CPR: Difficult timing

“Call it.” Two simple words, but they are the culmination of one of the toughest decisions a doctor can make- when to stop CPR. Too short and someone dies when they might have survived. Too long and you're cracking ribs, protracting death and perhaps starting a heart again when the mind has died. There are no guidelines on how long CPR should be performed, partly because it's a very difficult topic to study. Imagine trying to get ethics committee approval for randomly assigning people to long or short CPR. Doubtful. Thank God.

Some evidence on CPR does exist, largely from observational studies such as the one published in The Lancet last week by Goldberger et al. One of the biggest studies of its kind, they used the world's largest registry of in-hospital cardiac arrests, including 64,339 patients who suffered a cardiac arrest at 435 hospitals in the United States from 2000-2008. Their aims were to assess whether hospitals spend different amounts of time on resuscitation attempts and whether a hospital's typical resuscitation time affected survival rates.

The study divided the hospitals in to 4 groups according to the median time they spent on resuscitation efforts in non-survivors. This was used as a measure of the hospital's tendency for longer attempts. Just 9 minutes separated those in the shortest group (16min) from those in the longest (25min). But time wasn't the only thing that separated the hospitals. The study team found that patients in hospitals which spent the longest on resuscitation events were 12% more likely to survive and go home than patients in hospitals with the shortest attempts.

Intuitively this might seem obvious- the longer you try, the more people you save, right? As one reader of the Washington University newspage commented: "*face palms and shakes her head* Jesus Mary and Joseph, people are just so stupid. Seriously, this was not obvious to doctors before the study?"

Nope. As we discussed at the outset longer isn't necessarily better- the authors expected to find that longer attempts were futile, resulting in people being 'saved' with minimal brain function. Yet this wasn't borne out in the study- hospitals with longer CPR attempts did not have higher rates of neurologically impaired survivors, just higher rates of survivors.

This brings us to every enquiring mind's favourite question: why? Well, let's start with what the study team think. They note that the patients who benefited most from longer resuscitation times were those whose type of cardiac arrest was “non-shockable”, which means they weren't suitable for defibrillation. One example is “asystole” which looks like this on an ECG.

Asystole. Image from: Ambulance Technician Study.

Note its got a bit of a wiggle to it, a perfectly “flatline” probably means your leads aren't connected, or you're in an episode of Casualty. In the UK, CPR guidelines advise against defibrillation in asystole. The study team suggest that in these non-shockable cases the extra time spent on CPR buys time for medics to figure out the underlying cause of the cardiac arrest and try to tackle it. In light of this, maybe CPR guidelines should state a minimum attempt time?

This seems reasonable, but that doesn't necessarily make it so. All this study has demonstrated is an association between the median duration of resuscitation attempts in non-survivors and post-CPR survival. This could be for other reasons- perhaps hospitals that deliver longer CPR also deliver more effective CPR or have more robust post-CPR care. Given these possible alternative explanations, this study alone isn't enough to justify a minimum CPR time for all. Goldberger himself agrees:

Dr Zachary Goldberger.
 Image:  University of Washington.

“The last thing we want is for the take-home message to be that everyone should have a long resuscitation”. A cardiologist with a-mazing glasses, a first author Lancet paper AND a recognition of the limitations of his research. No denying Zach's a catch ladies.

So, taking these limitations into account, what is the take home message? Reassurance. Reassurance that longer resuscitation times don't appear to lead to a significant increase in survivors with severe neurological damage. With this reassurance, hospitals whose resuscitation times are at the low end of the spectrum should seriously consider aiming to continue CPR for longer.

Whilst the timing of inpatient CPR timing will continue to be investigated and debated, its important to recognise this study is not applicable to people having CPR in the outside world. Just 15.4% of people in this study made it out of the hospital alive. This is because they were sick enough to be in the hospital in the first place. None of this data is transferable to when people have a cardiac arrest in the outside world. Should you ever find yourself in that situation, deciding when to stop CPR is far easier: DON'T. Unless:

1. The person starts to show signs of regaining consciousness AND starts to breathe normally
2. Professional help arrives to take over
3. You physically cannot keep doing CPR

For a CPR refresher, have a read of this and a look at this.

Reference: Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study. Goldberger et al. The Lancet, Early Online Publication, 5 September 2012 doi:10.1016/S0140-6736(12)60862-9. Accessed: 16/09/12

Bleeding science

Cambridge was a strange place. Take our physiology practicals- over the course of a year they made us collect our pee in the lab, stab ourselves and deliver electric shocks to our arms. And then document it all. For one experiment we had to drink one of three liquids (water, cranberry juice or a mystery alkaline cocktail of the departments making, eeeps) then titrate our pee. I kid you not. Can't for the life of me remember the point, or the results, but I'll never forget the boys competing to see who filled the biggest measuring cylinder, or the girl who spilled her pee across the desk . I never knew her name and forever after she was just the girl who pee'd on her practical book...But I digress. This week I've been reminded of a physiology blood glucose practical by an article in the New England Journal of Medicine. We skipped breakfast and took our own blood glucose, before and after a Mars bar. The chocolate was good, the repeated stabbing less so. Like us, the NEJM study was interested in fasting blood glucose- the blood glucose level after 8 hours of refraining from consuming anything other than water. Unlike us, they executed a pretty decent study on the topic which is worth discussing here.

The premise of the study is simple- elevated fasting plasma glucose is associated with an increase risk of cardiovascular disease. It's thought this is due to low background levels of insulin and therefore it has been hypothesised that correcting this deficiency would reduce cardiovascular disease. However, much of the evidence to date has been equivocal, with no clear reduction in cardiovascular disease and suggestions that treatment with insulin might carry an increased cancer risk. Recently, the balance shifted in favour of tight blood glucose with the publication of the UK Prospective Diabetes Study (UKPDS) which found that tighter blood glucose control in new diabetics was associated a 15% reduced risk of heart attack and a 13% lower mortality rate. So, perhaps tight blood glucose control is worthwhile?

Cue ORIGIN, the subject of our musings today. This study involved 12,537 people from 40 countries, who had elevated fasting glucose, impaired glucose tolerance (blood glucose is higher than normal 2hr after consuming glucose) or early Type 2 diabetes in addition to other cardiovascular risk factors. Participants were randomly allocated to receive either a) standard care or b) to inject insulin in addition to their normal glucose control regime aiming for a fasting blood glucose of 5.3 mmol/litre or less. They were then followed for 6 years.

So what did they find? Well, there was no difference between the two groups with regards cardiovascular outcomes (including stroke and heart attacks), cancer or overall mortality. However, they did find that the insulin group were less likely than the standard group to develop Type 2 diabetes (30% vs 35% at 100days after the end of the trial, p=0.05). So, aggressive blood glucose control in non-diabetics with raised fasting glucose or impaired glucose tolerance doesn't make a jot of difference to mortality at 6 years, but it might make you less likely to develop diabetes. Yay? Well, the downside was the insulin group were more likely to experience symptoms from low blood glucose (hypoglycaemia), which include shakiness, anxiety, headache and nausea. 57% of the insulin group experienced at least one episode of symptomatic hypolycaemia, compared to 25% of the standard group. The insulin group also experienced weight gain (median gain 1.6kg) which the standard group did not (median loss of 0.5kg).

Now, the study has its limitations- it's male dominated (65% of participants) and only includes the over 50s, making it hard to know how applicable it is to younger people and women. They only followed up for 6 years which isn't a very long time to catch relatively rare events. Plus only 44% of the eligible insulin group and 47% of the eligible standard group returned to be tested for diabetes at the 100 day point, which leaves a hefty chunk of unknown outcomes. 11% of the non-insulin group ended up taking insulin which further confuses the results. Also there's a depressingly epic list of investigators paid by pharmaceutical companies and the study itself was industry funded by the make of the insulin used. Nuff said.

But the overriding, screaming question for me is would you stab yourself every day, probably put on weight and suffer hypoglycaemia for the possibility that you might be one of the people who doesn't develop diabetes by doing all that? You have to be really motivated. The individuals selected for this trial were motivated and supported- they all said they were up for injecting insulin and they subsequently received regular contact from the trial organisers which can support people to stick with medications. Even in this environment 1 in 5 of those allocated to insulin had ditched it by the end of 5 years.

Diabetes comes with a host of awful complications- leg ulcers, kidney damage, eye damage. I know all this, but I'm still not sure I'd be up for daily insulin to moderately dial down my risk of getting diabetes. But then I paid tuition fees to collect my own pee and stab and electrocute myself, so perhaps sensible life choices are not my forte... What would you do?

Ref: Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia.The ORIGIN Trial Investigators. N Engl J Med 2012; 367:319-328 http://www.nejm.org/doi/full/10.1056/NEJMoa1203858

Imhotep: The mummy of all medics

Anyone who has ever watched The Mummy will find it hard to say Imhotep without chanting it in a menacing zombie voice. But the real Im-ho-tep was a long way from the silver screen's lovesick hotty, hellbent on destroying Brendan Fraser. He was chief architect to Pharaoh Djoser and one of the forefathers of methodical medicine.

Unlike the Pharaoh he came to serve, Imhotep wasn't born into wealth or power. He began life as a commoner. Yet after his death he was described as the son of Ptah, who was the chief God in Memphis, and the Greeks built temples in his honour. So how did Imhotep achieve this stellar trajectory? In the words of a small Belgian genius: Order and method.

These qualities define the Edwin-Smith papyrus, a scroll that stretches to almost 5 metres in length and dates to 1700BC. While its author is unknown, the papyrus is thought to have been copied from a far earlier scroll (circa 2500BC) which detailed the teachings of Imhotep. The black and red hieroglyphs scrawled across the papyrus outline 48 case histories, 8 spells and 5 prescriptions. 

(Image courtesy of http://en.wikipedia.org/wiki/File:Edwin_Smith_Papyrus_v2.jpg)

While the magic spells may capture the imagination, and milk poured into the ears for neurological problems intrigues, the true beauty of the papyrus lies in its deliciously mundane commitment to order. The cases are lined up in a deeply straightforward fashion, beginning at the head, before moving to the neck, then the arms and torso. The content of each study is presented in a divinely dull, disciplined manner that any medical student would find recognisable: type of injury, examination, diagnosis, prognosis and treatment. It is descriptive and detailed. Wounds should be closed with sutures, spinal injuries immobilised. Duh. The familiarity is electrifying. This is not new. It is very, very old. Over 4,500 years old. Think about how long ago the time of Jesus et al seems- 2000 years ago, its aaaages ago right? Well, that's how Hippocrates would have felt about Imhotep's world which existed 2000 years before old Hippocrates drew his first breath or wore his first nappy.

Yet ven back in antiquity Imhotep was doing what every good medic, indeed every good scientist, would do today- apply logic, turn the mystical into the familiar. The foundations of medicine are as simple and solid as they were 4, 500 years ago. Those guiding principles of order and method were good enough to make Imhotep a godlike figure. They're probably good enough for us too.

While there is minimal mystique and magic in the Edwin-Smith papyrus, Imhotep made up for it in his death. There is no clear record of how or when he died and the location of his tomb has eluded every explorer. Some might see this as a loss, only Ra knows what wisdom Imhotep had buried with him for the next life. But this is foolish. I hope Imhotep evades those who wish to wake him from his slumber. After all, I've seen the movie....

Da Vinci: Connoisseur of corpses

Can you draw a heart? Not an I love you heart, a real ventricles and all heart? No? Maybe because you haven't seen one? I have, but I couldn't do it justice. The peak of my artistic talent came age 5 when I won a Disney drawing competition at school. Apparently my skillz with a crayon perfectly captured the true essence of Goofy. They displayed it in the local gallery. I could have been a contender. Now my stick men look forlornly out from the page, despairing with a wonky eye at my inability to endow them with legs of equal length. Sorry Bert.

One man who could definitely draw a symmetric stickman and a decent heart, though he probably never drew Goofy, was Leonardo Da Vinci. It's a name that conjures images of incredible inventions and divine paintings of deities, but Leonardo was also a connoisseur of corpses. He was an anatomist. Arguably the most accomplished anatomist, not only of his time, but ever. He described structures which weren't mentioned in the medical literature for another two to three centuries. Some of these findings were documented on paper, but others he painstakingly scratched into metal plates capturing every sinew of muscle and snaking nerve. What impresses even more than this raw artistic talent is the scale of his ambition. In the outline for his treatise on anatomy, he planned to trace every blood vessel, document every type of smile, and describe not only the form, but function of almost every structure in the human body.

One of Leonardo's most inspired attempts to understand function came in 1512, when he filled an ox heart with molten wax. From this he made a glass model of the heart and then pumped a grass seed suspension through it. Observing the turbulent movement of this suspension through the aortic valve Leonardo realised that the valve prevented blood re-entering the heart. This breakthrough flew in the face of how the world saw the circulatory system. It was widely believed that the venous and arterial systems were not linked, and that the heart simply pumped blood out and then sucked it back in. Now Leonardo Da Vinci, a genius by any standards, held in his hands evidence of how the heart worked. Surely this was a pivotal moment in medical science? Erm, no. Leonardo's mind, capable of such incredible leaps and bounds, could not release itself from the dogma of the day. Instead he scrabbled around for ways blood could re-enter the heart from the aorta, postulating ideas such as porous valves. Genius fail.

His mind remained shackled to this falsehood until his death in 1519, and with him died his drawings and discoveries. His collection was lost to the world for almost 400 years and by the time it was uncovered the knowledge it contained had been pieced together by Andreas Vesalius and other anatomists. The moral of this tale? Don't live with the results of other people's thinking, publish before you perish and even geniuses lack self belief.

As sad an ending as this is, it doesn't detract from the fact that Leonardo's drawings remain jaw droppingly awe inspiring 500 years on. I doubt anyone will be marvelling at my stickmen in 500 years. Sorry Bert.

If you want to marvel at Leonardo's handiwork, its on display at the Queen's Gallery until October 7th. If you don't live in London, or you don't want to pay the £10 entry fee, their website has a few examples online. Well worth a peek. 

Sandwiches with strings?

Pharmaceutical giant GlaxoSmithKline recently plead guilty to criminal charges and were fined $3billion. They admitted encouraging the prescription of the antidepressant Paxil to children despite trials showing it was ineffective. They also bribed doctors and failed to report safety issues with the diabetes drug Avandia. People are horrified that this happened. But should they be shocked? This is from an industry that has lobbied to protect their Intellectual Property in a way that will choke access to cheap generic HIV drugs in developing countries. And what about the medics they bribed? GSK have been taking most of the negative press, but the doctors who traded their professionalism for profit have much to answer for.

Loveline radio show host Dr Drew is one such medic. Prosecutors said he took $275, 000 to promote Wellbutrin for unapproved uses. He suggested the wonder drug could give women 60 orgasms a night and help them lose weight. Emmmm, not according to any decent clinical trial that's been conducted. He also promoted a website- intimacyanddepression.com- which told people about town hall meetings where depression experts would be talking about the illness. No mention was made of GSK. Today we know that GSK owns that website and it now redirects you to Wellbutrin.

Dr Drew intrigues as much as he disappoints. I wonder what his tipping point was- when he decided profit mattered more to him than professional ethics. Did he always feel that way, or was there once a young, altruistic Dr Drew?

Whilst our deceitful Dr Drew did particularly well out of GSK, he isn't alone in benefiting financially from pharmaceutical companies. GSK held luxury drug promotion events in Puerto Rico, Hawaii and California. According to the Guardian, “Those who attended were given $750, free board and lodging and access to activities including snorkelling, golf, deep-sea fishing, rafting, glass-bottomed boat rides, hot-air balloon rides and, on one trip, a tour of the Bacardi rum distillery, all paid for by GSK.” Now, in fairness to those attending they didn't promise GSK anything in return. Nevertheless the naïve complaints of one psychiatrist grate somewhat: “this is supposed to be a scientific meeting. To me, the music, lights, videos, emcees are offputting and a distraction, even demeaning ”. Really, you thought you were going to a scientific meeting where they just gave you $750?!

But I'm standing in a glass house hefting a fairly heavy stone. I've accepted gifts from drug companies- from post-it notes to syringe shaped pens- I've got a small pencil case worth of booty. As a medical student the prospect of a pharma-funded lunch always made a day seem better and enticed me to listen to their chat of BOGOF chemotherapy. Sometimes I was appeased with offerings of M&S goodies, other days I was handed a Tesco basics sandwich and muttered to myself about declining standards. A New England Journal of Medicine survey found 94% of physicians had some relationship with pharma- at 83% the most common connection was receiving food and beverages in the workplace. But are these small gifts really problematic? I honestly can't remember which companies provided which sandwiches, so how could I possibly have been influenced by it? And even if I had noticed, their agenda is so clear can't I just apply a cynical filter to what I'm being told and enjoy a free lunch?

But that same cynical part of me thinks that whilst this view is appealing (I want the free lunch to be ok soooo badly) it doesn't answer one gnawing question: If it doesn't work, why does the pharmaceutical industry spend hundreds of millions of pounds on it? They aren't stupid. So, are we?

I had a dig around for some guidance to help me with this dilemma and found that the American Medical Association recommends against any gift that expects anything in return. The pharmaceutical companies are more charitable than I if they expect NOTHING in return. If I give you a present, I don't necessarily expect a gift in return but a nice thank you and some warm fuzzy feelings towards me would be good. In an article on gifts published in the American Journal ofBioethics, Katz, Caplan and Merz argued that social convention dictates that when you receive a gift, even one you didn't ask for, you feel compelled to provide something in return. They give the example of the Disabled American Veterans charity which appeals for donations through direct-mail. The response rate is about 18% when no gift is included and 35% when the envelopes contain an inexpensive gift such as address labels. The guidance also puts an emphasis on the size of gift. Indeed in 2001 the AMA launched a $1 million campaign to educate doctors about not taking big gifts from drug companies. Roughly $600,000 of the cost was covered by nine drug companies. Do as I say, not as I do....

The American Government shares the AMA's preoccupation with gift size. The Physician Payment Sunshine Act is set to make it compulsory for pharmaceutical companies to declare any payments or perks made to medics that exceed $10. Whilst this is definitely a step in the right direction, I cant help wondering whether the AMA and the US government are missing a trick by assuming gifts can ever be string free.

I love a good bit of evidence but I haven't turned up anything that examines the impact of small gifts on actual prescribing behaviour- do hospitals that are visited more by one particular company see higher prescribing rates of those drugs? Do people have subconscious warm fuzzy feelings for Pfizer after a tasty lunch?

I think there are lessons to be learned from the drug industry's willingness to splash out on sandwiches and stationery. One is that part of the reason I cherished the opportunity to grab a pen or a set of post-its was because I had to supply my own at work. Maybe hospitals should take a tip from the pharma marketing execs. They could draw up a list of drug names commonly prescribed by brand when they should be generic and provide pens and post-its with the generic names on them. Small, unsolicited gifts might even be a minor morale booster. Lord knows hospital management need to do something to make staff feel warm and fuzzy towards them.

Finally, GSK tell us they have definitely learned lessons from this case. According to IMS Health, in the time period covered by their $3billion fine Avandia made $10.4bn in sales, Paxil $11.6bn, and Wellbutrin $5.9bn. What lessons do you think they learned?