-carcinogenic and ten times as potent as pronethalol. This marked the arrival of beta blockers in the therapeutic world and stood as the yardstick against which any improved version would be compared. All the other beta-blockers developed since then, retained the anti-anginal, anti-arrhythmic and antihypertensive properties of pronethalol.

The success of propranolol can be gauged by its existence in market even today.

Few hundred miles from ICI lab, one more team was evaluating the same compound – dichloroisoprenaline. But this centre called AB Hassle at Goteborg, Swedan was interested in potential anti-arrhythmic action. Short time after the launch of Propranolol, this centre developed and launched Alprenolol which very soon was acclaimed as an effective anti-arrhythmic with useful activity as anti-hypertensive medication. The success of this drug instigated other firms to take up active research in this group of drugs.

Another giant of a firm, Ciba, was successful in developing another beta-blocker called Oxprenolol, which retained partial agonist activity with beta1 and beta2-adrenoceptors. The advantage was immediately palpable. This agent did not produce as much bradycardia as the other beta-blockers, as this drug was capable of stimulating beta1-adrenoceptors in the heart. This property was termed as “instrinsic sympathomimetic activity” (ISA). This feature was useful in patients with peripheral vascular problems. Because of the ISA, oxprenolol did not cause feeling of coldness in extremities in patients with peripheral vascular disease, which was an undesirable feature of other beta-blockers. However, the stimulation of beta2-adrenoceptors in the lungs was suboptimal and oxprenolol was not proved sufficiently safe for use in asthmatic patients.

This led to the development of timolol, which which was initially used as antihypertensive. Some researchers found the utility of direct application of Timolol to the eye for the reduction of intraocular pressure in chronic simple glaucoma.

Few researchers kept Propranolol as the baseline drug and started improvising on it. The dihydro analogue of propranolol was the most promising and the compound was taken up by the Squibb Institute for Medical Research in Princeton. The ensuing compound led to nadolol. The dihydro component rendered it water soluble and less lipophilic. This property prevented it from entering the central nervous system, thereby reducing CNS side-effects such as sleep disturbance and nightmares associated with other beta-blockers. Also, low lipophilicity reduced the entry of the drug into liver cells. This reduced the rate of metabolism and ensured a longer duration of action.

The Mead Johnson lab could sense the potential market for beta-blokers by 1960. Their chief scientist, Larsen was a renowned name in the field of Sulfonamides. Logically, he used a sulphonamide side chain to isoprenaline in the place of phenolic group. This led to the development of Sotalol. Pharmacological evaluation showed all the components of beta-blockade. Also, as an added bonus, it also relaxed tracheal, uterine and intestinal muscles. Due to its hydrophilic nature, sotalol did not enter the CNS and had longer duration of action as nadolol.

The development of sotalol reached the ICI chemists. This led them to devise a series of its further analogues. Practolol was developed like this. Evaluation testing of Practolol had all the desired action on the heart but failed to antagonise the peripheral vasodilation caused by isoprenaline in anaesthetised dogs. For the first time a beta-blocker was selective for heart receptors. This literally caused a wave of elation in the medical community. This drug could avoid bronchospasm in patients with asthma or obstructive airways disease, which was actually a major clinical problem with beta-blockers. Practolol was marketed in 1970 for use in asthmatic patients with co-existing heart problems with much jubilation. But the excitement was short lived. Practolol on long term oral therapy could cause a serious oculomucocutaneous reaction, leading to blindness. This led to a seriously fast pursuit of alternative and better drugs and soon, practolol was abandoned. The new drug was Atenolol. As Practolol, it was relatively selective with regard to its action on beta2-adrenoceptors in the lung and on beta1-adrenoceptors in the heart. For a long time Atenolol was the most frequently prescribed beta-blocker and the third-best-selling drug in the world (after ranitidine and cimetidine). Its low lipophilicity prevented its entry into the CNS.

Atenolol, due to its phenomenal success, now stands as the baseline against which the new class of beta-blockers are developed. May & Baker developed acebutolol which could not replace Atenolol effectively. Acebutolol did not have much selectivity for cardiac receptors but it retained partial agonist activity.

Chemie Linz introduced a new developed beta-blocker compound called celiprolol. It was the first cardioselective beta-blocker with partial agonist activity. Labetalol was soon introduced by Allen & Hanbury, which had the added advantage of blocking the action of sympathomimetic amines both at beta-adrenoceptors and also at alpha1-adrenoceptors. Thus it was more effective anti-hypertensive at a lower level of adrenoceptor blockade.

Lateral thinking is a part of drug development industry! The scientists should analyse every bit of information to be better equipped to face challenges. Many drugs end up with severe side-effects, making the drug useless for the purpose. However sometimes the side-effects turn the table around – it becomes the main effect and form a therapeutic entity. Many such examples exist in the history of drug development. Beta-blockers have also contributed to this list. The side-effect associated with propranolol and other lipophilic beta-blockers was the vivid dreams or even hallucinations. The ICI scientists capitulated on this. When others in the world tried to reduce the lipophilicity to avoid CNS entry, brains at ICI prepared analogues of propranolol to increase lipophilicity further. This resulted in psychoactive drugs. In 1969 ICI patented viloxazine as an antidepressant drug. It was a relatively non-sedating antidepressant which inhibited both noradrenaline and 5-HT reuptake in the brain. The main use of this drug was in patients experiencing anticholinergic and cardiac side effects of antidepressant drugs such as imipramine and amitriptyline.

In the next post we shall see the “Developmental History” of one more class of cardiac drugs!

On a personal note, we are experiencing the “side-effects” of expansion! Incorporation of peripheral institute for high-end services is a part of growth of corporate hospitals. But the peripheral centres would not accept newly recruited specialists. They want the same specialists in the original corporate institute to attend their clientage. When the number of specialists is scarce, such demands would put extra stress on the existing specialists. This is a “no-win” situation for everyone, but is a part of the problem faced by expanding corporates also. The management which should handle such situations are usually clueless on such issues and would conveniently transfer their responsibilities to the head of the concerned speciality team. “How to...” is the major issue. If find a solution, I shall let you know!

We are witnessing a surge of patients from a neighbouring state due to a newly launched insurance scheme by state Government. This is letting us see adolescent age group with a newly diagnosed complex CHD. We saw TAPVC in second decade, Truncus at 8 years, many cases of TOF in late second decade, Eisenmengered DORV and so on. All these children would never have had a diagnosis also, let alone treatment if not for the support from Government. After the phenomenal success of Yeshaswini health insurance scheme (www.yeshaswini.org) of Karnataka state, many states have tried to emulate it. A large amount of credit for the success of Yeshaswini should be shared by Narayana Hrudayalaya also. Dr Devi Shetty was instrumental in devising and executing the scheme, which was adopted by the Government of Karnataka in a big and “never before in the country” way. One can get the entire story from multiple sources including Harvard journals, London school of Economics website, Wall Street Journal website and so on. Those who interested in the success story of Yeshaswini can Google for it with Dr Devi Shetty’s name.

How fast can a subaortic membrane recur? We have a 3.5-year-old who underwent SAM excision 2 years back with minimal obstruction post-operatively. The toddler has come back with severe LVOT obstruction with recurrence of SAM now. What might be the cause of such a fast recurrence? To begin with, what was the cause of such severe SAM at 1.5-year-old? Are these dynamics different from SAM in older age group? When SAM excision has not worked for 2 years also, how long it would work now? Is the pathophysiology of such subgroups different? Is there an additional problem with LVOT? Do such subgroups require different lines of surgical management? Should a Konno be performed in them? Is only Konno enough or a Ross-Konno is required? Should such an extensive surgery be done at the inception or on Re-do if required? Are cases of re-do for SAM in such young age described? Any inputs on these issues? If anyone has any data, please let me know. If references are also provided (if any), it would be much appreciated.

We had a 5-year-old with Tricuspid atresia IIB. The cath data was in favour of surgical intervention. However, this baby had veno-venous collateral. It was deemed that the collateral can decompress the PA pressure and the actual PA pressure would be much more than the measured PA pressure in the cath (12mmHg). Is there any way of putting a correction factor for such situations? Can we just presume something and change our plans? What would be more logical in such cases? Please put in your thoughts.

When we look for reversibility of PVRI in the cath studies, we use oxygen or NO or both. If the post-oxygen data turns out be good by drop in the PVRI, we operate. However, such patients don’t live with higher concentration of oxygen after the surgery. So, what is the logic behind the using these agents to check the reversibility? This question was popped up in one of our sessions and a satisfactory answer could not be obtained by the house. Any references on this?
Has anyone done any research in this? What was the original explanation be the researchers who devised these techniques? Please let me know.

How does a combination of obstructive lesion and a shunt lesion behave? I had put this question for last two posts in the case of a VSD and Coarctation. Is the logic different for PDA with coarctation? We had a toddler with large PDA and severe coarctation. Cath data showed a Qp/Qs of <1 and a PVRI of 16 Wood units.However, he was deemed operable and taken up, despite the cath data. Same data in an adolescent with VSD and coarctaion was termed inoperable. Is it because of age or the dynamics are different? This question is getting more interesting and tougher at the same time. Please put in your comments on it.

We saw a 9-year-old with TAPVC with Truncus! I had never come across such a combination before. The age was surprising. More surprising was the fact that the child was not cyanosed! Two cyanotic lesions with high Qp have failed to produce cyanosis till this age either by mixing or by high PVRI. Few people have a strong combo of luck and ill-luck running parallel!

We saw an infant who was stable with no features of increased Qp. He had a single S2 with a click and a continuous murmur. It was a perplexing clinical scenario. On echo, we found a type 2 truncus with mid segment narrowing of both PAs! This is the first time I came across a type 2 truncus with bilateral PA narrowing. Good for the kid!

What is the worldwide mortality pattern of PA bands? Is this practiced extensively in the west? Our surgeons continue to have a tough time with these surgeries. One of our senior surgeons was in favour of abandoning these surgeries for some time! Aren’t the indications for these surgeries getting modified in the current era?How are the centres across Europe and American continents doing? If you know about it, please enlighten us!

Some news from the department to share: The stork visited the Alvas! Dr Rashmi and Dr Prem Alva are the proud parents of a lovely daughter now. Best wishes for the new parents. Let the Almighty bless the newborn with all His might!

Applications are invited for the Fellowship in Pediatric Cardiology affiliated to Rajiv Gandhi University of Health Sciences, Bangalore. The fellowship would be of 18to 24 months duration. The training would happen entirely at Narayana Hrudayalaya. Doctors with post-graduate qualification in Pediatrics (MD or DNB) or Cardiology (DM) would be eligible to take the entrance exam and interview. For further details please visit the NH website: www.narayanahospitals.com

Click your comments. If you find any difficulty, feel free to communicate with me at drkiranvs@gmail.com I shall post the contents of your mail in comments on your behalf.

Regards

Kiran

Saturday, November 21, 2009

Welcome back to NH Pediatric Cardiology blog.

In the previous post, we saw the History of Digoxin. In the present post, we shall see the development of another important life saving class of drugs: The Diuretics.

Mercury can be considered as one of the oldest of all drug prototypes. The majority of drug prototypes come from the animal and vegetable sources; mercury belongs to a minority that was derived from the minerals. An ancient Hindu work by Nagarjuna, named “Rasa Rathnakara” had masterly description of using the mercury and related compounds to strengthen the weak hearts. Mercury had also been employed by Paracelsus in the treatment of dropsy.

The first diuretics were organomercurials; toxic, but effective. Their introduction into clinical medicine was in the late 1880s. Mercury benzoate, was the initially chosen one because it was slightly soluble in water. The fusion with of inorganic mercury with an organic compound was aimed at reducing the irritancy and toxicity of inorganic mercurials and to obtain a slow, sustained release of mercuric ions from the organic complex. This was followed by the marketing of a number of injectable organomercurials. One such compound was introduced in 1912 by F. Bayer & Company for the treatment of syphilis. This was called merbaphen, a double salt of sodium mercurichlorophenyloxyacetate with barbitone.

Serendipitous use struck gold seven years after the introduction of merbaphen when Arthur Vogl, a third year medical student at the Wenckebach Clinic in Vienna’s First Medical University, had ordered a 10% solution of mercury salicylate to be prepared by the hospital pharmacy. When he did not get the preparation, he went to the pharmacy and was told that a solution in that concentration could only be prepared as an oily injection. A colleague suggested Vogl to use merbaphen injection instead and was done. As a routine, the meticulous nursing staff maintained the chart of the urine output of the patient. Vogl was surprised to see that, the patient who was struggling to pass 500 ml of urine in 24 hours had passed 1200 ml in 24 hours after the very first dose of merbaphen. After the third daily injection, this had increased to 2 litres in 24 hours; a feat which no other known medication of that time could achieve! Interested in creating a cause-effect relationship, Vogl withheld the medication for a few days and dramatically, the urine outflow decreased. On resumption of the injections, urine output improved again. Vogl decided to extend this use in other patients. He chose to administer merbaphen to another syphilitic patient with advanced congestive heart failure. Conventional diuretics of those times had no effect on this man. Vogl was not surprised this time to see his patient passing massive amount of almost colourless urine with the first dose of merbaphen. The flow continued throughout the day and the night and by the next morning the patient had passed about 10 litres with thorough exhaustion and elation at the same time! Vogl found that profound diuresis was produced in any patient injected with merbaphen. But other antisyphilitic mercurials could not produce any effect close to this. After confirming this in multiple subjects, Paul Saxl decided to conduct a thorough clinical evaluation. This transformed the treatment of the severe oedema of congestive heart failure, allowing it to recover to normal function. No other medication used hitherto had any activity comparable to this.

The joy was short lived. It was soon recognised that merbaphen injections posed a risk of severe renal damage or fatal colitis. But the effect was not ignorable. So, improvisation process began and soon, merbaphen was replaced by another antisyphilitic agent, mersalyl, which was administered on an intermittent schedule to minimise toxicity.

Around the late nineteenth century that mercury and mercurous chloride were introduced as oral diuretics. Tablets combining finely dispersed metallic mercury with digitalis remained on the market until rendered obsolete by the introduction of the thiazide diuretics in the 1950s.

The demand for a non-toxic, potent diuretic was critical and the challenge was accepted by a team of researchers from Sharp & Dohme, under the direction of Karl Beyer in the early 1950s. The then recent developments in renal physiology had convinced him that the moment had come to design a safe, effective diuretic. The renal physiology had proved the role of renal tubules in the reabsorption of water from the glomerular filtrate. It was understood that the efflux of sodium ions across the tubule wall was the responsible factor. It was believed that mercurial diuretics interfered with movement of ions by inhibiting dehydrogenase enzymes inside the tubular cells. This prompted the Sharp & Dohme scientists to try designing mercury-free inhibitors of dehydrogenases in order to avoid the toxic effects of mersalyl.

Although, in theory, they had proved the requirement, practically, it was a daunting task that took many years of intensive research. After series of failures, they decided to reaffirm their hypothesis. They went back to understand the correct action of mercurials. This turned out to be the turning point. It was the realised that both merbaphen and mersalyl possessed a phenoxyacetic acid moiety. When an unsaturated ketone was attached to the 4-position of the benzene ring, potent hydrogenase inhibitor was obtained. When they sought the influence of additional substituents, it was shown that chlorine or methyl groups attached to the benzene ring further enhanced potency. Ultimately, ethacrynic acid emerged as a safe, orally active diuretic in 1962, five years after a separate group of Sharp & Dohme chemists had announced their discovery of the thiazide diuretics with similar properties.

Thaddeus Mann and David Keilin were the researchers working at the University of Cambridge in 1940. They had had isolated in an enzyme in pure state a year before which was known to play an important role in the output of carbon dioxide by the lungs. The enzyme was called carbonic anhydrase. They observed the fall in carbon dioxide binding power of the blood caused by some of the recently discovered antibacterial sulphonamides. They carried out an experiment to determine whether this could be accounted for by inhibition of carbonic anhydrase. The experiment confirmed their suspicions. Sulfanilamide was the prototype.

At the Harvard Medical School, researcher Horace Davenport discovered large amounts of carbonic anhydrase in the kidneys. Earlier, Rudolf Hober had observed alkaline diuresis in patients who had been given massive doses of sulphanilamide. Now it could be accounted for by increased excretion of sodium bicarbonate caused by carbonic anhydrase inhibition. The resorption of water from the tubules of the kidney depended principally on the absorption of sodium ions from the lumen. When the enzyme was inhibited, sodium ions were excreted in the urine because the process responsible for their reabsorption was blocked.

Davenport informed the data to Richard Roblin at the Lederle Division of the American Cyanamid Company and sought a more potent inhibitor of carbonic anhydrase from them. Thiophen-2-sulfonamide was provided in the belief that it would be more acidic than conventional sulfonamides and that this would enhance its ability to compete with carbon dioxide for the active site on the enzyme. It was about 40 times more potent than sulphanilamide in inhibiting carbonic anhydrase.

Boston physician William Schwartz in 1949 experimented with oral sulfanilamide to obtain diuretic effect. But he had to abandon this due to toxic side effects. But, this observation prompted Roblin’s interest in carbonic anhydrase inhibitors again. He and James Clapp restarted their experimentation and within a year, acetazolamide was synthesised. It was about 330 times more potent than sulfanilamide as an inhibitor of the enzyme.

Acetazolamide was available as orally active diuretic in 1952. Soon, it was noticed to have a variety of complications. The only way to use acetazolamide was on an intermittent schedule. Serendipitously, the inhibition of carbonic anhydrase in other parts of the body was turned to advantage, as in the treatment of glaucoma. Acetazolamide remains in use for this purpose even today.

Karl Beyer could not be left behind for long. Leading a new project for Merck, Sharp and Dohme, he analysed the problem with sulphanilamide. He found that that it inhibited carbonic anhydrase at the distal end of the renal tubules, rather than solely at the proximal end. This could be accounted for the increased excretion of bicarbonate. He sought a carbonic anhydrase inhibitor that acted in the proximal portion. Such a drug would have the advantage of being useful antihypertensive agent. It was the time when low salt diets were believed to be an effective means of controlling high blood pressure. The first carbonic anhydrase inhibitor that Beyer came out with the name of carzenide. But, in humans it was poorly absorbed from the gut and had weak diuretic activity. It still inspired James Sprague and Frederick Novello to research further. This led to the introduction of clofenamide which was a potent carbonic anhydrase inhibitor. Further medication of this was dichlorphenamide which produced an increase in chloride secretion in humans.

Dichlorphenamide served as a baseline drug for the future research. Further research was aimed at achieving better dieresis with no further reduction in chloride ion excretion.

Novello and colleagues made the N-formyl analogue with formic acid. This resulted in an unplanned ring closure to form a benzothiadiazide. As a matter of routine, this novel compound was entered in the screening programme. It was a matter of surprise and delight to the team when it was found to be a potent diuretic which did not increase bicarbonate excretion. Clinical tests confirmed the safety of this orally active diuretic with marked saluretic activity.

With the first reports in 1957 it was termed ‘chlorothiazide’. It had duration of action of 6–12 hours. Literally overnight, singlehandedly, it rendered mercurial diuretics obsolete for the treatment of cardiac oedema associated with congestive heart failure. Chlorothiazide still remains in use because of its low price.

On the other side, Ciba scientists led by George De Stevens replaced the formic acid used to produce chlorothiazide with formaldehyde and thereby obtained hydrochlorothiazide, which was ten times as potent as chlorothiazide. Since then, many other thiazides have been developed.

Dichlorphenamide was still the baseline drug for the research. Some modifications in the acidic side of it and replacement with a carboxyl group gave a new molecule. This led Hoechst to introduce frusemide (also known as ‘furosemide’) in 1962. It had a quicker onset of activity, more intense and of shorter duration than any other diuretic. Frusemide had a different site of action within the kidney tubule and became known as a loop diuretic because it acted in the region known as the loop of Henle. Loop diuretics were valuable in patients with pulmonary oedema arising from left ventricular failure. Despite thiazides being indicated for most patients requiring a diuretic, frusemide is widely prescribed.

Bumetanide is a more potent loop diuretic introduced by Leo researchers ten years after frusemide. Hoechst introduced its analogue known as piretanide when their patent on frusemide expired.

In the next post, we shall see the fascinating history of one more class of drugs.

On a personal note, the work at NH is getting heavier with all the addition of Tamil Nadu government insurance schemes. We ended up doing echoes for patients with eye burning, skin infections and healed fractures! The screening does not happen at any place for such patients. Most of them would like to take the advantage of the free services and would insist on getting all the investigations done free of cost. The ensuing load on doctors and the compromise in the quality of investigations done are nobody’s concern. We insisted on putting up a higher limit to the numbers everyday for the scheme patients. But, eventually, we would end up seeing loads of children who would probably not require echocardiography otherwise. I don’t know how much of quality compromise has happened due to extension of echo and OPD timings by at least 2 hours every day!

Is it possible to a Fontan repair in a case of interrupted IVC? The usual protocol is to do a Kawashima repair, which does not involve incorporation of hepatic veins into the venous circuit. The chances of AV fistulae are higher possibly due to the lack of hepatic factors. But, if by any chance we can incorporate the hepatic veins into the venous circuit, would this be called Fontan repair? In case of one such boy, our surgeons evaluated the cath images and were of the opinion that a Fontan repair can be done. Any inputs?

How often do we find a diverticulum in the RV? We had one such patient with DORV of single ventricle physiology. His RV angiogram showed an outpouch of contractile nature. The close DD would be an aneurysm which would be devoid of any contractile elements. Atrial diverticulae and LV diverculae are known. But this is first RV diverticulum we have come across in recent times.

In cases of older children with Tetralogy, if PA sizes are small and eventual McGoon ratio is low, should we consider Brock’s procedure? It is said that, as the age progresses, the PA sizes cannot improve with BTT shunt. Is the improved antegrade flow the best way of improving PA sizes? If so, can Brock’s be the way? It is true that the patient would through for bypass for this. But, if it has the potential to prepare the patient for the future complete correction, is it not worth it? Are there any repots of using Brock’s procedure for such a purpose? It is a “third world” problem and developed countries may not have seen such an eventuality. If anyone’s got any data or experience on this, please let me know.

Is there an oral inotrope that is as effective as IV? Can levosimendan qualify? In cases of chronic ventricular failures, the patients cannot be on IV inotropes for long. They can have some solace if they can be treated at home with some oral inotropes. The traditional drugs with inotropic action may not suffice all the times. If anyone had any personal experiences with their patients, please let me know.

In the last post, I had put up the case of sequential lesions. Our patient had a VSD and severe coarctation. The query was the operability assessment of VSD in the presence of severe Coarctation. We decided to balloon the coarctation and check for VSD operability. After successful balloon coarctoplasty, we found that the VSD had a PVRI of 18 wood units. Is there a way of assessing the same thing prior to coarctation intervention? Any experiences? Please let me know.

How many times do we come across cyanosis in ASD in children? It is a typical exam question and most of us know about 5 to 6 causes. But, we happened to see one child with ASD and cyanosis. The subcostal windows were suboptimal. All the causes we knew were verified, but with no gain. At last, we decided to do a contrast study and found to our surprise that the RSVC was entering directly into LA! There was no LSVC or PAPVC or TAPVC. How common is such a situation? I came across such a lesion for the first time.

We happened to see one 18-year-old boy with unobstructed TAPVC and dTGA with ASD and intact IVS. Is there any advantage of doing any surgical procedures now? Is it ethical leaving him as he is? Again, these are the “third world” dilemmas! What is the natural history of an untreated dTGA? Does the co-existing TAPVC has changed the course? Any inputs?

I would be happy to see your inputs. In case of any difficulty in posting a response, please send it to my email drkiranvs@gmail.com I shall post your response on your behalf.

Saturday, November 14, 2009

Welcome back to NH Pediatric Cardiology Blog

I started feeling a kind of vacuum after the History of Pediatric Cardiology was completed. A couple of sessions with Nobel prize winners could do no good to my feelings, as the research involved was neither extensive, nor satisfying. I sought suggestions from my team; and as usual, very few came in! I was suggested to go with some of the musings we came across in the wards and OPD. True life incidents involving parents’ feelings and doctors’ dilemmas were suggested. Incidents which changed our outlooks towards something was another suggestion. Miraculous survivals or an improvement in some of the patients and possible causes of it was another suggestion. All these are no doubt good, but they lack the sustenance value. They may be inserted as snippets, but cannot sustain an entire post. Also, their frequency is less. Nevertheless, I have received all these suggestions with great fervour, and hope to do justice to them sometime in future.

I have known people who are into pharma research. I happened to meet some of them, who have spent years together in developing an elusive drug, just to see nothing at the end of it! But, what a zest they have! I always had the admiration for the creators. It is in this spirit that I will be writing on the history of development of some of the cardiac drugs. They should read like a proper story albeit a true one. It is an ode to the people who have made it for all of us.

It might be prudent to make a beginning with the most famous and equally controversial yet indispensible drug of cardiology. Yes, the mighty DIGOXIN!

Foxglove (Digitalis purpurea Linn) was a folk remedy introduced into medicine in the 18th century. It grew throughout Europe. The term “Fox” was a misnomer as this shrub was originally known as the folksglove due to the shape of its flowers. The shape of the flowers and the colour gave its scientific name, which is derived from what was given to it in AD 1539 by Hieronymus Bock. He explained that
‘digitalis’ was an allusion to the German word fingerhut (finger stall), since the blossoms resembled the fingers of a glove.

Foxglove has a long history of folk use. The Ancient Celtic tribes know about it and made use of its medicinal properties. A family of 13th century Welsh healers applied it to the body by inunctions to relieve headache, abscesses and cancerous growths. It was also listed among herbs used by Edward III of England in the 14th Century.

In 1775, the English physician and botanist William Withering (1741–1799) was asked his opinion of a herbal tea prepared by an old lady on countryside for the relief of dropsy. Her medicinal preparation boasted of phenomenal success to dropsy, for which the then medical world did not have a proper remedy. The cause of dropsy was then unknown, so the possible explanation of the treatment was explained by expulsion of the excess body fluid. Withering, who was a trained botanist, very soon realised that among the 20 or so ingredients in the herbal tea, it was the foxglove that was most likely to be causing the violent vomiting and purging if taken in excess. During the next nine years, Withering treated 158 patients with it, of whom about two-thirds responded favourably. In 1785, he wrote his treatise entitled “An Account of the Foxglove, and Some of its Medical Uses: with Practical Remarks on Dropsy, and Other Diseases”. The write up was not only a list of his observations, but also, a description of how to determine the correct dosage, which was highly relevant since foxglove was a potent poison that was ineffective unless administered at near the toxic dose level. He took care to standardise the doses he used, to a level for determining the correct dosage for each patient. He also discussed different ways of preparing foxglove, preferring the use of powdered leaves.
However, what Withering did not realise was that the stimulant action of Foxglove on the heart which was responsible for its beneficial role in dropsy. It was paradoxical that in the year 1799, the year of his death, Ferriar suggested that the increased urinary output was of secondary importance compared with the power of foxglove to reduce the pulse rate.

Although it was not in great use at that period, some minds could identify the importance of this drug very soon. The need for isolating an active principle from digitalis was recognised and attempts were made in the 1820s for the same. To stimulate research, the Paris Pharmacological Society offered a prize of 500 francs for the isolation of a pure principle from the plant. As per the prevailing financial rule, this sum was to be doubled every five years if no claimant came forward. But, in 1841, the French pharmacists E. Homolle and Theodore Quevenne won the award for their isolation of an impure crystalline material which consisted mainly of impure digitoxin. They called this ‘digitalin’, a name also applied to various products obtained by other workers.

However, the principal cardiotonic glycoside present in the leaves of Digitalis purpurea which was termed Digitoxin, was isolated in 1875 by Schmiedeberg at the University of Strassburg in Germany. He obtained crystals from digitalis leaves.

It was an era when the apparent clinical success would not pave for the regular use of medicines. Because of the lack of a clear understanding of how it was able to affect dropsy, foxglove was rarely used as a cardiac stimulant during the 19th century. German pharmacologist Ludwig Traube revealed the stimulating effect of foxglove on heart muscle in 1850. But it was around 1901 that a clear understanding of the effects of foxglove on heart was revealed by the development of the polygraph by the Scottish physician James Mackenzie and the electrocardiograph by the Dutch physician Willem Einthoven. Subsequent investigations along these lines revealed some of the correct indications for the use of digitalis: atrial fibrillation or in certain forms of heart failure in sinus rhythm.

In 1920, Max Cloetta in Zurich hydrolysed digitoxin under acid conditions and isolated the aglycone, digitoxigenin, which had weak cardiotonic activity. Adolf Windaus finally obtained pure digitoxin in 1925, at the University of Gottingen.

The structure of digitoxigenin was determined by Walter Jacobs and his colleagues at the Rockefeller Institute in New York, but it was not until 1962 that chemists at Sandoz in Basle elucidated the structure of the sugar residue and hence that of the entire molecule of digitoxin.

In the late 1920s, it was discovered that the powdered leaves of Digitalis lanata, once popularly known as ‘woolly foxglove’, had greater physiological activity than those of Digitalis purpurea. This led Sydney Smith of Burroughs Wellcome in London to isolate digoxin. This is now used more than either powdered digitalis leaves or digitoxin since it does not bind as strongly to proteins in the tissues and plasma, resulting in less delay before a therapeutic concentration of unbound drug can build up. Clearance from the body is also faster as only unbound drug is filtered by the kidneys; consequently digoxin is less cumulative and thus safer to use. It has become the standard digitalis preparation in current usage.

Thanks to the painstaking efforts of Withering, experimental medicine was now able to exploit the single greatest breakthrough in the history of drug discovery. Progress from prehistoric times until then had been pitiful because two essential factors were missing: access to chemical compounds with consistent potency and effective methods of clinical investigation. Access to these during the past two hundred years has made it possible to identify and exploit beneficial drugs, free from the dogmatic teachings that were the legacy of the past and a major obstacle in the path of drug discovery. The discovery of Digoxin paved a new revolution in the field of drug discovery and its scientific analysis. The nature hides millions of such drugs, waiting for the mankind to explore with open mind. We need more “Witherings” to do it!

If we can name one more class of drugs used to a great extent in the clinical cardiology, it must be diuretics. The journey till the point of high ceiling diuretics has been equally fascinating. It all started with experimental medicine with keen eyes and mind with meticulous observations. We shall see the development of Diuretics in the next post.

On a personal note, we were wondering how much challenges this small filed of pediatric cardiology can pose! Someone had once told me, “You have 4 valves and 4 chambers. How much is there to learn in Pediatric Cardiology?” With every new challenge, I remember that person!

We saw an 11-year-old boy in our OPD with NYHA class 2 symptoms. On examination, he had RV apex, RV forces, wide fixed split, PSM at RLSB. Also had an ESM at RUSB. Except for the ESM, everything was fitting into the diagnosis of ASD. What we saw in echo was surprising. The IAS was intact. RV was hypertensive and dysfunctional. There was a severe TR. Further, the IVS was intact. MPA continues as RPA with absent LPA. RPA had a gradient of around 50mmHg. The fixed split and PSM were thus explained. Also, the ESM could find a place. But, what started first? Was it the RPA stenosis (which is underestimated now) the primary event? What might have caused RV dysfunction? We have no previous records. In such cases how to explain the chronology of events?

We saw a 17-year-old boy with Tetralogy of Fallot. Though echo windows were compromised, we could see a dilated origin of Left coronary artery. We subjected him for cath study, which showed a large Left coronary to PA collateral. This was second such instance we had seen such an anatomy with TOF. However, in this boy, the PAs were small. McGoon ratio was 1.2 How to go about? This boy had SO2 of 86%. BTT shunt is unlikely to improve his saturation or PA sizes. He had no angina pain and no indication of coronary steal. Dr Sunita suggested Treadmill test for inducible ischemia. TMT was terminated due to effort intolerance, but no angina. TMT did not show any ST-T changes. This boy had achieved 6.5 METS. The surgical team is keen on ligation of coronary to PA collateral and creation of BTT shunt. But the question remains same: Has the patient earned his surgery? Can we wait? Is it advantageous or not to wait? Please let me know your takes on this situation.

The enigma of sequential lesions never ends amusing us. We have a 4-year-old boy with VSD and a tight coarctation of aorta. Cath data is obviously has its limitations and usually not accepted well by surgeons. In this case, the cath data showed PVRI of 14 Wood units with oxygen. We suggested balloon dilatation of CoA and reassessment of VSD. However, the surgical team was in favour of doing both of them together. Is there any concrete data in determining operability in such sequential compound lesions? I would like to know the opinion from experienced. Also, please quote some references if anyone has.

What baseline saturation in OPD is the cut-off for Eisenmengarization? At OPD, we get both baseline SO2 at rest and with exercise whenever deemed necessary. Sometimes, the data does not match with the cath data. Is there a reasonable cut-off for the OPD saturation below which the cath is not necessary? If anyone knows any number for this, please let me know the reference.

Perloff defines the Anamolous Pulmonary Venous connection and Anamolous Pulmonary venous drainage separately. We happened to see an infant with all 4 pulmonary veins draining independently into the right atrium. The LA was fed by an ASD. There was no common confluence. Is it an abnormal connection or drainage? We have seen such a pattern earlier also, but never pondered on the embryological basis for such an anomaly. If anyone knows any case reports, please let me know.

Thanks to Dr Amit Misri for the comments. I have posted them on the comments section on the previous post.

I shall also welcome our new follower, Dr Sanjay Panda. Can you please introduce yourself for the others, Sir? The team would love to hear more about you.

Please send your inputs. Feel free to send it to my email drkiranvs@gmail.com I shall post it on your behalf.

Regards

Kiran

Sunday, November 8, 2009

Welcome back to the NH Pediatric Cardiology blog

We had seen some of the Nobel achievers in Cardiology. We would see the final instalment of this now.

American physician Dickinson Woodruff Richards Jr was born in 1895 in Orange, New Jersey. He received a B.S. degree from Yale University in 1917. Following service in the United States Army in World War I (1914-1918), he entered the College of Physicians and Surgeons of Columbia University, receiving an M.D. degree in 1923. Richard's association with Columbia as a researcher and professor of medicine began in 1928 and continued until his retirement in 1961, after which he became Emeritus Lambert Professor.
In the early 1930s Richards teamed with André Frédéric Cournand at New York's Bellevue Hospital, one of Columbia's teaching facilities, to investigate the interrelated functions of the heart, lungs, and circulatory system. One of Richards's key objectives was to measure precisely the changing levels of oxygen and carbon dioxide in blood as it circulated through the heart and lungs. Richards and Cournand had read of the experiments of Werner Forssmann, who a few years earlier had experimented with cardiac catheterization on himself. Richards and Cournand refined Forssmann's work, performing catheterization first on animals and then, in 1941, on humans. The ability to place a sensing device directly into the heart, where it could be safely left for hours, provided a wealth of new information on heart and lung function. Exact concentrations of carbon dioxide and other gases could be determined in specific locations of the heart. They made it possible to obtain precise measurements of blood pressure and blood volume in the heart and lungs. Richards and his collaborators gained new insight into many disorders such as those caused by malfunctions in the heart's valves. Later, during World War II (1939-1945), they performed crucial research on how the heart, lungs, and blood are affected by shock in reaction to injury.
Through his improvements to the procedure of cardiac catheterization, Richards greatly advanced the knowledge of how the heart and lungs function. Cardiac catheterization was an obscure and largely untried procedure before Richards and his colleagues refined it into the essential diagnostic tool. For their advancements in cardiac catheterization and circulatory system functions, Richards and French American physiologist André Frédéric Cournand were awarded the 1956 Nobel Prize in physiology or medicine, which they shared with German surgeon Werner Forssmann.
Richards also made important studies of the effects of the drug digitalis, given to patients to stimulate a weakened heart.

André Frédéric Cournand , the French-born American physician was born in 1895 at Paris. He received his B.S. degree from the Sorbonne, University of Paris, in 1913. He remained there to begin his medical studies, which were interrupted by World War I (1914-1918). After service in the French Army during the war, Cournand resumed his medical studies, finally receiving his M.D. degree in 1930. He then moved to the United States and an internship in the Columbia University division of Bellevue Hospital in New York City. In 1934 he joined the teaching staff of the Columbia College of Physicians and Surgeons, remaining there until his retirement in 1964. He became a U.S. citizen in 1941.
In the 1930s Cournand, along with his colleague Richards, set out to study how the heart, lungs, and circulatory system work together as an integrated unit. They believed that the technique of cardiac
catheterization, pioneered in Germany a few years earlier by Werner Forssmann, might provide the best tool for their research. Forssmann had demonstrated the safety of inserting a catheter into the heart by performing such procedures on himself. Cournand and Richards worked to improve Forssmann's procedure by experimenting with catheterization on laboratory animals. Within a few years, they had advanced the technique considerably, demonstrating that a catheter could remain in the heart for hours without harmful effect. The way was open to experiment with the procedure on humans. In 1941 Cournand and his colleagues performed their first catheterization on a human patient. Very soon, as their research progressed, their findings were providing a wealth of information on cardiopulmonary function and the interrelated action of the heart and lungs. For example, the catheter permitted the drawing of blood from directly inside the heart, providing samples that had never before been available. Using devices on the tip of the catheter, the researchers could also make precise readings of blood pressure, and measurements of oxygen and carbon dioxide in the circulating blood as it moved through the heart and lungs. Later Cournand and his colleagues used catheterization to study how the heart, lungs, and blood function during the state of shock brought on by traumatic injury. In short, the work of Cournand and his collaborators did much to clarify the workings of the heart and circulatory system in healthy subjects as well as in those suffering from cardiopulmonary disorders. Today cardiac catheterization remains an essential tool in cardiology.
Cournand and his colleagues helped clarify many important aspects of how the heart and lungs function. For their advances, Cournand and American physician Dickinson Woodruff Richards, Jr. received the 1956 Nobel Prize in physiology or medicine, which they shared with German physician Werner Forssmann.
In addition to the Nobel Prize, Cournand's other distinctions include the prestigious Albert Lasker Basic Medical Research Award of the American Public Health Association in 1949.

German physician Werner Forssmann was born in 1904 at Berlin. He completed his medical training at that city's Friedrich Wilhelm University in 1929. He then joined the Eberswalde Surgical Clinic near Berlin, where his key experiments with catheterization took place. Later in his career, as a surgeon specializing in urology, Forssmann was associated with hospitals in Berlin, Dresden, and Düsseldorf.
At Eberswalde, Forssmann was convinced that methods for diagnosing heart disorders and for injecting drugs directly into the heart could be improved. Having read earlier accounts of cardiac catheterization in laboratory animals, he began experimenting with this technique on human cadavers. In 1929 Forssmann performed a cardiac catheterization on himself as its first trial in a living human. Inserting a catheter into a vein in his arm, he pushed the tube up the vein until it entered the right side of his heart, where he observed it by means of a fluoroscope.
After continuing his research, Forssmann published a summary of his findings in 1931. The German medical establishment, however, refused to accept the validity of Forssmann's work, regarding his
experiments as stunts rather than as legitimate research. After being dismissed as a charlatan, Forssmann abandoned his catheterizaton experiments and in 1932 began training as a urological surgeon. Meanwhile, physiologists in the United States, including Cournand and Richards, read Forssmann's writings and continued to develop cardiac catheterizaton, achieving unprecedented insight into the workings of the heart and lungs. For his contribution to cardiac catheterization, Forssmann was jointly awarded the Nobel Prize in physiology or medicine along with French-American physiologist André Frédéric Cournand and American physician Dickinson W. Richards in 1956.

British pharmacologist Sir James Whyte Black was born in 1924. Working at the King's College Medical School in London, he developed several drugs for treating peptic ulcers and heart disease. Black shared the 1988 Nobel Prize in physiology or medicine with American biochemists Gertrude Belle Elion and George Herbert Hitchings.
Propranolol was the drug created by Black and his research team in 1964, binds to beta-receptors. Usually these beta-receptors bind to epinephrine and norepinephrine, hormones that stimulate the heart. For heart patients, too much stimulation of the heart is dangerous, and propranolol relieves this stress. Propranolol is also used to treat heart attacks, high blood pressure, and migraine headaches. Today this class of drugs is known as a beta-blocker. Black also developed cimetidine, for the treatment of ulcers.
In 1981 Black was knighted by Queen Elizabeth II of England for his service to medical research.

American chemist Gertrude Belle Elion was born in 1918 at New York city. Elion received an M.S. degree from New York University and began her long tenure (1944-1983) at the Burroughs Wellcome pharmaceutical company at the height of World War II (1939-1945). Before the 1940s few women worked as scientific researchers, but the war afforded more opportunities for women as men were called to the battlefront. At Burroughs Wellcome, Elion teamed up with American chemist George Herbert Hitchings. Together, they developed many drugs that have been proven effective against previously untreatable diseases. Elion and Hitchings shared the 1988 Nobel Prize in physiology or medicine with British pharmacologist Sir James Whyte Black.
Elion and Hitchings compared the functioning of normal human cells with that of bacteria, viruses, and cancer cells in order to find ways to inhibit or kill harmful invading cells without damaging healthy body cells. Elion and Hitchings concentrated on how cells synthesize the building blocks of deoxyribonucleic acid (DNA) called nucleotides. They successfully blocked the manufacture of new DNA in harmful cells; this stopped the cells from multiplying. The researchers accomplished this feat by developing chemical compounds that would fill in for key nucleotides. Because different sequences of nucleotides are manufactured by different cells, Elion and Hitchings were able to fabricate compounds that would attack the DNA only of the dangerous cells.
Over nearly four decades of research, Elion and Hitchings developed drugs for the treatment of many diseases and conditions, including cancer, malaria, leukemia, herpes, gout, heart disease, autoimmune diseases, bacterial infections, and transplant rejections. Their techniques are now standard in the pharmaceutical industry, but were revolutionary in the 1940s when they were first developed.
After her retirement in 1983, Elion taught, held various advisory positions, and continued consulting for the Burroughs Wellcome Company. In 1991 President Bush presented Elion with the National Medal of Science.

American pharmacologist Robert F. Furchgott was born in 1916 at Charleston, South Carolina, Furchgott earned his bachelor’s degree in chemistry in 1937 at the University of North Carolina and completed his doctoral studies in 1940 at Northwestern University in Illinois. Since 1956 he has been a professor in the Department of Pharmacology at the State University of New York (SUNY) Health Science Center in Brooklyn. In 1988 he earned the title of Distinguished Professor at the center. He is now Distinguished Professor Emeritus.
Furchgott helped demonstrate that nitric oxide (NO), a molecule produced in the form of a gas in the cells of humans and other life forms, can act as a signaling molecule. Signaling molecules are released by cells and transmit messages to other cells. Furchgott found that messages transmitted by NO play essential roles in the regulation of blood pressure and other cardiovascular functions.
His contributions opened an active field of research into the properties and actions of NO. This research has shown that NO is involved in many physiological processes, including memory and other nervous-system functions, as well as certain responses of the immune system to infection.
Furchgott’s breakthrough studies with NO can be traced to the late 1970s, when he investigated the relaxation of smooth muscle in the blood vessels of rabbits. He discovered that the blood vessels would not dilate unless the inner cellular lining of the vessel—a layer called the endothelium—was intact. He surmised that the endothelial cells produced a substance that acted as a signal to the smooth muscle cells surrounding the blood vessels, causing the muscles to relax and the vessels to dilate. Furchgott called this hypothetical agent endothelium-derived relaxing factor (EDRF). He then set out to identify this signaling molecule.
Meanwhile, other researchers were working on pieces of the same puzzle. Among them was American pharmacologist Ferid Murad, whose work at the University of Virginia and at Stanford University had demonstrated that nitroglycerin and other so-called vasodilators cause blood vessels to dilate by releasing NO. During the early 1980s, Furchgott began working on the theory that EDRF and NO were identical. At the time, the NO molecule was known primarily as an air pollutant resulting from the burning of nitrogen, for example, in fumes from automobile exhaust, and Furchgott’s theory seemed farfetched. Nevertheless, he officially proposed the theory at a meeting of biomedical scientists in July 1986. Another American pharmacologist, Louis J. Ignarro of the University of California, Los Angeles, who had been working independently of Furchgott, made the same proposal at the meeting. Subsequent research supported their theory.
Scientists have since intensively investigated NO and its properties. Now NO is known to play many roles in the body. Some types of brain cells, for example, communicate by releasing or receiving NO. White blood cells of the immune system release the gas to fight bacterial infection. Among its many cardiovascular functions, NO is involved in the blood flow involved in penile erection. The drug Viagra, which has helped millions of men overcome impotence, owes its success in part to the NO research sparked by Furchgott.
In 1998, the importance of Furchgott’s work was acknowledged with science’s highest honor, the Nobel Prize. Furchgott shared this prize with Ignarro and Murad. Furchgott’s other distinctions include the Gairdner Foundation International Award in 1991, the Wellcome Gold Medal from the British Pharmacological Association in 1995, and the Albert Lasker Basic Medical Research Award, which he shared with Murad in 1996.

American pharmacologist Louis J. Ignarro was born in 1941 at Brooklyn, New York. Ignarro earned his bachelor’s degree in pharmacy from Columbia University in 1962. He earned his Ph.D. degree in pharmacology in 1966 from the University of Minnesota. Between 1979 and 1985, Ignarro was a professor in the pharmacology department at the Tulane University School of Medicine in New Orleans, Louisiana. Since 1985 he has been a professor in the Department of Molecular and Medical Pharmacology at the University of California, Los Angeles, School of Medicine. Ignarro’s research helped solve a mystery first uncovered in the late 1970s by American pharmacologist Robert F. Furchgott. Furchgott noted that blood vessels would expand, or dilate, only if a specific cellular layer surrounding the vessels—the endothelium—was intact. He proposed that cells in the endothelium released a chemical factor that caused smooth muscle cells around the vessel to relax, with the result that the vessel would dilate and blood flow would increase. Ignarro set out to identify this agent, which Furchgott had named endothelium-derived relaxing factor (EDRF).
Ignarro’s experiments led him to suspect that EDRF might be the gas NO. The prospect seemed unlikely because at the time NO was known primarily as an air pollutant. Ignarro pressed on with his research,however, and at a meeting of biomedical scientists in 1986, he officially proposed his theory that EDRF was NO. Furchgott, who had independently pursued the same theory, presented the same proposal at the meeting. Subsequent research supported their conclusion. In the years following Ignarro and Furchgott’s discovery that EDRF and NO were the same substance, interest in NO virtually exploded. Based on the increasing knowledge of NO and its actions, scientists are pursuing new therapies for heart disease, cancer, septic shock, and other diseases. Even the celebrated anti-impotence drug Viagra owes a debt to Ignarro’s work. Viagra increases the blood flow in the penis, helping to produce an erection.
In 1998 Ignarro’s discoveries were honored with the Nobel Prize in physiology or medicine. He shared the prize with Furchgott and the American pharmacologist Ferid Murad, who had also achieved insights into NO’s cardiovascular function. He helped illuminate the cardiovascular role of nitric oxide. Ignarro was among the first to suggest that NO serves as a molecular signal—a substance that is released by one cell and influences the function of another cell. He also helped identify NO as a crucial agent in the process by which blood vessels widen, or dilate. Scientists now recognize that NO not only regulates blood pressure and other cardiovascular functions but also plays a role in many other processes. These processes are helping the body fight bacterial infection and sending messages between cells in the nervous system.
Other honors received by Ignarro include the Merck Research Award in 1974 and the Lilly Research Award in 1978.

American physician and pharmacologist Ferid Murad was born in 1936 at Whiting, Indiana. He earned his medical degree in 1958 from the medical school at Western Reserve University (now known as Case Western Reserve University). He remained at that institution to complete a doctoral degree in pharmacology, awarded in 1965. Murad has since held academic posts at the University of Virginia School of Medicine, Stanford University, and Northwestern University Medical School. During the early 1990s he served as a corporate officer in two Illinois-based biotechnology companies—first at Abbott Laboratories, and later at Molecular Geriatrics. In 1997 he returned to academic medicine by joining the faculty of University of Texas Medical School at Houston. In 1977, while at the University of Virginia, Murad sought to determine the physiological mechanism by which the drug nitroglycerin helps relieve heart-related chest pain. He found that nitroglycerin and related drugs produce NO in the cells surrounding blood vessels. The NO acts as a signal to other cells, causing the smooth muscle tissue in blood vessels to relax. In the process, the vessels dilate, or widen, increasing the flow of blood. In 1978, Murad formally published his theory that NO is a signalling molecule.
Since Murad’s initial discoveries, the investigation of NO has become an extremely active area of biomedical research. Scientists now recognize that NO is involved in many processes, such as the action of the nervous system and the immune system. Based on this knowledge, new treatments are being developed for heart disease, septic shock, and other diseases. In 1998 Murad received the Nobel Prize in physiology or medicine for his discoveries related to NO. He shared the award with American pharmacologists Robert F. Furchgott and Louis J. Ignarro, who had independently performed key NO research during the early 1980s. His work helped to demonstrate the role in the body of nitric oxide (NO), a gas produced in the cells of humans and other organisms. Murad determined that NO is a signaling molecule—a molecule that transmits messages from one cell to another. Murad investigated the action of NO in the blood vessels of the cardiovascular system. Thanks to extensive research that his findings helped to stimulate, scientists now know that NO plays a role not only in blood pressure and other cardiovascular functions but also in many of the body’s systems.
Murad has also been honored with the Albert Lasker Basic Medical Research Award, which he shared with Furchgott in 1996.

The above list is nowhere complete and exhaustive. They serve only as a matter of information, so that it helps in generating further interest.

On a personal note, our latest meeting on academic publication was a mixture of many sentiments! Although we were all falling short of our given deadlines, there were many who had completely forgotten about their assignment! Few of the team who have left for their future to other places also were not spared. An immediate phone call went to them so as to remind them of their due responsibility! Everyone enjoyed the plight of the other, till their turn came in! Just hope if we had one tenth of enthusiasm of our boss, Dr Sunita. Sometimes I feel how long we would take to match the energies of Dr Sunita!

What are the options in cTGA with VSD, PAH with Ebsteins malformation of TV with severe TR in a 2-month-old? Everything depends on how repairable the TV is. Is the age OK for any kind of repair? What would the plan B be? Let me know your take on it.

We have often come across the VSD and PDA with severe PAH in the same patient. When the VSD shunts bi-directional, the PDA would be predominantly left-to-right in the absence of PS. How to explain this analogy? Is it only the color dominance or any other explanation also exists?
We often come across masses in RA. Are they always pathological? Some of them may be thrombi or fungal mass. Sometime back, we had seen an organized mass in the RA. If it is of an acute origin, does it always require medication even in the absence of systemic symptoms and signs? Any guidelines?

Rheumatics continue to pose both diagnostic and therapeutic challenges. Not every child fulfils the Jones criteria. Many a times, parents would not be intelligent enough to observe and recall the symptoms. There are no clear cut guidelines on diagnosing RHD on echo. The impaired mobility of PML is not always found. Sometimes, children would fulfil Jones criteria, but the heart would show normal mobility of PML with regurgitant mitral valve. The involvement of aortic and mitral valves together in a young child also poses diagnostic challenges. The problems of third world find no guidelines on a regular basis.

Please send your inputs. Feel free to send it to my email drkiranvs@gmail.com I shall post it on your behalf.

Regards

Kiran