Rare presentation of a rare condition (which is a common presentation of a common exam condition)

In some ways, our job consists of making the colourful spectrum of real life medicine fit the black and white confines of the hospital protocol or the textbook definitions. Though the presentation of this next case was as black and white as it gets, the way it was dressed up to the AMU could lead you up the wrong path. As you go down the case you will get more clues; see how early you can figure it out.

A 59 year old man originally from Eastern Europe had felt tired for the past 3 months. He had seen his GP, who discovered a normocytic anaemia (Hb 7.4) with a normal WCC and platelets. (The patient’s haematinics were normal, making a mixed iron/folate/B12 deficiency unlikely. His reticulocyte count and kidney function were also normal.)

The patient reported no source of bleeding, including normal bowel habits. He had no skin or joint symptoms. He felt there was no change to his appetite, but did notice about 5 kg of weight loss over this time. There was no fever, but yes, there were occasional drenching night sweats.

PMH revealed rheumatic fever as a child, which left him with a systolic murmur of some sort that the GP was unable to classify further.

He took no regular medications.

Apart from this he was normally a fit and well builder. He had been unable to go to work in the past month because of the tiredness. He lives with his wife. Social history was otherwise unremarkable.

On examination, his obs were Pulse 105, BP 134/90, RR 16, Sats 99% on air and T 37.8. The clerking FY1 noted this:

Splinter Haemorrhage
Splinter Haemorrhage

On palpation there was splenomegaly.

On auscultation there was a loud pansystolic murmur radiating to the axilla.

Bloods confirmed a normocytic anaemia with a WCC of 10.1 and a CRP of 53. His U&Es, LFTs and Coagulation were all normal.

A urine dipstick showed haematuria (+++).

A transthoracic echo showed a mitral valve oscillating vegetation, with severe mitral regurgitation and normal LVEF.

Three sets of blood cultures returned two days later which all grew strep viridans sensitive to benzylpenicillin.

What is actually going on in IE?

As the under review HPA guidelines on blood cultures states:

“IE is infection of the heart valves and/or other areas of the endocardium. It usually occurs at the site of a predisposing cardiac lesion or congenital defect where there is turbulent blood flow, encouraging endocardial damage and adhesion of platelets. A fibrin clot is deposited on the damaged endocardial surface and becomes colonised with organisms which have entered the bloodstream, so forming infected vegetation. Viable bacteria may be present deep within the vegetation as well as on the surface making antimicrobial treatment difficult.”

Why did this man get IE?

Intact valvular endothelium is normally quite resistant to colonisation. The rheumatic fever caused some degree of valve damage, which makes it easier for any bacteria that happens to be in the blood to make a camp there.

What bugs are most likely in this case?

According to the UK guidelines (2012), the most common causes of NVE in non-intravenous drug users are currently S. aureus (28%), coagulase-negative staphylococci (CoNS; 9%), streptococci (35%) and enterococci (11%); 9% are culture-negative.

The main times staph aureus dominates over streptococci is healthcare associated IE, IVDU associated IE and in the first year following a prosthetic valve placement. Staph aureus is the second most common cause of IE in prosthetic valves in the first year after coagulase negative staphylococci. In fact, the closer it is now to the time of the prosthetic valve placement, the more likely that any IE the patient is currently having on that valve is caused by coagulase negative staphloccoci.

How should cultures be taken?

According to the UK guidelines:

“In patients with a chronic or subacute presentation, three sets of optimally filled blood cultures should be taken from peripheral sites with ≥6 h between them prior to commencing antimicrobial therapy.”

It adds:

“There is no evidence to support the commonly perpetuated view that blood cultures should be taken from different sites. All skin surfaces are colonized by bacteria and adequate skin disinfection is key to reducing contamination. Taking blood cultures at different times is critical to identifying a constant bacteraemia, a hallmark of endocarditis.”

In practice, this means it would be 12 hours from your first suspicion of IE to giving your first set of IV antibiotics in a patient with a chronic or subacute presentation.

But the sepsis six! Each hour’s delay results in a 7.8% increase in mortality! What should I do if the patient is septic with IE?

According to the same guidelines:

“In patients with suspected IE and severe sepsis or septic shock at the time of presentation, two sets of optimally filled blood cultures should be taken at different times within 1 h prior to commencement of empirical therapy, to avoid undue delay in commencing empirical antimicrobial therapy.”

If you spoke to a sepsis champion, they would feel very uncomfortable about knowingly delaying giving antibiotics in any patient with severe sepsis or septic shock. In fact, the guidance from the sepsis world is to give fluids, oxygen and antibiotics ASAP and only take cultures before giving antibiotics if this would not delay giving antibiotics.

I’ll have to cross check what to do in this situation with a sepsis don.

What is the most common extracardiac manifestation of IE? 

Though this man had a splinter haemorrhage, this could be related to his occupation as a builder. The patient was unsure if this line in his nail was new or old. Splinter haemorrhages are a pretty rare feature of IE in the developed world, where the presentation is usually fairly early. Janeway lesions, Osler nodes and clubbing are all subacute signs, and are also quite rare in the developed world.

Cerebral complications are the most severe extracardiac complications of infective endocarditis, as well as the most frequent (occurring in 15 to 20% of patients). A haemorrhagic or ischaemic stroke may result. In other words, if a patient has an unexplained stroke, we may question whether or not there is underlying IE (after dealing with the stroke).

To TOE or not to TOE?

Same guidelines:

Role of TOE in IE
Role of TOE in IE

What should the first line antibiotics be whilst awaiting culture results in this case?

According to the same guidelines:

Empirical antibiotics in IE
Empirical antibiotics in IE

Note amoxicillin rather than the benzylpenicillin. Although you should follow your hospital policy, it seems that amoxicillin has better activity against enterococci, which cause 11% of native value IE. The newest versions of the BNF support this.  Fully sensitive streptococci might still be managed with benzylpenicillin.


Thrombocytopenia made easy

A 34 year old woman complains of feeling depressed for the past month. She is not complaining of any other symptoms and has no medical or drug history. On examination, there is no splenomegaly.

Hb: 133 g/L
MCV: 91 fL (77-95 fL)
WCC: 6.6 x 109 cells/L
Platelets: 58 x10x9/L

Tests added based on platelet count:

LDH: 213 IU/L (105 – 333 IU/L)
INR: 1.1
APTT: 31s (30-50s)
B12: 434 pg/ ml (200 – 800 pg/mL)
Folate: 7.6 ng/mL (2 – 20 ng/mL)

Blood film:

Thrombocytopenia confirmed. No fragmented cells. Normal red and white cell morphology. Slightly large platelets.

What is the most appropriate treatment for the likely diagnosis? (Answer at the bottom of this post)

A Platelet transfusion

B No treatment necessary

C Prednisolone

D Immunoglobulin

E Plasma exchange

My MRCP Part 1 Score

What is a good score on the MRCP Part 1?

The MRCP people now give your score as a scaled number from 0 to 999, where 521 is the pass mark. They have stopped giving the exact number of questions you have got right.

Instead, the MRCP examination uses a method called equating (as seen in the USMLE). This is supposed to make it easier to compare scores across the diets. Previously, 60% in a 2008/2 paper could not be said to be better than 59% in the 2008/3 paper, because the exam difficulty could vary. Now the Royal Colleges say that a score of 600 is definitely better than a score of 590, whichever tests you are comparing.

What is the pass mark for MRCP Part 1?

We know that pass mark was less than 67.5% in 2009/1, as this scored a scaled score of 545, and 521 is the pass mark. 70% scored 545 in 2008/3, so there is a lot of variation year to year. In general, a raw score over 70% seems to be safe.

What is the pass rate for MRCP Part 1?

All candidates – around 44%

UK Graduates on their 1st attempt: 63%

Any tips for how to pass MRCP Part 1?

I’ll cover this more fully in a separate post. There are some comments at the bottom of this post with some tips for passing the MRCP Part I.

How did the author of this blog do?

Here’s my results for the Sept 2013 exam 🙂

My MRCP Part 1 results
My MRCP Part 1 results

By Viral Thakerar

Opening a can of interesting worms

Writing medical education materials as a full time job has been incredible. It makes you cross check everything, and discover things you had never thought about.

For example, I was writing a case of a patient with urosepsis and acute kidney injury (SCr increased by 2.3x from baseline). I wanted the 5th year students to notice the antibiotic plan was currently Gentamicin, and expected them to speak to their senior/microbiology to discuss an alternative. I was aware of renal dose gentamicin being used in chronic kidney disease. However, I did not expect to find guidelines that said to give gentamicin for UTI even in acute kidney injury. Our own hospital guidelines also offered a single dose of gentamicin followed by Augmentin for UTI, even in acute renal failure. Whilst discussing the case with the other clinical teaching fellows, we got some input from a middle grade doctor who had worked in renal units who advised that once off gentamicin is safely given in AKI.

To me, this seemed to contradict some pretty fundamental ideas about acute kidney injury. The Renal Association guidelines state at section 4.1 that “Nephrotoxic medications should be stopped.” with 1A evidence to support this. Surely the very last thing you would do is start gentamicin, unless absolutely unavoidable? Why is it first line even in acute kidney injury, albeit a once only dose, followed by something else?

Microbiologists love gentamicin because it is amazingly effective for gram negatives. The MICs of gram negative bacteria are usually less than 2 mcg/ml for gentamicin. Gentamicin has two distinct antibacterial effects:

  1. It kills bacteria in a concentration dependent way (irreversibly binding the 30S subunit of the bacterial ribosome, interrupting protein synthesis). This is most pronounced when the concentration of gentamicin in the serum is about 8-10 times the MIC.
  2. It has a post antibiotic effect, which means bacterial growth is suppressed even when levels drop below the MIC. The higher the aminoglycoside dosage, the greater the post-antibiotic effect, up to a certain maximal response. This is caused by leukocytes having enhanced phagocytosis and killing activity after exposure to aminoglycosides

The half life in plasma is about two to four hours if the renal function is normal, and can increase up to 60 hours in a patient with essentially no renal function. In contrast, the half life in the renal cortex is about 100 hours. This explains how prolonged courses, which would allow gentamicin to accumulate in the renal cortex, can lead to nephrotoxicity.

Gentamicin can be thought of as following a two-compartment model; the plasma being one compartment and the tissues (importantly renal cortex) being the other. With repeated doses, tissue levels rise and lead to a continous release of gentamicin into the plasma. This can be reflected in an elevated trough level. (An elevated trough level might also represent an ‘overdose’ of the last dose, which has not yet been fully cleared.)

Nephrologists hate gentamicin because it causes nephrotoxicity, usually manifest as a nonoliguric renal failure from acute tubular necrosis. It’s worth noting that it is perfectly possible to develop a tubular problem without any changes in the GFR/creatinine. In the case of gentamicin-induced acute tubular necrosis, tubular obstruction from dead crap in the tubule increases the hydrostatic pressure inside the tubule and in the Bowmans’ capsule, which reduces filtration pressure gradient and, therefore, the glomerular filtration rate (GFR).

My main question at the moment is how does a once only dose of gentamicin differ from 72 hours of gentamicin in terms of nephrotoxicity risk and why. There are many factors at play, but one consistent factor is that nephrotoxicity is nearly always accompanied by tissue accumulation of gentamicin. Have a look at this diagram:

Screen Shot 2013-10-02 at 22.54.58

(This is on page 77 of  NephrotoxicityInteraction of Drugs with Membranes Systems Mitochondria-lysosomes by Jean-Paul Fillastre, 1978. I can’t find the actual paper, but its one by Schentag.)
This study showed that in 53 hospitalised patients (baseline SCr ranged from 10 to 148) who needed gentamicin, those who developed nephrotoxicity (defined as 50% increased in SCr from the baseline, 6 patients) consistently had elevated tissue concentrations of gentamicin than those who did not (47 patients). The nephrotoxic patients were similar age, sex and baseline SCr to the non nephrotoxic patients. It is very interesting that those without tissue accumulation did not develop nephrotoxicity. This could therefore explain why a once only dose of gentamicin appropriate for the patient’s current GFR may be not totally disastrous in AKI, and why it may be sensibly considered as part of the risk:benefit balancing act for a patient with AKI from urosepsis. That said, I’ve also found a paper by the same author which suggested that although renal accumulation was a risk factor for nephrotoxicity, this could occur even after the first dose. I’ll have to discuss this further with a microbiologist and nephrologist.

All this from trying to make a straightforward final year student AKI case. Total can of worms.